Endocrine Complications in Patients With Thalassaemia Major

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Pediatric Endocrinology Reviews (PER) n Volume 5
No. 1
September 2007
INSTRUCTIONS FOR PREPARATION OF MANUSCRIPTS

PEDIATRIC ENDOCRINOLOGY REVIEWS (PER) publishes scholarly review articles in all areas of clinical and experimental Endocrinology, Diabetes, Nutrition and Metabolism in the widest sense of the word. PER is aimed at practicing pediatricians, pediatric endocrinologists, pediatric diabetologists, pediatric gastroenterologists, neonatologists, pediatric gynecologists, nutritionists, sport physicians and pediatricians-in-training. PER will also publish supplements on specific topics or as proceedings of scientific meetings in the above fields of interest. All articles, whether invited or direct contributions, will be peer-reviewed. PER will also publish correspondence, book reviews, meeting calendars and meeting reports. SUBMISSION Manuscripts should be submitted online to Mrs. Irit Lipner. info@medmedia.co.il If not possible send Hard Copy (high-quality original plus 2 copies) to: Zvi Laron, MD, Editor-in-Chief, Endocrinology and Diabetes Research Unit, Schneider Children's Medical Center, 14 Kaplan Street, Petah Tikva 49202, Israel. Tel:+972-3-9253610/1; Fax:+972-3-9222996; e-mail:laronz@clalit.org.il MANUSCRIPTS Must be in English, typewritten on one side of 81/2 x 11 inch (22 x 28 cm) heavy-duty white bond paper, sequentially numbered, double-spaced (including references, tables legends and footnotes). Abstract, references, tables and legends should each begin on a new page. Manuscripts should not exceed 16 printed pages including references, tables and Figures.(4300 characters with spaces per page) All accepted manuscripts are subjected to editing. There will be no handling or page charges. TRANSFER OF AUTHOR COPYRIGHT Please provide a release of copyright addressed to Y.S. Medical Media Ltd., which should include the title of the article, date and must be signed by all the authors. TITLE PAGE Should include authors names; academic degrees and departmental and institutional affiliations of each author. Designate one author as the correspondent and provide address: business and home; telephone numbers, fax number and e-mail. Include a running head and up to 8 key words. ABSTRACT Not exceeding 150 words, should incorporate data on background, objective or hypothesis and main data. The abstracts will be available on the web. REFERENCES Should be cited consecutively in the text as superscript numerals and listed in the same numerical order at the end of the paper. List the names of all authors. EXAMPLES OF REFERENCES Journal article: Woods KA, Camach-Hubner C, Savage MO, Clark AJL. Intrauterine growth retardation and postnatal deletion of the insulin-like growth factor I gene. N Engl J Med 1996 ;335:1363-1367 Book: Ghigo E, Boghen M, Casanueva FF, Dieguez C. Growth Hormone Secretagogues. Basic Findings and Clinical Implications. Amsterdam: Elsevier, 1994, pp. 325 Chapter in book: Hofman PL, Pescovitz OH. Growth hormone releasing hormone biological and molecular aspects. In: Handwerger S, ed. Molecular and Cellular Pediatric Endocrinology. Totowa, NJ: Humana Press, 1999;85-112 Personal communications should not be included in the list of references, but may be cited in the text in parentheses. Papers accepted and in press may be listed, mentioning the journal. ILLUSTRATIONS Figures should be numbered consecutively with Arabic numerals. Legends should be typed double-spaced on a separate sheet. Hard copies: submit one set of original glossy prints and two sets of clean, sharp photocopies. Name of first author and number and top of the Figure should be indicated by a soft pencil on the back of each Figure. On-line submission: see instructions on the web. The cost of color illustrations will be charged to the author if printed in the text. A limited number of color photos may be printed on the inner cover at no cost. TABLES Each table must be typed on a separate sheet and numbered consecutively using Arabic numbers. Large tables will be treated as Figures and must be of acceptable quality for printing. REPRINTS With galley proofs a reprint order form will be provided. GALLEY PROOFS Only printers errors may be corrected. ENQUIRIES, SUBSCRIPTIONS AND REPRINTS Enquiries concerning manuscripts in press, reprints or subscription should be addressed to the production editor, Mrs. Tzipi Sharoni, Y.S. Medical Media Ltd., POB 8214, Netanya, Israel 42504. Tel: 972-9-8641111 (ext. 124); Fax: 972-9-8656965, E-mail: tzipi@medmedia.co.il. All editorial correspondence, including planning of supplements, should be addressed to the Editor-in-Chief. ADVERTISING Advertising by commercial firms should be addressed to Mrs. Aliza Farkash. Y.S. Medical Media Ltd., POB 8214, Netanya, Israel 42504. Tel: 972-9-8641111 (ext. 116); Fax: 972-9-8656965, E-mail: aliza@medmedia.co.il. WEB All information concerning PER, including contents and abstracts for the current and past year, instructions to authors, can be found on the web www.medicalmedia.co.il/per
No. 1
September 2007
No. 1
September 2007
Forthcoming Articles
Forthcoming Supplement
No. 1
September 2007
Message from the Editors,
Good news, all PedEndo fellows in Canada will get a subscription of PER made possible by an Education Grant from Serono Canada. The number of subscribers in China has also increased.
New treatment approaches of childhood diabetes raise controversies. A meta analysis of the use of continuous sub-cutaneous insulin injections (CSII) and multiple daily injections (MDI) is the topic of a review in this issue.
Pay attention also to the editorial by Clarke and Kovatcher, PER 2007; 4: 314-316 on this issue. We continue to keep you informed of the latest advances in the Meeting Reports and take this opportunity to thank its many contributors.
Z. Laron
M. Geffner
T. Tanaka
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In
oriam Mem
Marvin Cornblath, MD 1925-2005

Lynne L. Levitsky, MD
Massachusetts General Hospital, Pediatric Endocrine Unit, 55 Fruit Street BHX410, Boston, MA 02114, USA Tel: (617) 726-2909; Fax: (617) 726-3044; e-mail:llevitsky@partners.org
Marvin Cornblath, a renowned pediatrician endocrinologist who received international recognition for his contributions to the understanding of disorders of carbohydrate metabolism in children and especially of neonatal hypoglycemia, died peacefully in the presence of his immediate family on January 20, 2005. He was 80 years of age. Dr. Cornblath was a founding member of the Lawson Wilkins Pediatric Endocrine Society and organized the first formal meeting of the Society, in association with the Pediatric Academic societies, in 1973. He was a pediatric pioneer with many enthusiasms and interests but his ability for intense focus was central to his success in academic medicine and as an investigator and educator. His belief in and teaching of evidenced-based medical care predated the current enthusiasm for this more scientific approach to patient management. Dr. Cornblath was Clinical Professor of Pediatrics at the University of Maryland and Lecturer in the Department of Pediatrics at the Johns Hopkins University School of Medicine at the time of his death. He was described by Samuel Katz, MD, Emeritus Chair at Duke University, as one of the great citizens of modern academic neonatology-pediatrics, Dr. Cornblaths contributions to the field of carbohydrate metabolism date from the early 1950s through to the 21st century. He extrapolated his initial laboratory investigation to the clinical arena and worked to establish legitimate criteria for the diagnosis of hypoglycemia, supporting this work with high quality basic laboratory investigation. His work helped set the stage for later metabolic research that contributed to the elucidation of mechanisms for neonatal metabolic adaptation and transition from fetal to newborn physiology.
Born in St. Louis, Missouri on June 18, 1925, Dr. Cornblath completed his undergraduate and medical education at Washington University. Following residency training in Pediatrics, Dr. Cornblath undertook post doctoral training as a Fellow of the National Heart Institute, United Public Health Service, working in the laboratory of Dr. C. F. Cori in the Department of Biological Chemistry at Washington University School of Medicine. Early on, Dr. Cornblath showed an interest in newborn and young infants. His first publication, which won the Gil Prize in Pediatrics at Washington University School of Medicine in 1947, demonstrated that well water methemoglobinemia resulted from the relative high pH in the gastric juice of young infants, allowing increased conversion of nitrate to nitrites in the gut. In addition, he was the first to show that epinephrine and glucagon increased hepatic phosphorylase activity, and that their actions were additive, suggesting two mechanisms of phosphorylase activation. He then spent two years as a research associate with Drs. Harry Gordon and Alexander Schaffer at Sinai Hospital in Baltimore, where he continued his contributions to neonatal metabolism, studying hormonal responses in infants of diabetic women and recognizing the phenomenon of transient neonatal hypogycemia. He moved from Baltimore to Chicago in 1959 and continued his academic career with an appointment at Northwestern University as a neonatologist, Within 4 years, he was
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appointed Professor of Pediatrics and Chief of the Neonatal Service at the University of Illinois Hospitals. His major research and clinical contributions to the understanding of neonatal hypoglycemia were carried out at the University of Illinois and at Cook County Hospital in Chicago. In 1959, Dr. Cornblath reported eight infants with transient symptomatic hypoglycemia. This work triggered worldwide investigation of neonatal hypoglycemia. His studies in understanding neonatal carbohydrate metabolism resulted in a series of papers entitled, Studies of Carbohydrate Metabolism in the Newborn Infant published in Pediatrics between 1956 and 1967. These articles expanded the definition and understanding of transient symptomatic hypoglycemia and examined tolerance curves for oral glucose, galactose and fructose. They helped to develop normative blood glucose values in normal infants, twins, and in premature infants. Dr. Cornblaths interest in the clinical manifestations and pathophysiology of hypoglycemia in the newborn culminated in the publication of Disorders of Carbohydrate Metabolism in Infancy in 1966, which he coauthored with Robert Schwartz, MD. This textbook, updated as a third edition in 1991 still offers clinical and laboratory pearls to inspire the present generation of investigators and clinicians. His organization and participation in a consensus conference on neonatal hypoglycemia resulted in a publication in Pediatrics in 2000, with distinguished co-authors, that redefined neonatal hypoglycemia, suggested operational thresholds and directed future research. He was recruited to Chair and rebuild the Department of Pediatrics at the University of Maryland in Baltimore, Maryland
in 1968. He maintained an active role as a clinical investigator and as an educator in pediatric metabolism and neonatology and also built a strong department of Pediatrics. During his tenure as Chairman, he was a leader in developing a residency program with strong community outreach and social programs. He taught residents how to address the needs of infants born to teen mothers. He had the vision to incorporate rotations with the Maryland State Department of Health, anticipating by many years the need to bring together physicians and administrators to create effective and fiscally responsible social programs. He was active in numerous organizations, including the Coalition for Children and Youth, the Baltimore City Health Department, School for Pregnant Teenagers, and various mental health organizations,and and served on the Maryland Governors Commission on Hereditary Disorders. He also served as a consultant to the NICHD, the National Diabetes Advisory Board, and the Medical Advisory Council of the Juvenile Diabetes Foundation. Dr. Cornblath is survived by his wife of 56 years, Joan Cornblath, and his children, Nancy and Dr. Solomon Mosh of Chappaqua, New York; Polly and Mark Mannin of Brookline, Massachussets; and Ben and Patty Cornblath of Houston, Texas, as well as his five grandchildren: Jared Mosh, Matthew and Max Mannin and Allyson and Katie Cornblath. Dr. Levitsky thanks Dr. Solomon Moshe for his major contribution to this biography and Dr. Marvin Cornblath, for continued training and support many years after completion of fellowship.
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Therapeutic Approach to Childhood Hypercholesterolemia

Raanan Shamir1, MD, Jonathan E Feig2, MD, Edward A Fisher2, MD
1Pediatric Gastroenterology and Nutrition Unit, Meyer Childrens Hospital of Haifa, 2Marc and Ruti Bell Vascular
Biology and Disease Program, Leon H. Charney Division of Cardiology/Department of medicine, New York University School of Medicine Corresponding author: Raanan Shamir, MD, Division of Pediatric Gastroenterology and Nutrition, Meyer Children's Hospital, Rambam Medical Center, POB 9602, Haifa, 31096, Israel, Tel: +972-4-8543388, Fax: +972-4-8541805, E-mail: shamirr@netvision.net.il lesions (reversible fatty streaks and non reversible fibrous plaques) are also associated with cardiovascular risk factors including LDL-C (3,4). The best example of the relationship between early atherosclerosis Ref: Ped. Endocrinol. Rev. 2007;5(2): and LDL-C is provided by homozygous familial hypercholesterolemia (FH). Children with homozygous FH develop significant CVD in the first decade of life and frequently die from myocardial infarction before the age of 20 (5,6). In heterozygous FH there is a direct association between the duration and severity of the hypercholesterolemia and extra vascular lipid deposition in tissues of these patients (7). In children that are FH heterozygotes, non invasive methods demonstrate that significant lowering of LDL-C attenuates the measured indices related to atherosclerosis (8,9). Although LDL-C is a risk factor that should be addressed in high risk children such as those with FH, it is unclear, at present, whether there is a certain plasma LDL-C level that would call for an intervention regardless of the etiology of elevated LDL-C. Therefore, at present, screening the entire population to identify subjects with hypercholesterolemia is not justified. Furthermore, in children, the lack of a family history of premature atherosclerosis (defined as a coronary event before the age of 50 years in males and 60 in females, usually a parent or grandparent) in Introduction a child with hypercholesterolemia questions the relevance It is well established that elevated levels of plasma of hypercholesterolemia in that particular case. Therefore, cholesterol (TC), low density the aims of this review are to lipoprotein cholesterol (LDL-C) Familial combined hyperlipidemia (FCHL) familiarize the reader with and apolipoprotein B (the major Familial Hypercholesterolemia (FH) inherited diseases that are apolipoprotein of the LDL particles, Familial Defective apoB-100 associated with elevated LDLwhich carry most of the cholesterol PCSK9* Mutations C and discuss the management i n t h e b l o o d ) a r e a s s o c i a t e d Autosomal Recessive Hypercholesterolemia (ARH) of children with elevated with increased risk of premature * PCSK9: Protein Convertase, Subtilisin/Kexin Type 9 LDL-C (Table 1). There are other cardiovascular disease (CVD) in diseases that are associated with Table 1. Monogenic Disorders Causing Hypercholesterolemia adults (1,2). Early atherosclerotic increased risk of atherosclerosis
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and the presence of hypercholesterolemia enhances the risk of accelerated atherosclerosis (Table 2). These diseases, as well as the management of hypertriglyceridemia (a marker for pathological lipid metabolism, but not a risk factor for premature CVD in children), are beyond the scope of this review. Obesity Diabetes Mellitus Metabolic Syndrome Kawasaki Disease Chronic Kidney Disease/End Stage Renal Disease Solid Organ Transplantation Systemic Lupus Erythematosis Hypothyroidism Sitosterolemia Cerebrotendinous Xanthomatosis
Table 2. Diseases Associated with Increased Risk of Atherosclerosis Not Caused by A Primary Genetic Defect in LDL-C Metabolism
cluster in FCHL (obesity, high blood pressure) should be as rigorously addressed. Familial Hypercholesterolemia (FH) FH is an autosomal dominant hypercholesterolemia with an estimated prevalence of about 1:500 (18). The disorder is the result of mutations in the LDL receptor gene located on chromosome 19, with the end result of reduced uptake of LDLC by its receptor. Most children and adults with FH are heterozygotes and the defect in one LDL receptor gene results in about 30% elevation of LDL-C blood levels. The clinical hallmark of the disease is tendon xanthomata, most commonly seen at the Achilles tendon and the tendons overlying the knuckles. These should usually be looked for in the parents since only a small fraction of children heterozygous for FH will have tendon xanthomata. In addition, the presence of corneal arcus or xanthelasma, which are not disease specific, are pathognomonic when present in an adolescent with elevated LDL-C blood levels. If it remains untreated, subjects with heterozygous FH may suffer from myocardial infarction as early as the fourth decade of life, with about 50% of males and 15% of women dying before the age of 60 years (19). Homozygous FH is a rare disorder affecting approximately 1 in a million in the general population (20). LDL-C blood levels are 6-10 fold higher then normal, with cutaneous and tendinous xanthoma present by the age of 6 years and younger. If left untreated, acute myocardial infarction and death are expected at the second decade of life (21,22). Diagnosis of heterozygous FH is made by demonstrating elevated LDL-C (usually twice the normal values or more) in the proband and one of his parents, combined with clinical features in the proband and/or one of his parents. The diagnosis can also be made by identifying an LDL receptor gene mutation or by studying LDL receptor function in cultured cells. Although LDL-C blood levels overlap with LDL-C levels in the general population (23), in FH families, LDL-C levels allow accurate diagnosis of FH in childhood (24). This may differ from the adult population, where mutations in the LDL receptor were found in only 52.3% of hypercholesterolemic patients previously diagnosed as heterozygous FH (25). Familial Defective apoB-100 This autosomal dominant cause for hypercholesterolemia was reported in about 3% of the referrals in pediatric lipid clinics in France (26) and in 5% of an adult cohort in the UK (27). This disorder results from a single mutation (substitution of glutamine to arginine at codon 3500) in the gene encoding the apoB 100 protein, decreasing the binding of LDL to the LDL receptor. Phenotypically, subjects with this disorder are similar to those with heterozygous FH. Interestingly, despite the autosomal
Diseases Associated with Hypercholesterolemia

Familial Combined Hyperlipidemia (FCHL) FCHL is the most common inherited lipid disorder abnormality found in children attending a lipid clinic (10,11). The term FCHL was coined by Goldstein J. Et al, describing a monogenic trait (autosomal dominant) found in the families of survivors of premature myocardial infarction with both hypercholesterolemia and hypertriglyceridemia present in the pedigree (12). There are no clinical findings in children with FCHL and the diagnosis is based on elevated LDL-C, TG or both in the child and one of his parents (10). The lipid profile of FCHL patients includes elevated TC, elevated triglycerides, elevated apolipoprotein B and predominance of small dense LDL-C particles (13). Patients may also have high VLDL-C and low HDL and fluctuation in lipid levels is often seen (14). Linkage of FCHL with particular genes or chromosomal regions has yielded a few possible chromosomal regions (15,16), but to date, no consensus implicating a common locus has been obtained. FCHL overlaps with the metabolic syndrome and it is unclear whether obesity is responsible for the hypertriglyceridemia observed in FCHL or is a consequence of the basic metabolic defect (17). Since premature CVD is often found in parents of children with FCHL, as discussed below, elevated LDL-C is treated in these children in a similar manner as in FH. However, it is unclear whether treatment results in similar improvement in non invasive atherosclerosis indices and it is obvious that treatment of other risk factors that tend to
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dominant nature of the disease, some siblings carrying the same mutation as the proband, but having normal LDL-C blood levels, have been described. Autosomal Dominant Hypercholesterolemia due to Mutation in the PCSK9 (Protein Convertase Subtilisin/Kexin Type 9) Gene Recently, another monogenic hypercholesterolemia was identified (28,29). The PCSK9 (protein convertase subtilisin/ kexin type 9) gene, found on chromosome 1, is a member of the subtilisin serine protease family and its expression is regulated by dietary cholesterol in mice and by cellular sterol levels in human cell culture via the sterol regulatory element binding protein transcription factors (30). Thus, mutations that increase PCSK9 activity (gain of function mutations) will result in reduced LDL receptors and increased LDL-C blood levels (31). Autosomal Recessive Hypercholesterolemia (ARH) In ARH, TC levels approach those of homozygous FH and are differentiated from FH by the recessive mode of inheritance (normal TC levels of the parents). A mutation in a putative adaptor protein, mapped to chromosome 1p35, results in disruption of LDL receptor activity in liver cells and not in fibroblasts (32). The liver specific disruption of activity suggests that the mutated protein has a tissue-specific role in LDL receptor function (32,33). Polygenic Hypercholesterolemia The term polygenic hypercholesterolemia is applied whenever the clear pattern of autosomal dominant inheritance does not exist. Tendon xanthomata do not appear in polygenic hypercholesterolemia, but corneal arcus and xanthelesma may appear. It is conceivable that some of the patients identified as having polygenic hypercholesterolemia will be diagnosed as having a single gene mutation as other genes causing elevated LDL-C blood levels are identified. for hypercholesterolemia, such as hypothyroidism and renal disease need to be ruled out and our practice is to perform a biochemistry panel and TSH for this purpose. However, evidence for the cost-effectiveness of such an approach is lacking (34). Inherited hypercholesterolemia (Table 1) and diseases associated with increased risk for atherosclerosis (Table 2) may overlap both in diagnosis and treatment. Recently an AHA (American Heart Association) expert panel, endorsed by the AAP (American Academy of Pediatrics) published guidelines suggesting an outline for evaluating and managing children at high cardiovascular risk (CVD manifested before the age of 30 years including Homozygous FH, Diabetes mellitus type 1, chronic and end stage renal disease, post-orthostatic heart transplantation and Kawasaki disease with current coronary aneurism), moderate risk (accelerated atherosclerosis including heterozygous FH, Kawasaki disease with regressed coronary aneurism, diabetes mellitus type 2, chronic inflammatory disease) and at risk category (in risk setting for accelerated atherosclerosis including post-cancer treatment survivors, congenital heart disease and Kawasaki disease without detected coronary involvement) (2). The 2006 AHA publication rightly emphasizes the need to address as many risk factors as possible in each of the above cited conditions. However, some of the diseases addressed by the AHA expert panel are not necessarily associated with accelerated atherosclerosis (for example there is no evidence to suggest that inflammatory bowel is associated with increased risk of atherosclerosis) and setting an LDL-C cut off point for drug treatment may be adequate in adults at high risk for developing CVD, but not necessarily in children. Nevertheless, when LDL-C levels are within the range found in children that are heterozygous FH, most experts agree, without hard evidence, that the management of the elevated LDL-C should be similar to the management of children with FH. Non invasive methods such as ultrasound evaluation of carotid-intima medial thickness (CIMT) or flow mediated dilatation (FMD) of arteries can be used to assess blood vessels of hypercholesterolemic children. Significantly, the indices that are provided by these methods correlate with cardiovascular risk factors in children as well as adults (35-37) and thus can help evaluating the risk for accelerated atherosclerosis in children. In children heterozygous for FH, it was shown that mean CIMT values of children who were heterozygotes for FH was significantly greater than that of unaffected siblings (38). In that study, a significant deviation in intimamedia thickness was noted from age 12 years in children with FH. Furtheromore, in children, it has been shown that non invasive methods (especially FMD) are valuable in assessing response to treatment (8,9). Although evidence is still lacking of the value and cost-effectiveness of using CIMT or FMD in the evaluation and management of hypercholesterolemic children,
Approach to Pediatric Patients with Hypercholesterolemia

The initial evaluation of a child with hypercholesterolemia includes a comprehensive family history for hypercholesterolemia and premature coronary disease and assessment of other risk factors. Lipoprotein profiles of all immediate family members will help in establishing the mode of inheritance and the etiology, as well as identifying undiagnosed family members. By a lipoprotein profile we mean a fasting lipoprotein analysis (TC, TG, HDL-C and LDL-C). Lipoprotein profiles should be performed twice, due to large variability within individuals that may be due to measurement error, regression-to-the-mean, day-to-day variability, seasonal variability and, specifically in children, change with age, growth and pubertal status. Secondary causes
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we find their use helpful in assessing the need for drug therapy in this population and for routine yearly follow-up. Although these methods require dedicated personnel, they are easy to use, inexpensive and radiation free. This should be kept in mind when newer and more accurate non-invasive methods (CT, MRI) are introduced in our arsenal of non-invasive tools. values. In that context, trials in adults have demonstrated that the risk of death from CHD in adults declines by 2% for every 1 mg% decline in TC levels and it is reasonable to assume that diet would have a larger impact in children. The effectiveness of dietary treatment can also be limited by the concomitant reduction in HDL-C levels and the observation that long term adherence is difficult to achieve. Furthermore, at low fat intake there is higher carbohydrate intake (up to > 65% of energy). In that context, the role of carbohydrate intake in the development of adult onset disease (e.g. insulin resistance syndrome, obesity) has not been adequately studied in children, as well as the use of high fat/ low glucose diet and the use of low glycemic index food. Also, in low fat diets there is an increased risk of inadequate vitamin E, alpha linoleic and linoleic acid intake. Other additives to the diet that have been found to be successful in reducing LDL-C levels are the use of soluble fiber like psyllium (not demonstrated in all studies) and the use of stanol and sterol esters (43). The nutritional safety of stanol esters in children is yet to be determined. Other risk factors for CHD, such as obesity, physical inactivity and cigarette smoking are noted during childhood and adolescence. Recommendations should be made for appropriate lifestyle modifications, such as maintaining a desirable weight, increasing exercise, reducing sedentary activities (e.g. television watching) and stopping smoking. Involving all family members in the dietary changes and lifestyle modifications is important for long-term adherence to these treatment modalities. Pharmacologic Management Drug treatment should be considered in children only after dietary management and life style modification were practiced for a few months. The reason for this approach stems from the synergistic effect of dietary and drug management and the observation in a small subset of hypercholesterolemic children that dietary management would be sufficient. Nevertheless, in children with FH (heterozygotes) combining dietary and drug therapy are essential, but the response to diet alone is limited (42). In 1991, the NCEP provided its first guidelines for drug treatment for elevated LDL-C (1). It recommended that drug therapy should be considered for children older than 10 years of age who have had an adequate trial of dietary treatment for 6-12 months with LDL-C levels remaining above the 99th percentile (LDL-C above 190 mg/dL). In addition, the NCEP suggested that drug therapy should be considered when LDL-C levels remain above the 95th percentile (LDL-C above 160 mg/dL) in the presence of a positive family history of premature CHD or the child has two or more CHD risk factors (these risk factors include cigarette smoking, elevated blood pressure, low HDL-C (lower than 35 mg/dL), severe obesity (above 30% overweight), diabetes mellitus and physical inactivity). These
Management of Children with Hypercholesterolemia

