Androgens in Polycystic Ovary Syndrome: The Role of Exercise and Diet

Francesco Giallauria, M.D., Ph.D.,1 Stefano Palomba, M.D., Ph.D.,2 Carlo Vigorito, M.D.,1 Maria Giovanna Tafuri,3 Annamaria Colao, M.D.,4 Gaetano Lombardi, M.D.,4 and Francesco Orio, M.D., Ph.D.4,5

ABSTRACT

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in premenopausal women and is characterized by chronic ovulatory dysfunction and hyperandrogenism. Clinical studies have shown that hyperandrogenism is linked with insulin resistance/metabolic syndrome in PCOS women. This review article summarizes the several potential mechanisms for the association of androgen excess with insulin resistance, including both direct and indirect actions of androgens on insulin target tissues. This review article also focuses on the benecial effects of exercise training and diet on glucose metabolism and hyperandrogenism in PCOS women, pointing out that whether in conjunction with pharmacotherapy or as a stand-alone treatment, diet and exercise training represent a fundamental strategy in the treatment of PCOS women.
KEYWORDS: Polycystic ovary syndrome, exercise training, diet, hyperandrogenism, insulin resistance

common endocrine disorder in premenopausal women, with 6 to 7% prevalence worldwide.1,2 This syndrome is a heterogeneous disorder characterized by chronic ovulatory dysfunction and hyperandrogenism.3 Androgen excess is the central defect in PCOS patients, yet it is triggered by other factors, with obesity and insulin resistance being frequently involved.4 The metabolic-hormonal complexity observed in PCOS represents an intriguing biological model illustrating the relationship between hormonal pattern and cardiovascular risk prole.5,6 Indeed, these women, even at an early age, have a clustering of cardiovascular
1 Department of Clinical Medicine, Cardiovascular and Immunological Sciences, University of Naples Federico II, Naples, Italy; 2Department of Obstetrics and Gynaecology, University of Catanzaro Magna Graecia, Catanzaro, Italy; 3Teaching and Methods of Sportive Activity, Faculty of Exercise Sciences, University of Naples Parthenope, Naples, Italy; 4Department of Molecular & Clinical Endocrinology and Oncology, University of Naples Federico II, Naples, Italy; 5 Endocrinology, Faculty of Exercise Sciences, University of Naples Parthenope, Naples, Italy. Address for correspondence and reprint requests: Orio Francesco,

Polycystic ovary syndrome (PCOS) is the most

features, such as obesity7 and insulin resistance,8 hypertension,9 impaired cardiopulmonary functional capacity,10,11 autonomic dysfunction,12 and low-grade chronic inammation.13,14 Metabolic syndrome should also be considered in the clinical evaluation and management of PCOS.15 Insulin resistance and the consequent development of hyperinsulinemia appear to be central in the pathophysiologic mechanism that links PCOS to its concurrent metabolic derangements (Fig. 1). Compensatory hyperinsulinemia is important in the development of metabolic abnormalities and also contributes to the high androgen levels observed in women with
M.D., Ph.D., Department of Molecular & Clinical Endocrinology and Oncology, University of Naples Federico II, Naples, Italy (e-mail: francescoorio@virgilio.it). Venus and the Heart: Endocrine Inuences on Cardiovascular Health in Women; Guest Editors, Alice Y. Chang, M.D., M.S., and Richard J. Auchus, M.D., Ph.D. Semin Reprod Med 2009;27:306315. Copyright # 2009 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-0029-1225258. ISSN 1526-8004.

306

ANDROGENS IN PCOS/GIALLAURIA ET AL

307

Figure 1 Flowchart illustrating the relationship between insulin resistance and androgens in PCOS. Clinical evidence suggests that elevated insulin levels cause hyperandrogenism, and not the other way around, as shown by the decrease in serum androgen levels observed when circulating insulin concentrations are lowered by the administration of insulin-sensitizing drugs or drugs that inhibit insulin secretion (see text for details).

PCOS.1621 Insulin binds to its cognate receptor on the ovarian theca cell, enhancing the luteinizing hormone (LH)-stimulated androgen production.1621 Insulin can also act indirectly to raise the serum concentration of free testosterone, the level of which does not seem to be tightly regulated in women, by inhibiting the hepatic production of sex-hormonebinding globulin (SHBG).17 For that reason, an improvement in insulin sensitivity in women with PCOS leads to a decrease in ovarian androgen biosynthesis, an increase in the concentration of SHBG, and a resultant decrease in free testosterone concentration.22 The aim of the current review article will be to dene the potential mechanisms for the association of androgen excess with insulin resistance, exploring the effects of pharmacotherapy, exercise training, and diet (alone or combined) on the endocrine-metabolic pattern in women with PCOS.