Dietary Management The goal of dietary treatment is to reduce LDL-C levels in children and adolescents with elevated LDL-C blood levels (39). The recommended initial management to achieve this goal in children is to institute a "heart-healthy diet," i.e. one that is low in cholesterol and saturated fat, high in complex carbohydrates and adequate in energy for growth and the maintenance of a desirable weight. The American Heart Association Step I diet is well established for this purpose in adults and children older than two years and is detailed elsewhere (39). More therapeutically potent and restrictive is the step II diet (lower content of saturated fat and cholesterol). When implementing a Step II diet, there is the potential to develop nutritional deficiencies (given a more limited food selection), necessitating observation by a nutritionist. The Step I or II diet does not mention trans unsaturated fatty acids, the product of commercial hydrogenation of vegetable oils; These fatty acids increase LDL-C serum levels and decrease serum HDL-C serum levels (saturated fats increase both LDL-C and HDL-C serum levels) and their consumption should be minimized (40). In the most recent guidelines published by the AHA (2005), the recommendations for dietary management of patients older than 2 years and their families include daily intake of vegetables and fruits, reduced saturated and trans fatty acid intake, increased fiber intake, reduced intake of sugar-sweetened beverages and foods, reduced salt intake and a recommendation to eat more fish (increased intake of omega-3 polyunsaturated fatty acids) and to use non fat or low fat milk and dairy products (41). The goal of dietary treatment is to achieve normal LDL-C blood levels. However, in many cases this will not be possible. There are multiple reasons for the failure of dietary intervention; the child may already consume a reasonably heart-healthy diet, the elevation may be high enough so that the percent reduction of LDL-C achieved by dietary modification (typically no more than 20% and frequently less than 10%) still may not lower LDL-C to the target goal and that children with inherited hypercholesterolemia tend to have a smaller response to dietary modification (42). Therefore, a more realistic goal for children and adolescents with a high level of LDL-C is to reduce the level as much as possible and to look at the percentage reduction rather than at absolute
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recommendations were recently updated (2), suggesting that in certain conditions (diabetes mellitus type 1, homozygous FH, Kawasaki disease with aneurisms, end stage renal disease), after dietary treatment, the LDL-C target is < 100 mg/dL, while in children at moderate risk (such as heterozygous FH) the target for drug therapy would be LDL-C< 130 mg/dL. Finally, for children only at risk (congenital heart disease, cancer survivors), the target LDL-C is <160 mg/dL. Critical evaluation of these new guidelines is beyond the scope of this review, but the main deficiency of the current guidelines is the lack of evidence to support a link between defined LDL-C serum levels and CHD risk reduction in children. Furthermore, these recommendations follow the NCEP guidelines in adults suggesting that LDL-C target level should be 70 mg/dL in very high-risk adult patients and 100 mg/dL in high risk adult patients (44). However, a recent critical review, in adults, failed to find conclusive evidence that setting and achieving a specific target is either beneficial or safe (45). Thus, identifying and treating children with hypercholesterolemia is more important than setting or achieving specific LDL-C targets. This is demonstrated elegantly in studies of populations with loss of function mutations in the PCSK9 gene. These subjects inherit high activity of the LDL receptor and thus LDL-C levels are lower throughout life. In subjects with several mutations, LDL-C was reduced by 38 mg/ dL and the prevalence of CHD was reduced by 88% (46). Since in adults, 5 years reduction of LDL-C reduces the incidence of CHD only by 40% (47), the main lesson from these observations is that reduction of LDL-C that begins early in childhood has a stronger impact on CHD risk reduction then larger reductions later in life (48). Historically, bile salt sequestrants (cholestyramine) were used as the first line of therapy. These are bile acid-binding resins that bind bile salts and increase their fecal excretion, thus decreasing cholesterol absorption and as a consequence increase hepatic LDL receptor activity. In children, cholestyramine reduces LDL-C levels by more than 15%, but compliance appears to be a major problem. Despite the lack of systemic effects, nausea, epigastric fullness, bloating, flatulence and constipation are frequently seen and more than 50% of children discontinue the medication after less than one year (49). Newer preparations may prove to be associated with better adherence and are currently being studied in children. Despite the goals established by the AHA Expert Panel in 2006 (2), it is important to emphasize that the percentage of reduction in LDL-C is more important than the absolute blood level achieved and that normal blood levels can not always be expected in children with elevated LDL-C. When drug therapy other than cholestyramine is considered, the next step is the usage of HMG-CoA inhibitors (statins). A comprehensive review of the use of statins in children was recently published (50). In short, statins inhibit the major step in cholesterol synthesis and cause a significant reduction in LDL-C, a modest decrease in blood levels of triglycerides and slightly increased blood levels of HDL-C. Statins may have other anti atherogenic properties that may curb the inflammatory response and the recruitment of inflammatory cells to the atherosclerotic plaque (50). In adults, these drugs have proved successful in both secondary and primary prevention of CHD. In children, short-term treatment with various statins reduces LDL-C blood by an average of 40% (8,9,51-54). Furthermore, statins seem to attenuate the atherosclerotic process as demonstrated by improved flow mediated dilatation in children with heterozygous FH to levels observed in control children (8) and a significant reduction of CIMT in treated heterozygous FH compared to controls (9). Furthermore, in a recent study, following children (age 8-18 years) on statins for an average of 4.5 years, Multivariate analyses revealed that age at statin initiation was an independent predictor for CIMT and that early initiation of statin treatment was associated with a subsequently smaller CIMT (55). The authors conclude that early initiation of statin therapy in children with familial hypercholesterolemia might be beneficial in the prevention of atherosclerosis in adolescence. These recent findings combined with the protective effect of genes that lower LDL-C (46) provide arguments for lowering the age of initiation of statin treatment at least for children with heterozygous FH. Statins are safe, elevations of liver enzyme levels and creatine kinase are uncommon and growth, hormonal and nutritional status is not impaired during adolescence (for a recent meta-analysis see ref. 56). Other drugs include ezetimibe, an inhibitor of cholesterol absorption, but currently information on efficacy and safety in children is minimal (57). In adults, ezetimibe was reported to rarely cause severe cholestatic hepatitis, or acute autoimmune hepatitis (58). The scarcity of information and the possibility of having severe side effects mandate caution when using this drug in children. Nicotinic acid has been used successfully alone or in combination to treat childhood hypercholesterolemia. However, due to the high prevalence of side-effects, particularly flushing and tingling, we do not recommend the use of nicotinic acid, The treatment of homozygous FH is beyond the scope of this review and has been recently reviewed elsewhere (59). In short, plasmapheresis and preferably LDL apheresis when possible should be started at the youngest age possible and aggressive drug treatment should be provided when it has an added effect. Liver transplantations have also been used in some patients, given that approximately 60% of the whole body content of LDL receptors is in that organ. Finally, children with hypercholesterolemia should be followed periodically with monitoring of growth, nutrition, lipoprotein profile, management of other risk factors and monitoring for drug side effects. As indicated above, non invasive methods to assess surrogate markers of cardiovascular
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risk status are becoming an invaluable tool in the monitoring of these children.
17. Shamir R, Tershakovec AM, Liacouras CA, et al. The influence of age and relative weight on the expression of familial combined hyperlipidemia in childhood. Atherosclerosis 1996;121:85-91 please complete all authors names 18. Neil HA, Hammond T, Huxley R, et al. Extent of underdiagnosis of familial hypercholesterolaemia in routine practice: prospective registry study. BMJ 2000;321:148 please complete all authors names 19. Durrington P. Dyslipidaemia. Lancet 2003;362:717-731 20. Goldstein JL,Hobbs HH, Brown MS. Familial hypercholesterolemia In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic and molecular bases of inherited disease. McGraw-Hill, New York, NY, 8th edition, 2001;2863-2913 please complete all authors names 21. Marks D, Thorogood M, Neil HA, et al. A review on the diagnosis, natural history and treatment of familial hypercholesterolaemia. Atherosclerosis 2003;168:1-14 please complete all authors names 22. Rodenburg J, Vissers MN, Wiegman A, et al. Familial hypercholesterolemia in children. Curr Opin Lipidol. 2004;15:405-411 please complete all authors names 23. Humphries SE, Galton D, Nicholls P. Genetic testing for familial hypercholesterolaemia: practical and ethical issues. QJM 1997;90:169-181 24. Wiegman A, Rodenburg J, de Jongh S, et al. Family history and cardiovascular risk in familial hypercholesterolemia. Data in more then 1000 children. Circulation 2003;107;1473-1478 please complete all authors names 25. van Aaalst-Cohen ES, Jansen AC, Tanck MW, et al. Diagnosing familial hypercholesterolaemia: the relevance of genetic testing. Eur Heart J 2006;27:2240-2246 please complete all authors names 26. Defesche JC, Pricker KL, Hayden MR, et al. Familial defective apolipoprotein B-100 is clinically indistinguishable from familial hypercholesterolemia. Arch Intern Med 1993;153:2349-2356 please complete all authors names 27. Myant NB. Familial defective apo B-100: a review, including some comparisons with familial hypercholesterolaemia. Atherosclerosis 1993;104:1-18 28. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genet 2003;34:154-156 please complete all authors names 29. Timms KM, Wagner S, Samuels ME, et al. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Human Genet 2004;114:349-353 please complete all authors names 30. Maxwell KN, Fisher EA, Breslow JA. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA 2005;102:2069-2074 31. Tall AR. Protease variants, LDL and coronary heart disease. N Engl J Med 2006;354:1310-1312 32. Garcia CK, Wilund K, Arca M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 2001;292(5520):1394-1398 please complete all authors names 33. Harada-Shiba M, Takagi A, Miyamoto Y, et al. Clinical features and genetic analysis of autosomal recessive hypercholesterolemia. J Clin Endocrinol Metab 2003;88:2541-2547 please complete all authors names 34. Franklin FA, Dashti N, Franklin CC. Evaluation and management of dyslipoproteinemia in children. Endocrinol Metab Clin North Am 1998;27:641-654 please complete all authors names 35. Davis PH, Dawson JD, Riley WA, et al. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study. Circulation 2001;104:2815-2819 please complete all authors names 36. Li S, Chen W, Srinivasan SR, et al. Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. JAMA 2003;290:2271-2276 please complete all authors names
References
1. National Cholesterol Education Program Coordinating Committee. Report of the Expert Panel on Blood Cholesterol in Children and Adolescents. Bethesda, MD: National Heart, Lung and Blood Institute. NIH Publication No 1991;91:2732 Kavey RE, Allada V, Daniels SR, et al. Cardiovascular risk reduction in high-risk pediatric patients. Circulation. 2006;114:2710-2738 please complete all authors names Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Relationship of Atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking. JAMA 1990;264:3018-3024 Berenson GS, Srinivasan SR, Bao W, et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. N Engl J Med 1998;338:1650-1656 please complete all authors names Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, et al (eds). The Metabolic Basis of Inherited Disease. New York, McGraw-Hill 1995;1981-2030 please complete all authors names Sprecher DL, Schaefer EJ, Kent KM, et al. Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients. Am J Cardiol 1984;54:20-30 please complete all authors names Schmidt HH, Hill S, Makariou EV, et al. Relation of cholesterol-year score to severity of calcific atherosclerosis and tissue deposition in homozygous familial hypercholesterolemia. Am J Cardiol 1996;77:575-580 please complete all authors names de Jongh S, Lilien MR, op't Roodt J, et al. Early statin therapy restores endothelial function in children with familial hypercholesterolemia. J Am Coll Cardiol 2002;40:2117-2121 please complete all authors names Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004;292:331-337 please complete all authors names Cortner JA, Coates PM, Liacouras CA, et al. Familial combined hyperlipidemia in children: clinical expression, metabolic defects and management. J Pediatr 1993;123:177-184 please complete all authors names Shamir R, Lerner A, Fisher EA. Hypercholesterolemia in children. Isr Med Assoc J 2000;2:767-771 Goldstein JL, Schrott HG, Hazzard WR, et al. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest 1973;52:1544-1568 please complete all authors names Ayyobi AF, McGladdery SH, McNeely MJ, et al. Small dense LDL and elevated apolipoprotein B are the common characteristics for the three major lipid phenotypes of familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol 2003;23:1289-1294please complete all authors names McNeely MJ, Edwards KL, Marcovina SM, et al. Lipoprotein and apolipoprotein abnormalities in familial combined hyperlipidemia: a 20-year prospective study. Atherosclerosis 2001;159:471-481 please complete all authors names Shoulders CC, Jones EL, Naouva RP. Genetics of familial combined hyperlipidemia and risk of coronary heart disease. Hum Mol Genet 2004;13:R149-R160 Suviolahti E, Lilja HE, Pajukanta P. Unraveling the complex genetics of familial combined hyperlipidemia. Ann Med 2006;38:337-351
2. 3.
4.
5.
6. 7.
8.
9.
10.
11. 12.
13.
14.
15. 16.
No. 2
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37. Knoflach M, Kiechl S, Kind M, et al. Cardiovascular risk factors and atherosclerosis in young males: ARMY study (Atherosclerosis RiskFactors in Male Youngsters). Circulation 2003;108:1064-1069 please complete all authors names 38. Wiegman A, de Groot E, Hutten BA, et al. Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia. Lancet 2004;363(9406):342-343 please complete all authors names 39. Shamir R, Fisher EA. Dietary therapy for children with hypercholesterolemia. Am Fam Physician 2000;61:675-682 40. Willett WC. Trans fatty acids and cardiovascular diseaseepidemiological data. Atheroscler 2006;7(Suppl):5-8 41. Gidding SS, Dennison BA, Birch LL, et al. Dietary recommendations for children and adolescents: a guide for practitioners: consensus statement from the American Heart Association. Endorsed by the American Academy of Pediatrics. Circulation. 2005;112:2061-2075 please complete all authors names 42. Dixon LB, Shannon BM, Tershakovec AM, et al. Effects of family history of heart disease, apolipoprotein E phenotype and lipoprotein(a) on the response of children's plasma lipids to change in dietary lipids. Am J Clin Nutr 1997;66:1207-1217 please complete all authors names 43. Vuorio AF, Gylling H, Turtola H, et al. Stanol ester margarine alone and with simvastatin lowers serum cholesterol in families with familial hypercholesterolemia caused by the FH-North Karelia mutation. Arterioscler Thromb Vasc Biol 2000;20:500-506 please complete all authors names 44. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239 please complete all authors names 45. Hayward RA, Hofer TP, Vijan S. Narrative review: Lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med 2006;145:520-530 46. Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL and protection against coronary heart disease. N Engl J Med 2006;354:1264-1272 please complete all authors names 47. Baigen C, Keech A, Kearney PM, et al (Cholesterol Treatment Trialists' (CTT) Collaborators). Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-1278 please complete all authors names 48. Brown MS, Goldstein JL. Lowering LDL-not only how low, but how long? Science 2006;311:1721-1723 49. Tonstad S, Knudtzon J, Sivertsen M, et al. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia. J Pediatr 1996;129:42-49 please complete all authors names 50. Belay B, Belamarich PF, Tom-Revzon C. The use of statins in pediatrics: Knowledge base, limitations and future directions. Pediatrics 2007;119:370-380 51. Stein EA, Illingworth DR, Kwiterovich PO Jr, et al. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial. JAMA 1999;281:137-144 please complete all authors names 52. Hedman M, Matikainen T, Fohr A, et al. Efficacy and safety of pravastatin in children and adolescents with heterozygous familial hypercholesterolemia. J Clin Endocrinol Metab 2005;90:1942-1952 please complete all authors names 53. McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial. J Pediatr 2003;143:74-80 54. Clauss SB, Holmes KW, Hopkins P, et al. Efficay and safety of lovastatin therapy in adolescent girls with heterozygous familial hypercholesterolemia. Pediatrics 2005;116:682-688 please complete all authors names 55. Rodenburg J, Vissers MN, Wiegman A, et al. Statin Treatment in Children With Familial Hypercholesterolemia. The Younger, the Better. Circulation 2007;116:664-668 please complete all authors names 56. Avis HJ, Vissers MN, Stein EA, et al. A systematic review and meta-analysis of statin therapy in children with familial h y p e r c h o l e s t e r o l e m i a . A r t e r i o s c l e r T h r o m b Va s c B i o l 2007;27:1803-1810 please complete all authors names 57. Gagne C, Gaudet D, Bruckert E, et al. Efficacy and safety of ezetimibe co administered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002;105:2469-2475 please complete all authors names 58. Stolk MF, Becx MC, Kuypers KC, et al. Severe hepatic side effects of ezetimibe. Clin Gastroenterol Hepatol 2006;4:838-839 please complete all authors names 59. Thompsen J, Thompson PD. A systematic review of LDL apheresis in the treatment of cardiovascular disease. Atherosclerosis 2006;189:31-38
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Endocrine Complications in Patients with Thalassaemia Major

Meropi Toumba, MD, Constantinos Kanaris, MD, Nicos Skordis, MD
Pediatric Endocrine Unit, Department of Pediatrics, Makarios Hospital, Nicosia, Cyprus Corresponding author: Meropi Toumba, MD, Business Address: Pediatric Endocrine Unit, Makarios Hospital, Nicosia 1474, Cyprus, Home Address: 10, Imbrahim Kiazim, 8016, Paphos, Cyprus, Tel: 00357 22405000, 00357 99573633, Fax: 00357 26848300, E-mail: meropitoumba@cytanet.com.cy
Abstract
atients with multi-transfused thalassaemia major may develop severe endocrine complications due to iron overload. The anterior pituitary is particularly sensitive to iron overload which disrupts hormonal secretion resulting in hypogonadism, short stature, acquired hypothyroidism and hypoparathyroidism. Glucose intolerance and diabetes mellitus are also common in thalassaemic patients. The severity of the clinical manifestation and laboratory findings in thalassaemia largely depends on the genotype; thus homozygotes or compound heterozygotes for the mutations 0 or + depend for life on frequent transfusions. A multicenter study in Cyprus including 435 patients showed hypogonadotrophic hypogonadism in 32.5%, short stature in 35%, acquired hypothyroidism in 5.9%, hypoparathyroidism in 1.2% and diabetes mellitus in 9.4%. A slowing down of growth velocity and a reduced or absent pubertal growth spurt is observed in early adolescence leading to short adult height. Delayed or absent puberty and hypogonadism may result in fertility problems which affect enormously the life of thalassemics. Glucose intolerance in adolescence and diabetes mellitus later in life are also frequent complications mainly due to iron overload, chronic liver disease and genetic predisposition. Primary hypothyroidism and hypoparathyroidsm usually appear in the second decade of life; are related to iron overload and may be reversible at an early stage by intensive chelation. Osteopenia and osteoporosis due to a complicated pathogenesis represent prominent causes of morbidity in young adults of both genders with thalassaemia. Early recognition and prevention of the endocrine complications, by early and regular chelation therapy, is mandatory for the improvement of the quality of life and psychological outcome of these patients.
Ref: Ped. Endocrinol. Rev. 2007;5(2): Key Words: Thalassaemia Major; Endocrine Complications; -Globin Gene Mutations, Multiple Transfusions; Iron Chelation Therapy
Introduction
Patients with multi-transfused Thalassaemia Major (TM) may develop severe endocrine complications. Iron overload due to multiple transfusions is the main cause of such complications hence proper and effective iron chelation therapy is essential for the reduction of iron deposition on various endocrine glands reversing, thus, the endocrine abnormality (1-3). The anterior pituitary is particularly sensitive to iron overload causing hormonal secretion abnormalities. Consequently patients with TM develop hypogonadism, short stature, acquired hypothyroidism and hypoparathyroidism. Glucose intolerance and Diabetes Mellitus (DM) is another common endocrine complication in TM of multifactorial aetiology. Iron accumulates in tissues with high levels of transferrinreceptor such as liver, heart and endocrine glands (3). Iron is connected to the protein transferrin. When the storage capacity of transferrin is exceeded, pathological quantities of the metabolically active iron are released intracellularly in the form of haemosiderin and free iron. Free iron catalyzes the formation of free radicals which damage membrane lipids and other macromolecules in the cells, leading to cell death and eventually organ failure (3). Iron accumulation is documented by measuring levels of ferritin, serum iron and transferring, and calculation of the percentage of iron saturation (4). Magnetic resonance methods such as quantitative MRI and SQUID and biomagnetic liver susceptometry have recently become available for measurement of iron deposition (4,5). Although iron overload plays a critical role in the appearance of endocrine complications, the severity of clinical
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Endocrine Complications in Thalassaemia

manifestations largely depends on the type of underlying mutations of the -globin gene, which are mostly point mutations or gene deletions. The majority of patients, who are homozygotes or compound heterozygotes for the mutations 0 or +, depend on frequent transfusions for life. TM patients, who also carry mutations of the -globin gene, produce lesser amounts of - chain and therefore have a milder clinical phenotype (6). Additionally chronic liver disease as a complication of iron overload and hepatic viral infections, mainly hepatitis C virus, due to multiple transfusions play a key role in the endocrinopathies of TM patients, especially in the development of diabetes mellitus (7,8).
Figure 1. Standing Height and Sitting Height (SDS) in Different Age-Groups
The Cyprus Experience

Cyprus is a Mediterranean country with a considerable experience in the field of Thalassaemia due to the significant number of TM patients, compared to the small size of the island. The prevalence of endocrine complications in 435 patients with TM is shown on Table 1, where a comparison with other reports is also shown (9-12). Short stature and hypogonadotrophic hypogonadism are the commonest complications as expected. A previous study showed the characteristic pattern of growth in thalassaemic patients (12). Both sitting and standing heights were normal until the age of 6-9 years but gradually decreased in older ages with particular shortening of the sitting height (figure 1). These patients had a height below -2SDS attributed to thalassemia only, regardless of target height. GH secretion following GHRH stimulation was found to be normal in these patients, when compared to controls and, interestingly, the peak GH was higher in pubertal compared to prepubertal patients as found in the normal population (figure 2). It is therefore evident that other contributing factors, rather than GH abnormal secretion, account for the growth impairment in these patients. Hypogonadotrophic hypogonadism is the second commonest complication found in the cohort of these 435 patients. The genotype seems to play a role in the development of hypogonadism as shown in a recent Study No of Patients Hypogonadism Short Stature Short Sitting Height Hypothyroidism Hypoparathyroidism DM/IGT Cyprus 435 32.5 35 72 5.9 1.2 9.4 Greece 1995 (10) 262 42 32 ---4 4 5/27
study by Skordis et al (13). This study with 126 thalassemics showed that patients who carry no mitigating factor in their genotype were consuming larger amounts of blood on transfusions and were more likely to develop hypogonadism compared to patients carrying one or more mitigating factors despite their similar mean ferritin levels (13). Another study of 101 women aged 15-50 years proved the impact of iron overload and genotype on gonadal function in this group of patients (14). Figure 3 shows the serial values of FSH and LH of these women after a GnRH stimulation test. Gonadotrophin levels were lower in women with Primary and Secondary amenorrhea compared to those who had normal menstrual cycles. All these women had a normal gonadal function revealing that there was only a central damage due to iron overload (14). Our data on fertility showed that the number of pregnancies is increasing throughout the years. In our population, 98 women managed to conceive, gestate and deliver 158 babies out of 149 pregnancies (15). The same report showed that 59 males with TM (54 normal and 5 hypogonadal, who received combined treatment with hCG and hMG) were able to father 97 children (15). The presence of DM was found in 9.4% of our patients. Figure 4 shows the age of diagnosis in relation with the year of birth. It seems that younger patients, who are more frequently transfused in order to maintain the Hb above 9-10 mg/dl have the tendency to develop abnormalities of glucose homeostasis at younger ages. From these patients only 15% were HCV RNA positive (12). TIF 2004 (9) 3817 40.5 30.8 ---3.2 6.9 3.2/6.5
Italy 1995 N. America (35) 2004 (11) 1861 49 ------6.2 3.6 4.9 342 35 ------9 4 10
Complications in Growth
The child with TM has a particular growth pattern which is relatively normal until the age of 9-10 years; after this age a slowing down of growth velocity and a reduced or absent pubertal growth spurt are observed. Growth failure as well as delayed puberty, an additional cause of growth deterioration, is mainly due to chronic anemia, ineffective erythropoiesis, iron overload and
Table 1. Prevalence of Endocrine Complications in Thalassaemia Patients in Cyprus Multicenter Study and in Other Studies
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Figure 3. FSH (a) and LH Levels (b) after GnRH Stimulation in Thalassaemic Women with Normal Menstrual Cycles, Primary Amenorrhea and Secondary Amenorrhea. X-Axis: Time in Minutes, YAxis FSH and LH in miu/l
Figure 2. GH Response to GHRH in (a): thalassaemic patients compared to the controls and (b) prepubertal and pubertal thalassaemic children. X-axis: time in minutes after GHRH administration. Y-axis: GH levels in miu/l
intensive use of chelating agents (16,17). A final height below the 10th centile was observed in 50% of males and 36% of females in the study of De Sanctis et al (16). Subnormal sitting height in both pubertal and prepubertal children with TM was ensued by previous reports leading to the conclusion that delayed puberty is not the only cause of truncal shortening (18-21). Furthermore truncal shortening was observed in children with good chelation therapy compliance and low ferritin levels (19). Several studies showed the high prevalence of short stature in TM children and adolescents treated intensively with desferrioxamine (18,21). Paradoxically, premature chelating therapy, between the ages 2 and 5 years, may have deleterious effects on growth (19-21). Desferrioxamine is proven to inhibit cell proliferation, DNA synthesis, collagen formation and trace mineral deposition such as cooper and zinc. Mineral depletion may result in a decrease of alkaline phosphatase activity, a zinc-dependant enzyme. This complex mechanism results in platyspondylosis with flattening of the vertebral bodies and consequent shortening of the spinal height (21). By contrast,
patients treated with desferrioxamine after the age of 3 years, even with large doses may not develop the same bone abnormalities (21). It is recommended that growth in both standing and sitting positions should be assessed at 6-monthly intervals in order to detect growth failure. Desferrioxamine administration should be initiated only after iron accumulation is established, namely, around 3 years of age, after 20 to 30 transfusions (21). However, the dose regimens should be individualized based on the dose response pattern of the patient and the degree of iron overload (19). In patients who develop signs of toxicity, desferioxamine should be stopped and replaced with other chelating agents like oral deferiprone or deferasirox although some bone lesions remain irreversible (22).
Figure 4. Age at Diagnosis of Diabetes Mellitus in Relation to the Year of Birth of Thalassaemia Patients
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The secretion of GH is found to Study n Age (y) IGT (%) IDDM (%) be the same as that in the normal population; also as that of patients De Sanctis V et al, Arch Dis 448 17 (Mean) ----6.4 with idiopathic short stature (23). Child 1988 (46) However,, other studies showed 50 <15 24 6 El Hazmi MA J Trop Ped 1994 impaired GH response to GHChern JP et al, Diabetes Care challenge tests in TM patients aged 82 14.86.9 (Mean) 19.5 8.5 2001 (47) 10-23 years (24,25). Recent studies reported 3.1% of thalassemics Khalifa AS et al, Pediatr 56 10-31 (Range) 14.6 10.4 Diabetes 2004 (48) to have GHRH-GH-IGF axis 11-14 16.3 0 dysfunction (26), which is attributed Kattamis C et al, Ped End Rev After 4y 39 0.5 263 to multiple mechanisms such 2004 (49) After 10y 39 2.4 as neurosecretory dysfunction, 10.9 (HCV+) 15.2 (HCV+) Mowla A et al, Ped End Rev hypothalamic GH-releasing hormone 98 15.24 (Mean) 2004 (50) 7.6 (HCV-) 1.9 (HCV-) (GHRH) deficiency and increased 15 0.5 s om a t os t a t i n a c t i v i t y ( 2 7 - 2 9 ) . During 30y Gamberini M et al, Ped End Rev 273 30 4.2 Thalassemic patients with delayed 2004 (51) Follow Up 28 0.7 puberty do not exhibit a normal growth spurt; their GH peak amplitude Table 2. Incidence of Diabetes Mellitus (DM) and Impaired Glucose Tolerance (IGT) in Different Studies is reduced as well as their nocturnal compliant to chelation therapy (14,35). However, damage GH levels (27,28). In such patients, one should use sex steroid of the hypothalamus and pituitary in women with Secondary priming before GH testing and normalize thyroid function. Low Amenorrhea is progressive, even when intensive chelating IGF-1 and IGFPB3 levels, but normal GH and GHBP levels, may therapy is given (14). Ovarian function of TM women is normal account for GH resistance (24). The dose of rhGH ranges from as they produce the expected number of ova after stimulation 0.5-1U/kg/week but higher doses should be given to patients therapy (15,36). with a low response (30,31). However, non-GH deficient TM Male patients may complain of impotence and have patients treated with higher doses did not show satisfactory decreased sperm volume. Sperm abnormalities in the quality, growth improvement (32). Glucose tolerance must be monitored morphology and motility of spermatozoa are well documented especially of patients with high dose of rhGH. in TM (37,38). Azoospermia is a common finding in thalassaemic patients both to those who fail to enter puberty at a normal Delayed Puberty- Hypogonadotrophic age but also in those who manifest hypogonadism later in Hypogonadism life. There is evidence for sperm DNA damage in iron overload patients (37). Primary gonadal failure in men was evidenced Iron deposition on gonadotrophic cells leads to disruption by lack of testosterone response to HCG (15,36). Successful of gonadotrophin production and consequently to delayed induction and maintenance of spermatogenesis in thalassemic puberty and hypogonadotrophic hypogonadism. In the majority males as well as restoration of their gonadal function is of patients the function of gonads is normal. However, important for the improvement of the self-image and quality gonadal iron deposition occasionally occurs. The association of life. of hypogonadotrophic hypogonadism with the genotype has already been proven (6,13,14). An additional contributing Hypothyroidism factor, although playing a weak role, is the impaired synthesis of leptin in thalassaemic patients which seems to be related to Primary hypothyroidism usually appears in the second transferrin receptor levels (33,34). decade of life, when other endocrine complications Adolescent thalassemics may present with delayed puberty are already manifest and is related to iron overload. The (50-100%) or arrested puberty (35,36). In such patients reported prevalence varies depending on the number as the pubertal onset may be normal but the full pubertal well as on the age composition of the study population from development is not completed and remains at Tanner stage 3 0-18% (9,10,12,39). Primary thyroid dysfunction occurs before of puberty for over a year. In boys the volume of the testes is any iron-induced damage of the TRH-TSH axis thus secondary less than 6-8 ml for longer than a year. Similarly in girls breast hypothyroidism due to pituitary haemosiderosis is rare. development is constant at stage 3 for over a year. More than Abnormal thyroid function may be reversible at an early stage 50% of girls with TM fail to reach menarche and present with by intensive chelation. However, the progression of subclinical Primary Amenorrhea (14,35,36). Secondary Amenorrhea will hypothyroidism to overt disease may take many years (40). invariably develop with time especially in patients poorly Thyroid function tests should be checked in patients with TM.
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Ultrasound of the thyroid gland is not diagnostic. A recent report speculated that thyroid ultrasound may be useful in the management of thalassaemic patients with patterns indicative of thyroid damage. In the majority of the patients (73.3%), the volume of the thyroid gland was normal while hypoechogenicity was found in 46.6% of the patients, without a corresponding clinical picture. However, these findings are not specific for the thalassaemic patients and no correlation was found to thyroid damage (41). patients with a non-favorable genotype of thalassaemia lead to secondary heamochromatosis which results in both liver and pancreatic damage (7). Additional factors such as viral hepatic infections mainly hepatitis C and hormonal treatment for other endocrinopathies increase the risk of liver disease and cirrhosis (8). Pancreatic and liver dysfunction results in hyperinsulinemia as a consequence of increased insulin secretion, impaired hepatic removal and porta-systemic shunting of insulin. In addition, increased iron content in muscle cells in patients with haemosiderosis results in peripheral insulin resistance probably due to abnormalities of insulin receptors or glucose transporters, related to increased production of cytokines such as tumor necrosis factor-c or of non-esterified fatty acids (3). Thalassaemics with liver disease are at greater risk of glucose intolerance compared to those with normal liver function (54). Factors such as family history, splenectomy, hepatitis C infection, elevated Ferritin levels and the presence of the IVS II nt 745 mutation were proven to correlate with the development of IGT in Thalassaemia (48). IGT may start early in the second decade of life parallel to puberty and often precedes the development of DM. It is well documented that insulin resistance occurs during puberty in both normal children and children with diabetes (52). The combined adverse effects of both puberty and Thalassemia associated risk factors on insulin action may partly explain the increase of insulin resistance in adolescent thalassemics. Insulin response to OGTT and sensitivity show a negative correlation with the degree of haemosiderosis (53). In a recent study by Kattamis et al the prevalence of IGT in thalassaemics aged 11 to 19 years was increased from 17.9% to 36.2% in five years and then remained stable for at least 2 years. In the same cohort DM was increased from 0% to 2.4% in 5 years (49). The natural history of DM in thalassaemia is unique. During the initial stage of insulin resistance, the pancreatic beta cell is gradually exhausted leading to the development of insulin deficiency (55). However, it differs from the classic form of type I DM in that it is rarely complicated with diabetic ketoacidosis and there is no relation to islet cell antibodies (ICA) and HLA-DR3 and DR4 (56). Thalassaemics with DM have a lower risk of developing retinopathy, probably due to the low levels of IGF 1 (57) and a higher risk of developing diabetic nephropathy, probably due to an additional oxidative injury by the elevated aldehyde concentrations (58). Early recognition of glucose abnormalities is essential. OGTT should be done in every patient with thalassaemia after the age of ten or earlier if needed. Serum fructosamine levels may be helpful in monitoring long-term glycemic control in diabetic thalassaemia patients as the measurement of HbA1C is not helpful at all (59). Screening for hepatitis infections and regular chelation therapy are important measures in preventing the development of diabetes. Initial management is based on intensive chelation therapy, special diet and regular exercise (60). Limited data on the effect of oral antidiabetic
Hypoparathyroidism
Hypoparathyroidism is a rare complication in thalassaemia which develops in late adolescence. A recent study reported prevalence up to 13.5% with no sex differences (42). Iron overload with deposition on parathyroid cells and tissue fibrosis are the main causes of hypoparathyroidism while chronic anaemia is an additional factor causing parathyroid dysfunction (43). The condition presents with the typical biochemical picture of hypoparathyroidism of low calcium and high phosphate levels. PTH may be normal or low and 1, 25 dihydroxycholecalciferol (Vitamin D) low. Low calcium and phosphorus is found in the 24hour urine collection. Bone x-rays are characterised by osteoporosis. Recently abnormal cerebral CT findings have been reported to be related to hypoparathyroidism in thalassemics (42,43). When hypoparathyroidism is suspected, one needs to have in mind the risk of hypocalcaemia which has to be treated without delay.
Hypoadrenalism
Pituitary haemosiderosis may cause abnormal ACTH secretion. The ACTH diurnal variation is lost in the 25% of thalassaemics while cortisol and aldosterone secretory patterns are normal after ACTH infusion (44). Low androgens relative to bone age with absence of adrenarche especially in girls have also been reported (45).
Diabetes Mellitus
Impaired glucose tolerance (IGT) and insulin dependent diabetes mellitus are frequently observed in patients with TM. The prevalence of glucose homeostasis disturbances varies from 4% to 20%, uncommon during the first years of life and progressively increase with age (46-51,54). Table 2 shows the prevalence of DM and IGT in different studies (46-51,54). The variation in prevalence is related to differences in age distribution, severity of clinical phenotypes and therapeutic management of the patients. The pathogenesis of IGT and DM is very complicated, involving multiple mechanisms. Iron overload, chronic liver disease, viral hepatic infections and genetic predisposition seem to be the main risk factors for the development of DM in thalassemics. Multiple transfusions especially in those
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drugs such as glibenglamide or a- glycosidase inhibitors, are reported (60,61). and proper management is crucial for every patient. Numerous research studies in the pathogenesis, manifestations and treatment options in association with modern advances in the medical care of thalassemia patients as mentioned in this review enable these patients to leave a better life.
Osteoporosis
Osteopenia and osteoporosis represent prominent causes of morbidity in young adults of both genders with thalassaemia (62). During the last decade, the presence of osteopenia or osteoporosis in well-treated thalassaemics has been described in different studies with a high prevalence of up to 50% (63). The pathogenesis of osteoporosis in TM is very complicated and differs from the pathogenesis of bone deformities characteristically found in non-transfused patients who develop bone distortion mainly due to ineffective haemopoiesis and progressive marrow expansion. Several factors are implicated in the reduction of bone mass in TM. Delayed sexual maturation, diabetes, hypothyroidism, parathyroid gland dysfunction, GH and IGF-1 deficiency, ineffective haemopoiesis with progressive marrow expansion and direct iron toxicity on osteoblasts have been indicated as possible causes of thalassaemia-induced osteoporosis (63). Furthermore, iron chelation has correlated with growth failure and bone abnormalities and high desferrioxamine dosage has been associated with cartilage alterations (18,21,63). Genetic factors seem to play an important role in the development of low bone mass and osteoporotic fractures. These factors have been implicated in the pathogenesis of postmenopausal osteoporosis, as regulator genes of BMD, but have not been studied thoroughly in thalassaemia-induced osteoporosis (64). Despite the improvement of hemoglobin levels, adequate hormone replacement and effective iron chelation, patients continue have an increased risk of osteopenia and osteoporosis (64,65). Good nutrition with adequate vitamins and trace elements intake including vitamin D and calcium could increase BMD and prevent bone loss. Additionally sex steroids should be used to induce puberty at the proper age (about 13 years in girls and 14 years in boys) (65). Several studies showed the positive effect of bisphosphonates in thalassaemia osteoporosis. Alendronate, pamidronate and zoledronic acid seem to have the greatest efficacy (62). However, more trials must be conducted in order to clarify the exact role of each bisphosphonate, the long-term benefit and side effects as well as the effects of the combination of bisphosphonates with other effective agents, such as hormonal replacement, in thalassaemia-induced osteoporosis.
References
1. Berkovitch M, Bistritzer T, Milone S, Periman K, Kucharczk W, Koren G, Olivieri NF. Iron deposition in the anterior pituitary in homozygous beta-thalassaemia: MRI evaluation and correlation with gonadal function. J Pediatr Endocrinol Metab 2000; 13:179-184 Brittenham GM, Griffith PM, Nienhuis AW, McLaren CE, Young NS, Tucker EE, Allen CJ, Farrell DE, Harris JW. Efficacy of desferrioxamine in preventing complications of iron overload in patients with thalassaemia major. N Engl J Med 1994;331:567-573 Esposito BP, Breuer W, Sirankapracha P, Pootrakul P, Hershko C, Cabantchik ZI. Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood 2003;102: 2670-2677 Chan YL, Li CK, Lam CW, Yu SC, Chik KW, To KF, Yeung DK, Howard R, Yuen PM. Liver iron estimation in beta-thalassaemia: comparison of MRI biochemical assay and histological grading. Clin Radiol 2001;56:911-916 Fischer R, Piga A, Harmatz P, Nielsen. Monitoring long-term efficacy of iron chelation treatment with biomagnetic liver susceptometry. Ann N Y Acad Sci 2005;1054:358-372 Jensen CE, Tuck CM, Old J, Morris RW, Yardumian A, De Sanctis V, Hoffbrand AV, Wonke B. Incidence of endocrine complications and clinical disease severity related to genotype analysis and iron overload in patients with thalassaemia. Eur J Haematol 1997;59:76-81 De Sanctis V, D'Ascola G, Wonke B. The development of diabetes mellitus and chronic liver disease in long term chelated beta thalassaemic patients. Postgrad Med J 1986;62:831-836 Labropoulou-Karatza C, Goritsas C, Fragopanagou H, Repandi M, Matsouka P, Alexandrides T. High prevalence of diabetes mellitus among adult beta-thalassaemic patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 1999;11:1033-1036 De Sanctis V, Eleftheriou A, Malaventura C, on behalf of the Thalasaemia International Federation (TIF) Study Group on Growth and Endocrine Complications. Prevalence of endocrine complications and short stature in patients with thalasaemai major: a multicenter study by the TIF. Pedriatr Endocrin Rev 2004;2(suppl 2):249-255 Kattamis CA, Kattamis AC. Management of thalassaemia: growth and development, hormone substitution, vitamin supplementation and vaccination. Sem Hematol 1995;32:269-279 Cunningham M, Macklin E, Neufeld E, Cohen A, for the Thalassemia Clinical Research Network. Complications of thalassemia major in North America. Blood 2004;104:34-39 Skordis N. Endocrine complications in Cypriot Thalassaemic patients. In: S. Ando and C. Brancati (eds): Endocrine Disorders in Thalassaemia. Heidelberg: Springer Verlag Publ 1995;83-89 Skordis N, Michaelidou M, Savva SC, Ioannou Y, Rousounides A, Kleanthous M, Skordos G, Christou S. The impact of genotype on endocrine complications in thalassaemia major. Eur J Haematol 2006 Jun 26 Skordis N, Gourni M, Kanaris C, Toumba M, Kleanthous M, Karatzia N, Pavlides N, Angastiniotis M. The impact of iron overload and genotype on gonadal function in women with thalassaemia major. Pediatr Endocrinol Rev 2004;2 (Suppl2):292-295 Skordis N, Petrikkos L, Toumba M, Siammonian K, Hadjgavriel M, Sitarou M, Kolnakou A, Skordos G, Pangalou E, Christou S. Update on Fertility in Thalassaemia. Pediatr Endocrinol Rev 2004;2(Suppl 2):296-302 De Sanctis V, Roos M, Gasser T, Fortini M, Raiola G, Galati MC, Italian Working Group on Endocrine Complications in Non-Endocrine Diseases. Impact of long-term iron chelation therapy on growth and endocrine functions in thalassaemia. J Pediatr Endocrinol Metab 2006;19:471-480 Skordis N. The growing child with thalassaemia. J Pediatr Endocrinol Metab 2006;19:467-469 Olivieri, NF, Koren G, Harris J, Khattak S, Freedman MH, Templeton DM, Bailey JD, Reilly BJ. Growth failure and bony changes induced by deferoxamine. Am J Pediatr Hematol Oncol 1992;14:4856 De Sanctis V, Katz M, Vullo C, Bagni B, Ughi M, Wonke B. Effect of different treatment regimes on linear growth and final height in -thalassaemia major. Clin Endocrinol 1994;40:791-798 De Luca F, Simone E, Corona G, Pandullo E, Siracusano MF, Arrigo T. Adult height in thalassaemia major without hormonal treatment. Eur J Pediatr 1987;146: 494-496
2.
3. 4. 5. 6.
7. 8.
9.
10. 11. 12. 13. 14.
15. 16.
Conclusion
It is obvious that several endocrine glands may be affected in patients with TM in childhood, adolescence and adulthood. Pituitary damage due to iron overload as well as non-favourable genotypes are main risk factors in the development of severe complications that adversely affect the life expectancy of patients with thalassemia. Close follow up
17. 18. 19. 20.
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21. De Virgillis S, Congio M, Frau F, Argiolu F, Diana G, Cucca F, Varsi A, Sanna G, Podda G, Fodde M, Pirastu GF, Cao A. Desferrioxamine induced growth retardation in patients with thalassaemia major. J Pediatr 1988;113:661-669 22. Wang CH, Wu KH, Tsai FJ, Peng CT, Tsai CH. Comparison of oral and subcutaneous iron chelation therapies in the prevention of major endocrinopathies in beta-thalassemia major patients. Hemoglobin 2006;30:257-262 23. Leger J, Girot R, Crosnier H, Poste-Vinay MC, Rappaport R. Normal growth hormone (GH) response to GH-releasing hormone in children with thalassaemia major before puberty: a possible age related effect. J Clin Endocrinol Metab 1989;69:453-456 24. Soliman AT, EL Banna N, Ansari BM. GH response to provocation and circulating IGF-1 and IGF-binding protein-3 concentrations, the IGF-1 generation test and clinical response to GH therapy in children with betathalassaemia. Eur J Endocrinol 1998;138:394-400 25. De Luca G, Maggiolini M, Bria M, Caracciolo M, Giorno A, Salemo M, Marisco S, Lanzino M, Brancati C ando S. GH secretion in thalassaemia patients with short stature. Horm Res 1995;44:158-163 26. De Sanctis V. Growth and puberty in thalassaemia. Horm Res 2002;58(Suppl 1):72-79 27. Leheup BP, Cisternino M, Bozzola M, Donsset B, Marvadi PL, Antoniazzi F, Tato L, Severi F, Sommelet D, Pierson M. Growth hormone response following growth hormone releasing hormone injection in thalassaemia major: influence of pubertal development. J Endocrinol Invest 1991;14:37-40 28. Shehadeh N, Hazani A, Rudolf MCJ, Peleg I, Benderly A, Hochberg Z. Neurosecretory dysfunction of growth hormone secretion in thalassaemia major. Acta Paediatr Scand 1990;79:790-795 29. Karamifar H, Karimi M, Amirhakimi G, Sharbatialaei M, De Sanctis V. Reduced insulin growth factor I concentrations in iron-overloaded beta thalassaemic patients with normal growth hormone secretion and liver function. Pediatr Endocrinol Rev 2004;2(Suppl 2):256-258 30. Katzos G, Papakonstantinou-Athanasiadou E, Athanasiou-Metaxa M, Harsoulis F. Growth hormone treatment in short children with betathalassaemia major. J Pediatr Endocrinol Metab 2000;131:163-170 31. Arcasoy A, Oral G, Kemahli S, Berberoglu M, Yildirmak Y, Canatan D, Akcurin S, Akar N, Uysal Z, Adiyaman P, Cetinkaya E. Recombinant human growth hormone treatment in children with thalassaemia major. Pediatr Int 1999;41:655-661 32. Low LC, Kwan EY, Lim YJ, Lee AC, Tam CF, Lam KS. Growth hormone treatment of short Chinese children with beta-thalassaemia major without GH deficiency. Clin Endocrinol (Oxf) 1995;42:359-363 33. Perrone L, Perrotta S, Raimondo P, Mucerino J, De Rosa C, Siciliani MC, Santoro N, Del Giudice EM. Inappropriate leptin secretion in thalassaemia: A potential cofactor of pubertal timing derangement. J Pediatr Endocrinol Metab 2003;16:877-881 34. Dedousis GVZ, Kyrtsonis MC, Andrikopoulos NE, Voskaridou E, Loutradis A. Inverse correlation of plasma leptin and soluble transferrin receptor levels in -thalassaemia patients. Ann Hematol 2002;81:543-547 35. Italian Working Group on Endocrine Complications in Non-Endocrine Diseases. Multi-centre study on prevalence of endocrine complications in thalassaemia major. Clin Endocrinol (Oxf) 1995;42:581-586 36. De Sanctis V, Vullo C, Katz M, Wonke B, Tanaw R, Bagni B. Gonadal function in patients with beta-thalassaemia major. J Clin Pathol 1988;41:133-137 37. Perera D, Pizzey A, Campbell A, Katz M, Porter J, Petrou M, Irvine DS, Chatterjee R. Sperm DNA damage in potentially fertile homozygous betathalassaemia patients with iron overload. Hum Reprod 2002;17:1820-1825 38. Jensen CE, Abdel-Gadir A, Cox C, Tuck SM, Wonke B. Sperm concentrations and quality in beta-thalassaemia major. Int J Androl 1996;19:362-364 39. Magro S, Puzzonia P, Consarino C, Galati MC, Morgione S, Porcelli D, Grimaldi S, Tancre D, Arcuri V, De Santis V, Alberti A. Hypothyroidism in patients with thalassaemia syndromes. Acta Haematol 1990;84:72-76 40. L a n d a u H , M a t o t h I , L a n d a u - C o r d o v a Z , G o l d f a r b A , Rachmilewitz EA, Glaser B. Cross-sectional and longitudinal study of the pituitary-thyroid axis in patients with thalassaemia major. Clin Endocrinol (Oxf) 1993;38:55-61 41. Pitrolo L, Malizia G, Lo Pinto C, Malizia V, Capra M. Ultrasound thyroid evaluation in thalassemic patients: correlation between the aspects of thyroidal stroma and function. Pediatr Endocrinol Rev 2004;2(Suppl 2):313-315 42. Angelopoulos NG, Goula A, Rombopoulos G, Kaltzidou V, Katounda E, Kaltsas D, Tolis G. Hypoparathyroidism in transfusion-dependent patients with beta-thalassaemia. J Bone Miner Metab 2006;24:138-145 43. Karimi M, Habibzadeh F, De Sanctis V. Hypoparathyroidism with extensive intracerebral calcification in patients with beta-thalassaemia major. J Pediatr Endocrinol Metab 2003;16:883886 44. Sklar CA, Lew LQ, Yoon DJ, David R. Adrenal function in thalassaemia major following long-term treatment with multiple transfusions and chelation therapy. Evidence for dissociation of cortisol and adrenal androgen secretion. Am J Dis Child 1987;141:327-330 45. Pasqualetti P, Colantonio D, Collacciani A, Casale R, Natali G. Circadian pattern of circulating plasma ACTH, cortisol and aldosterone in patients with beta-thalassaemia. Acta Endocrinol (Copenh) 1990;123:174-178 46. De Sanctis V, Zurlo MG, Senesi E, Boffa C, Cavallo L, Di Gregorio F. Insulin dependent diabetes in thalassaemia. Arch Dis Child 1988;63:58-62 47. Chern JP, Lin KH, Lu MY, Lin DT, Lin KS, Chen JD, Fu CC. Abnormal glucose tolerance in transfusion-dependent beta-thalassemic patients. Diabetes Care 2001;24:850-854 48. Khalifa AS, Salem M, Mounir E, El-Tawil MM, El-Sawy M, Abd Al-Aziz MM. Abnormal glucose tolerance in Egyptian beta-thalassemic patients: possible association with genotyping. Pediatr Diabetes 2004;5:126-132 49. Kattamis C, Ladis V, Tsoussis D, Kaloumenou I, Theodoridis C. Evolution of glucose intolerance and diabetes in transfused patients with thalassaemia. Pediatr Endocrinol Rev 2004;2(Suppl 2):267-271 50. Mowla A, Karimi M, Afrasiabi A, De Sanctis V. Prevalence of diabetes mellitus and impaired glucose tolerance in beta-thalassemia patients with and without hepatitis C virus infection. Pediatr Endocrinol Rev 2004;2(Suppl 2):282-284 51. Gamberini MR, Fortini M, De Sanctis V, Gilli G, Testa MR. Diabetes mellitus and impaired glucose tolerance in thalassaemia major: incidence, prevalence, risk factors and survival in patients followed in the Ferrara Center. Pediatr Endocrinol Rev 2004;2(Suppl 2):285-291 52. Amiel SA, Sherwin RS, Simonson DC, Lauritano AA, Tamborlane WV Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes. N Engl J Med 1986;315:215-219 53. Dmochowski K, Finegood DT, Francombe W, Tyler B, Zinman B. Factors determining glucose tolerance in patients with thalassemia major. J Clin Endocrinol Metab 1993;77:478-483 54. el-Hazmi MA, al-Swailem A, al-Fawaz I, Warsey AS, al-Swailem A. Diabetes mellitus in children suffering from beta-thalassaemia. J Trop Pediatr 1994;40:261-266 55. Messina MF, Lombardo F, Meo A, Miceli M, Wasniewska M, Valenzise M, Ruggeri C, Arrigo T, De Luca F. Three-year prospective evaluation of glucose tolerance, beta-cell function and peripheral insulin sensitivity in nondiabetic patients with thalassemia major. J Endocrinol Invest 2002;25:497-501 56. Pollack MS, Levine LS, Oberfield SE, Markenson AL. HLA A, B, C and DR antigen frequencies in relation to development of diabetes and variations in white cell antibody formation in highly transfused thalassaemia patients. Transfusion 1982;22:279-282 57. Incorvaia C, Parmeggiani F, Mingrone G, Sebastiani A, De Sanctis V. Prevalence of retinopathy in diabetic thalassaemic patients. J Pediatr Endocrinol Metab 1998;11(Suppl 3):879-883 58. Loebstein R, Lehotay DC, Luo X, Bartfay W, Tyler B, Sher GD. Diabetic nephropathy in hypertransfused patients with beta-thalassemia. The role of oxidative stress. Diabetes Care 1998;21:1306-1309 59. Austin GE, Wheaton R, Nanes MS, Rubin J, Mullins RE. Usefulness of fructosamine for monitoring outpatients with diabetes. Am J Med Sci 1999;318:316-323 60. Ladis V, Theodorides C, Palamidou F, Frissiras S, Berdousi H, Kattamis C. Glucose disturbances and regulation with glibenclamide in thalassemia. J Pediatr Endocrinol Metab 1998;11(Suppl 3):871-878 61. Mangiagli A, Campisi S, De Sanctis V, Nicoletti MC, Cardinale G, Galati MC, Raiola G, Rigano P, Saviano A. Study Group of the Italian Pediatric and Diabetes Society (SIEDP) on Endocrine Complications in NonEndocrine Disease. Effects of acarbose in beta-thalassaemia major patients with normal glucose tolerance and hyperinsulinism. Pediatr Endocrinol Rev 2004;2 (Suppl 2):272-275 62. Di Stefano M, Chiabotto P, Roggia C, Garofalo F, Lala R, Piga A, Isaia GC. Bone mass and metabolism in thalassaemic children and adolescents treated with different iron-chelating drugs. J Bone Miner Metab 2004;22:53-57 63. Voskaridou E, Terpos E. New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br J Haematol 2004;123:730-737 64. Lasco A, Morabito N, Gaudio A, Buemi M, Wasniewska M, Frisina N. Effects of hormonal replacement therapy on bone metabolism in young adults with beta-thalassaemia major. Osteoporos Int 2001;12:570-575 65. Carmina E, Di Fede G, Napoli N, Renda G, Vitale G, Lo Pinto C, Bruno D, Malizia R, Rini GB. Hypogonadism and hormone replacement therapy on bone mass of adult women with thalassaemia major. Calcif Tissue Int 2004;74:6871
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Exercise and Diabetes Mellitus Type 1 in Youth; Review and Recommendations

M. Rachmiel1,2, MD B, Med, Sc, J. Buccino1, MEd RD CDE, Denis Daneman1, MB, BCh, FRCPC
Please complete full first names
1Division of Endocrinology, Hospital for Sick Children, Toronto, Canada, 2Division of Pediatrics, Assaf-Harofeh Medical
Center, Zerifin, affiliated to Sackler School of Medicine, Tel Aviv University, Israel Corresponding author: Denis Daneman, MB, BCh, FRCPC, Chair, Department of Pediatrics University of Toronto, Pediatrician-inChief - The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8 Canada, Tel: 416-813-6120, Fax: 416-813-7479, E-mail: denis.daneman@sickkids.ca
Abstract
egular physical activity has been one of the cornerstones of type 1 diabetes mellitus (T1DM) therapy for decades. The benefits attributed to regular physical activity include increased sense of well being, quality of life, improved body composition, improved blood pressure and more. The beneficial effect in individuals with T1DM includes decreased risk of diabetes-related complications and mortality. In view of the recent recommendations for physical activity in healthy youth, advocating daily participation in 60 minutes of moderate to vigorous physical activity, we review the recent literature regarding physical activity in the context of youth with T1DM. We discuss its physiological and metabolic effects in youth with T1DM, its health promoting benefits and challenges that exercise poses in these individuals. Regular physical activity has been one of the cornerstones of type 1 diabetes mellitus (T1DM) therapy for decades, starting even before the discovery of insulin (1). The importance of lifestyle changes, specifically the inclusion of physical activity in daily routines is currently emphasized for adults and children, whether obese or lean as well as those with type 1 and type 2 diabetes mellitus (T1DM, T2DM). This is more pertinent than ever given the presence of the so-called obesity epidemic. The physiological and psychological benefits attributed to regular physical activity include increased sense of well being, improved quality of life, enhanced self esteem, decreased anxiety and depression, improved physical work capacity,
better body composition, decreased blood pressure and lipid profile (2-5). The beneficial effects of physical activity specifically in individuals with T1DM has been documented in a cohort of 548 T1DM patients, in whom it was shown to significantly decrease both the risk of diabetes-related complications and mortality (6). The American Diabetes Association (ADA) recently published a position statement regarding the important benefits and challenges of physical activity in adults with T1DM and T2DM. The ADA suggested applying the same principles in children as for adults without complications, with the awareness that this population is prone to greater variability in blood glucose levels (7). The ADA further provided a statement discussing the current standards of care in children and adolescents with T1DM, recommending physical activity as part of management for youth with T1DM, with emphasis on the need for careful supervision for the prevention or management of hypoglycemia (8). At the same time, Strong et al (9) have developed evidencebased recommendations for physical activity in healthy youth, advocating that school-aged youth should participate in 60 minutes of moderate to vigorous physical activity daily. These statements have encouraged us to review the recent literature regarding physical activity in the context of youth with T1DM, its physiological and metabolic effects and to summarize the available evidence-based recommendations for managing the challenges of exercise/physical activity in youth with T1DM. We have attempted to address both the health promoting benefits of exercise in youth with T1DM
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as well as the challenges that exercise poses in these individuals. Ref: Ped. Endocrinol. Rev. 2007;5(2): Key words: Moderate; Vigorous; Exercise; Diabetes Mellitus Type 1; Youth; Hypoglycemia which can potentially improve morbidity (10,12,13). The reported effects in youth on physical fitness, fasting blood glucose (FBG), glycemic control, insulin sensitivity and lipids profile imply similar effects. However, reports are few and inconsistent, as summarized in Table 1. How Does Regular Physical Training Potentiate the Effect of Exercise on Insulin Sensitivity? The molecular basis for the effect of exercise on insulin sensitivity is not completely clear. From adult studies it appears to depend on a combination of factors: a. an increment in the number of insulin receptors on working muscle cells during exercise as demonstrated on monocytes in healthy and diabetic participants (14-16); b. an increase in muscular oxidative capacity (17); c. increased number of capillaries/muscle fiber (17)
Impact of Regular Physical Activity on Glycemic Control and Other Metabolic Aspects of T1DM
Animal studies demonstrate that a bout of exercise increases muscle glucose uptake similar to an injection of insulin. Also the period after exercise is characterized by elevated rates of basal and insulin-stimulated glucose uptake, since the muscle remains more sensitive to the actions of insulin (10,11). Studies in adults with diabetes show that regular daily moderate physical activity has significant positive metabolic effects, including increased physical fitness, increased insulin sensitivity, decreased waist-to-hip ratio, decreased blood pressure and improved lipids profile,
Exercise Metabolism Physiology in Youth with and without Diabetes