DIAGNOSTIC CRITERIA In 2003, the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine organized a consensus workshop that was held in Rotterdam, The Netherlands. The resulting denition of PCOS requires the presence of two of the three following criteria: clinical and/or biochemical hyperandrogenism, chronic oligo-ovulation, and polycystic ovaries on ultrasound.4 Of note, the last criterion

requires the presence of an ovarian volume above 10 mL or the presence of 12 or more follicles of 2- to 9-mm diameter in at least one ovary.4 It should be highlighted that the Rotterdam criteria include those patients diagnosed by the National Institute for Child Health and Human Development (NICHD)23 criteria but add two new phenotypes: hyperandrogenism with polycystic ovary morphology and oligo-ovulation with polycystic ovary morphology but with no evidence for clinical or biochemical hyperandrogenism.4 The 2006 Androgen Excess Society (AES) evidence-based denition sustains a diagnosis of PCOS in the presence of clinical and/or biochemical hyperandrogenism in association with either oligo-ovulation and/or polycystic ovary morphology.24 Essentially, these criteria are those of the Rotterdam denition, yet the phenotype consisting of oligo-ovulation and polycystic ovary morphology was not included because only a minority considered the possibility that there may be forms of PCOS without overt evidence of hyperandrogenism and recognized that more data are required before validating this hypothesis.25

OVARIAN AND ADRENAL ANDROGEN EXCESS Steroid hormones are produced from cholesterol via the action of six cytochrome P450 (CYP) enzymes, aided by

308

SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 27, NUMBER 4

2009

3b- and 17b-hydroxysteroid dehydrogenases (3bHSD and 17bHSD).2628 The enzyme CYP17A1 catalyzes the hydroxylation of both pregnenolone and progesterone; as well as the conversion of 17a-hydroxypregnenolone to dehydroepiandrosterone (DHEA).2628 Lyase activity for the 17a-hydroxyprogesterone intermediate in the D4 pathway, however, is negligible.2628 The D5 pathway is thus the androgen synthesis pathway in humans, and in this pathway, 3bHSD competes with CYP17A1 for the same substrates, pregnenolone and 17a-hydroxypregnenolone.2628 The rst and rate-limiting step in the biosynthesis of all steroid hormones is the conversion of cholesterol to pregnenolone by the mitochondrial cholesterol side chain cleavage enzyme, CYP11A1, which is thus the quantitative regulator of steroidogenesis. The qualitative regulator, however, is microsomal CYP17A1, which sequentially catalyzes both 17a-hydroxylase and 17,20lyase activities.2931 In the absence of either activity of CYP17A1, adrenal pregnenolone is directed toward the biosynthesis of mineralocorticoids. When only 17a-hydroxylase activity is present is the resulting 17a-hydroxypregnenolone converted to cortisol; when both the 17a-hydroxylase and 17,20-lyase activities are present, the C19 steroid DHEA is produced. DHEA then can be converted to androstenedione by 3bHSD type 2, and androstenedione is converted to testosterone and estradiol by isozymes of 17bHSD and by aromatase (CYP19A1).32 The biosynthesis of all sex steroids proceeds through DHEA because human CYP17A1 does not convert 17a-hydroxyprogesterone to androstenedione.26,30 Thus, CYP17A1 and 3bHSD type 2 are key enzymes required for the synthesis of all androgens. One of the hallmarks of PCOS is hyperandrogenism, and elevation of free testosterone or the free androgen index (FAI) or other clinical manifestations of hyperandrogenism are required for diagnosis.4 Studies of ovarian theca cells propagated from patients with PCOS demonstrate that increased testosterone production in PCOS theca cells is from increased synthesis of testosterone precursors rather than alterations in the synthesis of testosterone itself, through dysregulation of androgenic 17bHSD activity or altered expression of aldo-keto reductase that may express 17bHSD activity.33 It has recently been shown that hyperandrogenic females with a compromised 3bHSD phenotype have similar characteristics in other respects to PCOS and may actually represent a variant of PCOS as there is ultimately no abnormality in the HSD3B2 gene.34 This evidence suggests that hyperandrogenism in PCOS may proceed via dysregulated paracrine/endocrine control of androgen synthesis that might reside at the level of both 3bHSD and CYP17A1 activity as a whole and is in keeping with the observation that the ratio of 17,20lyase to 17a-hydroxylase activities is similar in normal and PCOS theca cells.33 It has also long been acknowl-