The metabolic adaptation of the body is designed to meet the energy needs of exercising muscle, while maintaining glucose homeostasis: Effect on Insulin Sensitivity* NA NA
Study Design Interview, Self Report, n=142, 6-18y (70) Questionnaire, Self Report, n=143, 1-16y (71) Comparison between 2 Matched Groups of 15 Adolescent Diabetics. 9 of them Training for 12 Week (65) Comparison between Two Matched Groups of 19 Diabetics, 5-11y Old; 9 of them Training for 12 Week (60) Comparison between Two Groups of 22 Diabetics, 9-15 y Old; 14 of them Training in a Program(25) Assessment of Physical Fitness, n=59, 13-18y(3) Cross-Sectional Assessment of Level of Physical Activity during a 24 Hours Continuous Heart Rate Monitoring. 127 Diabetics, 200 Healthy, 3-16y (26) Assessment of Time Spent Exercising, n=91, 10-18 y (66)
Effect on VO2, HbA1c and Metabolic Parameters Spare Time and Competitive No Correlation of HbA1c to Amount of Activity Activities Type of Activity Habitual Physical Activity 45 Minutes of Moderate Exercise, 3 Sessions per Week 30 Minutes of Vigorous Exercise, 3 Sessions per Week 60 Minutes of Moderate Exercise, 2 Sessions per Week + Daily Practice Progressive Bicycle Ergometry On a Regular Single Weekday. Light, Moderate and Vigorous Activities Light, Moderate and Vigorous Activities None No Change in HbA1c (121%) VO2 HbA1c by Average of 1.2% in FBG, VO2 HbA1c by Average of 1.3% No Change in VO2 VO2 Correlated Inversely with HbA1c, LDL, TG and Cholesterol Average Annual HbA1c (7-8%) was Negatively Correlated to the Activity in School Aged Children Mean HbA1c was Lower for Those Exercising for Longer Periods per Week Glucose Utilization was Inversely Related to HbA1c
NA No Change in Insulin Dose VO2 Correlated Inversely with Insulin Dose NA
NA IMGU was Positively Related to the State of Fitness
Comparison of Physical Fitness in 27 Progressive Bicycle Diabetics and 10 Non Diabetics,11-19 y (72) Ergometry to Exhaustion
Table 1. Reported Metabolic Effects of Regular Physical Activity in Youth with T1DM *Insulin sensitivity was assessed by euglycemic clamp technique IMGU - Insulin Mediated Glucose Utilization
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a. at all rates of activity - mild, moderate and vigorous b. in all states of nutrition - fasting and post meal c. for variable duration. It is hypothesized that hormones and sympathetic nerve activity regulate these adaptations (18). The determination of oxygen consumption (VO 2 ) during physical activity is an acceptable measurement of level of activity and can be easily determined for every performed activity. The maximal oxygen consumption (VO 2max ) is a reproducible index of functional and anatomical capacity of the body (heart, lung and muscles) and a measure of aerobic fitness (aerobic capacity) (19,20). Mild to moderate activities are defined as activity with VO2 which is <60% of VO2max, intense (vigorous) activity is defined as activity with VO2 which is >80% of VO2max. In assessing the various studies in the pediatric population, one should remember that there is a gradual increase in VO2max with growth, with greater rates of increment in males than females after the age of 13 years (19). Studies of the exercise capacity of diabetic youth compared to non-diabetic youth have produced highly conflicting results. Komatsu et al (21) showed that adolescents with T1DM in fair glycemic control (meanSD HbA1c 8.12.2%) demonstrated reduced capacity and became exhausted earlier during the exercise than their non-diabetic peers, with similar anthropometric conditions. Similar decreased physical working capacity (VO2max) was demonstrated by Huttenen and Poortmans and their colleagues in male, but not female, children and adolescents with T1DM and was reported to be inversely correlated to HbA1c (22,23). Rating of perceived exertion in adolescents was higher by 2-3 points in adolescents with T1DM after 60 minutes of moderate exercise (24). On the other hand, Dahl-Jorgensen et al (25) and Massin et al (26) have reported that adolescents with diabetes have VO2max levels within the range of the non-diabetic population. Those who suggest impaired exercise capacity in patients with T1DM attribute it to abnormally functioning glycosylated collagen fibers, with decreased pulmonary functions (gas diffusion, air flow, volumetric capacity) and limited joint mobility in diabetics compared to non diabetic controls (27-31). These older studies were largely performed in the era prior to intensification of diabetes management. Whether different outcomes would be obtained with current therapeutic approaches warrants thorough investigation.
What Happens during Mild to Moderate Exercise (60% VO2max) in Nondiabetic Subjects (e.g. jogging, cycling)?
This type of exercise is considered aerobic, where the increased oxygen uptake by the muscle raises whole body requirements of glucose by 2-3mg/kg/min of exercise. Fuel sources and their regulation in these situations are presented in Figure 1. Muscular glucose utilization in the non-diabetic individuals during exercise seems to be mostly independent of insulin, also called non-insulin mediated glucose utilization (NIMGU) and relies mainly on muscle contraction-induced translocation of GLUT4 glucose transporters from intracellular stores to the plasma membrane and transverse tubules (32-34). The specific pathway as to how muscle contraction or its downstream effects stimulate glucose transport remains uncertain (34). Data suggest that acute exercise enhances insulin-induced GLUT4 translocation both Figure 1. Fuel source during mild to moderate exercise (60% VO2max) in non-diabetic subjects is based while exercising and for initially on muscle glycogen, when depleted on nonesterified fatty acids (NEFA) and only when exercise a f e w h o u r s f o l l o w i n g continues on hepatic glucose production (HGP). Muscle glycogen stores are the early source of fuel, first utilizing the working muscle and later the inactive muscles, inducing glycogenolysis. The arterial NEFA levels e x e r c i s e ( 1 1 , 1 8 , 3 5 ) . increase due to an increase in lipolysis and a decrease in their re-esterification, facilitated by decreased The post-exercise state insulin secretion and glucagon stimulated hepatic fat oxidation. The numbers represent order of recruitment requires glycogen synthesis according to activity duration (18). The arterial glucose levels change very little because of tight matching and regulation between glucose uptake and utilization (50). Catecholamines concentration may increase only and repletion of stores, leading to more sustained 2-4 fold, increasing gluconeogenesis only after prolonged exercise (> 2 hours) (18,32). Muscular glucose utilization seems to be mostly independent of insulin, called non insulin mediated glucose adaptations (18).
utilization (NIMGU).
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control and those at a state of ketosis. The glucose levels increased significantly during exercise when initial BG was higher than 18 and plasma ketones higher than 0.74 mmol/l, suggesting possible risk for worse ketosis and hyperglycemia when exercise is performed when initial hyperglycemia and ketonuria were present. However, hyperglycemia per se is not a reason to recommend avoidance of exercise in youth and exercise is very unlikely to be a cause for DKA. The DirecNet study group (37,38), recently reported the effects of 60 minutes of moderate aerobic exercise, with three 5 minutes breaks, performed in the afternoon, in children and What Factors are Important during Mild to Moderate adolescents (10-18 years) with T1DM, treated by multiple daily Exercise (60% VO2max) in Youth with T1DM? injection regimen (MDI) or Continuous Subcutaneous Insulin a. Fuel Source and Hormonal Balance Infusion pumps (CSII, pumps) (average HbA1c 7.8%). Each child In general, the fuel source in adolescents with T1DM is served as his/her own control on a sedentary day, receiving the similar to that of the non-diabetic population, with some same meals and insulin dosages. Most manifested a significant differences in cases due to moderate or poor control mean decrease in blood glucose (BG) of 40% during and after and in over-insulinized states, as presented in Table 2. exercise, irrespective of the baseline level, with 83% of the This different milieu in T1DM is attributed primarily to children experiencing a greater than 25% drop in BG. The only the inability to regulate insulin secretion according to significant predictive factor for development of hypoglycemia muscle contraction and oxygen consumption, leading (defined as BG 3.3mmol/l) was the baseline glucose at to potentially hazardous extremes of hypoglycemia and exercise initiation, with increasing tendency for hypoglycemia ketosis. with lower blood glucose, with the majority occurring when Berger et al (36) demonstrated that the glycemic response the starting BG was lower than 6.6 mmol/l. HbA1c, BMI, age, to exercise is dependent on the initial BG and ketone levels, insulin injection route were not significantly associated with with different metabolic response in diabetics with moderate hypoglycemia. The glucose levels were significantly lower on glucose monitoring overnight after the exercise day with more frequent episodes of nocturnal hypoglycemia compared to the postsedentary day. The risk for hypoglycemia, whether on sedentary or exercise days was correlated only with being more active in general and with 09:00 pm (pre-bedtime) BG levels lower than 7.2 mmol/l and not with the HbA1c level (38). The postexercise late-onset hypoglycemia Figure 2. Fuel source during intense exercise (>80% VO2max), in non-diabetic subjects is based exclusively on glucose and glycogen. Glucose is mobilized from muscle and liver and utilizes the anaerobic oxidation with (also called late postproduction of lactate. In some, the increase in glucose production exceeds the rate of glucose utilization, exercise hypoglycemia, contributing to a state of hyperglycemia by the end of the exercise (32,81) LPEH) was previously Plasma insulin either declines minimally or remains constant during exercise, but increases rapidly during the postexercise recovery period, enabling restoring normal plasma blood glucose and replenishment of muscle described in young adults glycogen (32,81). and youth in a prospective Fuel source in diabetic subjects is similar. However, since hyperinsulinemia is responsible for the recovery case finding study. LPEH of hyperglycemia after the immediate state, without extra postexercise insulin administration there may be sustained hyperglycemia. usually occurred 6-15 hours The early normal response of muscular glucose uptake is preserved since it relies NIMGU on proportional after the completion of changes in the number of glucose transporters on the muscle cells membrane and not on insulin mediated exercise or play, not related uptake. What Happens during Intense Exercise (>80% VO2max), in Nondiabetic Subjects (e.g. sprints, basketball, hockey)? This type of exercise is considered anaerobic since it involves short bouts of intense activity, with brief rest intervals. Intermittent high-intensity exercise is typical for most team, field sports and often with spontaneous childhood games. During this amount of oxygen uptake the whole body requirements of glucose increase by 5-6 mg/kg/min of exercise. Glucoregulation under such conditions is presented in Figure 2.
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Diabetes in Moderate Control
Metabolic Effect Glucagon/Insulin Ratio
Nondiabetic
Under-Insulinized State
Over-Insulinized State
Same As Non-Diabetic. / , Lack of Sufficient Only after 90 Minutes within A Few Minutes Others Showed Blunted Hepatic Glucose and Twice More of Exercise Glucagon Response Production Enhanced Fat Oxidation of Muscle Fat Store E a r l i e r a n d 4 F o l d Lack of Glycerol for Higher Gluconeogenesis
Free fatty Acids (FFA) Gradually and Ketons
Blood Glucose
Same as Non-Diabetic, Initially, but During Exercise and but with a Lesser Decline S t e a d i l y d u r i n g Decreases within 30-60 after, due ro Persistent during and after Vigorous Exercise Period Minutes of Exercise Muscle over-Sensitivity Exercise
up to Eight Fold C o u n t e r - Re g u l a t o r y Mild of GH after 60-90 Higher and Earlier of of GH, Others Suggest Only Marginal Hormones * Minutes GH Failure of Response NIMGU IMGU NIMGU Impaired Glucose Uptake and Utilization in Animal Models NIMGU Attributed to Insulin Effect on Arterial Glucose Levels
Glucose Utilization
NIMGU
Table 2. Metabolic and Hormonal Effects of Prolonged Moderate Exercise (>120min) in non Diabetic and in Diabetic Patients in Cases of Over and under Insulinization. (18,24,32-34,36,43, 59,61-63,73,74,75-80) NIMGU - Non Insulin Mediated Glucose Utilization, IMGU - Insulin Mediated Glucose Utilization * Similar counter-regulatory hormonal changes were demonstrated, whether receiving insulin injections or being treated by a continuous subcutaneous insulin infusion (CSII)
to better degrees of glycemic control. In more than half of the reported cases the hypoglycemia was severe (39). McMahon et al (40), have recently demonstrated through glucose clamp studies, that glucose requirements in adolescents with T1DM performing afternoon moderate physical activity increase in a biphasic manner: during and shortly following exercise and also between midnight and 04:00 am. A few studies in youth and adults with T1DM have assessed the effect of alterations in glucose and insulin intake on the development of hypoglycemia: 1. A decrease in insulin dosing: Schiffrin et al (41) showed in a cross-over study in 13 adolescents treated by 5 different insulin regimens, that a reduction in premeal insulin dose by 30-50% prior to 45 minutes of physical activity resulted in a decreased frequency of hypoglycemic events. A similar study in adults with good glycemic control also demonstrated that reduction in premeal insulin by 25-75% according to duration and intensity of activity is beneficial in reducing the risk for hypoglycemia (42). Sonnenberg et al (43) examined the metabolic response to physical activity in seven young adults whose T1DM was well controlled using an insulin pump. The participants performed the same physical activity while receiving various basal and bolus insulin combinations. The most suitable basal and premeal bolus insulin adjustment combination that decreased the risk
for early-exercise and late-onset-hypoglycemia was a combination of discontinuing the basal rate completely during exercise, reducing the premeal insulin bolus and decreasing the post-exercise basal rate by 25%. Admon et al (44) examined the effect on BG of an unplanned exercise performed 2 hours after a meal. The effect of the exercise was assessed in two similar occasions; with the pump suspended or at a 50% reduced basal rate. All participants received additional 20 grams of complex carbohydrates prior to the activity and 15 minutes after the exercise, irrespective of glucose level and their regular bolus dose of insulin. No significant difference was seen in hormonal responses and in the incidence of hypoglycemic events during exercise (20%, most asymptomatic) and 2.5-12 hours after exercise (90% when pump was on. 50% basal rate and 60% when the pump was suspended) in both cases. If the pump is suspended during exercise, care must be taken to ensure that it is restarted as soon as the exercise period has been completed. The DirecNet study group demonstrated among 49 adolescents with pumps that hypoglycemia during exercise occurred less frequently when the basal insulin was discontinued than when it was continued at a lower rate (16 vs. 43). However, the development of hyperglycemia 45 min after the completion of exercise was more
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frequent when basal insulin was discontinued compared to decreased (27 vs. 4%) (45). 2. Additional carbohydrates prior to and during the activity without insulin dose adjustments: The opinions regarding additional carbohydrates associated with physical activity are inconsistent. Riddell et al (46) demonstrated that glucose ingestion equal to total carbohydrates utilization attenuates the drop in blood glucose in cases of physical activity without adjustment of insulin dose to activity and reduces the likelihood of hypoglycemia during exercise in adolescents with T1DM. The amount of total additional carbohydrates used was estimated as 0.5-1.5 gm/kg body weight/hour of training, according to the time after insulin was injected, with higher amounts given with exercise closer to injection time (47). Riddell et al (24) assessed glucose utilization in matched diabetic and non-diabetic adolescents, performing the same moderate exercise for 60 minutes, with and without additional average 17 gram glucose intake during the whole exercise period (based on 1.5 gm/kg/h). The glucose level was significantly higher by 4.81.8mmol/l during and after exercise with the additional glucose. Schiffrin et al (41) also suggested 15 grams of glucose in anticipation of each 45 minutes of moderate activity and 15-30 gram at end of activity may prevent hypoglycemia when insulin was not adjusted. On the other hand, Pirnay et al (48), had not found benefit in additional exogenous carbohydrates prior to activity. They measured the extent to which a labeled oral load of glucose is oxidized during prolonged exercise. They report that additional exogenous glucose prior to milder exercise (<50% VO2max) was associated with linear correlation between exogenous glucose oxidation and relative work load. However, exogenous glucose oxidation tended to level off, whereas endogenous carbohydrate oxidation was markedly enhanced during moderate exercise (51-60% VO2max). This was attributed to a decrease in the oxidation in the muscles or to a lesser availability of the exogenous glucose. We do suggest in our daily clinical practice to add carbohydrates prior to unplanned activity according to Riddell et al (24) suggestions. b. Inter and Intra-Individual Response Variability It had been demonstrated by intersession observations, that the BG responses to prolonged moderate intensity exercise were reliable and repeatable when pre-exercise meal, exercise and insulin regimens were kept constant in the individual subjects, indicating possibly future intrasubject response prediction to each specific type of exercise (49). Other factors which may influence the effects include the humidity and/or temperature of the environment, as well as the conditions under which the exercise is performed (e.g. competition versus friendly play) (50-52). c. Site of Insulin Administration It had been suggested in studies conducted among adult diabetics that the region where insulin is injected may influence its affect. In some sites absorption may be accelerated by exercise so that the maximal effect of the insulin is earlier than expected (53,54). Koivisto et al (55) demonstrated that the absorption of rapid acting insulin from the leg during the first 10 minutes of cycling was increased by 135% compared to abdomen and arm injection, a finding which was well correlated with decreasing glucose levels. Furthermore, abdominal injection reduced hypoglycemic response by 89% compared to leg injection and enabled BG levels to return more rapidly to base-line levels (1 hour compared to 2-5 hours). On the other hand, Peter et al (56) demonstrated, that there is no increased absorption of glargine, when injected in the leg on the night prior to exercise. d. Possible Affect of Timing of Exercise Jones et al (57), have demonstrated that sleep impairs counter-regulatory-hormone responses to hypoglycemia in adolescents with diabetes and normal subjects without respect to physical activity. Galassetti et al (58), demonstrated in young adults that 2 bouts of moderate exercise significantly reduced glucagon, catecholamines and growth hormone responses to subsequent hypoglycemia. Those findings may contribute to the LPEH during sleep when activity is performed in late afternoon by diabetic youth. Effects of Intensive (Vigorous) Exercise (>80% VO2max) in T1DM Metabolic and hormonal changes in patients with T1DM (studied predominantly in adults) are demonstrated in figure 2 and table 2. Purdon et al, (59) suggested that intense exercise, unlike less strenuous exercise, would not be expected to lead to post exercise hypoglycemia; on the contrary, it would be expected to cause robust hyperglycemia if insulin replacement were suboptimal or associated with moderate or marked hyperglycemia prior to activity. Based on the physiological alterations they suggested avoiding rapidly assimilated carbohydrates when vigorous activity is performed and additionally to consider administration of a subcutaneous bolus of insulin analog at the end of exercise which may mimic the physiological acute hyperinsulinemia post exercise. Campaigne et al (60) and Guelfi et al (61,62) demonstrated that vigorous physical activity in youth caused a significantly lesser decline in BG levels during and after the activity compared to moderate exercise, which was attributed to elevated levels of lactate, catecholamines and growth hormone without any identified difference in cortisol, glucagons and FFA levels. This statement supports the need for less pre-exercise CHO with vigorous activity than with moderate activity. On the other hand, personal experience in the pediatric population supports the opposite; late post-exercise
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hypoglycemia does appear. It may be attributed to an abnormal adaptive counter-regulatory-hormonal response to intense exercise, as demonstrated in a group of young subjects with diabetes by Galassetti et al (63) or due to possible loss of glucose stores released after an episode of intense exercise, leaving the individual without glucose stores for compensation hours after the exercise. In individuals susceptible to late postexercise hypoglycemia, post-exercise repletion of calories may prevent hypoglycemia. Specific Questions and Recommendations for Exercise in Youth with T1DM: Based on the available evidence, we have developed a series of recommendations for common situations facing youth with T1DM during and after exercise/physical activity. What is clear is that there are significant inter- and intraindividual differences that need to be taken into account, necessitating the need for frequent blood glucose monitoring and individualization of therapy. Q1: Should Children with T1DM be Restricted in their Physical Activity? Recommendation 1: Youth with diabetes should not be restricted in their participation in all physical activities. However, participation in those activities that may endanger lives (such as scuba-diving, parachuting or rock climbing) should be carefully monitored or restricted. Youth with T1DM and their families should be educated early after their diagnosis about engaging in an active lifestyle. School-aged youth should be instructed to participate daily in 30-60 minutes or more of cumulative, moderate to vigorous physical activity that is enjoyable (9,64). Q2: How Often should Blood Glucose (BG) be Monitored? Recommendation 2: Capillary BG should be monitored rigorously in advance of, immediately and at regular intervals (e.g. 2 hours after completing exercise) after moderate and vigorous activities until individual predictable patterns of BG changes emerge (59). The awareness of BG prior to activity is important since it has emerged as the most important predictor for development of exercise-related hypoglycemia (37). If lower than 6.6 mmol/l, the risk of hypoglycemia is very strong (37); on the other hand, the combination of a glucose concentration higher than ~18 mmol/ l and the presence of urinary ketones may indicate the need for treatment and delay of physical activity until the ketones have cleared and the glucose is better controlled (7,36,67). BG monitoring during activity, a few hours after exercise and in the middle of the night after late afternoon or evening exercise is important for observing early and late postexercise hypoglycemia. It is important to monitor BG even without symptoms due to the high frequency of asymptomatic hypoglycemia in children (3,37-39,65,66). Exercising in extraordinary settings such as competition and heat should merit even more vigilance. Q3: Is there an Effect to the Injection Site and CSII Insertion Site? Recommendation 3: injections and CSII insertion sites on day of physical activity should be administered in a non-exercising area, preferably the abdomen. The bedtime injections (prior to exercise the following day) may be given in the leg area. Q4: How Can We Prevent Hypoglycemic Episodes in Cases of Mild-Moderate Exercise? Recommendation 4: With planned exercise, a reduction in premeal insulin dose by 30-50% is recommended, according to the intensity and duration of activity (41). Recommendation 5: In cases of non-planned activity, if an insulin adjustment has not been performed, then intake of simple sugars (or concentrated CHO) is encouraged during exercise and in the postexercise state. An extra 15-30 grams carbohydrates per every 60 minutes of moderate activity should be added and 15-30 grams after the activity ends. Another option is to calculate required additional glucose at a dose of 0.5-1.5 gram/kg body weight/hour of training, according to the time after insulin was injected, (higher end of the range closer to injection time) (7,24,41,46,47,67). Q5: What is the Recommended Amount of Carbohydrates in Cases of Hypoglycemia during Exercise? Recommendation 6: Treatment with 30-45 grams of oral simple glucose is recommended to treat hypoglycemia during exercise (37). Previous studies demonstrated that 15 grams of oral glucose were insufficient to reliably treat hypoglycemia during moderate exercise and treatment with 15 grams (as per current routine recommendations) resulted in only 1 mmol rise in glucose concentrations. 30 grams were required to correct exercise induced hypoglycemia in cases of moderate activity for 45 minutes, where premeal insulin was not decreased (37,41). In order to prevent severe hypoglycemic complications, physical education instructors and sports coaches must be taught and able to recognize and assist with treatment of hypoglycemia. A quick-acting source of glucose and the students meter should always be available (68). However, exercise should not provide an opportunity to indulge in foods, e.g. candy bars that are usually avoided. Q6: How Can We Prevent Late-Onset (Nocturnal) Hypoglycemic Episodes? Recommendation 7: Pre-bedtime blood glucose should be higher than 7.2 mmol/l on days of afternoon or evening activity (38). Ingestion of slowly absorbed carbohydrate (complex carbohydrates) and larger than usual bedtime snack with low glycemic index or protein foods in addition to the carbohydrates are recommended if exercise was performed during evening or late afternoon or if late hypoglycemia is anticipated (38,69). In cases of prolonged moderate exercise in the afternoon a reduced overnight insulin dose (by injection
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or SCII) should be considered (10-30% according to trial and error) (67). Q7: Should we Routinely Recommend Additional Carbohydrates Prior to and during Exercise? Recommendation 8: In cases of planned exercise, appropriate reduction in insulin dose and pre-exercise BG of >6.6 mmol/l, additional carbohydrates may not be required on a regular basis. However, if prolonged exercise takes place or a decreasing trend of BG is evident, additional carbohydrates should be administered. Q8: Are there Special Recommendations Regarding Vigorous Exercise? Recommendation 9: It is recommended to avoid rapidly assimilated carbohydrates before or during vigorous activity unless there is a trend of significantly declining blood glucose. We would consider additional bolus of insulin only after studying the individuals response to vigorous activity on several occasions documenting significant prolonged hyperglycemia especially if combined with ketonuria. Q9: Should We Suggest Exercise with or without Suspension of the Pump in CSII-Treated Youth? Recommendation 10: In cases of preplanned exercise: a. premeal bolus insulin should be reduced by 50% and; b. basal rate during activity should be decreased by at least 50% or suspended. The decision between those 2 options should be guided according to individual responses (43). Recommendation 11: in cases of unplanned exercise: a. the pump should be suspended; b. an addition of a complex carbohydrate pre-exercise snack of 15-30 grams should be added without bolusing for every 60 minutes of exercise or an estimation of extra carbohydrate intake for exercise according to 0.51.5 gram/kg/hour of training. In all cases the post exercise basal rate should be decreased by 25% for up to 12 hours post exercise in order to prevent late onset hypoglycemia. In summary, we have provided an overview and synopsis of both recent as well as earlier studies describing the benefits of regular physical activity in youth with T1DM. In the Diabetes Clinic at the Hospital for Sick Children, Toronto, Canada, we have developed an information page for families regarding the benefits of exercise in children with T1DM and a checklist of recommended precautions. We recommend distribution of such information regarding exercise among families of children and youth with T1DM. We also encourage future studies which may use the continuous glucose monitoring system (CGMS) to evaluate the effects of various types, intensities and durations of activity on BG in pediatric large cohorts, in order to improve the current recommendations.
2. 3. 4. 5. 6. 7. 8. Norris R, Carroll D, Cochrane R. The effects of aerobic and anaerobic training on fitness, blood pressure and psychological stress and wellbeing. J Psychosom Res 1990;34:367-375 Austin A, Warty V, Janosky J, Arslanian S. The relationship of physical fitness to lipid and lipoprotein(a) levels in adolescents with IDDM. Diabetes Care 1993;16:421-425 Sonstroem RJ, Morgan WP. Exercise and self-esteem: rationale and model. Med Sci Sports Exerc 1989;21:329-337 Morgan WP. Affective beneficence of vigorous physical activity. Med Sci Sports Exerc 1985;17:94-100 Moy CS, Songer TJ, LaPorte RE, Dorman JS, Kriska AM, Orchard TJ, Becker DJ, Drash AL. Insulin-dependent diabetes mellitus, physical activity and death. Am J Epidemiol 1993;137:74-81 Zinman B, Ruderman N, Campaigne BN, Devlin JT, Schneider SH. Physical activity/exercise and diabetes. Diabetes Care 2004;27(Suppl 1):S58-S62 Silverstein J, Klingensmith G, Copeland K, Plotnick L, Kaufman F, Laffel L, Deeb L, Grey M, anderson B, Holzmeister LA, Clark N. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care 2005;28:186-212 Strong WB, Malina RM, Blimkie CJ, Daniels SR, Dishman RK, Gutin B, Hergenroeder AC, Must A, Nixon PA, Pivarnik JM, Rowland T, Trost S, Trudeau F. Evidence based physical activity for school-age youth. J Pediatr 2005;146:732-737 Goodyear LJ, Kahn BB. Exercise, glucose transport and insulin sensitivity. Annu Rev Med 1998;49:235-261 Borghouts LB, Keizer HA. Exercise and insulin sensitivity: a review. Int J Sports Med 2000;21:1-12 Holm G, Bjorntorp P. Metabolic effects of physical training. Acta Paediatr Scand 1980;283(Suppl):9-14 Lehmann R, Kaplan V, Bingisser R, Bloch KE, Spinas GA. Impact of physical activity on cardiovascular risk factors in IDDM. Diabetes Care 1997;20:1603-1611 Soman VR, Koivisto VA, Deibert D, Felig P, DeFronzo RA. Increased insulin sensitivity and insulin binding to monocytes after physical training. N Engl J Med 1979;301:1200-1204 Koivisto VA, Soman V, Conrad P, Hendler R, Nadel E, Felig P. Insulin binding to monocytes in trained athletes: changes in the resting state and after exercise. J Clin Invest 1979;64:1011-1015 Pedersen O, Beck-Nielsen H, Heding L. Increased insulin receptors after exercise in patients with insulin-dependent diabetes mellitus. N Engl J Med 1980;302:886-892 Wallberg-Henriksson H, Gunnarsson R, Henriksson J, DeFronzo R, Felig P, Ostman J, Wahren J. Increased peripheral insulin sensitivity and muscle mitochondrial enzymes but unchanged blood glucose control in type I diabetics after physical training. Diabetes 1982;31:1044-1050 Wasserman DH, Zinman B. Exercise in individuals with IDDM. Diabetes Care 1994;17:924-937 Thoren C. Exercise testing with special reference to children with diabetes mellitus. Acta Paediatr Scand 1980;283(Suppl):29-32 Astrand PO. Methods of ergometry in children. Definitions, testing procedures, accuracy and reproduceability. Acta Paediatr Scand 1971;217(Suppl):9-12 Komatsu WR, Gabbay MA, Castro ML, Saraiva GL, Chacra AR, de Barros Neto TL, Dib SA. Aerobic exercise capacity in normal adolescents and those with type 1 diabetes mellitus. Pediatr Diabetes 2005;6:145-149 Huttunen NP, Kaar ML, Knip M, Mustonen A, Puukka R, Akerblom HK. Physical fitness of children and adolescents with insulin-dependent diabetes mellitus. Ann Clin Res 1984;16:1-5 Poortmans JR, Saerens P, Edelman R, Vertongen F, Dorchy H. Influence of the degree of metabolic control on physical fitness in type I diabetic adolescents. Int J Sports Med 1986;7:232-235
9.
10. 11. 12. 13. 14. 15. 16. 17.
18. 19. 20. 21. 22. 23.
References
1. Joslin EP. The treatment of diabetes mellitus. 10th ed. Philadelphia: Lea & Febiger 1979
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December 2007
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24. Riddell MC, Bar-Or O, Gerstein HC, Heigenhauser GJ. Perceived exertion with glucose ingestion in adolescent males with IDDM. Med Sci Sports Exerc 2000;32:167-173 25. Dahl-Jorgensen K, Meen HD, Hanssen KF, Aagenaes O. The effect of exercise on diabetic control and hemoglobin A1 (HbA1) in children. Acta Paediatr Scand 1980;283(Suppl):53-56 26. Massin MM, Lebrethon MC, Rocour D, Gerard P, Bourguignon JP. Patterns of physical activity determined by heart rate monitoring among diabetic children. Arch Dis Child 2005;90:1223-1226 27. Asanuma Y, Fujiya S, Ide H, Agishi Y. Characteristics of pulmonary function in patients with diabetes mellitus. Diabetes Res Clin Pract 1985;1:95-101 28. Strojek K, Ziora D, Sroczynski JW, Oklek K. Pulmonary complications of type 1 (insulin-dependent) diabetic patients. Diabetologia 1992;35:1173-1176 29. Schuyler MR, Niewoehner DE, Inkley SR, Kohn R. Abnormal lung elasticity in juvenile diabetes mellitus. Am Rev Respir Dis 1976;113:37-41 30. Buckingham B, Perejda AJ, Sandborg C, Kershnar AK, Uitto J. Skin, joint and pulmonary changes in type I diabetes mellitus. Am J Dis Child 1986;140:420-423 31. Baraldi E, Monciotti C, Filippone M, Santuz P, Magagnin G, Zanconato S, Zacchello F. Gas exchange during exercise in diabetic children. Pediatr Pulmonol 1992;13:155-160 32. Marliss EB, Vranic M Intense exercise has unique effects on both insulin release and its roles in glucoregulation: implications for diabetes. Diabetes 2002;51(Suppl 1):S271-283 33. Freemark M. 2005 Therapeutic approaches to insulin resistance in children. New York: Nova science publishers,Inc. 34. Wijesekara N, Thong FSL, Antonescu CN, Klip A. Diverse signals regulate glucose uptake into skeletal muscle. Canadian journal of Diabetes 2006;30:80-88 35. Koistinen HA, Zierath JR. Regulation of glucose transport in human skeletal muscle. Ann Med 2002;34:410-418 36. Berger M, Berchtold P, Cuppers HJ, Drost H, Kley HK, Muller WA, Wiegelmann W, Zimmerman-Telschow H, Gries FA, Kruskemper HL, Zimmermann H. Metabolic and hormonal effects of muscular exercise in juvenile type diabetics. Diabetologia 1977;13:355-365 37. Tansey MJ, Tsalikian E, Beck RW, Mauras N, Buckingham BA, Weinzimer SA, Janz KF, Kollman C, Xing D, Ruedy KJ, Steffes MW, Borland TM, Singh RJ, Tamborlane WV. The effects of aerobic exercise on glucose and counterregulatory hormone concentrations in children with type 1 diabetes. Diabetes Care 2006;29:20-25 38. Tsalikian E, Mauras N, Beck RW, Tamborlane WV, Janz KF, Chase HP, Wysocki T, Weinzimer SA, Buckingham BA, Kollman C, Xing D, Ruedy KJ. Impact of exercise on overnight glycemic control in children with type 1 diabetes mellitus. J Pediatr 2005;147:528-534 39. MacDonald MJ. Postexercise late-onset hypoglycemia in insulindependent diabetic patients. Diabetes Care 1987;10:584-588 40. McMahon SK, Ferreira LD, Ratnam N, Davey RJ, Youngs LM, Davis EA, Fournier PA, Jones TW. Glucose requirements to maintain euglycemia following moderate intensity afternoon exercise in adolescents with type 1 diabetes are increased in a biphasic manner. J Clin Endocrinol Metab 2006 Please fill the volume no. and pages 41. Schiffrin A, Parikh S. Accommodating planned exercise in type I diabetic patients on intensive treatment. Diabetes Care 1985;8:337-342 42. Rabasa-Lhoret R, Bourque J, Ducros F, Chiasson JL. Guidelines for premeal insulin dose reduction for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen (ultralente-lispro). Diabetes Care 2001;24:625-630 43. Sonnenberg GE, Kemmer FW, Berger M. Exercise in type 1 (insulindependent) diabetic patients treated with continuous subcutaneous insulin infusion. Prevention of exercise induced hypoglycaemia. Diabetologia 1990;33:696-703 44. Admon G, Weinstein Y, Falk B, Weintrob N, Benzaquen H, Ofan R, Fayman G, Zigel L, Constantini N, Phillip M. Exercise with and without an insulin pump among children and adolescents with type 1 diabetes mellitus. Pediatrics 2005;116:e348-e355 45. Tsalikian E, Kollman C, Tamborlane WB, Beck RW, Fiallo-Scharer R, Fox L, Janz KF, Ruedy KJ, Wilson D, Xing D, Weinzimer SA. Prevention of hypoglycemia during exercise in children with type 1 diabetes by suspending basal insulin. Diabetes Care 2006;29:2200-2204 46. Riddell MC, Bar-Or O, Ayub BV, Calvert RE, Heigenhauser GJ. Glucose ingestion matched with total carbohydrate utilization attenuates hypoglycemia during exercise in adolescents with IDDM. Int J Sport Nutr 1999;9:24-34 47. Francescato MP, Geat M, Fusi S, Stupar G, Noacco C, Cattin L. Carbohydrate requirement and insulin concentration during moderate exercise in type 1 diabetic patients. Metabolism 2004;53:1126-1130 48. Pirnay F, Crielaard JM, Pallikarakis N, Lacroix M, Mosora F, Krzentowski G, Luyckx AS, Lefebvre PJ. Fate of exogenous glucose during exercise of different intensities in humans. J Appl Physiol 1982;53:1620-1624 49. Temple MY, Bar-Or O, Riddell MC. The reliability and repeatability of the blood glucose response to prolonged exercise in adolescent boys with IDDM. Diabetes Care 1995;18:326-332 50. Riddell MC, Perkins BA. Type 1 diabetes and vigorous exercise: applications of exercise physiology to patient management. Canadian journal of Diabetes 2006;30:63-71 51. Hargreaves M, Angus D, Howlett K, Conus NM, Febbraio M. Effect of heat stress on glucose kinetics during exercise. J Appl Physiol 1996;81:1594-1597 52. Defrin R, Josefsberg Z, Karp M. (The effect of acute physical activity on blood glucose levels of children with insulin-dependent diabetes mellitus). Harefuah 2004;143:856-860, 912, 911 53. Larsson Y. Physical exercise and juvenile diabetes--summary and conclusions. Acta Paediatr Scand 1980;283(Suppl):120-122 54. Zinman B, Murray FT, Vranic M, Albisser AM, Leibel BS, Mc Clean PA, Marliss EB. Glucoregulation during moderate exercise in insulin treated diabetics. J Clin Endocrinol Metab 1977;45:641-652 55. Koivisto VA, Felig P. Effects of leg exercise on insulin absorption in diabetic patients. N Engl J Med 1978;298:79-83 56. Peter R, Luzio SD, Dunseath G, Miles A, Hare B, Backx K, Pauvaday V, Owens DR. Effects of exercise on the absorption of insulin glargine in patients with type 1 diabetes. Diabetes Care 2005;28:560-565 57. Jones TW, Porter P, Sherwin RS, Davis EA, O'Leary P, Frazer F, Byrne G, Stick S, Tamborlane WV. Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med 1998;338:1657-1662 58. Galassetti P, Mann S, Tate D, Neill RA, Costa F, Wasserman DH, Davis SN. Effects of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia. Am J Physiol Endocrinol Metab 2001;280:E908-E917 59. Purdon C, Brousson M, Nyveen SL, Miles PD, Halter JB, Vranic M, Marliss EB. The roles of insulin and catecholamines in the glucoregulatory response during intense exercise and early recovery in insulin-dependent diabetic and control subjects. J Clin Endocrinol Metab 1993;76:566-573 60. Campaigne BN, Gilliam TB, Spencer ML, Lampman RM, Schork MA. Effects of a physical activity program on metabolic control and cardiovascular fitness in children with insulin-dependent diabetes mellitus. Diabetes Care 1984;7:57-62 61. Guelfi KJ, Jones TW, Fournier PA. Intermittent high-intensity exercise does not increase the risk of early postexercise hypoglycemia in individuals with type 1 diabetes. Diabetes Care 2005;28:416-418 62. Guelfi KJ, Jones TW, Fournier PA. The decline in blood glucose levels is less with intermittent high-intensity compared with moderate exercise in individuals with type 1 diabetes. Diabetes Care 2005;28:1289-1294 63. Galassetti PR, Iwanaga K, Crisostomo M, Zaldivar FP, Larson J, Pescatello A. Inflammatory cytokine, growth factor and counterregulatory responses to exercise in children with type 1 diabetes and healthy controls. Pediatr Diabetes 2006;7:16-24
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64. Pate RR, Pratt M, Blair SN, Haskell WL, Macera CA, Bouchard C, Buchner D, Ettinger W, Heath GW, King AC, et al. 1995 Physical activity and public health. A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. Jama 273:402-407 Please complete names of authors 65. Landt KW, Campaigne BN, James FW, Sperling MA. Effects of exercise training on insulin sensitivity in adolescents with type I diabetes. Diabetes Care 1985;8:461-465 66. Bernardini AL, Vanelli M, Chiari G, Iovane B, Gelmetti C, Vitale R, Errico MK. Adherence to physical activity in young people with type 1 diabetes. Acta Biomed Ateneo Parmense 2004;75:153-157 67. Wolfsdorf JI. Children with diabetes benefit from exercise. Arch Dis Child 2005;90:1215-1217 68. Kollipara S, Warren-Boulton E. Diabetes and physical activity in school. School Nurse News 2004;21:12-16 69. Kalergis M, Schiffrin A, Gougeon R, Jones PJ, Yale JF. Impact of bedtime snack composition on prevention of nocturnal hypoglycemia in adults with type 1 diabetes undergoing intensive insulin management using lispro insulin before meals: a randomized, placebo-controlled, crossover trial. Diabetes Care 2003;26:9-15 70. Raile K, Kapellen T, Schweiger A, Hunkert F, Nietzschmann U, Dost A, Kiess W. Physical activity and competitive sports in children and adolescents with type 1 diabetes. Diabetes Care 1999;22:1904-1905 71. Ludvigsson J. Physical exercise in relation to degree of metabolic control in juvenile diabetics. Acta Paediatr Scand 1980;283 (Suppl):45-49 72. Arslanian S, Nixon PA, Becker D, Drash AL. Impact of physical fitness and glycemic control on in vivo insulin action in adolescents with IDDM. Diabetes Care 1990;13:9-15 73. Viberti GC, Home PD, Bilous RW, Alberti KG, Dalton N, Keen H, Pickup JC. Metabolic effects of physical exercise in insulin-dependent diabetics controlled by continuous subcutaneous insulin infusion or conventional injection therapy. Acta Endocrinol (Copenh) 1984;105:515-520 74. Garlaschi C, di Natale B, del Guercio MJ, Caccamo A, Gargantini L, Chiumello G. Effect of physical exercise on secretion of growth hormone, glucagon and cortisol in obese and diabetic children. Diabetes 1975;24:758-761 75. Mathoo JM, Shi ZQ, Klip A, Vranic M. Opposite effects of acute hypoglycemia and acute hyperglycemia on glucose transport and glucose transporters in perfused rat skeletal muscle. Diabetes 1999;48:1281-1288 76. Riddell MC, Bar-Or O, Hollidge-Horvat M, Schwarcz HP, Heigenhauser GJ. Glucose ingestion and substrate utilization during exercise in boys with IDDM. J Appl Physiol 2000;88:1239-1246 77. Raguso CA, Coggan AR, Gastaldelli A, Sidossis LS, Bastyr EJ, 3rd, Wolfe RR. Lipid and carbohydrate metabolism in IDDM during moderate and intense exercise. Diabetes 1995;44:1066-1074 78. Berger M, Hagg S, Ruderman NB. Glucose metabolism in perfused skeletal muscle. Interaction of insulin and exercise on glucose uptake. Biochem J 1975;146:231-238 79. Wahren J, Hagenfeldt L. Free fatty acid and ketone body metabolism during exercise in diabetes. Acta Paediatr Scand 1980;283(Suppl):39-44 80. Galassetti P, Tate D, Neill RA, Morrey S, Wasserman DH, Davis SN. Effect of antecedent hypoglycemia on counterregulatory responses to subsequent euglycemic exercise in type 1 diabetes. Diabetes 2003;52:1761-1769 81. Marliss EB, Kreisman SH, Manzon A, Halter JB, Vranic M, Nessim SJ. Gender differences in glucoregulatory responses to intense exercise. J Appl Physiol 2000;88:457-466
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Phenotypic Features of 46, XX Females with StAR Protein Mutations

Amrit Bhangoo1, MD, Erkan Buyuk2, MD, Kutluk Oktay3, MD, Svetlana Ten1, MD
1Pediatric Endocrinology Division of Infant's and Childrens Hospital of Brooklyn at Maimonides, Brooklyn, NY 11219, USA, 2Department of Obstetrics and Gynecology, Maimonides Medical Center, Brooklyn, NY 11219, USA, 3The Center
for Reproductive Medicine and Infertility, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY 10021, USA Corresponding author: Svetlana Ten, MD, 977 48th Street, Brooklyn, NY 11219, USA, Tel: 718-283-8894, Fax: 718-635-7276, E-mail: tenlana@aol.com
Running Title: ???????

Abstract
bjective: To understand the basis of the phenotypic variations of 46, XX girls with mutations in the gene for Steroidogenic Acute Regulatory (StAR) Protein. The patients with mutation in both the alleles of the StAR gene result in deficiency of all the steroidal hormones and severe adrenal insufficiency. The majority of the 46, XX females spontaneously undergo puberty but the underlying defect ultimately leads to the development of ovarian cysts and premature menopause. The mechanism of the lesion in the ovary remains to be understood completely. Design: We compiled the description of the clinical information and biochemical data of patients with StAR mutation from published manuscripts. These articles were collected from the NCBI website (www.pubmed.org) and from the subsequent reference searches of retrieved articles. The data of the 46,XX patients with proven StAR mutation were included for the review. Results: The majority of StAR 46,XX females developed irregular menses and ovarian cysts. The ovarian cyst enlargement progressively led to torsion and presented as a life-threatening emergency. The fertility of 46,XX StAR patients is severely compromised as ultimately premature menopause ensued. Conclusions: Early hormonal replacement is warranted to prevent the progressive ovarian cyst formation. Newer techniques to preserve the fertility of these patients can be implied early in the pubertal developmental process if patients desire pregnancy.
Abbreviations: LHRH - Luteinizing Hormone Releasing Hormone; hMG -Human Menopausal Gondotrophin; LH Luteinizing Hormone; FSH- Follicle Stimulating Hormone; StAR-Steroidogenic Acute Regulatory Protein; P450scc-Side Chain Cleavage Enzyme; Lipoid CAH- Lipoid Congenital Adrenal Hyperplasia Ref: Ped. Endocrinol. Rev. 2007;5(2): Key words: Lipoid CAH; StAR; Steroidogenesis; Lipoid Accumulation; Gonadal Development; Irregular Periods; Ovarian Cysts; Menopause
Introduction
Mutations in the gene encoding for the steroidogenic acute regulatory (StAR) protein lead to Lipoid Congenital Adrenal Hyperplasia (Lipoid CAH), a disorder characterized by adrenal insufficiency and deficient gonadal steroid synthesis, resulting in female external genitalia in both genetic sexes. StAR plays an essential role in cholesterol transfer from the outer to the inner mitochondrial membrane, thus providing the substrate for steroid hormone biosynthesis (1-4). The fetal ovary lacks steroidogenic enzymes and steroidogenic capacity in contrast to the testis and adrenal gland (5,6). The ovary in XX subjects is spared from damage because steroidogenesis is delayed until the time of puberty. Hypothalamic secretion of FSH stimulates androgen production by theca and interstitial cells for aromatization to estrogen (Figure 3A). Correspondingly, StAR and P450scc are detected
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in these cells at this time (5,18). Granulosa cells become competent to produce steroid with the onset of P450scc expression after the estrogenic surge (18). However, these cells do not synthesize StAR until after the LH surge. Levels of StAR remain high in both theca and granulosa cells as they differentiate to form the corpus luteum. Steroidogenesis continues in this structure until luteolysis. Expression of StAR is lost in the residual corpus albicans (6,18,19). hypergonadotropic hypogonadism (7-13). In the course of time these patients develop acute emergencies, like ovarian cysttorsion, infertility and early menopause. In this review we present the phenotype and biochemical analysis as published in the respective papers and the fertility interventions available today. The patients are assigned numbers to make the discussion easier.
Discussion
We reviewed the description of the published 46,XX female patients with mutation of the StAR protein. Manuscripts describing the StAR 46,XX girls were searched on the NCBI website www.pubmed.org. The search words used were as follows: - StAR-Steroidogenic Acute regulatory Protein, Congenital Lipoid Adrenal Hyperplasia (Lipoid CAH), ovarian cysts and premature menopause. The time interval searched is from years 1995 to 2006. The search tools were applied on the Internet and obtaining the published manuscripts. The search criteria included all patients with 46,XX patients with proven StAR mutations. The patients have been discussed in a different section according to their main features.
Pubertal Development
Now thirty-four 46,XX patients have been described with StAR mutation. The data regarding thelarche were analyzed in 14 described cases. Menarche was analyzed in 12 described cases. Thelarche and menarche occur in usual time in girls with StAR mutation. The peak age of breast development was at 12 years (Figure 1). The average age of menarche is 13 years (Figure 2). However, they develop pubertal failure and early menopause before 25 yrs of age. Patient 3 at 11 yrs of age manifested Tanner stage II breast development. Menarche occurred at the age of 12 yrs; the baseline values of LH and FSH serum E2 were normal. At evaluation at 16 yr of age, the patient reported cyclic vaginal bleeding. Pubic hair had not appeared by the age of 16 yr and breast development remained at Tanner stage II (8). Patient 4, the younger sister of patient 3, had Tanner stage II breast development at the age of 9 yrs. She has not menstruated at her present age of 13 yrs (8,10). All but one of the nineteen patients who were in the pubertal age underwent spontaneous puberty. Patient 5 after reaching the pubertal age (16.4 years) did not develop any secondary sexual features or menarche. Baseline LH and FSH levels were elevated with low E2 levels indicating primary ovarian failure (10). Patient 6 underwent puberty. The analysis done at 12 yrs of age showed normal LH, FSH and E2 levels (10). Patient 7 also underwent spontaneous puberty. She was 20 yrs old when she reported. The LH levels were elevated whereas both FSH and E2 were normal. With lack of clinical information it is not possible to interpret the results accurately (10).
Figure 3. A. The Ovarian Steroidogenesis in the Presence of StAR Protein, Androstenedione is Produced from the Thecal Cells after LH Stimulation. The androstendione is transferred to the granulosa cells where the enzyme Aromatase is stimulated by FSH. The androstendione is converted by aromatase to estrone and subsequently to E2 and thus released into circulation. In the granulosa cells FSH stimulates the StAR protein and thus stimulates the formation of progesterone.
With the rise of tropic hormones, LH and FSH initiate ovarian steroidogenesis and eventually lead to progressive damage to the ovary in these patients (7,8). The progression of puberty then stimulates the maturation of individual ovarian follicles, leading to some estrogen synthesis by the ovary that is independent of StAR protein mediated transport (4,8). In the ovary, with each cycle the previously un-stimulated follicles are recruited, which explains estradiol (E2) production. It has been hypothesized that cholesterol esters accumulate and destroy the steroidogenic capacity of each stimulated follicles. The progesterone production is lacking, suggesting that different mechanism of progesterone and E2 production might exists in the ovary. There is wide variation in the pubertal development of these XX patients. The majority of the XX females who spontaneously go through puberty develop irregular menses, anovulatory cycles and/or ovarian cysts, progressive ovarian failure and
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Patient 8 was 20 yrs old when described and had developed the secondary sexual characteristics. Her LH was mildly elevated, while FSH and E2 were in the normal range (10). Patient 9 had regular menstrual bleeding at the start of puberty, but experienced menopause at 24 yrs of age (9). Patient 12 started breast development at 14 yrs of age and menarche at 15 yrs. The LHRH stimulation test performed at 17 yrs of age revealed a normal response of FSH and an exaggerated response of LH. She had no evidence of ovarian cysts on pelvic sonogram (11). patients (11,12). Out of the five with regular menses three (Patients 2,3,15) ultimately developed polycystic ovaries (8,10,12) and one developed premature menopause at 24 years of age (9). Patient 14 was 10 yrs of age when the LHRH stimulation test was done. The LH response was compatible with normal pre-pubertal females. Serum FSH and its response to LHRH were lower than normal prepubertal females. Serum E2 levels failed to rise after hMG administration for 5 days. The patient had thelarche at 14 yrs of age. LH, FSH and E2 levels were 12.8, 6.5 mIU/ml and <10 pg/ml respectively. She attained menarche at 15 yrs of age. LH, FSH and E2 levels were 46.2, 12.6 mIU/ml and 12 pg/ml respectively. At 18 yrs of age patient had Tanner V breast and Tanner II-III pubic hair. She ultimately developed irregular periods. She did not have any polycystic changes in the ovaries on repeated pelvic ultrasonography (12). In contrast, only patient 16 continued to experience regular periods till 25 years of age (14). Patient 16 started breast development at 11.6 yrs of age. She underwent spontaneous normal menarche at 14.2 yrs. Menstrual periods have always been regular without any dysmenorrhea until her last followup. Her hormonal profile was measured between the ages of 2 yrs and 12 yrs. The levels of LH and FSH were always reported to be normal and E2 levels were low - consistent with pre pubertal status (14). The Clomiphene stimulation test was done and the results are enumerated in Table 2. Regular monthly cycles are possible, as patients ovaries retain large numbers of follicles that remained relatively undamaged before recruitment. Such monthly cycles, which may persist for years, are probably anovulatory. However, these cycles can produce extremely large ovarian cysts, which can undergo torsion and present as a life-threatening acute abdominal condition.
Figure 1. Thelarche was analyzed in 14 described cases; one girl, case 5 never developed thelarche. The peak of breast development was at 12 years.
Polycystic Ovaries
Seven of the 46,XX StAR patients (Patients 1-3,10,11,13 & 15) were reported to have developed ovarian cysts (7,8,10-12). Patient 1 started breast development at 11.5 years of age and developed pubic hair soon after. Patient had only one episode of vaginal bleeding at 13.75 yr of age. Treatment with medroxyprogesterone depot was initiated thereafter. At 15.5 yrs she completed puberty with both pubic hair and Tanner stage V breasts. Pelvic ultrasonography showed a normal pubertal size uterus and bilateral ovarian cysts (7). Patient 2 was 21-yr-old when reported. The authors wanted to study the pituitary-ovarian axis before and after puberty. At the age of 5yrs, a luteinizing hormone releasing hormone (LHRH) stimulation test demonstrated an exaggerated response of peaks of LH and FSH. By 10 yrs of age, the patient manifested Tanner stage II breast development. At this time, the LHRH stimulation test showed an exaggerated response for LH and
Figure 2. Menarche was analyzed in 12 described cases; one girl, case 5 never started to develop secondary sexual features. The average age of menarche is 13 years. Thelarche and menarche occur in usual time in girls with StAR mutation.
Menstural Cyclicity
Clinical information relating to the periods was available for review in 9 patients. Periods were irregular in 4
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Table 2. Biochemical Profile of 46,XX Females with StAR Protein Mutation
normal for FSH. Her E2 level was normal at 10 years and, at 12 years of age, E2 increased when menarche occurred. The LH-RH stimulation test that was repeated again revealed an exaggerated response of LH and a low response of FSH. She attained pubarche at the age of 12.9 years. Until 15 yr of age the patient reported periodic vaginal bleeding. Breasts developed to Tanner stage III, but pubic hair remained at stage II. By the age of 20 yrs polycystic changes in the ovaries were identified on a pelvic MRI. Her serum E2 levels ranged from low to normal, while progesterone remained undetectable. LH levels were increased whereas FSH levels were not elevated (8). Patient 3 was having regular menstrual periods; pelvic ultrasonography identified normal sized ovaries and uterus although MRI revealed polycystic changes in the ovaries (8) (Table 1). Patient 10 started breast development at 9 yrs of age and developed menarche at 10. Her periods were irregular from the beginning and at 11years of age she experienced an episode of acute abdominal pain and was subsequently diagnosed with bilateral ovarian cysts (11). Patient 11 underwent thelarche at the age of 12 yrs and by 13 yrs had started to have her menstrual periods. The periods were irregular at times. On pelvic sonogram she was found to have cysts in the right ovary, a CT scan confirmed the presence of cysts in both ovaries (11). Patient 13 at the age of 11 yrs had breast development. Serum LH was elevated basally and it responded exaggeratedly to LHRH, while basal FSH and its response to LHRH were almost within the normal range. Serum E2 levels increased after the intramuscular injection of human menopausal gonadotrophins (hMG) for 5 days (Table 2). At 12 yrs of age patient attained menarche. Patients menstrual periods were regular until she presented with an acute
abdomen due to bilateral ovarian cyst torsion and underwent bilateral ovariectomy (12). Patient 15 was prepubertal when a LHRH stimulation test was performed. The baseline LH and FSH were suppressed and increased normally after stimulation. The serum E2 levels were undetectable and did not rise after hMG administration. Patient started breast development at 12 yrs of age and had menarche at 13 yrs of age. The periods were regular however non-biphasic. The LH at the time was high with FSH and E2 in the normal range (Table 2). By 17 yrs of age the patient had reached the development of Tanner IV breasts and the pubic hair had only progressed to Tanner II. At 23 yrs of age, a CT scan showed bilateral ovarian cysts (12). The hyperstimulation of LH may have an important role in the development of polycystic changes in the ovaries of patients with the StAR mutation. The hypothalamic-pituitary-ovarian axis was studied by a few authors. The response to LHRH was noted in few pubertal patients (Table 2). Upon stimulation LH levels were excessively high, with normal response of FSH and E2 production (8,11). The baseline levels of LH were high and the FSH was normal indicating the important role of LH in the pathogenesis of polycystic ovaries in patients with StAR mutation (10).
Hormonal Replacement
Hormonal replacement therapy was reportedly started in only 4 patients: patient 1 was put on Medroxyprogesterone (7); patients 10 and 13 were started on combined estrogen and progesterone replacement (11,12). Patient 10 developed bilateral ovarian cysts at 14 yrs of age, estrogen and progesterone replacement was started, relieving the abdominal pain and diminishing the
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Table 1. Phenotypic Features of 46,XX Patients with StAR Mutation
size of the ovarian cysts (11). Patient 13 was started on estrogen and progesterone replacement after she underwent bilateral ovariectomy 12. Patient 17 reportedly underwent spontaneous menarche at 14 yrs and the menses eventually stopped at age 18 yrs, thus the treatment with oral contraceptives was begun 13. Patient 18 was started on leuprolide acetate (lupron) depot soon after LH levels were detected. The treatment with lupron will suppress the secretion of LH & FSH from the anterior pituitary. This is intended to prevent the steroidogenesis from the beginning and thus prevent the progressive damage to the ovaries (Table 1). Patient 18 was followed with serial LH, FSH and E2 levels before the clinical signs of puberty had appeared. These were in the prepubertal range between 9.75 yrs to 12.2 yrs of age. MRI of the pelvic area was consistent with a normal prepubertal uterus and the ovaries showed no evidence of cysts. At the age of 12.8 yrs, patient was found to have a detectable LH level on an ultrasensitive assay, patient subsequently developed breasts. The patient was thereafter started on Leuprolide depot to prevent the progressive damage to the ovaries (15).
the E2 was undetectable (10). Patient 22 was 4 yrs old and prepubertal when described. Her LH and FSH were both in the pubertal range while the E2 was undetectable (10). Patient 23 was prepubertal when a stimulation test with hMG (Human Menopausal Gondotrophin) was administrated for 5 days. The peak E2 level rose normally at day 2 of the test (16). Patient 29 was 7.8 yrs of age and prepubertal on the last examination. The LH and FSH levels were undetectable on an ultrasensitive assay. MRI of the pelvic area was consistent with a normal uterus and normal ovaries (15). The hormonal testing was included in this review and gives a good understanding of the baseline activity before puberty.
Fertility in 46,XX StAR Patients

Preservation of fertility is becoming an important issue, especially among cancer patients, since these patients survive their diseases due to advances in cancer therapy (20). However, this issue is not always addressed and cancer survivors indicate that this is a major concern for them once they are cured of their disease (21). This approach may be extrapolated to StAR patients who frequently become infertile due to premature depletion of their follicles. Fertility preservation options available to cancer patients receiving chemotherapy and at risk of POF (Premature Ovarian Failure) may also be offered to StAR patients while undergoing puberty. Oocyte, embryo and ovarian tissue cryopreservation and success rates may be
Pre-Pubertal Patients
Patient who have had not entered puberty before the manuscripts where published were included in the review. Patient 21 was 6 yrs old and prepubertal when described. Although her LH and FSH were both in the pubertal range
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menopause in these patients. The heterogeneity of the disorder precludes any prediction of the course of the disease for a given patient.
Conclusions
Most of these patients were able to produce some quantities of E2 sufficient to promote pubertal changes and endometrial growth. There could be one of two possible explanations: the mechanism in case of StAR KO in ovaries is different from the adrenals and testes; an independent cholesterol transport mechanism exists. In coexpression studies in the StAR KO COS-1 cells a small amount of pregnenolone is produced from cholesterol (4). The histological picture of the mice ovaries had deposition of the lipids in the interstitium of the ovaries. The granulosa and the theca cells did not show lipid accumulation (17). 2) In the case of StAR protein mutation, a StAR-independent pathway may exist in the Theca cells. FSH stimulated progesterone production in the Granulosa cells is affected, the progesterone levels in these patients being undetectable (Figure 3B). It can be concluded that the pubertal-aged 46, XX patients spontaneously developed secondary sexual characteristics and menstruation with detectable serum E2. This suggests that there exists a StAR-independent pathway for ovarian steroidogenesis. It is possible that the role of StAR protein in adrenals, testes and gonads are different. Therefore, there is heterogeneity in the degree to which gonadal steroidogenesis is functionally impaired in lipoid CAH (10). For example some only develop breasts without pubarche (10). One patient did not develop any secondary sexual characteristics when she reached the pubertal age (10), whereas one reported patient developed puberty normally, attained menarche and had regular periods until 25 years of age at the last follow-up (14). These patients need to be followed closely for accumulation of more long-term data and for the understanding of the pathophysiology of StAR mutation in the ovary. Complications like the acute emergency of ovarian cyst-torsion and infertility and early menopause can be prevented by the early diagnosis of StAR mutation and hormonal replacement or other interventional therapies.
Figure 3.B. In the case of StAR protein mutation, FSH stimulated progesterone production in the Granulosa cells is affected, the progesterone levels in these patients are undetectable. StARindependent pathway may exist in the Theca cells.
discussed with families and patients and the most appropriate procedure may be chosen depending on the patients condition. For prepubertal patients with StAR mutation, oocyte or embryo cryopreservation is neither ethical nor medically feasible since these patients should undergo ovarian stimulation with gonadotropins and egg retrievals and followed up with transvaginal ultrasounds. Since cholesterol accumulates in the ovaries once these patients undergo puberty and start to synthesize steroids, ovarian cryopreservation and later transplantation before achieving puberty may be an option for these patients. In ovarian tissue cryopreservation, Step 1 the cortex of ovary is stored in liquid nitrogen in the form of pieces until they are transplanted back to the patient once fertility becomes a concern (22,23). With this approach, Step 2) follicle growth may be stimulated with gonadotropins after the transplantation and in vitro fertilization-embryo transfer may be performed. The down side of this approach is the fact that once transplanted back and stimulated, the ovaries will start to accumulate cholesterol again which will be toxic to the ovaries. On the other hand, since the transplantation will be done once the patients desire fertility, follicles may be stimulated and eggs may be collected and fertilized before the ovaries undergo complete depletion of the follicles. Another approach may be stimulation of the follicles as soon as the patient undergoes puberty with retrieval and cryopreservation of the oocytes (23). This approach will be adequate in patients who have undergone puberty since they will be mature enough to undergo ovarian stimulation and follow up with sonograms. The disadvantage of this approach is the possibility of follicle depletion with very early premature
References
1. 2. Stocco DM, Sodeman TC. The 30-kDa mitochondrial proteins induced by hormone stimulation in MA-10 mouse Leydig tumor cells are processed from larger precursors. J Biol Chem 1991;266:19731-19738 Clark BJ, Wells J, King SR, Stocco DM. The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 1994;269:28314-28322 Bose HS, Sugawara. T, Strauss III JF, Miller WL. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. New Eng J Med 1996;335: 1870-1878
3.
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4. 5. 6. 7. Lin D, Sugawara T, Strauss III JF, Clark BJ, Stocco DM, Saenger P, Rogol A, Miller WL. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 1995;267:1828-1831 Kiriakidou M, McAllister JM, Sugawara T, Strauss III JF. Expression of steroidogenic acute regulatory protein (StAR) in the human ovary. J Clin Endocrinol Metab 1996;81;4122-4128 Pollack SE, Furth EE, Kallen CB, Arakane F, Kiriakidou M, Kozarsky KF, Strauss III JF. Localization of the steroidogenic acute regulatory protein in human tissues. J Clin Endocrinol Metab 1997;82:4243-4251 Bose HS, Pescovitz OH, Miller WL. Spontaneous feminization in a 46,XX female patient with congenital lipoid adrenal hyperplasia due to a homozygous frameshift mutation in the steroidogenic acute regulatory protein. J Clin Endocrinol Metab 1997;82:1511-1515 Fujieda K, Tajima T, Nakae J, Sageshima S, Tachibana K, Suwa S, Sugawara T, Strauss III JF. Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene. J Clin Invest 1997;99:1265-1271 Bose HS, Sato S, Aisenberg J, Shalev SA, Matsuo N, Miller WL. Mutations in the steroidogenic acute regulatory protein (StAR) in six patients with congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 2000;85:3636-3639 Nakae J, Tajima T, Sugawara T, Arakane F, Hanaki K, Hotsubo T, Igarashi N, Igarashi Y, Ishii T, Koda N, Kondo T, Kohno H, Nakagawa Y, Tachibana K, Takeshima Y, Tsubouchi K, Strauss III JF, Fujieda K. Analysis of the steroidogenic acute regulatory protein (StAR) gene in Japanese patients with congenital lipoid adrenal hyperplasia. Hum Mol Genet 1997;6:571-576 Shima M, Tanae A, Miki K, Katsumata N, Matsumoto S, Nakajima S, Harada T, Shinagawa T, Tanaka T, Okada S. Mechanism for the development of ovarian cysts in patients with congenital lipoid adrenal hyperplasia. Eur J Endocrinol 2000;142:274-279 Tanae A, Katsumata N, Sato N, Horikawa R, Tanaka T. Genetic and endocrinological evaluations of three 46,XX patients with congenital lipoid adrenal hyperplasia previously reported as having presented spontaneous puberty. Endocr J 2000; 47:629-634 Chen X, Baker BY, Abduljabbar MA, Miller WL. A genetic isolate of congenital lipoid adrenal hyperplasia with atypical clinical findings. J Clin Endocrinol Metab 2005;90:835-840 Khoury K, Ducharme L, LeHoux JG. Family of two patients with congenital lipoid adrenal hyperplasia due to StAR mutation. Endocr Res 2004;30:925-929 Bhangoo A, Gu WX, Pavlakis S, Anhalt H, Heier L, Ten S, Jameson JL. Phenotypic features associated with mutations in steroidogenic acute regulatory protein. J Clin Endocrinol Metab 2005;90:6303-6309 16. Okuyama E, Nishi N, Onishi S, Itoh S, Ishii Y, Miyanaka H, Fujita K, Ichikawa Y. A novel splicing junction mutation in the gene for the steroidogenic acute regulatory protein causes congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 1997;82:2337-2342 17. Hasegawa T, Zhao L, Caron KM, Majdic G, Suzuki T, Shizawa S, Sasano H, Parker KL. Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice. Mol Endocrinol, 2000;14:1462-1471 18. Ronen-Fuhrmann T, Timberg R, King SR, Hales KH, Hales DB, Stocco DM, Orly J. Spatio-temporal expression patterns of steroidogenic acute regulatory protein (StAR) during follicular development in the rat ovary. Endocrinology 1998;139:303-315 19. Pon LA, Orme-Johnson NR. Acute stimulation of steroidogenesis in corpus luteum and adrenal cortex by peptide hormones. Rapid induction of a similar protein in both tissues. J Biol Chem 1986;261:6594-6599 20. Jemal A, Clegg LX, Ward E, Ries LA, Wu X, Jamison PM, Wingo PA, Howe HL, Anderson RN, Edwards BK. Annual report to the nation on the status of cancer, 1975-2001, with a special feature regarding survival. Cancer 2004;101:3-27 21. Partridge AH, Gelber S, Peppercorn J, Sampson E, Knudsen K, Laufer M, Rosenberg R, Przypyszny M, Rein A, Winer EP. Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol 2004;22:4174-4183 22. Oktay K, Buyuk E, VeeckL, Zaninovic N, Xu K, Takeuchi T, Opsahl M, Rosenwaks Z. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;363:837-840 23. Shamonki MI Oktay K. Oocyte and ovarian tissue cryopreservation: indications, techniques, and applications. Semin Reprod Med 2005;23:266-276 24. Katsumata N, Tanae A, Shinagawa T, Nagashima-Miyokawa A, Shimizu M, Yasunaga T, Tanaka T, Hibi I. Detection of the missense mutation A218V in the steroidogenic acute regulatory protein gene of a Japanese patient with congenital lipoid adrenal hyperplasia. Clin Pediatr Endocrinol 1997;6:33-37 25. Takaya J, Ishihara R, Kino M, Higashino H, Kobayashi Y. A patient with congenital lipoid adrenal hyperplasia evaluated by serial abdominal ultrasonography. Eur J Pediatr 1998;157:544-546 26. Achermann JC, Meeks JJ, Jeffs B, Das U, Clayton PE, Brook CG, Jameson JL. Molecular and structural analysis of two novel StAR mutations in patients with lipoid congenital adrenal hyperplasia. Mol Genet Metab 2001;73:354-357 27. Yoo HW, Kim GH. Molecular and clinical characterization of Korean patients with congenital lipoid adrenal hyperplasia. J Pediatr Endocrinol Metab 1998;11:707-711
8.
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10.
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13. 14. 15.
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Continuous Insulin Infusion (CSII) or Modern Type of Multiple Daily Injections (MDI) in Diabetic Children and Adolescents A Critical Review On A Controversial Issue
Johnny Ludvigsson MD, PhD, Ulf Samuelsson, MD, PhD Div of Pediatrics and Diabetes Research Centre, Linkping University, Linkping, Sweden
Abstract
bjective: There is a common opinion that CSII is superior to MDI. CSII offers the most physiological insulin substitution. Method: Review of recent publications (Cochrane criteria), on modern multiple daily injections (MDI) based on insulin analogues, modern self-control and education. Results: There is a lack of randomised controlled studies comparing CSII with modern MDI in children and adolescents. In some studies CSII seems to give a slight decrease of HbA1c, a slightly better quality of life, perhaps less hypoglycemia. However, serious hypoglycemia, sometimes fatal, occurs, DKA seems to increase, weight gain and local infections at injection sites may occur and CSII is more expensive than MDI. Conclusion: CSII is a useful tool. It is reasonable to use it when there are appropriate indications. CSII does not solve all problems but has to be combined with other important parts of diabetes treatment. Ref: Ped. Endocrinol. Rev. 2007;5(2): Key words: Type 1 Diabetes, CSII, Insulin Pump, MDI, Children, Adolescents, Metabolic Control, Quality of Life, Diabetes Complications
the importance of intensive insulin therapy for achieving good blood glucose control and prevention of diabetes complications. Multiple daily injections (MDI) is one alternative and continuous insulin infusion (CSII) by insulin pump is another to reach this goal. CSII was introduced in the 1970s. Theoretically, CSII offers the most physiological way of insulin delivery due to its ability to more closely simulate the normal pattern of insulin secretion, allow more flexibility of life style and give more precise insulin delivery than MDI. Furthermore, to decrease the number ofinjections is of important benefit especially to some children However, there are also disadvantages with CSII. It is important to base decisions regarding use of insulin regimens not only because it is fashionable or on personal experience but also on existing scientific evidence.
Previous Comparisons between CSII and MDI

Quality of Life CSII has over the last decades gained increasing popularity among adolescents and children with diabetes (5-8). However, according to literature, quality of life (QoL) seems to be improved by CSII in some but not all studies (9,10,11). Metabolic Control During the years numerous randomised controlled trials, mainly in adults, but some also in paediatric populations, have compared the effect of CSII and MDI on glycemic control. Some of these studies have shown similar mean blood glucose values and glycosylated haemoglobin (9,12,13), while others have found that CSII is accompanied by improved mean glucose and
Introduction
The Diabetes Control and Complications Trial (DCCT) as well as other studies (1-4), have clearly demonstrated
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CSII or MDI in Children

glycosylated haemoglobin (14-16). Meta analysis of randomised controlled studies indicates that CSII is associated with better glycaemic control than MDI, also when rapid-acting insulin analogues are used (10,17,18). Hypoglycemia Almost all children with type 1 diabetes experience hypoglycemia with any type of insulin treatment (19). Hypoglycemia is unpleasant. Furthermore, severe episodes of hypoglycemia in young children have been associated with neurocognitive dysfunction (20) even though other studies indicate that the long-term effects on neurocognitive function may be less pronounced after hypoglycemia compared to longer periods of hyperglycemia (21). The fear of hypoglycemia, prevalent in both parents of diabetic children and among teenagers, may become a serious consequence of hypoglycemia as it poses a barrier to good metabolic control (22,23). As variations of insulin uptake and serum insulin profiles when using long-acting insulin is one major cause of hypoglycemia, one would expect CSII to be very useful in preventing hypoglycemia (24) and repeated severe hypoglycemia is therefore one of the main clinical indications for the use of pumps. However, it has not been possible to show that treatment with CSII leads to any significant difference in the frequency of severe hypoglycemia in children compared to MDI (9,12,14). Teutsch et al in the USA found 35 deaths among 3,500 pump users, mainly adults, which number was not different to that in non-pump users, wile 2 deaths were caused by the pump (25). Steel in the UK reported on an intrauterine death of a fetus because of incorrect pump use (26) and a 13 year old boy on CSII was found dead in bed, most probably because of an overdose of insulin given by mistake (27). DKA Some reports have shown that the risk of this serious side effect is increased by CSII (27,28). Thus, although careful evaluation and education at initiation of pump therapy may decrease the risk of DKA (27,29),, in practice the risk of DKA has been regarded as one of the major arguments against using CSII. Weight Gain Concerns have been raised regarding CSII and weight gain, but studies in paediatric patients have shown that CSII rather decreases BMI or results in no weight change (30, 31). Even though both determir and glargine theoretically should be superior to NPH it has not been easy to show improvement in the level of HbA1c. Thus, in a review of analogue trials Gough (32) reports that the benefits of detemir and glargine with respect to HbA1c are minimal. Combinations of direct acting and basal analogues might reduce HbA1c but more studies are needed (32).
Aim of this Review

There is a need for a critical review of existing evidence for and against CSII when modern MDI is used, based on insulin analogues, modern type of self-control and education. We have therefore conducted a search in the literature for trials which have compared CSII with MDI therapy using both direct acting and long-acting insulin analogues glargine or detemir. In addition we made an up-dated search for trials that have compared CSII and MDI or TDI using NPH or ultralente as basal insulin.
Methods
We planned to follow the criteria for evidence-based medicine according to Cochrane33 and have therefore primarily included randomised controlled trials in children/adolescents. However, as we found a relatively small number of such trials, we decided to include also reports with a lower degree of evidence such as non-randomised trials (Table 1). As we only found 4 trials which compared CSII with MDI using a long acting analogue (MDI-G) in children and adolescents (Table 2), we have also considered trials in adult patients which compared CSII with MDI-G but report them separately (Table 3). As most studies using determir and glargine have been performed since year 2000 we have limited our search for trials for CSII compared with conventional MDI or TDI to the same time period, when other components of diabetes treatment influencing metabolic control should be comparable. To be included in our review the trials/studies must have met certain criteria: 1. be original reports published in peer-reviewed journals; 2. the study period must be at least one month; 3. the results had to be presented as means and SD or SE for HbA1c, BMI, insulin dose and blood glucose; 4. in the trials where CSII and conventional MDI or TDI were compared we included only studies in children and/or adolescents. Data from text, tables and graphs were extracted, and type of pumps, type of insulin and previous treatment was recorded. We calculated the 95% confidence interval of HbA1c, insulin dose, blood glucose and BMI in each study using the method by Gardner and Altman (34). A weighted summary mean difference
Long-Acting Insulin Analogues as Basal Insulin May Reduce the Benefit of CSII?
One important advantage of CSII is to get a more stable basal insulin supply. In recent years two long-acting analogues, glargine and detemir, have become available, which may also give a more stable basal insulin supply.
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Mean SD Duration of DM Years Weintrob 6.0 (Median) 10.9 (Median) N et al 2.5 9.2 13.7 (Range) (43) 11(Range) Cohen At Least 2 D J et al 14.5 17.9 Years (44) DiMeglio 3.8 0.8 1.8 0.6 L et al 3.7 0.7 (MDI) 1.8 0.6 (41) 47.5 4.8 (SE) Fox L et 15.3 3.4 45.3 4.3 al (9) 19.7 4.1 (Months) Ahern J 10.3 Years et al(6) 3.8 2.7 1,5 18 (Range) Authors Mean SD Age (Years) 4.5 1.4 Willi S et al (30) Sulli N et al(42) Hanas R et al(31) Shedadeh N et al(45) Jeha G et al(46) Litton J et al (47) Plotnick L et al (35) Nabhan Z et al (36)
Liberatore R et al37
Type of Study Randomised Crossover Randomised Crossover Randomised Open Randomised Parallel Prospective Prospective Prospective Prospective Prospectrive Prospective Prospective Prospective Retrospective Retrospective Retrospective Retrospective
No of Participants CSII MDI 23 16 21 21 (42) 13 13 (26) 161 65 51 42 23 15 10 9 95 93 73 70
Study Duration 7 (Months) 12 (Months) 6 Months 6 (Months) 32 9 Months 19 57 (Range) 48 Months 24 (Months) 4 (Years) 5 Years 12 Months 6 (Months)
Previous Treatment
Type of Pump Minimed 508 Disetronic Minimed 508 Minimed/ Medtronic ? ? ? ? Minimed/ Disetronic Minimed Paradigm ? Mimed/ Disetronic ? Minimed 508 ?
Type of Insulin NPH/ Regular Lispro NPH Regulart Lispro NPH Lispro/ Aspart ? ? Lispro/ Aspart Lispro/ Aspart
NPH Regular MDI