edged that the hyperandrogenism in many women with PCOS may also be due to adrenal androgen excess3537 (as measured via increased dehydroepiandrosterone sulphate [DHEAS]) with a prevalence of $50% in anovulatory PCOS.38,39 It has subsequently been shown that these women also have decreased levels of DHEAS after the administration of a gonadotropin-releasing hormone (GnRH) agonist,40,41 which is a treatment that should only suppress the ovary, suggesting ovarian-adrenal crosstalk in the pathogenesis of adrenal hyperandrogenism. In addition, studies do not support a role for mutations in the 21-hydroxylase (CYP21A2) gene or polymorphism of CYP17A1 as the source of adrenal androgen excess in PCOS.42,43 This analysis suggests that a single mechanism may drive both ovarian and adrenal hyperandrogenism leading to excess DHEAS. Doi et al recently tested the hypothesis that a woman with high 3bHSD activity will not develop adrenal hyperandrogenism28; however, these researchers were only able to demonstrate that the presence of neuroendocrine dysfunction and/or irregular cycles was associated with increased 3bHSD activity.28 These ndings support the contention that insulin enhances peripheral steroidogenesis while inducing a relative impairment of CYP17A1 activity, leading mainly to testosterone excess without androstenedione and DHEAS excess.44 Therefore, adrenal androgen excess in PCOS would be expected to occur if a PCOS woman is insulin sensitive and has decreased activity of 3bHSD, the latter being preferentially present in women with regular cycles or without neuroendocrine dysfunction.

RELATIONSHIP BETWEEN ANDROGENS AND INSULIN RESISTANCE Even if the primary defect in PCOS is probably exaggerated androgen synthesis and secretion, hyperinsulinemia either of endogenous or exogenous origin is a well-known triggering factor.45 In vitro studies have shown that insulin acts synergistically with LH to stimulate the synthesis of testosterone by ovarian theca cells.46 This effect involves the binding of insulin to insulin, insulin-like growth factor 1 (IGF-1), and hybrid receptors in the ovary46 and also the upregulation of IGF-1 receptors, reduction of IGF-binding protein 1 (IGFBP-1), and activation of the IGF-1 system.47 Insulin might act in concert with gonadotropins on the ovary, enhancing ovarian LH-induced androgen synthesis and secretion.46 In addition, hyperinsulinemia may stimulate the development of antral follicles, increasing the sensitivity of granulosa cells to folliclestimulating hormone (FSH), thus increasing the number and growth of follicular cysts and the ovarian volume in animals and humans.4850 A similar mechanism of

ANDROGENS IN PCOS/GIALLAURIA ET AL

309

insulin facilitation of the adrenocorticotropic hormone (ACTH)-stimulated adrenal androgen secretion has been proposed to underlie the adrenal androgen excess frequently found in PCOS patients.46 Because insulin may facilitate androgen synthesis in the ovary and the adrenal gland, it would be expected that any clinical situation in which circulating insulin levels are increased is associated with an increased prevalence of functional hyperandrogenism, including PCOS. The nding of hyperinsulinemia in these patients, however, raised the question of whether hyperandrogenism led to insulin resistance and hyperinsulinemia, or rather hyperinsulinemia was responsible for hyperandrogenism. Clinical evidence suggests that elevated insulin levels cause hyperandrogenism, and not the other way around, as shown by the decrease in serum androgen levels observed when circulating insulin concentrations are lowered by the administration of insulin-sensitizing drugs51 or drugs that inhibit insulin secretion such as diazoxide52 or somatostatin analogues53 (Fig. 1). On the other hand, decreasing serum androgen levels even with extreme measures such as bilateral oophorectomy54 or administration of GnRH agonists (GnRH-a)55 has not shown any signicant short-term effects on circulating insulin levels. However, androgen excess during fetal life, infancy, and adolescence may favor a predominately abdominal and visceral deposition of body fat favoring the occurrence, later in life, of insulin resistance and hyperinsulinemia.56 The facilitation of insulin resistance by androgen excess through the induction of abdominal adiposity would close the vicious circle of insulin resistancehyperinsulinism in PCOS patients.57

it was believed that skeletal muscle was the only insulin target tissue with a major role in glucose homeostasis. However, recent studies have challenged this view. Mice with adipose tissuespecic knockout of GLUT4 had 50% reduction in insulin-stimulated whole-body glucose uptake (i.e., glucose uptake into muscle in vivo was impaired despite preserved GLUT4 expression), suggesting that insulin resistance in adipose tissue secondarily induces insulin resistance in skeletal muscle.60