NPH/ Ultralente Lispro
NPH Lispro/ Aspart NPH Regular/ Lispro ? NPH/ Regular/ Analog. NPH/ Regular/ Lispro MDI MDI TDI
1.8 1.2 4.0 2.6 5.1 3.0 6.9 3.7 ? 1.88 1.38 13.7 3.0 5.6 3.3 4.7 3.1 6.0 ?
7.2 3.4 12.2 3.4 13.5 3.2 3.8 1.2 3.65 1.34 34.1 (Months) 20 58 (Range) 12.0 3.1 11.6 3.1 12.9 9.1 2.9
Aspart Aspart Lispro Lispro ? Lispro ?
NPH 12.7 (Months) Regular/ 7 - 19 (Range) Lispro 28 Months (Md) 2.4 0.8 Years 6 30 Months 336 58.5 (Days) 6 Months 12.2 (635months) Regular MDI ?
NPH/ Ultralente Lispro NPH/ Ultralente Regular/ Lispr
MackFogg J et al (38) Conrad et al (39) Maniatis (7)
11.5 3.2
4.7 2.6
Retrospective
65
Minimed Disetronic/ Minimed
Lispro
17.0 3.3
7.6 4.5
Retrospective
56
Table 1. The Included Studies that Compared CSII with Conventional Therapy (MDI or TDI). Studies are presented in decreasing order with respect to type of study and the number of participants. Bold text = randomised study, italic=prospective study, ordinary text = retrospective study.
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Mean Mean SD Duration SD Type of Study Authors Age of DM (Years) (Years) 14.7 Alemzadeh 1.9 6.2 3.1 Prospective et al (52) 14.6 6.5 3.3 Open/Parallel 1.4 (MDI) 12.5 Doyle E et al 3.2 6.8 3.8 Randomised (14) 13.0 5.6 4.0 Open 2.1 (MDI) Wilson D et al (12) Sciaffini R et al (56) 3.6 1.0 14.6 1.8 11.9 3.4 (MDI) 1.4 0.6 Randomised Open Retrospective Parallel No of Participants CSII MDI-G 40 40 (80) Study Duration CSII MDI-G 12 12 (Months)
Previous Treatment
Type of Pump
Type of Insulin
Ultralente Lispro
Mimed Disentronic
Glargine Lispro
16 16 (32) 9 10 (19) 20 16 (36)
16 16 (Weeks)
MDI BID NPH/Lente/ Glargine NPH Regular?
Minimed Paradigm
Glargine Aspart
1 Year
Lispro Minimed 508 Glargine/NPH/ Lente H-tron D-tron Glargine Analogues
5.5 1.9 5.5 2.3
12 12 (Months)
Table 2a. The Studies that Compared CSII with MDI Using Rapid-Acting Insulin Analogues Together with Glargine (MDI/G) in Children. Studies are presented in decreasing order with respect to type of study and the number of participants. Bold text = randomised study and ordinary text = retrospective study.
over the studies was computed followed by a 95% CI of this mean to determine whether the difference in mean outcome was of statistical significance. A 95% CI not including the figure 0 is considered as significant.
Results
The criteria were fulfilled by 18 studies6,7,9,30,31,35-47 with a total of 935 children and adolescents which compared CSII with conventional MDI or TDI of which 4 studies were randomized (9,41,43,44) (107 patients) (Table 1). Mean age of the participants was 10.2 3.0 years with a duration of type 1 diabetes of 4.5 2.7 years. Corresponding figures when only including randomized studies were 6.9 4.2 and about 2.3 years, respectively. In two of the non-randomised studies in table 1 the treatment was changed from MDI to CSII because of elevated HbA1c-values, unstable glycaemic control and other problems (42,47). The other non-randomised studies described no specific indication for CSII treatment apart from certain ages, patient (or diabetes team) interest in CSII. Some of the studies (38,41,46) in table 1 were supported by Medtronic Minimed. The study by Jeha (46) et al was also supported by NovoNordisk and the study by DiMeglio (41) also by Roche Diagnostics and Cohen et al (44) by Tayco Ltd. In addition we identified 13 trials with a total of 1180 participants comparing CSII with MDI using rapid-acting insulin analogues together with glargine (12,14,48-58) (MDI-G) but found no trials with detemir as basal insulin. Only four of these studies included just children or adolescents (12,14,52,56) of which 3 were randomised (12,14,52) (Table 2a). The mean
age of the participants in these 4 studies was 12.8 1.9 years with a duration of diabetes of 5.6 2.8 years. The remaining 9 studies included only adults and only three were randomised (50,53,55) (Table 2b). Mean age of the participants was 34.5 10.4 years with a duration of diabetes of 17.6 10.3 years (Table 2b). Since the study by Bode et al (55) focused on the transition from CSII to MDI-G for short periods it was not included in our review. Two of the studies (12,14) in table 2 were supported by Medtronic Minimed. Of the studies in table 2b was the study by Pickup et al (57) supported by Medtronic Minimed ant the study by Hirch et al (50) by Novo Nordisk The non-randomised study in table 2a reported that the patients were put on CSII because of poor metabolic control (56). The same reason was given in three of the other studies (54,57,58). The other studies seemed to have indications for CSII based on the interest of patients and/or the diabetes team. Glycated Haemoglobin All studies that compared CSII with MDI/TDI in children had the opinion that CSII therapy gave a better metabolic control than MDI/TDI. One study (40), although not randomised, also showed that there was no problem with the metabolic control when toddlers with pump received daytime care from paid caregivers. Table 3 shows that the percentage of glycated haemoglobin was lower in patients with CSII therapy in all included studies comparing CSII with MDI/TDI. The standardised mean difference in the randomised trials was -0.31 (95%CI = -0.51 to -0.11). The non-randomised studies had a higher mean difference -0.6 (95%CI = -0.69 to -0.51). When including all
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Mean SD Age (Years) Mean SD Duration of DM (Years) No of Participants CSII MDI-G 50 50 (100) 28 29 (57) 18 (1:1) 20 (1:2) 30 12 (30) 45 45 (90) 24 24 (48) Study Duration CSII MDI-G 55 (Weeks) 66 (Months) 77 (Months) 2 -11 5 (Months) 12 12 Months 12 12 (Months)
Authors
Type of Study Randomised Crossover Randomised Open
Previous Treatment CSII Lispro ?
Type of Pump ? ?
Type of Insulin Aspart Glargine Glargine Lispro Glargine Lispro Glargine Lispro/Aspart Glargine ? Lispro Glargine
Hirsch I et al 43 11.1 21.8 11.9 (50) Bolli G (53) ? 40.7 9.5 38.6 10.8 (1:2) 41.6 11.0 ? ?
Bode B et al (55) Pickup J et al (57) Adana et al (51) Lepore G et al(54)
21.1 8.9 19.5 10.9
Randomised
CSII
23.4 11.3 ? 19.8 9.5 18.1 11.4
Crossover Open Parallel Open Parallel
NPH NPH ? NPH Lispro/Regular
Minimed H-Tron ? ?
38 9.4 41 14 (MDI 37.7 11.2 Lepore G et al 42.9 (58) 15.6 (MDI) 31.0 Garg S et al 10.1 (48) 32.0 9.9 (MDI) Harmel et al (49) ?
19.6 9.2 14.7 11.1
Open Parallel
16 16 (32)
12 12 (Months)
NPH Regular/Lispro
Glargine Lispro
17.1 9.4 Retrospective 15.7 10.3 Rtrospective Parallel
216 299 (515) 58 43 (103)
11.60.2 13.1 0.3 (Months) 165.8 11.63.8 (Months)
Glargine Lispro/Aspart Glargine Lispro/Aspart
Table 2b. The Studies that Compared CSII with MDI Using Rapid-Acting Insulin Analogues Together with Glargine (MDI-G) in Adults. Studies are Presented in Decreasing Order with Respect to Type of Study and The Number of Participants. Bold text = Randomised Study, Italic=Prospective Study, Ordinary Text = Retrospective Study.
studies the standardised mean difference was -0.55 (95% CI = -0.64 to -0.46). The same pattern was seen in the trials comparing CSII with MDI-G in children and adolescents. For the randomised studies the difference was -0.46 (95%CI = -0.64 to -0.28) (Table 4a). The standardised mean difference in the studies including adults was less pronounced -0.15 (95%CI= -0.19 to -0.11) with no obvious difference between randomised or non-randomised studies (Table 4b). In fact, one study by Garg et al (48) found that the HbA1c value decreased more with MDI-G than with CSII. Insulin Dose All studies comparing CSII with MDI/TDI and also reported insulin dose, with the exception of the study by Litton et al (47), showed that a lower HbA1c-value during CSII was reached with a reduced total daily insulin dose (Table 3).
However, we found, no difference between randomized and non-randomized studies as they had about the same reduction of the insulin dose (-0.14 units/kg/d) (Table 3). The four studies that compared pump treatment with MDI-G and included children also used units/kg/d and found lower insulin doses during pump treatment (Table 4a). Taken together the randomised trials showed about the same reduction as the randomised trials comparing CSII with MDI/TDI; -0.15 vs. -0.14 units/kg/d, respectively (Table 3 and Table 4a). The trials in adults used units/24h instead of units/kg/d. The study by Garg et al (48) was an exception since they found a higher insulin dose with CSII than previously and a lower dose with MDI-G. Three other studies which evaluated insulin dose showed a significantly lower insulin requirement with CSII than with MDI-G. The randomised study showed a somewhat smaller difference (-5.2 units/24h) than the two non-randomised studies (-11.3 and -9.4 units/24h, respectively) (Table 4b).
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HbA1c Authors Weintrob N et al Cohen D J et al Previous Treatment 8.3 1.1 8.58 0.82 8.48 1.4 (MDI) CSII 8.0 0.7 MDI 8.2 0.8 8.57 0.44 8.7 0.7 7.5 0.2 Difference -0.2 (-0.38 -0.02) -0.43- 0.09) = -0.52 (-0.88 -0.16) -0.2 (-0.61 0.21) -0.2 (- 0.1) = -0.1 (-0.46 0.26) -0.63 (-0.88 -0.38) -0.4 (-0.72 0.08) -0.45 (-0.81 -0.09) -0.7 (-1.12 -0.28) -0.5 (-1.12 -0.12) -0.64 (-1.32 0.04) -1.1 (-1.8 -0.4) -1.6 (-1.97 -1.23) -0.4 -0.5 (-0.75 -0.25) -0.8 (-1.14 -0.46) -0.5 (-0.75 -0.25) -0.1 (-0.43 0.23) -0.2 (-0.63 0.43) -0.31 (-0.51 -0.11) -0.6 (-0.69 0.51) -0.55 (-0.64 -0.46) Previous Treatment 0.95 0.22 0.99 0.24 0.98 0.3 ? ? 1.06 0.5
Insulin Dose CSII MDI 0.84 0.16 1.09 0.21 0.96 0.24 1.05 0.24 ? ? 0.88 0.36 -0.18 (-0.28 -0.08) Difference CSII-MDI -0.25 (-0.29 -0.21) -0.03-(0.07) = -0.1 (-0.18 -0.02)
Episodes of DKA CSII MDI 0 0 1 0 0/0 1 0 2/1 4/0 Difference 0 1 0 1 1 4
8.15 1.3 8.5 0.6 7.2 0.3 7.21 1.07 (p<0.02) 7.0 0.9 (p<0.01 7.9 0.1 p<0.01 8.2 0.9 (p<0.0001)) 8.4 1.2 (1 year) 8.18 0.9 (p<0.05) 7.5 0.7 (p<0.01) 7.9 0.3 p<0.001 7.7 (p<0.001) 8.2 0.8 (p<0.001) 7.5 1.1 (p<0.0001) 7.3 0.7 (p<0.0001 8.3 1.0 8.3 1.2 (p=0.045)
DiMeglio L 9.0 0.6 (TDI) et al Fox L et al Ahern J et al Weinzimer et al Willi S et al Sulli N et al Hanas R et al Shedadeh N et al Jeha G et al Litton J et al Plotnick L 7.4 0.5 7.6 0.3 (MDI) 7.84 1.16 (TDI) 7.4 1.0 (TDI) 8.35 0.15 (MDI) (SEM) 8.9 1.0 (MDI) (1 Year) 8.9 0.8 (MDI) 8.82 0.98 (MDI) 8.6 0.8 (TDI) 9.5 0.4 (MDI) (SEM)
0.9 0.03
0.81 0.03
-0.09 (-0.17 - 0.01) -0.27 (-0.38 -0.16)
? 0.05/ 0.03 + 1/? 0 0 0 0 0 0..02
1.03 0.32
0.76 0.18 ?
? 0.7 0.1 0.61 0.02 ? ? 1.1 0.31
? 0.5 0.1 (p<0.05) 0.71 0.07 ? ? 0.87 0.17 (p<0.00001) ? -0.23 (-0.31 -0.15) -0.2 (-0.29 -0.11 ) 0.10 (-0.06 0.26)
0/0 0.06 0.06 1/1 ? 3/? 2/0
8.1 et al Nabhan Z 8.7 0.9 (MDI) et al Liberatore 8.3 1.0 R et al Mack-Fogg 7.8 0.8 (TDI) J et al Conrad 8.4 0.9 (MDI) et al Maniatis A 8.5 1.1 (MDI) et al
Only Randomised Not Randomised
1.0 0.3 ?
? ? -0.14 (-0.23 -0.05) -0.14 (-0.24 -0.14) -0.17(-0.21 0.13)
0/? ? 2 7 9
All Studies
Table 3. HbA1c-value, insulin dose and episodes of DKA during treatment with MDI/TDI and CSII followed by the mean difference between the two types of treatment. The figures within parenthesis are 95%CI around mean. =Units/kg/d, + = events/patient per year, ++ = episodes per month.
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HbA1c Authors Alemzadeh et al Doyle E et al Previous Treatment 8.4 1.0 8.5 1.1 (MDI) 8.1 1.2 8.2 1.1 (MDI) 8.0 0.8 ? 8.5 1.8 8.9 1.7 (MDI) CSII 7.8 0.8 (p<0.002) 7.2 1.0 p<0.02 -0.21 0.67 (change) 7.6 1.2 (p<0.05) MDI/G 8.2 0.9 (n.s) 8.1 1.2 n.s 0.04 0.71 (change) Difference CSII-MDI/G -0.6 - (-0.3)=0.3 (-0.64 0.04) -0.9-(-0.1)=0.8 (-1.09 -0.51) -0.25 (-0.91 0.41) Previous Treatment 0.97 0.2 1.1 0.2 1.4 0.5 1.1 0.3 0.68 0.17 Insulin dose CSII MDI-G 0.91 0.2 0.97 0.2 0.9 0.2 (p<0.01) 1.2 0.2 (n.s) 0.62 0.12 0.73 0.20 0.74 0.15 (p<0.01) 0.96 0.2 (n.s) Episodes of DKA CSII DifferMDI-G ence 2 0 1 0 0 0 2
Difference CSII-MDI-G -0.06-(0.13)=0.07 (0.03 0.11) -0.5-(0.1)=-0.6 (-0.68 -0.52) -0.11 (-0.27 0.05) -0.19-(-0.04)=0.15 (-0.19 -0.11) -0.14 (-0.18 -0.10) -0.15 (-0.33 0.03)
Wilson D et al
Sciaffini R et al All studies Randomised
8.3 0.9 -0.9-(-0.6)=-0.3 (n.s) (-0.65 0.05) -0.43 (-0.77 -0.09) -0.46 (-0.64 -0.28)
0.93 0.22 1.0 0.20
No diff 3
Table 4a. HbA1c-value, insulin dose and episodes of DKA during treatment with MDI/MDI-G and CSII followed by the mean difference between the two types of treatment. The figures within parenthesis are 95%CI around mean. =Units/kg/d HbA1c Authors Previous Treatment 7.5 0.8 7.7 0.7 7.8 0.6 (MDI) 8.5 1.4 9.0 1.3 8.6 1.1 (MDI 9.2 1.6 8.5 1.3 (MDI) 7.7 0.1 (SE) 8.0 0.1 (MDI) ? CSII 7.2 0.7 (p<0.01) 7.0 0.8 7.3 0.9 (p<0.001) 8.0 1.0 (p<0.001) 8.2 1.2 (p<0.001) 7.5 0.1 (p<0.001) 6.8 1.1 MDI/G 7.2 0.7 (p<0.01) 7.2 0.7 8.3 1.3 (n.s) 7.9 1.2 (p<0.001) 7.9 1.2 (p<0.001) 7.7 0.1 (p<0.001) 6.8 0.9 Difference CSIi MDI-G 0 -0.7- (-0.6)=-0.1 (-0.19 -0.09) -1.2-(-0.2)=-1.0 (-1.2 -0.8) -1-(-0.7)=-0.3 (-0.71 0.11) Previous Treatment 41.9 16.9 ? ? Insulin Dose CSII MDI-G 40.9 18.4 46.1 19.4 ? ? -12.1-(-0.8)=11.3 (-13.77 -8.83) -10.3-(-0.9)=9.4 (-11.09 -7.71) 1.3+4.0=6.7 (6.37 7.03) Difference CSII - MDI-G -5.2 (-5.91 -4.49) Episodes of DKA CSII DifferMDI-G ence 1 0 0 ? ? 1 0
Hirrsch I et al Bolli G Pickup J et al Lepore G et al
Lepore G et al
48.0 35.9 8.5(p<0.001) 11.7 43.6 10.9 (n.s) 44.4 10.2 50.4 40.1 13.1 -1.0-(-0.6)=-0.4 18.0 (p<0.001) (-0.74 -0.06) 44.0 11.1 43.1 11.1 (n.s) -0.2 - (-0.2)=0.1 43.2 1.1 (0.08 0.12) 60.0 1.5 0 -0.15 (-0.19 -0.11) -0.07 (-0.21 0.07) ? 44.5 1.2 56.0 1.4 ?
? 12 0 2 0
Garg S et al Harmel et al All studies Randomised
12 2 14 1
-6.3 (-7.2 -5.4)
Table 4b. HbA1c-value, insulin dose and episodes of DKA during treatment with MDI/MDI-G and CSII followed by the mean difference between the two types of treatment. The figures within parenthesis are 95%CI around mean. = units/24h.
Blood Glucose Very few trials evaluated blood glucose. Thus only one of the seventeen trials that compared CSII with MDI/TDI and one
of the four trials that compared CSII with MDI/G evaluated the blood glucose values. The first study found a lower blood glucose value (mean difference 1.5 mmol/l) (Table 5) while
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Blood Glucose Previous CSII Difference Treatment MDI CSII-MDI ? ? ? ? ? ? ? ? ? ? BMI CSII MDI ? 0.23 0.45 0.25 0.44 ? ? 0.85 1.19 0.7 1.1 (p<0.002) ? 0.82 0.6 0.81 1.2 ? 16.3 1.7 ? 20.3 0.3 23.5 4.0 (p<0.00003) ? ? 23.2 4.1 (p<0.001) -0.1 (-1.66 1.46) 0.1 (-0.61 0.71) 1.5 (0.77 2.23) 0.13 0.6 (-0.9 2.1) -0.05 (-0.31 0.21) -0.2 (-0.39 0.19) No Difference -0.01 (-0.29 0.27) 0.16 (-0.57 0.89) -0.07-(0.05)=0.12 (-0.26 0.02) No Difference Severe Hypoglycaemic Events CSII Difference MDI 1/3 1 4 1/1 0/1 38/56 37/78 ? 20 20 6/11 0.29* 0.36 ? 0.09/0.52*** 12 18 20/? 0.22/0.46* 0/3 9.5** 12.3 -0.24 -3 -2.8 -0..43 -6 -2 -3 0 -1 -18 -41
Authors Weintrob N et al Cohen D J et al DiMeglio L et al Fox L et al Ahern J et al Weinzimer et al Willi S et al Sulli N et al Hanas R et al Shedadeh N et al Jeha G et al Litton J et al Plotnick L et al Liberatore R et al Mack-Fogg J et al Conrad et al Maniatis A et al
Previous Treatment ? 0.3 0.38 0.2 0.39 ? ? 0.9 0.98# 0.9 1.1#
Difference CSII-MDI/PT
? ? ? ? 11.7 1.8 ? ?
? ? ? ? 10.3 -1.4 1.4 (-2.93 0.13) ? ?
? 0.83 0.67# 0.65 1.2## ? 16.4 1.6& ? 20.2 0.2& 22.0 3.9&
0 -5 -0.07
? ? ?
? ? ?
? ? 22.6 4.1&
Table 5. The mean values and SD for Blood glucose (mmol/l), BMI and events of severe hypoglycemia during the treatment CSII, MDI or PT and the mean difference between the treatment forms. Figures within parentheses are the 95%CI of the mean value. # = BMI z scores, &= kg/m2, ## = BMI standard deviation score, = BMI SDS, * = events per patient/year. ** = events per 100 patient years. *** = episodes per month
the second study just mentioned that blood glucose was lower in the CSII group (Table 6a). It was somewhat clearer in adults where three studies, one randomised, compared the two treatment forms with regard to blood glucose. The randomised study did not find any significantly lower blood glucose in the CSII group, while the two non-randomised studies found significantly lower blood glucose values in patients treated with CSSS (Table 6b). BMI Several of the studies that compared CSII with MDI/TDI evaluated the development of BMI. Some trials used kg/m2 and others used BMI or BMI SDS. The results are heterogeneous. Five of the studies, one randomised, found a slight, but
not significant decrease of BMI when using CSII. Two studies, one randomised, found no difference regarding BMI while five, all non-randomised, found a slight increase of BMI during treatment with CSII (Table 5). Only two studies that compared CSII with MDI-G in children evaluated BMI. One was randomised and showed that BMI increased more with CSII than with MDI-G while the other study showed a s l i g h t d e c r e a s e ( Ta b l e 6 a ) . A l s o i n t h e adult studies BMI showed a heterogeneous pattern (Table 6b) DKA and Severe Hypoglycaemia The data for DKA and SH is to some extent uncertain since different studies have used different definitions. With this in
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Blood glucose Authors Previous Treatment ? CSII MDI/G ? Lower in the CSII Group Difference CSII-MDI/G Previous Treatment 21.6 3.2& 21.9 3.9 BMI CSII MDI-G 23.0 3.0 22.6 3.8 ? ? 1.24 1.2 0.67 1.4 0.03 - 0.06= -0.03 (-0.32 0.26) Difference CSII MDI-G 1.4 - 0.7 = 0.7 (-0.02 1.42) Severe Hypoglycaemic Events CSII Difference MDI-G 8.2** 7.5 2 5 1 1 -0.05 (change)* -0.04 (change) 0.7
Alemzadeh et al
Doyle E et al Wilson D et al Sciaffini R et al All Studies (events)
? ?
? ?
? ? 1.21 1.2## 0.61 1.3
-3 0
-0.01
-3
Table 6a. The mean values and SD for Blood glucose (mmol/l), BMI and events of severe hypoglycemia during the treatment with CSII, MDI/MDI/G and the mean difference between the treatment forms. Figures within parenthesis are the 95%CI of the mean value. &= kg/m2, ## = BMI standard deviation score, * = events per patient/year, ** = events per 100 patient years.
mind we found that the four randomised trials in children, which compared CSII with MDI or TDI, noted 2 more episodes (in about 63.4 patient years), of DKA with CSII than with MDI. The eight non-randomised trials noted 7 more episodes of DKA with CSII (as seen in Table 1 it is not possible to extract or calculate patients years but according to the study periods one can see that there must be a much more patients years than in the randomised studies) (Table 3). Also the three randomised studies in children that compared CSII with MDI-G reported more episodes with DKA during CSII, while the non-randomised study found no difference (Table 4a). The trials in adults reported also more episodes OF DKA during CSII (Table 4b). Twelve of the 14 studies in children and adolescents, 3 randomised, that compared CSII with MDI or TDI found less episodes of SH with CSII. Two studies, of which one was randomised, found no difference (Table 5). In studies with a paediatric population comparing CSII and MDI-G one randomised study (52) found more episodes of SH with CSII, two trials less and the third randomised (12) study no difference (Table 6a). Four of the adult studies evaluated severe hypoglycaemic events and three, one randomised, reported less episodes with CSII and one non-randomised study found no difference (Table 6b). Infections Infection at the catheter insertion site is sometimes considered as a problem with pump treatment. Nine of the studies comparing CSII with MDI/TDI did not mention this problem at all. Four studies (46,47), of whom two were randomised (9,41), reported no such complication while 5 studies (7,35,42,45), one randomised (43), reported a total of 30, mostly superficial, site infections treated with compresses
and/or antibiotics or no treatment. Of the trials regarding CSII vs. MDI-G one randomised in children (52) and one nonrandomised in adults (58) reported together 5 site infections of which 3 infections were in children. Quality of Life and Economy The patients in several studies seem to prefer CSII to MDI/ TDI. In four studies (9,41,43,46) all patients chose to continue CSII therapy after the study completion, two of these studies were randomised (41,43). Two randomised studies measured Quality of Life (QOL) and one of these (44) reported that the QOL was higher in CSII therapy than MDI, while the other found no difference (43). Two studies, both randomised and in children, reported that QOL was the same for CSII and MDI/G (12,14). The children/ adolescents seem, as with MDI, to choose CSII before MDI-G. In one study 14/16 continued with CSII and 12/16 in the MDI-Ggroup switched to the pump (14). Several trials in the adult population (49,51,58), of which one was randomised (53), reported that both CSII and MDI-G are about equal to reach good metabolic control (49, 51,53,58) but as CSII is much more expensive (48,53) MDI-G is considered as more cost-effective (53). One randomised study found that MDI-G is a good and safe transition for patients taking a pump holiday (55), while the randomised study with most children/ adolescents proposed that both CSII and MDI-G is superior to MDI (52).
Discussion
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Blood Glucose Authors Hirrsch I et al Bolli G Previous Treatment ? 9.11 2.27 8.89 1.67 (MDI) 6.65 3.74 6.69 3.01 CSII MDI/G ? 8.11 1.78 8.0 1.11 3.37 1.47 5.08 2.22 8.1 2.8 10.5 3.1 -0.11 (-0.36 0.14) -1.67 -2.36 -0.98 -2.0 (-2.85 1.15) Difference CSII - MDI-G Previous Treatment BMI CSII MDI/G Difference CSII- MDI-G No Difference Severe Hypoglycaemic Events CSII Difference MDI-G 2 -3 5 ? -0.25 (change)* -0.25 (change) ?
? 23.9 3.9 22.9 2.4 24.6 4.0 22.9 3.0 76.2 1.1 77.3 0.9 ?
Lepore G et al
23.5 3.7& 22.8 2.6
0.3 (-0.16 0.76) 0.1-(0.1)= -0.2 (-1.1 0.7)
Lepore G et al
11.9 3.5 12.3 3.9
24.7 4.2& 22.8 2.9 75.2 1.1(kg) 76.2 0.9 ?
Garg S et al Harmel et al All Studies (Events)
-0.1 kg
0.4 0.1* 0.6 0.1 1 2
-0.2
-1 -4
Table 6b. The Mean Values and SD for Blood Glucose (mmol/l), BMI and Events of Severe Hypoglycemia During the Treatment with CSII, MDI/MDIG and the Mean Difference Between the Treatment Forms. Figures within parenthesis are the 95%CI of the mean value. &= kg/m2, * = events per patient/year.
Conclusions from the Meta-Analysis Few randomised controlled studies are done in children and adolescents, but most publications report what has been seen when patients for different reasons have been transferred from MDI to CSII. Such a design tends to overestimate the advantages of a new treatment regimen. Even so the picture is not black and white. The decrease in HbA1c is usually rather small when patients are treated with CSII, not always statistically significant. An improvement of quality of life can be expected with less injection pain and a more flexible life and this advantage probably explains that most patients put on CSII prefer to continue. However in controlled studies even improved quality of life has been difficult to prove, and there are patients who prefer to return to MDI after having had CSII for some time. The benefits have to be weighed against side effects such as increased BMI, increased risk of infections at the injection site and the increased economical costs. Furthermore, it seems rather clear that although the incidence of DKA is low this very serious, life-threatening complication occurs more often on CSII. And even though the number of serious hypoglycemia tends to decrease, there are described cases of fatal hypoglycemia. Even though insulin pumps should be very
safe and modern generations are equipped with electronic memory and safety lockout features, it is probably impossible to fully exclude technical errors. It is even more difficult to prevent patient mistakes. When a patient wakes up from sleep or during confusion because of hypoglycemia, insulin is easily available and extra doses can be given by mistake. There are patients with recorded bolus doses taken while asleep in the middle of the night, resulting in severe hypoglycemia in the morning. Few very serious accidents resulting in either DKA or serious hypoglycemia may weigh more heavily than a slight increase in quality of life or a slight decrease of HbA1c. Thus the risks with CSII have to be taken into account when this regimen is selected. Our Conclusions from Own Experience and Based on Literature A. Indications for CSII in Children The child and its parents have to be willing and able to provide the necessary support and to understand the information if CSII is used. In practice psychosocial problems may be a contraindication, although we should be aware that diabetes is a life-threatening disease with a serious and complicated treatment in any case, with or without pump. Thus all diabetic children and teenagers are potential
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candidates for pump treatment. But certain indications are especially strong Wide blood glucose fluctuations, especially when leading to repeated severe hypoglycemia Other efforts have failed to improve poor metabolic control with high HbA1c. Then there are relative indications such as neonates and infants with diabetes children who have injection phobia eating disorders in teenagers. patients just do want a pump. B. Why does CSII Not Always Lead to Good Metabolic Control? The fact that patients on CSII do not always get better metabolic control than patients on MDI may have different explanations. There may be an overrepresentation of patients with poor metabolic control who fail to improve their control by getting CSII. But there are also other explanations: several patients with good metabolic control tend to deteriorate their metabolic control when they change from MDI to CSII, perhaps because the patients themselves take over the responsibility from their parents, who have less control of the treatment. several patients hope and believe, sometimes supported by the diabetes team, that they can live a very flexible, irregular life, eat when and whatever they want, as it is supposed to be so easy to adapt insulin by using CSII some patients tell that they find it more difficult to remember bolus doses when using CSII than when on MDI. Even with the pump certain criteria have to be fulfilled to get good blood glucose balance: The basal insulin supply has to be adequate. This should be easy but is not. The dose can very well be inadequate, either because of wrong recommendation from the diabetes team or because the patient does not follow the correct recommendations or because the supply too often is interrupted. The supply can be interrupted by mistake, or deliberately if the patient does not want to have the pump going during sports, dances, swimming or in several other situations The bolus doses have to be given. In a large study where insulin given by pump has been downloaded, it was found that number of bolus doses was correlated to a lower HbA1c (59).The strongest association was found between poor control and a very low number of bolus doses, so low that it is probable that the patients forget or omit deliberately insulin even to their main meals or main snacks. The bolus doses have to be adequate. This is self-evident with MDI as well as with CSII. However, with MDI the need for injections tend to keep the patient on less frequent and more regular meals, while one of the ideas with pump is regarded to be the freedom to eat more irregularly. This is supposed to be compensated for by carbohydrate counting and skilful adjustment of insulin doses, but that is not very easy. In practice it is quite difficult to count carbohydrates correctly and it is difficult to calculate the correct bolus doses. Furthermore, insulin has not the only function to take care of carbohydrates, but other contents of the meal play a role. And insulin has a feed-back on other hormones and a direct effect on gluconeogenesis. Thus, very irregular insulin doses may disturb a complicated feed-back system and lead to more rather than less blood glucose fluctuations
Summarising Conclusions
CSII is a very valuable tool in the treatment of children with diabetes. It is both reasonable and to be expected that better and better pumps will improve both treatment and quality of life of diabetic children and adolescents. However, CSII does not automatically lead to good metabolic control or to very much improved life quality and may increase the risk of acute complications, at least DKA, and sometimes hypoglycemia. Initiation of CSII should be foregone by careful education and these patients need at least as careful follow-up as other patients, including repeated education on how to avoid hypoglycemia and DKA. Any type of insulin regimen, also CSII, has to be combined with other important parts of diabetes treatment to get a good long-term result.
References
1. Diabetes Control and Complications Trial research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-983 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with Type 2 diabetes (UKPDS33). Lancet 1998;352:837-857 Bojestig M, Arnqvist HJ, Hermansson G, Karlberg BE, Ludvigsson J. Declining incidence of nephropathy in insulin-dependent diabetes. N Engl J Med 1994;330:15-18 Nordwall M, Bojestig M, Arnqvist HJ.Ludvigsson J. Declining incidence of severe retinopathy and persisting decrease of nephropathy in an unselected population of type 1 diabetes the Linkping Diabetes Complications Study. Diabetologia 2004;47:1266-1272 Tamborlane WV, Shervin RS, Genel M, Felig P. Reduction to normal of plasma glucose in juvenile diabetics by subcutaneous administration of insulin with a portable infusion pump. N Engl J Med 1979;300:578 Ahern JH, Boland EA, Doanne R, Ahern JJ, Rose P, Vincent M, Tamborlane WV. Insulin pump therapy in pediatrics: a therapeutic alternative to safely lower HbA1c levels across all age groups. Pediatr Diabetes 2002;3:10-15 Maniatis AK, Klingensmith GJ, Slover RH, Mowry CJ, Chase HP. Continuous subcutaneous insulin infusion therapy for children and adolescents: an option for routine diabetes care. Pediatrics 2001;107:351-356 Weinzimmer SA, Swan KL, Sikes KA, Ahern JH. Emerging evidence for the use of insulin pump therapy in infants, toddlers, and preschool-aged children with type 1 diabetes. Pediatr Diabetes 2006;7(suppl 4):15-19
2.
3. 4.
5. 6.
7.
8.
No. 2
December 2007
509

9. 10. 11. Fox LA, Buckloh LM, Smith SD, Wysocki T, Mauras N. A randomized controlled trial of insulin pump therapy in young children with type 1 diabetes. Diabetes Care 2005;28:177-1281 Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R. Insulin pump therapy. A meta-analysis. Diabetes Care 2003;26:1079-1087 Glaser NS, Iden SB, Green-Burgeson D, Bennet C, Hood-Johnson K, Styne DM. Goodlin-Jones B. Benefits of an insulin dosage calculation device for adolescents with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2004;17:1533-1544 Wilson DM, Buckingham BA, Kunselman EL, Sullivan MM, Paguntalan HU, Gitelman SE. A two-center randomized controlled feasibility trial of insulin pump therapy in young children with diabetes. Diabetes Care 2005;28:15-19 Bode BW, Steed RD, Davidsson PC. Reduction in severe hypoglycaemia with long term continuous subcutaneous insulin infusion in Type 1 diabetes. Diabetes Care 1996;19:324-327 Doyle EA, Weinzimmer SA, Steffen AT, Ahern JA, Vincent M, Tamborlane WV. A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care 2004;27:1554-1558 Hanaire-Broutin HH, Melki V, Bessieres-Lacombe S, Tauber J-P, the study group for the development of pump therapy in diabetes. Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment. Diabetes Care 2000;23:1232-1235 Hoogma RPLM, Hammond PJ, Gomist R, Kerr D, Bruttomesso D, Bouter KP, Wiefels KJ, de la Calle H, Schweitzer DH, Pfohls M, Torlone E, Krinelke LG, Bolli GB on behalf on the 5 nations study group. Diabet. Med 2006;23:141-147 Pickup J, Mattock M, Kerry S, Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes. A meta-analysis of randomised controlled trials. BMJ 2002;324:1-6 Retnakaran R, Hochman J, Hans De Vries J, Hanaire-Broutin H, Heine RJ, Melki V, Zinman B. Continuous subcutaneous insulin infusion versus multiple daily injections. Diabetes Care 2004;27:25902596 Ludvigsson J, Nordfeldt S. Hypoglycaemia during intensified insulin therapy of children and adolescents. J Pediatr Endocrinol Metabol 1998;11(Suppl 1):159-166 Bober E, Buyukgebiz A. Hypoglycemia and its effects on the brain in children with type 1 diabetes mellitus. Pediatr Endocrinol Rev 2005;2:378-382 Schoenle EJ, Shoenle D, Molinari L, Largo RH. Impaired intellectual development in children with type 1 diabetes: association with HbA1c, age at diagnosis and sex. Diabetologia 2002;45:108-114 Marreo DG, Guare JC, Vandagriff JL, Fineberg NS. Fear of hypoglycaemia in the parents of children and adolescents with diabetes: maladaptive or healthy response? Diabetes Educ 1997;23:281-286 Cryer PE. Hypoglycemia is the limiting factor in management of diabetes. Diabetes Metab Res Rev 1999;15:42-46 Ludvigsson J, Bolli GB. Intensive insulin treatment in diabetic children. Diabetes Nutr. Metabol 201;14:292304 Teutsch SM, Herman WH, Dwyer DM, Lange JM. Mortality among diabetic patients using continuous subcutaneous insulin-infusion pumps. N Engl. J Med 1984;310:361 368 Steel J. Intrauterine death of baby because of incorrect pump use BMJ (Clin Res Ed) 1985;290:1787 Hanas R, Ludvigsson J. Hypoglycemia and ketoacidosis with insulin pump therapy in children and adolescents. Pediatr Diabetes 2006;7(Suppl 4):32-38 Knight G. Risks with continuous subcutaneous insulin infusion can be serious. BMJ 2001;323:693694 29. Boland EA, Grey M, Oesterle A, Fredrickson L, Tamborlane WV. Continuous subcutaneous insulin infusion: a new way to lower risk of severe hypoglycaemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes. Diabetes Care 1999;22:1779-1784 30. Willi SM, Planton J, EgedeL, Schwarz S. Benefits of continuous subcutaneous insulin infusion in children with type 1 diabetes. J Pediatr 2003;143:796-801 31. Hanas R, Adolfsson P. Insulin pumps in pediatric routine care improve long-term metabolic control without increasing the risk of hypoglcemia.Pediatr Diabetes 2006;7:25-31 32. Gough SCL. A review of human and analogue insulin trials. Diabetes Res Clin Pract 2006 (in press) 33. Higgens JPT, Green S, editors. Cochrane Handbook for Systemic Reviews of Interventions 4.26 (updated September 2006), http://www. cochrane.org/resources/ handbook/hbook.htm (accessed 6th October 2006) 34. Gardner MJ and Altman DG. Statistics with confidence confidence intervals and statistical guidelines. BMJ London 1989 35. Plotnick LP. Clark LM, Brancati FL, Erlinger T. Safety and effectiveness of insulin pump therapy in children and adolescents with type 1 diabetes. Diabetes Care 2003;26:1142-1146 36. Nabhan ZM, Rardin L, Meier J, Eugster EA, DiMeglio LA. Predictors of glycemic control on insulin pump therapy in children and adolescents with type 1 diabetes. Diabetes Res Clin Pract 2006;74:217-221 37. Liberatore R, Perlman K, Buccino J, Artiles-Sisk A, Daneman D. Continuous subcutaneous insulin infusion pump treatment in children with type 1 diabetes mellitus. JPEM 2004;17:223-226 38. Mark-Fogg JE, Orlowski CC, Jospe N. Continuous subcutaneous insulin infusion in toddlers and children with type 1 diabetes mellitus is safe and effective. Pediatr Diabetes 2005;6:17-21 39. Conrad SC, McGrath MT, Gitelman SE. Transition from multiple daily injections to continuous subcutaneous insulin infusion in type 1 diabetes mellitus. J Pediatr 2002;140:235-240 40. Weinzimer SA, Ahern JH, Doyle EA, Vincent MR, Dziura J, Steffen AT, Tamborlane WV. Persistence of benefits of continuous subcutaneous insulin infusion in very young children with type 1 diabetes: a follow up report. Pediatrics 2004;114:1601-1605 41. DiMeglio LA, Pottorf TM, Boyd SR, France L, Fineberg N, Eugster EA. A randomized controlled study of insulin pump therapy in diabetic preschoolers. J Pediatr 2004;145:380-384 42. Sulli N, Shashaj B. Long-term benefits of continuous subcutaneous insulin infusion in children with type 1 diabetes: a 4 year follow-up. Diabet Med 2006;23:900-906 43. Weintrob N, Benzaquen H, Galatzer A, Shalitin S, Lazar L, Fayman G, Lilos P, Dickerman Z, Phillip M. Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens in children with type 1 diabetes: a randomised open crossover trial. Pediatrics 2003;112:559-564 44. Cohen D, Weintrob N, Benzaquen H, Galatzer A, Fayman G, Phillip M. Continuous subcutaneous insulin infusion versus multiple daily injections an adolescents with type 1 diabetes mellitus: a randomized open crossover trial. JPEM 2003;16:1047-1050 45. Shehedeh N, Battelino T, Galatzer A, Naveh T, Hadash A, de Vries L, Phillip M. Insulin pump therapy for 1 6 year old children with type 1 diabetes. IMAJ 2004;6:284-286 46. Jeha GS, Karaviti LP, Anderson B, Smith O, Donaldson S, McGirk TS, Haymond MW. Insulin pump therapy in preschool children with type 1 diabetes mellitus improves glycemic control and decreases glucose excursions and the risk of hypoglycemia. Diabetes Technol Ther 2005;7:876-884 47. Litton J, Rice A, Friedman N, Oden J, Lee MM, Freemark M. J Pediatr 2002;141:490-495 48. Garg SK, Walker AJ, Hoff HK, DSouza AO, Gottlieb PA, Chase HP. Glycemic parameters with multiple daily injections using insulin glargine versus insulin pump. Diabetes Technol Ther 2004;6:9-15
12.
13. 14.
15.
16.
17.
18. 19. 20. 21. 22.
23. 24. 25. 26. 27. 28.
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49. Harmel AP, Mathur R. Similar A1C Outcomes in type 1 diabetic patients undergoing intensive diabetes management with preprandial rapidacting insulin and either CSII or glargine. Diabetes care 2004;27:272-273 50. Hirsch IB, Bode BW, Garg S, Lane WS, Sussman A, Hu P, Santiago OM, Kolaczynski JW for the insulin aspart CSII/MDI comparison study group. Diabetes Care 2005;28:533-538 51. Adana MR, Dominquez M, Machado A, Martin V, Gonzalez S, Esteva I, Anarte M, Soriguer F. Comparison of two programmes of intensive insulin therapy for type 1 diabetes: continuous subcutaneous insulin infusion (CSII) vs. insulin glargine. Diabet Med 2006;23(Suppl.4);337 52. Alemzadeh R, Ellis JN, Holzum MK, Parton EA, Wyatt DT. Beneficial effects of continuous subcutaneous insulin infusion and flexible multiple daily insulin regimen using insulin glargine in type 1 diabetes. Pediatrics 2004;114:91-95 53. Bolli GB, Capani F, Home PD, Kerr D, Thomas R, Torlone E, Selam JL, Sola-Gazagnes A, Vitacolonna E. Comparison of a multiple daily injection regimen with once-daily insulin glargine basal insulin and mealtime lispro, to continuous subcutaneous insulin infusion: a randomised, open, parallel study. American Diabetes Association (ADA) Annual Meeting 2004. Abstract 455-P 54. Lepore G, Dodesini AR, Nosari I, Trevisan R. Effect of continuous subcutaneous insulin infusion vs multiple daily injection with glargine as basal insulin: an open parallel long-term study. Diabetes Nutr Metab 2004;17:84-89 55. Bode BW Steed R, Schleusener DS, Strange P. Switch to multiple daily injections with glargine and insulin lispro from continuous subcutaneous insulin infusion with insulin lispro: a randomized, openlabel study using a continuous glucose monitoring system. Endocrine Practice 2005;11:157-164 56. Schiaffini R, Ciamalini P, Spera S, Cappa M, Crino A. An observational study comparing continuous subcutaneous insulin infusion (CSII) and insulin glargine in children with type 1 diabetes. Diabetes Metab Res Rev 2005;21:347-352 57. Pickup JC, Kidd J, Burmiston S, Yemane N. Determinants of glycaemic control in type 1 diabetes during intensified therapy with multiple daily insulin injections or continuous subcutaneous insulin infusion: importance of blood glucose variability. Diabetes Metab Res Rev 2006;22:232-237 58. Lepore G, Dodesini AR, Nosari I, Trevisan R Both continuous subcutaneous insulin infusion and a multiple daily insulin injection regimen with glargine as a basal insulin are equally better than traditional multiple daily insulin injection treatment. Diabetes care 2003;26:1321-1322 59. Danne T, Batelino T, Jarosz-Chobot P and the pedpump Study Group. The Pedpump Study: a low percentage of basal insulin and more than five daily boluses are associated with better centralized HbA1c in 1041 children on CSII from 17 countries. Diabetes 2005;(suppl 1):A453(Abstract)
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The 7th ESPE Growth Plate Working Group Symposium - EUROGROP June 27th 2007, Helsinki, Finland
Razvan L Miclea1, MD, Moshe Phillip2, MD, Lars Svendahl3,MD, Jan M Wit1, MD
1Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands, 2Institute for Endocrinology
and Diabetes, National Center for Childhood Diabetes, Schneider Childrens Medical Center of Israel and Felsenstein Medical Research Center, Petah Tikva, Israel, 3Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden Corresponding author: Razvan L Miclea, MD, Department of Pediatrics, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands, Tel: +31 71 526 1833, Fax: +31 71 524 8198, E-mail: r.l.miclea@lumc.nl
Abstract
ongitudinal bone growth occurs within the epiphyseal growth plate, a highly organized biological structure located at the distal ends of the long bones, via endochondral bone formation. This developmentally regulated process is finely tuned through the interaction of circulating systemic hormones and locally produced peptide growth factors, the net result of which is to trigger changes in gene expression by growth plate chondrocytes. These molecular events lead to carefully orchestrated alterations in chondrocyte size, extracellular matrix components, secreted enzymes, growth factors and receptor expression. These events finally result in calcification of the matrix, chondrocyte death, vascular invasion and the completion of endochondral bone formation. Although the past several years have seen important progress in the identification of numerous important factors, which, in a complex and integrated network, control longitudinal bone growth, many of the signaling pathways and their interactions in the growth plate remain poorly understood. The ESPE Growth Plate Working Group (EUROGROP) was established in
2000 with the aim of bringing together both basic and clinical European research groups with an interest in the biology and pathology of the growth plate. The 7th EUROGROP Symposium was held as an official ESPE working group of the 46th ESPE Annual Meeting held in Helsinki, Finland, 2007. It enabled researchers, coming from all parts of the world to discuss their ongoing studies and exchange technical information. The program consisted of three lectures and four original papers, all followed by attractive discussions. This report summarizes the data presented and provides some comments on each of the presentations. Abbreviations: 11-HSD: 11 Beta-Hydroxysteroid Dehydrogenase; Agc: Aggrecan; Aln: Alendronate; Asb4: Ankyrin Repeat and SOCS Box-Containing Protein 4; Atf6: Activating Transcription Factor6; BSP: Bisphosphonates; Calca: Calcitonin, Alpha Cdkn2a: Cyclin-Dependent Kinase Inhibitor 2A; Col1: Collagen 1; Col2: Collagen 2 Col10: Collagen 10; Dex: Dexamethasone; Elk1: Member of ETS Oncogene Family; Esr1: Estrogen Receptor 1 (Alpha); Fli1: Friend Leukemia Integration 1; Gabp: GA Repeat Binding Protein; GC: Glucocorticoids; Ghr: Growth Hormone Receptor; Hif-1: Hypoxia-Inducible
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Factor 1 Alpha; hMSCs: Human Mesenchymal Stem Cells; Igf1: Insulin-Like Growth Factor 1; Igfbp1: Insulin-Like Growth Factor Binding Protein 1; Igf1r: Insulin-Like Growth Factor 1-Receptor; Igf2: Insulin-Like Growth Factor 2; Igf2r: Insulin-Like Growth Factor 2-Receptor; Nfe2l2: Nuclear Factor, Erythroid Derived 2, Like 2; Nrf1: Nuclear Respiratory Factor 1; Pam: Pamidronate; Prss11: HtrA Serine Peptidase 1; PTU: Propylthiouracil; Pycard: PYD and CARD Domain Containing; Rxrg: Retinoid X Receptor Gamma; Tam: Tamoxifen Ref: Ped. Endocrinol. Rev. 2007;5(1):516-525 Key words: Chondrocyte; Growth Plate; Catch-Up Growth; Glucocorticoids; Hypothyroidism; Nutrition; GeneExpression; Tamoxifen; Dedifferentiation; Bisphosphonates of p21 in cultured chondrocytes, p21 null-mice were equally susceptible to the adverse growth effects of Dex as wild-type controls suggesting that p21 does not mediate the Dex effects. His group also performed Affymetrix microarray analysis of the murine chondrogenic cell line ATDC5, incubated with Dex. Genes confirmed by qRT-PCR to be upregulated included Lipocalin-2 (LCN2). LCN2, an acute phase transport protein, is expressed in proliferative chondrocytes and overexpressing cells proliferate slower and differentiate faster. Dr. Farquharson concluded that LCN2 might provide a novel mechanism for GC-induced growth retardation.
Catch-up Growth after Hypothyroidism is Associated with Delayed Growth Plate Senescence
O. Nilsson Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden Chondrocytes within the growth plate are spatially organized in three distinct zones according to defined stages of differentiation: the resting, proliferative and hypertrophic zones (14). The proliferative zone is responsible for active cell replication and thus plays a crucial role in endochondral bone formation (15). Dr. Nilsson pointed out that over time, functional and structural changes occur in the growth plate. Decreases in longitudinal bone growth and chondrocyte proliferation are associated with a decline in both the growth plate height and the number of resting and proliferating chondrocytes. All these changes, which appear to be due to a mechanism intrinsic to the growth plate, are referred to as growth plate senescence (16). They will cause longitudinal bone growth to slow down with age and eventually cease resulting in the attainment of adult body length/height (17). In humans, the age-dependent longitudinal bone growth decline is briefly interrupted by a pubertal growth spurt, after which the deceleration resumes and the growth rate approaches zero (18). In rats, a similar dramatic decline in growth rate occurs, but without a superimposed pubertal growth spurt. By performing microarray analysis on RNA isolated from 3 to 12 weeks old castrated male rats growth plates, the group of Dr. Nilsson has proven that growth plate senescence is accompanied by changes in gene expression. Markers of growth plate senescence could be considered genes like Igf2, Asb-4 or Rxrg that significantly decrease their expression in time, as well as Cdkn2a, Pycard, Calca, Igfbp1 and Prss11 that significantly increase their level of expression. Catch up growth is defined as a linear growth rate greater than expected for age after a period of growth inhibition (19). Recent evidence suggests that catch-up growth is associated with delayed growth plate senescence. In young rabbits, inhibition of longitudinal bone growth by systemic treatment with Dex decelerated the senescent decline in the growth
The Regulation of Catch-up Growth Following Exposure to Glucocorticoids

C. Farquharson Bone Biology Group, Roslin Institute, University of Edinburgh, United Kingdom Between 3-10% of all live neonates are born small-forgestational age (SGA) (1) and up to 15% do not experience catch up growth by 2 years (2,3). Dr. Farquharson highlighted that the underlying pathophysiology of this process and the failure of catch-up growth are yet unclear. SGA infants have higher levels of endogenous glucocorticoids (GC) at birth (4) and GC retard growth prenatally in many mammals (5). Both pre- (6) and postnatal (7,8) exogenous administration of GC also results in growth retardation. The degree of growth retardation may be dependent on the exposure of growth plate chondrocytes to GC (9,10). Such exposure is regulated by the 11-HSD shuttle at the pre-receptor level (11). Evidence suggests that the balance of expression of the 11-HSD isoenzymes by growth plate chondrocytes is altered by proinflammatory cytokines to potentially result in a net increase in GC exposure (12). Therefore, endogenous synthesis of GC may continue to inhibit growth recovery even after cessation of GC therapy. Laboratory studies have shown that GC inhibit metatarsal growth by altering chondrocyte proliferation and differentiation rates and this can be reversed by IGF-I treatment (9). Furthermore, such adverse effects on chondrocyte dynamics and growth are not seen with AL-438, a non-steroidal antiinflammatory agent that acts through the GC receptor (13). Such compounds may prove important in the search for new anti-inflammatory treatments for children. To gain further insight into the mechanisms involved in GC-induced growth retardation, Dr. Farquharsons group has investigated the role of the cyclin-dependent kinase inhibitor - p21 - which promotes cell cycle exit in Dexamethasone (Dex) mediated growth retardation. Although Dex increased the expression
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rate, chondrocyte proliferation rate, growth plate height, proliferative zone height, and hypertrophic zone height (20). To explain this finding, Dr. Nilssons group hypothesized that catch-up growth occurs because growth-inhibiting conditions conserve the limited proliferative capacity of growth plate chondrocytes. When the growth-inhibiting condition resolves, the growth plates might be less senescent and therefore grow more rapidly than normal for age. To test this hypothesis, Propylthiouracil (PTU) was administered to newborn female rats for 8 wks to induce hypothyroidism, then the PTU was stopped to allow catch-up growth, and multiple functional, structural, and molecular markers of growth plate senescence were examined. Proximal tibial growth plates of untreated controls displayed a senescent decline in the chondrocyte proliferation rate, growth plate height, resting zone height, number of resting zone chondrocytes, number of proliferative and hypertrophic chondrocytes per column, terminal hypertrophic cell height and column density. All known molecular markers of growth plate senescence exhibited age-related changes in mRNA expression. In treated animals, after stopping PTU, all of these functional, structural, and molecular senescent changes were delayed. Similarly, the normal senescent decline in longitudinal growth rate was delayed in the previously treated animals, resulting in catchup growth. Dr. Nilsson concluded that hypothyroidism is associated with delayed growth plate senescence. The growth-inhibition due to hypothyroidism slows the entire developmental program of growth plate senescence, including the normal decline in the rate of longitudinal bone growth and that this delayed decline in growth rate is responsible for catch-up growth. growth plate (25-30). To study the possible mechanisms governing the changes within the growth plate during food restriction and immediately after refeeding, Dr. Phillips group has used mouse and rat models that were first deprived of food for 10 days and thereafter fed either normally or ad libitum. Changes in the growth plate gene expression pattern after the period of food restriction and again after food replenishment were examined and particular attention was given to genes that showed a reduced expression following food restriction and an increased expression at onset of the catch-up growth process. Most of the genes aligning to this expression pattern are involved in basic cell functions or are transcription factors affected by nutritional manipulation: Elk1, Fli1, Gabp, Hif-1, NFe2e2, Nrf1, Atf6. In the last part of his talk, Dr. Phillip discussed the role of Hif-1 in the human growth plate. Conditional knockout of Hif-1 in mice has demonstrated that this transcription factor is critical for survival of hypoxic chondrocytes, negatively regulates chondrocyte proliferation, and increases matrix accumulation (31,32). In addition, it plays an important role in glycolysis and extracellular matrix metabolism (33). During nutritional catch-up growth, animals displayed high levels of Hif-1 in the growth plates, especially in the proliferative zone, whereas the expression in the resting zone was normal. Therefore, Hif-1 might represent a potential regulator of linear bone development during nutritional catch-up growth. Dr. Phillip concluded that there is an indubitable connection between nutrition and growth, yet the exact molecular mechanisms underlying this link are yet to be unraveled. Understanding the interaction between the systemic and local factors during the catch-up period may help develop new ways of coping with the deleterious effect of chronic diseases on linear growth.
Nutritional Catch-Up
M. Phillip, N. Even-Zohar, G. Gat-Yablonski Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Childrens Medical Center of Israel and Felsenstein Medical Research Center, Petah Tikva, Israel Normal human growth is influenced by the interaction between genetic and environmental factors. Both systemic and local molecular signals regulate chondrogenesis and bone formation in the growth plate (21). Many chronic illnesses, malnutrition or other pathological conditions impair linear growth (22). In most cases, when the growth-inhibiting condition is resolved, spontaneous catch-up growth occurs and, as a result, final height is improved, although this recovery of adult stature is frequently incomplete. The wellrecognized inhibiting effects of poor nutritional status on linear growth (23,24) are mediated via changes induced by malnutrition or food restriction on levels of insulin, IGF-1, thyroid hormone, gonadotropins, glucocorticoids and leptin which together affect local pathways that coordinate and couple chondrocyte proliferation and differentiation at the
Molecular Regulation of the Growth Plate: Genome-Wide Expression Analysis of Human Growth Plate Chondrocytes. An ESPE-RU Update
M. Karperien 1 , J. Emons 1 , S. van Gool 1 , E. Decker 2 , A. S. Chagin3, L. Savendahl3, G. Rappold2, J. M. Wit1 1Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands, 2Department of Human Molecular Genetics, University of Heidelberg, Germany, 3 Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden It has become increasingly clear that frequently used in vivo and in vitro animal models are insufficient to obtain a complete understanding of the processes that take place in the human growth plate. Frequently used in vivo and in vitro animal models are insufficient to obtain a complete understanding of the processes that take place in the human epiphyseal growth plate. This is partly due to the fact that the two most commonly used animal models, mice and rats,
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in contrast to humans, do not undergo estrogen-induced growth plate fusion at the end of puberty (34). Thus, there is a need for studies specifically focusing on the regulation of the human growth plate. Three research groups with a common interest in growth plate regulation (Andrei Chagin and Lars Svendahl from Stockholm; Eva Decker, Antonio Marchini and Gudrun Rappold from Heidelberg; Joyce Emons, Sandy van Gool, Marcel Karperien and Jan Maarten Wit from Leiden) started an ESPE Research Unit project in order to share complementary expertise and to combine scarce collected growth plate specimens. In the past years, the participating groups have collected human growth plate material and also developed in vitro models for chondrocyte differentiation using human Mesenchymal Stem Cells (hMSCs), primary chondrocytes and organ cultures of human growth plate slices. Dr. Karperien provided an overview of the results obtained so far in this ESPE Research Unit-subsidized project as well as an outline of the strategy for the next year. To obtain a genome wide overview of gene expression in human growth plates, high quality RNA was isolated with an optimized standardized procedure from 8 human growth plate specimens of different pubertal stages collected in Leiden and Stockholm. The samples have been analyzed in duplicate on Affymetrix human Genome U133 Plus 2.0 array by the Heidelberg group. After initial data extraction and normalization, bioinformatic approaches for data interpretation were explored. This involved various steps including a principal component analysis to identify differentially expressed genes over time. Subsequently these genes were used to identify pathways and genetically regulatory circuits. Although providing interesting results, this approach had its limitations, since the growth plate specimens were isolated from different bones of patients with well established pathological conditions. Dr. Karperien pointed out that fetal instead of childhood growth plates would correspond better for such a study, since the former represent large primary growth plates that could be isolated from presumably healthy, aborted fetuses. In the first year of the grant, the team has also obtained microarray data from hMSCs differentiating into chondrocytes. Results from these experiments indicated that hMSCs originating from fetal bone marrow have the highest capacity of differentiating into chondrocytes. In the up-coming year, the research groups involved will try to increase the number of growth plate specimens isolated and to perform additional microarray hybridizations. Endocrinology, Department of Internal Medicine, Sahlgrenska University Hospital, Gteborg, Sweden Tamoxifen (Tam) is a selective estrogen receptor modulator traditionally used in the treatment of breast carcinoma due to its anti-ESR1 activity, acting to block the growth-stimulatory effects of estrogen on estrogen dependent tumors (35,36,37). It has also been proposed as a safe and effective therapy for pubertal gynecomastia (38,39), while a recent report indicates that, in clinically relevant concentration, Tam inhibits growth of bone explants in vitro (40). To investigate the potential negative effects of Tam on linear bone growth and to determine if catch-up growth occurs once Tam administration is stopped, Elham Karimian designed an experiment using 4week old intact male rats. Animals that were administered Tam for either 1 or 4 weeks showed a significant decrease in nose-anus and tibia lengths compared to controls, while only estradiol did not affect skeletal growth. When following the animals for an additional 14 weeks, Elham observed that the 1 week Tam-treated animals showed complete catchup growth, whereas the rats treated with Tam for 4 weeks still had significantly shorter bone lengths in comparison to controls. Only this latter group showed increased apoptosis in growth plate chondrocytes, while both groups displayed increased chondrocyte proliferation. IGF-1 serum level was not affected in the rats that were given Tam for 1 week, but it was decreased when Tam was administered for 4 weeks, implying that the GH-IGF-1 axis is not involved in the observed catch-up growth following Tam treatment. Elham concluded that Tam, in a clinically relevant dosing regimen, induces permanent growth retardation in young male rats, and that this is an effect mediated through increased apoptosis of growth plate chondrocytes.
Three-Dimensional Culture of Porcine Growth Plate Chondrocytes

G. Haeusler1, C. Albrecht1,2, M. Egerbacher3, M. Helmreich3, T. Jagersberger2, B. Tichy2, R. Plasenzotti4, S. Marlovits2 1Department of Pediatrics, University of Vienna, 2Department of Traumatology, University of Vienna, 3Institute of Histology, Department of Pathobiology, University of Veterinary Medicine, Vienna, 4Institute of Biomedical Research, University of Vienna, Austria In vitro models of primary growth plate chondrocyte cultures are difficult to establish due to rapid dedifferentiation of chondrocytes in monolayer culture. Studies in articular cartilage have shown that already during the first culture passages, chondrocytes obtain a more fibroblast-like appearance, produce fewer glycosaminoglycans and switch from production of the hyaline cartilage specific Col2 to production of Col1 (41). Studies aiming to first expand and subsequently re-differentiate primary chondrocyte cultures have used three-dimensional cultures like agarose gels (42)
Catch-up Growth Following Tamoxifen Treatment in Young Intact Male Rats

E. Karimian 1 , A. S. Chagin 1 , J. Gjerde 2 , E. A. Lien 2 , C. Ohlsson3, L. Svendahl1 1Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden, 2The Hormone Laboratory, Department of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway, 3Division of
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or alginate beads (43). Dr. Haeuslers group has performed primary cultures of growth plate chondrocytes. For this purpose, tibial and femoral growth plates of 8 week old pigs were cultured in monolayer for 1 to 5 weeks, while epiphyseal cartilage from the same animals was used for comparison. After 1 week of monolayer culture, cells were seeded in alginate beads and kept in three-dimensional culture for 2, 3 and 4 weeks. Using real-time RT-PCR, the expression of Col1, Col2, Col10, Agc, Ghr, Igf1, Igf1r, Igf2, Igf2r and Esr1 were determined in native tissue, after 1, 2 and 5 weeks of monolayer culture and after 2, 3 and 4 weeks of alginate culture. Col2 and Col10 were both down-regulated after one week of monolayer culture of growth plate chondrocytes, whereas Col1 was slightly up-regulated. After 5 weeks of monolayer culture the differentiation index (ratio Col2/Col10) was zero and Agc synthesis was reduced. Already after 2 weeks of alginate culture, the differentiation index, Agc and Col10 expression returned to the expression pattern of native tissue. After 4 weeks of alginate, there was still a stable expression of Col10 and a reduction in Agc. Importantly, Ghr, Igf1r and Igf2r increased during monolayer culture and returned to native values during alginate culture, while Esr1 expression was downregulated during monolayer culture but re-expressed after alginate culture. Dr. Haeusler concluded that growth plate chondrocytes show rapid dedifferentiation during monolayer culture, whereas three-dimensional culture restores basal conditions and favours matrix production. Reexpression of Esr1 is of particular importance, whilst increase in Col10 expression points to further differentiation to a hypertrophic phenotype. cultures of E20 rat metatarsals in the presence of Aln or Pam, while in other experiments, the metatarsals were cultured in the presence of BSP in combination with Dex, and observed that BSP have dose-dependent effects on longitudinal bone growth. High BSP concentrations blocked longitudinal bone growth, while low concentrations had no effect. Interestingly, a clinically more relevant concentration (1 M) of both Aln and Pam was significantly stimulatory to bone growth both in length and in width. This effect was due to increased chondrocyte proliferation, whereas differentiation and apoptosis were not affected. However, BSP did not prevent Dex-induced growth retardation in fetal rat metatarsal bones. Based on her experiments, Dr. Heino concluded that both Aln and Pam appear safe to use in growing children, at least regarding their effects on bone growth. However, they may not be the treatment of choice for the prevention of glucocorticoidinduced growth retardation.
References
1. Alkalay AL, Graham JM Jr, Pomerance JJ. Evaluation of neonates born with intrauterine growth retardation: review and practice guidelines. J Perinatol 1998;18:142-151 2. Karlberg J, bertsson-Wikland K. Growth in full-term small-forgestational-age infants: from birth to final height. Pediatr Res 1995;38:733-739 3. Hokken-Koelega AC, De Ridder MA, Lemmen RJ, Den HH, De Muinck Keizer-Schrama SM, Drop SL. Children born small for gestational age: do they catch up? Pediatr Res 1995;38:267-271 4. Goland RS, Jozak S, Warren WB, Conwell IM, Stark RI, Tropper PJ. Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-retarded fetuses. J Clin Endocrinol Metab 1993;77:1174-1179 5. Murphy VE, Smith R, Giles WB, Clifton VL. Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus. Endocr Rev 2006;27: 141-169 6. Reinisch JM, Simon NG, Karow WG, Gandelman R. Prenatal exposure to prednisone in humans and animals retards intrauterine growth. Science 1978; 202:436-438 7. Crofton PM, Ahmed SF, Wade JC, Stephen R, Elmlinger MW, Ranke MB, Kelnar CJ, Wallace WH. Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia. J Clin Endocrinol Metab 1998;83:3121-3129 8. Ahmed SF, Tucker P, Mushtaq T, Wallace AM, Williams DM, Hughes IA. Short-term effects on linear growth and bone turnover in children randomized to receive prednisolone or dexamethasone. Clin Endocrinol (Oxf) 2002;57:185-191 9. Mushtaq T, Bijman P, Ahmed SF, Farquharson C. Insulin-like growth factor-i augments chondrocyte hypertrophy and reverses glucocorticoid-mediated growth retardation in fetal mice metatarsal cultures. Endocrinology 2004;145:2478-2486 10. Baron J, Huang Z, Oerter KE, Bacher JD, Cutler GB Jr. Dexamethasone acts locally to inhibit longitudinal bone growth in rabbits. Am J Physiol 1992;263: E489-E492 11. Cooper MS, Walker EA, Bland R, Fraser WD, Hewison M, Stewart PM. Expression and functional consequences of 11beta-hydroxysteroid dehydrogenase activity in human bone. Bone 2000;27:375-381 12. MacRae VE, Owen HC, Ahmed SF, Farquharson C. The role of the 11hsd shuttle in modulating the effects of proinflammatory cytokines on the growth plate. J Bone Miner Res 2006;21:S214
Bisphosphonates Stimulate Linear Growth of Fetal Rat Metatarsal Bones but do not Rescue from Dexamethasone-Induced Growth Retardation
T. J. Heino, A. S. Chagin, L. Svendahl Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden Bisphosphonates (BPS) suppress osteoclast-mediated bone resorption and are widely used in the management of patients with skeletal disorders (44). In children, their use is mainly limited to patients with osteogenesis imperfecta (45). However, their powerful effects on bone turnover have raised concern about their long-term effects on the growing skeleton (46). To study the effects of two commonly used BSP, Alendronate (Aln) and Pamidronate (Pam) on bone growth and the possible potential of these drugs to prevent glucocorticoid-induced growth retardation, Dr. Heino used an in vitro fetal rat metatarsal organ culture model previously described (40). She performed long-term
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13. Owen HC, Miner JN, Ahmed SF, Farquharson C. The growth plate sparing effects of the selective glucocorticoid receptor modulator, AL-438. Mol Cell Endocrinol 2007;264:164-170 14. Nilsson O, Parker EA, Hegde A, Chau M, Barnes KM, Baron J. Gradients in bone morphogenetic protein-related gene expression across the growth plate. J Endocrinol 2007;193:75-84 15. Kember NF, Walker KV. Control of bone growth in rats. Nature 1971;229:428-429 16. Baron J, Klein KO, Colli MJ, Yanovski JA, Novosad JA, Bacher JD, Cutler GB Jr. Catch-up growth after glucocorticoid excess: a mechanism intrinsic to the growth plate. Endocrinology 1994;135:1367-1371 17. Parker EA, Hegde A, Buckley M, Barnes KM, Baron J, Nilsson O. Spatial and temporal regulation of gh-igf-related gene expression in growth plate cartilage. J Endocrinol 2007;194:31-40 18. Tanner JM, Davies PS. Clinical longitudinal standards for height and height velocity for north american children. J Pediatr 1985;107:317-329 19. PRADER A, Tanner JM, von HG. Catch-up growth following illness or starvation. an example of developmental canalization in man. J Pediatr 1963;62:646-659 20. Gafni RI, Weise M, Robrecht DT, Meyers JL, Barnes KM, De-Levi S, Baron J. Catch-up growth is associated with delayed senescence of the growth plate in rabbits. Pediatr Res 2001;50:618-623 21. Nilsson O, Marino R, De LF, Phillip M, Baron J. Endocrine regulation of the growth plate. Horm Res 2005;64:157-165 22. Gafni RI, Baron J. Catch-up growth: possible mechanisms. Pediatr Nephrol 2000;14:616-619 23. Price DA, Wit JM, van Buul-Offers S, Korteland-van Male AM, van Rooyen-Wehmeijer AK, Hoogerbrugge C, Van den Brande JL. Serum somatomedin activity and cartilage metabolism in acutely fasted, chronically malnourished, and refed rats Endocrinology 1979;105:851-861 24. Allen LH. Malnutrition and human function: a comparison of conclusions from the INCAP and nutrition CRSP studies. J Nutr 1995;125:1119S-1126S 25. Schlechter NL, Russell SM, Spencer EM, Nicoll CS. Evidence suggesting that the direct growth-promoting effect of growth hormone on cartilage in vivo is mediated by local production of somatomedin. Proc Natl Acad Sci USA 1986;83:7932-7934 26. Wang J, Zhou J, Bondy CA. Igf1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy. FASEB J 1999;13:1985-1990 27. Buckler JM, Willgerodt H, Keller E. Growth in thyrotoxicosis. Arch Dis Child 1986;61:464-471 28. Stevens DA, Hasserjian RP, Robson H, Siebler T, Shalet SM, Williams GR. Thyroid hormones regulate hypertrophic chondrocyte differentiation and expression of parathyroid hormone-related peptide and its receptor during endochondral bone formation. J Bone Miner Res 2000;15:2431-2442 29. Silvestrini G, Ballanti P, Patacchioli FR, Mocetti P, Di GR, Wedard BM, Angelucci L, Bonucci E. Evaluation of apoptosis and the glucocorticoid receptor in the cartilage growth plate and metaphyseal bone cells of rats after high-dose treatment with corticosterone Bone 2000;26:33-42 30. Maor G, Rochwerger M, Segev Y, Phillip M. Leptin acts as a growth factor on the chondrocytes of skeletal growth centers. J Bone Miner Res 2002;17:1034-1043 31. Pfander D, Cramer T, Schipani E, Johnson RS. HIF-1alpha controls extracellular matrix synthesis by epiphyseal chondrocytes. J Cell Sci 2003;116:1819-1826 32. Schipani E, Ryan HE, Didrickson S, Kobayashi T, Knight M, Johnson RS. Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes Dev 2001;15:2865-2876 33. Denko NC, Fontana LA, Hudson KM, Sutphin PD, Raychaudhuri S, Altman R, Giaccia AJ. Investigating hypoxic tumor physiology through gene expression patterns. Oncogene 2003;22:5907-5914 34. Hughes PC, Tanner JM. The assessment of skeletal maturity in the growing rat. J Anat 1970;106: 371-402 35. Goldenberg GJ, Froese EK. Drug and hormone sensitivity of estrogen receptor-positive and -negative human breast cancer cells in vitro. Cancer Res 1982; 42:5147-5151 36. Ferlini C, Scambia G, Marone M, Distefano M, Gaggini C, Ferrandina G, Fattorossi A, Isola G, Benedetti PP, Mancuso S. Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines. Br J Cancer 1999;79:257-263 37. Perry RR, Kang Y, Greaves B. Effects of tamoxifen on growth and apoptosis of estrogen-dependent and -independent human breast cancer cells. Ann Surg Oncol 1995;2:238-245 38. Lawrence SE, Faught KA, Vethamuthu J, Lawson ML. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J Pediatr 2004;145:71-76 39. Derman O, Kanbur NO, Kutluk T. Tamoxifen treatment for pubertal gynecomastia. Int J Adolesc Med Health 2003;15:359-363 40. Chagin AS, Karimian E, Zaman F, Takigawa M, Chrysis D, Savendahl L. Tamoxifen induces permanent growth arrest through selective induction of apoptosis in growth plate chondrocytes in cultured rat metatarsal bones. Bone 2007;40:1415-1424 41. Takigawa M, Shirai E, Fukuo K, Tajima K, Mori Y, Suzuki F. Chondrocytes dedifferentiated by serial monolayer culture form cartilage nodules in nude mice. Bone Miner 1987;2:449-462 42. Benya PD, Shaffer JD. Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell 1982;30:215-224 43. Bonaventure J, Kadhom N, Cohen-Solal L, Ng KH, Bourguignon J, Lasselin C, Freisinger P. Reexpression of cartilage-specific genes by dedifferentiated human articular chondrocytes cultured in alginate beads. Exp Cell Res 1994;212:97-104 44. van Beek ER, Cohen LH, Leroy IM, Ebetino FH, Lowik CW, Papapoulos SE. Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates. Bone 2003;33:805-811 45. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998;339:947-952 46. Rauch F, Glorieux FH. Treatment of children with osteogenesis imperfecta. Curr Osteoporos Rep 2006;4:159-164
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The 9th European Congress of Endocrinology

Andrea Luczay1, MD, Rita Bertalan2, MD, Karoly Racz2, MD
12nd Department of Pediatrics, 22nd Department of Medicine, Semmelweis University, Budapest, Hungary
Corresponding author: Karoly Racz, MD, 2nd Department of Medicine, Semmelweis University, 46 Szentkiralyi, H-1088, Budapest, Hungary, Tel/Fax: +36 1 266 0816, E-mail: racz@bel2.sote.hu
Ref: Ped. Endocrinol. Rev. 2007;5(2): Key words: Meeting Report, ECE2007, Pediatric Endocrinology The 9th European Congress of Endocrinology was held on April 28 May 2, 2007 in Budapest, Hungary. Hailing from 67 countries, more than 2000 delegates attended the Congress. The scientific program comprised 2 prize lectures (European Journal of Endocrinology Prize and Geoffrey Harris Prize), 7 plenary lectures, 25 symposia, 12 meet-the-expert sessions and 12 oral communication sessions. More than 600 posters were also presented. In the European Journal of Endocrinology Prize Lecture, Professor B.R Walker (Edinburgh) spoke about the role of cortisol and the activation of the hypothalamic-pituitaryadrenal axis which may exert programming effects on events in the early life of low-birth-weight subjects. He presented original studies on 11-hydroxysteroid dehydrogenase type 1, which is considered as a new therapeutic target in obesity and diabetes. The Geoffrey Harris Prize Lecture was given by Professor H. Vaudry (Rouen). He and his colleagues investigated the effects of neurotransmitters and neuropeptides on biosynthesis of neurosteroids in an animal model. They showed that glial cells containing the octadecaneuropeptide (the endogenous ligand of central-type benzodiazepine receptor) make contact with neurosteroid-producing neurons. Also, they found that steroid producing neurons are innervated by neuropeptide Y and gonadotropin-releasing hormone fibers. According to their proposal, some of the activities exerted by neurotransmitters
and neuropeptides in the brain may be mediated via regulation of neurosteroid production. In a plenary lecture, A. Aranda (Madrid) presented in vitro and in vivo data obtained from animal models which suggest the existence of a relevant cross-talk between the ras oncogene and thyroid hormone receptors. Their results defined this receptor as a potent suppressor of cell transformation and tumorgenesis. One of the Young Investigator Awards of the European Society of Endocrinology was given to D. Cordella (Milan). She analysed TSH receptor mutations in a large group of pediatric patients with non-autoimmune mild isolated hyperthyrotropinemia. Her findings may be important clinically, as the genetic diagnosis of TSH resistance may help to offer a more appropriate management of these subjects. Meet-the-expert sessions, symposia and oral presentation sessions covered several emerging areas of endocrine research and clinical endocrinology. Here we review some of the lectures presented in the field of pediatric endocrinology. In the Imaging in Endocrinology session, P. Nuutila (Turku) reported that the (18)F-fluorodihydroxiphenylalanine (DOPA) may be the most promising tracer for the PET assessment of focal form of congenital hyperinsulinism in infancy. In his lecture entitled Carney complex and primary pigmented nodular adrenocortical disease Professor J. Bertherat (Paris) showed recent data on germline inactivating mutation of the PDE11A4 gene, which causes isolated primary nodular adrenocortical disease in patients younger than 8 years of age. M. Niedziela (Poznan) presented a paper on endocrine disorders of puberty. It was pointed out that newly detected genetic factors regulating the hypothalamic-pituitary-gonadal
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axis (KISS-1, GPR-54 or FGFR1) will improve our understanding of normal variation in pubertal timing and will provide further directions for treatment. M. Kuro-o (Dallas) reviewed data showing that a defect in klotho gene expression in mice leads to a syndrome resembling aging and that overexpression of this gene extends life span in the mouse. Thus klotho gene functions as an aging suppressor gene. Klotho binds to multiple fibroblast growth factor (FGF) receptor and enhances the ability of FGF23 to activate FGF signaling. Both Klotho-deficient mice and FGF23-deficient mice exhibit elevated serum phosphate levels. In these mice many aging like phenotypes were rescued by restriction of dietary phosphate or ablation of vitamin D activity. Their findings imply a novel concept that FGF signalling and phosphate metabolism may participate in the regulation of aging in mammals. S. Vaulont and co-workers (Paris) presented data on the iron regulatory Hepcidin, the 25-aminoacid cystein-rich peptide. Hepcidin synthesis is induced by iron stores and inflammation and inhibited by anemia and hypoxia. As Hepcidin is the pathogenic factor in most systemic iron disorders, it should provide important opportunities for improving the diagnosis and treatment of these disorders. L. Persani (Milan) showed interesting data of a cohort of congenital hypothyroidism with gland in situ. These babies usually have a mild TSH elevation. This group of congenital hypothyroidism is extremely heterogeneous with variable thyroid phenotype and non-thyroid malformations. New genetic causes have been discovered recently, but a more complete pathogenic classification of the gland in situ cases is necessary for an improved and evidence based clinical management of these patients. In a meet-the-expert session A. Tsatsoulis (Ioannina) presented his view on the fetal programming by androgen excess. Although in polycystic ovary syndrome the potential role of increased androgen activity in fetal life is not clear, the prenatal androgenization of the female fetus may programme differentiating target tissues towards the development of polycystic ovary syndrome in adult life. In another meet-the-expert session dealing with Turner syndrome, E. Malecka-Tendera (Katowice) emphasised the importance of the transition from pediatric to adult healthcare. All the medical problems of Turner patients present in childhood should be carefully monitored in adulthood. M. Bonomi (Milan) and co-workers analysed the TRH receptor gene in 5 cases of idiopathic central hypothyroidism. TRHreceptor mutation was found in only 1 patient, suggesting the existence of still unknown genes for idiopathic central hypothyroidism. D. Dewailly and co-workers (Lille) examined the prevalence of metabolic abnormalities in adolescents with polycystic ovary syndrome. According to their findings, low serum HDL-cholesterol (<0,5g/l) may be the most sensitive marker in patients below the age of twenty, while the waist
circumference above 80 cm seemed to be less sensitive in these young patients than in adults. H. Christesen (Odense) investigated the possible role of uncoupling protein 2 (UCP2) gene in congenital hyperinsulinism. Among 45 patients with congenital hyperinsulinism who were negative for known disease-causing gene mutations, the UCP2 gene mutations were absent. Delegates of the Congress presented abstracts in poster format in nearly all fields of endocrine research and clinical endocrinology. N. Amador and co-workers (Leon) showed a high prevalence of the I27L polymorphism of hepatic nuclear factor1 in young patients with autosomal dominant inheritance of diabetes mellitus. These patients had no typical clinical and biochemical characteristics of type 1 diabetes. D. Sobel and co-workers (Washington) presented data that low doses of cyclosporine and metothrexate may induce remission in patients with new onset type 1 diabetes. This treatment was associated with a decrease in the amount of insulin required for treatment and in 4 of the 7 patients insulin therapy could be withheld for 2-12 months. S. Bergamaschi and co-workers (Milan) studied 9 children with idiopathic isolated growth hormone deficiency. None of the children developed adrenocortical insufficiency during treatment with human recombinant growth hormone. J. Tke (Budapest) and her colleagues characterized a novel de novo inactivating mutation of the calcium-sensing receptor gene in patients with neonatal severe hyperparathyroidism. They showed that the disease gradually reverted to a benign condition resembling familial hypocalciuric hypercalcaemia without any surgical intervention of the parathyroid gland. F. Erdogan (Kayseri) investigated the hypothalamic-pituitary-gonadal axis in 48 women with epilepsy. It was found that women on epilepsy treatment had a high prevalence of polycystic ovary syndrome, ovarian dysfunction and insulin resistance. M. Gueorguiev (London) studied 19 families with familial pituitary adenoma and identified mutations in the aryl hydrocarbon receptor interactive protein (AIP) gene in 4 families. The penetrance of the pituitary adenomas was 64%, which indicates a considerably higher penetrance of the disease compared to findings in earlier studies. B. Wikiera (Wroclaw) and his colleagues studied the lipid metabolism of 87 girls with Turner syndrome. They found that growth hormone therapy seems to reduce serum interleukin 6 level and probably augments the adiponectin concentration. Because women with Turner syndrome more frequently develop cardiovascular disease, growth hormone treatment may be protective against ischemic heart disease. S. Mszros and co-workers (Budapest) showed that multiple allergic children treated with H1 histamin receptor antagonist have decreased bone resorption markers. After the hardworking days several social programmes including a cheese-wine party, sailing on the Danube and an Hungarian folklore evening were offered to the participants of the Congress.
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Contents of Previous Issues and Supplements

Volume 4 No. 1 September 2006
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Low Birth Weight and Endocrine Dysfunction in Postnatal Life

Veronica Mericq, MD
Inactivating Mutations of LH and FSH Receptors from Genotype to Phenotype

Ana Claudia Latronico, MD, Ivo Jorge Prado Arnhold, MD
Children Born Small for Gestational Age (SGA) who Fail to Achieve Catch Up Growth By 2-8 Years of Age are Short from Infancy to Adulthood: Data from a Cross-Sectional Study of 486 Spanish Children
Antonio Carrascosa, MD, PhD, Enric Vicens-Calvet MD, PhD, Diego Yeste MD, PhD, Rosa M. Espadero, MD, Angeles Ulied, MD and the SGA Spanish Collaborative Group
Adrenocortical Tumors and Hyperplasias in Childhood Etiology, Genetics, Clinical Presentation and Therapy
Jennifer A. Sutter, MD, Adda Grimberg, MD, FAAP
Osteogenesis Imperfecta and its Molecular Diagnosis by Determination of Mutations of Type I Collagen Genes
Elisa Tedeschi, PhD, Franco Antoniazzi, MD, Giacomo Venturi, PhD, Giorgio Zamboni, MD, Luciano Tat, MD
Volume 4 No. 2 Dec 2006 Jan 2007

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For Debate: A Simple Diagnostic Screening Test for Children with Short Stature with Emphasis on Genetic Defects along the GH Axis
Zvi Laron, MD, Aviva Silbergeld, MSc
The Molecular Basis of Diabetic Microangiopathy

Zhirajr H. Mokini, MD, Francesco Chiarelli, MD
Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia

Saroj Nimkarn, MD, Maria I New, MD
Meeting Reports: The Sixth ESPE Growth Plate Working Group Symposium (EUROGROP), June 30th, Rotterdam, The Netherlands, A Multidisciplinary Approach to Growth Plate Biology
Cortistatin -A New Neuroendocrine Hormone?

Hadara Rubinfeld, PhD, Ilan Shimon, MD
Joyce Emons, MD, Moshe Phillip, MD, Jan M. Wit, MD, Lars Svendahl, MD
Endocrine Effects on the Growth, Development and Function of the Eye

Dan H. Bourla, MD, Nirit Bourla, MD, Ruth Axer-Siegel, MD
Report of the 31st European Thyroid Association (Eta) Annual Meeting, Held in Naples-Italy 2-6 September 2006
Gerasimos E. Krassas MD, PhD
The Clinical Diagnosis and Molecular Genetics of Kearns-Sayre Syndrome: a Complex Mitochondrial Encephalomyopathy
Jarosaw Maceluch, PhD, Marek Niedziela, MD, PhD
First International Conference on Therapies of Obesity: Perspectives for Pharmaceutical and Natural Products (Paris Anti Obesity Therapies 2006), May 18-19 2006, Institut Pasteur, Paris, France
Marvin Edeas, MD

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At What Stage of Childhood Obesity Should the Psychosocial Team Intervene?

Silvana Fenning, MD, Zvi Laron, MD
Meeting Reports Use and Abuse of Growth Hormone: Introduction

Minoru Irie, MD
Nutritional Stunting
amil Hizli, MD, Ayhan Abaci, MD, Benal Bykgebiz, MD,Atilla Bykgebiz, MD
Endocrine Complications of Childhood Cancer Therapy: Evaluation and Management

Michael J. Haller, MD, Desmond A. Schatz, MD
Debate on the Use of Growth Hormone in the Treatment of Children with Idiopathic Short Stature (ISS) (Pro and Con)
Alan D. Rogol, MD, PhD, Jan M. Wit, MD, PhD
Traumatic Brain Injury and Hypopituitarism in Children and Adolescents: Is the Problem Under-Estimated?
Harald J Schneider, MD, Ginevra Corneli, MD, Ilonka KreitschmanAndermahr, MD, Silvia Rovere, MD, Simonetta Bellone, MD, Gianni Bona, MD, Ezio Ghigo, MD, Gianluca Aimaretti, MD
Beyond Reasonable Doubt: Catching the Growth Hormone Cheats

Richard IG Holt, PhD, FRCP
Human Studies of Growth Hormone and Aging
Michael O. Thorner, MB BS, DSc, FRCP, MACP, Ralf Nass, MD
Disorders of Gonadal Development: A Broad Clinical,

Cytogenetic and Histopathologic Spectrum
Zeynep iklar, MD, Merih Berberolu, MD, Pelin Adiyaman, MD, Mustafa Salih, MD, Ajlan Tkn, MD, Ergun etinkaya, MD, Zehra Aycan, MD, Olcay Evliyaolu, MD, Aya T Ergur, MD, Gnl al, MD
The 10th International Congress of Inborn Errors of Metabolism (ICIEM) Makuhari Messe (Tokyo), Japan, September 2006
Anthony Luder, MD
Prevention of Thyroid Associated-Ophthalmopathy in Children and Adults: Current Views and Management of Preventable Risk Factors
Gerasimos E. Krassas, MD, PhD, Petros Perros, MD, FRCP
The 40th Annual Meeting of the Japanese Society for Pediatric Endocrinology (JSPE), Hamamatsu, Japan, 27-29 September 2006
Toshiaki Tanaka, MD
Volume 4 No. 4 June 2006

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For Debate: The Artificial Pancreas: How Close Are We to Closing the Loop?
William L Clarke, MD, Boris Kovatchev, PhD Delbert A Fisher, MD
Meeting Reports: The 4th International Congress on the Insulin Resistance Syndrome
Dennis M Styne, MD
Thyroid Function and Dysfunction in Premature Infants Estrogens and Growth: Review The Empty Sella
Andrei S Chagin, PhD, Lars Svendahl, MD, Phd Soe Naing, MD, Lawrence A Frohman, MD
The Third International Congress of the GRS and the IGF Society, November 11-15, 2006, Kobe, Japan
Disorders of Sex Development and Gender Identity Outcome in Adolescence and Adulthood: Understanding Gender Identity Development and its Clinical Implications
Annelou LC de Vries, MD, Theo AH Doreleijers, MD, PhD, Peggy T CohenKettenis PhD
Toshiaki Tanaka, MD, Shin-Ichiro Takahashi, PhD, Noriyuki Katsumata, MD, Yasuhiko Okimura, MD, Susumu Yokoya, MD, Yutaka Takahashi, MD, Katsuhiko Tachibana, MD, Yukihiro Hasegawa, MD
XVIII Annual Meeting of the Sociedad Latinoamericana De Endocrinologia Pediatrica (SLEP)

Alejandro Martinez, MD
Risk of Major Congenital Malformations Associated with Infertility and its Treatment by Extent of Iatrogenic Intervention
Jacob Farhi, MD, Benjamin Fisch, MD, PhD
II

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Message from the Editors In Memoriam - Jo Anne Brasel, MD (1934-2007)

Delbert A Fisher, MD
Diseases and Clinical Applications of the Calcium Sensing Receptor

Uri S Alon, MD
For Debate: The Endocrinologic Advantage of Newborn Circumcision 5/30/07

Edgar J. Schoen, MD
Gynecomastia: Review
Ayhan Abaci, MD, Atilla Buyukgebiz, MD
Environmental Thyroid Toxicants and Child Endocrine Health

Francesco Massart, MD, PhD,Valentina Meucci, MD
Varicocele in the Adolescent
Vincenzo De Sanctis, MD, Vincenzo Ficarra, MD, Guglielmo Mazzoni, MD, Bernadette Fiscina, MD, Giuseppe Raiola, MD, German Castellano, MD, The Reproductive Health Care Study Group of SIMA
Growth Hormone and Developmental Ocular Function: Clinical and Basic Studies
Stephen Harvey, PhD, DSc, Marie-Laure Baudet, PhD, Esmond J. Sanders, PhD
Sufficiently Long-Term Treatment with Combined Growth Hormone and Gonadotropin-Releasing Hormone Analog Can Improve Adult Height in Short Children with Isolated Growth Hormone Deficiency (GHD) and in Non-GHD Short Children
Toshiaki Tanaka, MD
Meeting Report: The 35th Annual Meeting of the Lawson Wilkins Pediatric Endocrine Society (LWPES) Toronto May 4-6, 2007
Clifford Bloch, MD, Christine Burt Solrzano, MD, Lily Chao, MD, Sherry Franklin, MD, Joshua May, MD, Pisit Pitukcheewanont, MD
III
Endocrine and Gynecological Problems in Adolescent Girls

Guest Editors: George Mastorakos, MD, George Creatsas, MD and Bessie Spiliotis, MD Foreword Premenstrual Syndrome in Adolescents: Diagnosis and Treatment
Andrea J. Rapkin, Judith A. Mikacich
Volume 3 Supplement 1 January 2006

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Development and Biological Function of the Female Gonads and Genitalia in IGF-I Deficiency - Laron Syndrome as a Model
Zvi Laron
Growth and Long-term Hormonal Therapy

Bessie E. Spiliotis
Adolescent Menstrual Health

Paula J. Adams Hillard
Non-Classical Congenital Adrenal Hyperplasia

Catherine Dacou-Voutetakis, Maria Dracopoulou
Menstrual patterns under hormonal contraception in adolescent girls and young women
Dr. Marlene Heinz E. Deligeoroglou John Tzafettas
Hyperandrogenemia: Pathophysiology and its Role in Ovulatory Dysfunction in PCOS

Evanthia Diamanti-Kandarakis, Joanna Papailiou, Sotiria Palimeri
Menstrual Disorders During Adolescence Painful Menstruation Hormonal Contraception Compliance in Teenagers
Jos Enrique PONS Robert T. Brown
Polycystic Ovarian Disease: The Adrenal Connection

George B. Maroulis, Ioannis K. Triantafillidis
Treatment Options of Polycystic Ovary Syndrome in Adolescence

Zapanti Evangelia, Kiapekou Erasmia, Loutradis Dimitrios Christina Kanaka-Gantenbein
Pregnancy and Abortion in Adolescents Adolescent Pregnancy and Perinatal Outcome

Malamitsi-Puchner A, Boutsikou T
Hormone Replacement Treatment in Turner Syndrome Predictors of Bone Loss in Young Women with Restrictive Eating Disorders
Vincenzina Bruni et al
The Hypothalamic-Pituitary-Adrenal and The HypothalamicPituitary-Gonadal Axes Interplay

George Mastorakos, Maria G. Pavlatou, Maria Mizamtsidi
Health Education for Youth

E. Alexopoulou
Yannis Tountas, Christine Dimitrakaki
Precocious Puberty
Asteroula Papathanasiou MD, ScD, Charalambos Hadjiathanasiou
Hysterography - New Techniques
Volume 3 Supplement 2 April 2006

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Growth, Growth Hormone and Obesity

Guest Editor: Linda Carlson, PhD, MBA
GH Stimulation Testing in Pediatric Patients: The GHMonitorSM Experience

Jim Brentzel
Short Stature, Obesity, and Growth Hormone Deficiency in Pseudohypoparathyroidism Type 1a

Emily L. Germain-Lee, MD
Mechanisms for Delaying Epiphyseal Fusion and Improving Adult Height in Pubertal Patients with Hypopituitarism
Erica A. Eugster, MD
Adrenal Insufficiency in Growth Hormone-Treated Patients: A Reassessment

Robert Rapaport, MD
Obesity in Childhood Cancer Survivors

Robert H. Lustig, MD
Cortisol and Growth Hormone: Clinical Implications of a Complex, Dynamic Relationship

Constantine A. Stratakis, MD, DSc
Update on Genetic Regulation of Pituitary Development

Ronald N. Cohen, MD
GHMonitorSM Update: Patient Outcomes in the GHMonitorSM

Paul Desrosiers, MD, Sally Rodriguez, MS, Linda Carlson, PhD, MBA
IV
Volume 3 Supplement 3 August 2006

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Genetic Endocrine Diseases

John A. Phillips, USA
Guest Editors: A. Bykgebiz and Z. Laron New methods in genetic diagnosis including prenatal diagnosis
John A. Phillips, USA
Growth hormone gene deletion Genetic aspects of Laron syndrome (Primary Growth hormone insensitivity)
Orit Shevach, Zvi Laron, Israel
Consanguinity in Arab and Jewish populations

Ltfi Jaber, Israel
Genetics of CAH
Shoshana Israeli, Israel
Non classical CAH

Fahrettin Kelestimur, Turkey
Athyreosis, dysgenesis and dyshormonogenesis in congenital hypothyroidism

A. Kemal Topaloglu, Turkey
17 ketoreductase deficiency
Ariel Rossler, Israel
MEN 2, TURK-MEN study

Murat Faik Erdogan, Turkey
5 alpha reductase deficiency in Turkey

Pelin Adiyaman, Turkey
Genetic aspects of childhood type 1 DM

Christos Bartsocas, Greece
Vitamin D receptor defects

Ruth Koren, Israel
MODY type diabetes

Galia Gat Yablouski, Israel
Vitamin D receptor gene polymorphism in nutritional rickets

Abdullah Bereket, Turkey
Hyperinsulinemia
Feyza Darendeliler, Turkey
Severe Childhood Obesity, Pathophysiology and Treatment

Guest Editors: Jose Bernardo Quintos and Salvador Castells Genetic Aspects of Severe Childhood Obesity
I. Sadaf Farooqi, MD
Volume 3 Supplement 4 December 2006

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The Prevalence of Metabolic Syndrome in Inner City Obese African-American Youth

Jose Bernardo Quintos, MD, Hiren Mazumdar, MD, Minu George, MD, Arlene B. Mercado, MD, Haiyan Lu, MD, Alex Sternberg, MD, Madu Rao, MD Salvador Castells, MD
Roles of Adipose Tissue-derived Factors in Obesity

Vatcharapan Umpaichitra, MD
The Brain-Gut Axis in Regulation of Appetite and Obesity

Shefali Dham, MD, Mary A. Banerji, MD Tania S. Burgert, MD
Glucose and Insuline Metabolism in Obese Youth Pamcreatic -Cell Hyperactivity in Morbidly Obese Adolescents
Arlene B. Mercado, MD, Salvador Castells, MD
Transient Pituitary Dysfunction, Empty Sella, Pseudotumor Cerebri in a Morbidly Obese Adolescent
Jose Bernardo Quintos, MD, Arathi Shah, MD, Salvador Castells, MD Hire Muzumdar, MD, Madu Rao, MD
Pulmonary Dysfunction and Sleep Apnea in Morbid Obesity The Downstart Program: A Hospital-Based Pediatric Healthy Lifestyle Program for Obese and Morbidly Obese Minority Youth
Alex Sternberg, ScD, Hiren Muzumdar, MD, Eugene Dinkevich, MD, Jose Bernardo Quintos, MD, Galia Austin-Leon, MD, Terrel Owens, RD, Cheryl Murphy, BS, Geraldine Dapul, MS, Madu Rao, MD
Management of Metabolic Syndrom in Mordibly Obese Children and Adolescents

Jose Bernardo Quintos, MD, Salvador Castells, MD
Intensive Therapy for Severe Pediatric Morbid Obesity

Silvana Fennig, MD, Shmuel Fennig, MD
Growth Hormone: The Transition Period and the Genetic and Molecular Understanding of Water and Carbohydrate Metabolism
Guest Editor: Nerissa C. Kreher, MD, MSc Diabetes Insipidus: Clinical and Basic Aspects
Joseph A. Majzoub, MD, Abhinash Srivatsa, MD

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Hypoglycemia in the Neonate

Charles A. Stanley, MD
Stephen M. Rosenthal, MD, Brian J. Feldman MD, PhD, Gabriel A. Vargas, MD, PhD, Stephen E. Gitelman, MD Mark A. Sperling, MD
Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD): a Paradigm for Activating Mutations Causing Endocrine Dysfunction The Genetic Basis of Neonatal Diabetes Mellitus
Transition of Childhood-Onset Growth Hormone-Deficient Patients to Adult Healthcare

Robert Rapaport, MD, David M. Cook, MD
The GHMonitor Registry: an Update of the Last Three Years

Joel Steelman, MD
Treatment Perspectives in Idiopathic Short Stature with a Focus on IGF-I Deficiency

Guest Editor: Ron G. Rosenfeld, MD Part I: Clinical Diagnosis of IGF-I Deficiency Part II: Defining and Managing Growth Hormone Treatment Failure Part III: Algorithms for the Evaluation and Management of Short Stature
Stephen Rosenthal, MD, Pinchas Cohen, MD, Peter Clayton, MD, MRCP, FRCPCH, Philippe Backeljauw, MD, Peter Bang, MD, PhD, MSci, Svetlana Ten, MD

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Central Precocious Puberty: An Update on Natural History and Treatment Outcomes

Guest Editors: Peter A. Lee, MD, PhD, Lawrence A. Silverman, MD Two Perspectives on Changes in the Normal Age for the Onset of Puberty in Girls: Cross-Sectional Studies of Normal Children vs Frequency of Different Causes of Referral for Early Puberty
Paul Kaplowitz, MD, PhD
Volume 4 Supplement 3 June 2007

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Obesity and Puberty The Impact of Childhood Obesity on Central Precocious Puberty
Josephine Z Kasa-Vubu, MD, MS, Mark Daniels, MD
Variations in Tempo of Normal Pubertal Progression

Mitchell E. Geffner, MD
Affecting Height Outcomes in Children with Precocious Puberty

Karen Oerter Klein, MD
Long Term Safety of GnRH Agonist Therapy in Precocious Puberty: An Evaluation of Reproductive Function, Bone Density and Body Composition
Peter A. Lee, MD, PhD, Lawrence A. Silverman, MD
Behavioral Problems and Idiopathic Central Precocious Puberty: Fact or Fiction?

Emily C. Walvoord, MD, Tom Mazur, PsyD
VI
Volume 4 Supplement 4 August 2007

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McCune-Albright Syndrome: From Pathophysiology to Therapeutics

Guest Editors: Erica A. Eugster, MD, Michael T. Collins, MD Genetic and Molecular Aspects of McCune-Albright Syndrome
Steven A Lietman, William F Schwindinger, Michael A Levine
Persistent Hyperestrogenism after Precocious Puberty in Young Females with Mccune-Albright Syndrome
Roberto Lala, Maria Andreo, Angela Pucci, Patrizia Matarazzo
The Role of Stem Cells in Fibrous Dysplasia of Bone and the Mccune-Albright Syndrome
Pamela Gehron Robey, Sergei Kuznetsov, Mara Riminucci, Paolo Bianco
Thyroid Disease in Patients with McCune-Albright Syndrome

Valentina Congedo, Francesco S Celi
GNAS Mutation Detection is Related to Disease Severity in Girls with McCune-Albright Syndrome and Precocious Puberty
Heather A Wagoner, Rosemary Steinmetz, Kathleen E Bethin, Erica A Eugster, Ora H Pescovitz, MD, Tamara S Hannon
Fibrous Dysplasia, Phosphate Wasting and Fibroblast Growth Factor 23

Erik A Imel, Michael J Econs
Bisphosphonate Therapy for Fibrous Dysplasia

Linda A DiMeglio
The Pathology of Fibrous Dysplasia and the McCune-Albright Syndrome

Mara Riminucci, Pamela Gehron Robey, Paolo Bianco
Surgical Management of Fibrous Dysplasia in McCuneAlbright Syndrome

Robert P Stanton, Leigh Diamond
The Spectrum of McCune Albright Syndrome

Margaret Zacharin
McCune-Albright Syndrome in Adulthood

Philippe Chanson, Sylvie Salenave, Philippe Orcel
Treatment of Precocious Puberty in McCune-Albright Syndrome

Jakub Mieszczak, Erica A Eugster
Principles and Pitfalls in Pediatric Endocrine Laboratory Testing

Guest Editors: John Fuqua, MD, Jon Nakamoto, MD, PhD Dedication to Delbert Fisher, MD
Jon Nakamoto, MD, PhD, John Fuqua, MD, Zvi Laron, MD
Volume 5 Supplement 1 October 2007

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Interpretation of Pediatric Endocrine Laboratory Tests: Pitfalls in Steroid Hormone Measurements and Genotyping
Phyllis W Speiser, MD
Laboratory Assays in Pediatric Endocrinology: Common Aspects

Jon Nakamoto, MD, PhD, John S Fuqua, MD
Evaluation of Bone and Mineral Disorders
Laleh Ardeshirpour, MD, David EC Cole, MD, PhD, Thomas O Carpenter, MD
Indications, Limitations and Pitfalls in the Determination of Human Growth Hormone, IGF-I and their Binding Proteins
Zvi Laron, MD, Martin Bidlingmaier, MD, Christian Joseph Strasburger, MD
Laboratory Testing of Gonadal Steroids in Children

Lindsey Albrecht, MD, Dennis Styne, MD
Pediatric Thyroid Testing Issues
Mark D DeBoer, MD, Stephen H LaFranchi, MD
Understanding and Interpreting Laboratory Test Results in the Clinical Management of Diabetes Mellitus
George S Jeha, MD, Morey Haymond, MD
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Endocrine Complications in Patients With Thalassaemia Major

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Endocrine Complications in Patients With Thalassaemia Major

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Editor-in-Chief: Zvi Laron, MD, PhD (Hon)

Associate Editor: Mitchell E. Geffner, MD

Associate Editor for Japan and Pacific Area Toshiaki Tanaka, MD

Robert Rapaport Vincenzo de Sanctis

Stenvert L.S Drop

Fima Lifshitz Louis C.K. Low

Desmond Schatz Lars Savendahl

Angel Ferrandez Longas John A. Phillips

Chief Executive Officer: Aliza Farkash

Pediatric Endocrinology Reviews (PER) n Volume 5

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Pediatric Endocrinology Reviews (PER) n Volume 5

Pediatric Endocrinology Reviews (PER) n Volume 5

Pediatric Endocrinology Reviews (PER) n Volume 5

Message from the Editors,

Pediatric Endocrinology Reviews (PER) n Volume 5

Marvin Cornblath, MD 1925-2005

Pediatric Endocrinology Reviews (PER) n Volume 5

Pediatric Endocrinology Reviews (PER) n Volume 5

Therapeutic Approach to Childhood Hypercholesterolemia

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Pediatric Endocrinology Reviews (PER) n Volume 5

Diseases Associated with Hypercholesterolemia

Pediatric Endocrinology Reviews (PER) n Volume 5

Approach to Pediatric Patients with Hypercholesterolemia

Pediatric Endocrinology Reviews (PER) n Volume 5

Management of Children with Hypercholesterolemia

Pediatric Endocrinology Reviews (PER) n Volume 5

Pediatric Endocrinology Reviews (PER) n Volume 5

Pediatric Endocrinology Reviews (PER) n Volume 5

Pediatric Endocrinology Reviews (PER) n Volume 5