EFFECTS OF ANDROGENS ON INSULIN ACTION IN ADIPOSE TISSUE AND SKELETAL MUSCLE Insulin Action in Skeletal Muscle and Adipose Tissue Insulin stimulates glucose transport in skeletal muscle and adipose tissue and has multiple other metabolic actions including stimulation of glycogen, protein, and lipid synthesis and inhibition of lipolysis and gluconeogenesis.58 Insulin-mediated glucose transport is dependent on translocation of the glucose transporter GLUT4 to the cell membrane. Insulin action on glucose uptake is initiated by the activation of the insulin receptor tyrosine kinase, which results in phosphorylation of insulin receptor substrate 1 (IRS-1) on tyrosine residues. These phosphotyrosine residues act as docking sites for SH2 domain-containing proteins, including phosphatidylinositol (PI)-3-kinase.58 Considering that skeletal muscle accounts for 85% of whole body insulin-stimulated glucose uptake,59

Effects of Androgens on Insulin Action in Skeletal Muscle The effects of androgens on insulin action in skeletal muscle have been studied in female rats and the molecular mechanisms investigated,6166 but there are no published studies examining the effects of androgens on skeletal muscle insulin signaling in women. Testosterone administration to female adult rats for 8 to 12 weeks achieving plasma total testosterone levels of 3 to 5 nmol/L (86 to 144 ng/dL) caused hyperinsulinemia in both intact and ovariectomized animals.63 In the ovariectomized animals, testosterone markedly reduced whole-body insulin sensitivity, as measured by euglycemic-hyperinsulinemic clamp, and caused a 50% reduction in insulin-stimulated glucose uptake into skeletal muscle.63,66 This effect of testosterone was attenuated in intact rats, suggesting that estrogen was protective.63 The impaired insulin sensitivity in the testosterone-treated ovariectomized rats was associated with fewer type 1 bers and increased type 2 bers in skeletal muscles, features expected to result in reduced insulin sensitivity of this tissue.63 However, whether these changes in muscle morphology preceded or followed the development of insulin resistance was not determined. Of note, the deterioration in insulin sensitivity in the ovariectomized animals occurred rapidly, within 48 hours of testosterone exposure, and was associated with impaired muscle glycogen synthase activity and minor changes in muscle ber composition.62 Interestingly, this acute reduction in insulin sensitivity was not associated with increased circulating free fatty acids or glycerol levels, suggesting that the effect was not mediated by increased lipolysis.64 Decreased skeletal muscle capillary density leading to reduced tissue delivery of insulin in the testosterone-treated animals may have also contributed to impaired insulin action.63,65 The molecular mechanisms for testosterone-induced insulin resistance in skeletal muscle of this rat model have not been fully elucidated but appear to involve postinsulin receptor signaling events.66

Effects of Androgens in Adipose Tissue Androgens regulate multiple aspects of adipose cell function. In the adipose tissue of male mice, androgens

310

SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 27, NUMBER 4

2009

modulate the levels of transcripts involved in the regulation of diverse cell functions.67 Androgens bind to the androgen receptor, which mediates most of their physiologic functions through transcriptional activation of downstream genes. Functional androgen receptors are present in human adipose tissue, both in stromal cells and mature adipocytes68 and in adipocytes differentiated in vitro.69 Androgen receptor expression is higher in intra-abdominal than in subcutaneous abdominal fat depots.70

DRUG INTERVENTION Several studies have investigated whether insulin resistance in hyperandrogenic women is reversible to some extent by treatment with androgen receptor antagonists or suppression of ovarian steroidogenesis with GnRH-a.7184 In many cases, the interpretation of these studies is limited by the use of indirect methods for assessing insulin sensitivity (i.e., fasting insulin levels, homeostasis model assessment of insulin [HOMA-IR]) versus the gold-standard method, euglycemic-hyperinsulinemic clamp, as well as short duration of treatment and small numbers of subjects.7184 Intervention studies using the euglycemic-hyperinsulinemic clamp technique have produced conicting results.7184 In a study of 43 hyperandrogenic women (hirsutism alone or PCOS) treated with either GnRH-a or the androgen receptor antagonists spironolactone or utamide, the impairment in insulin-stimulated glucose uptake at baseline was partially reversed at 3 to 4 months after therapy.71 Similarly, in two studies each of eight women with PCOS, treatment with GnRH-a for 6 months resulted in improved insulin sensitivity.74,75 In contrast, in 18 women with PCOS treated with utamide for 3 months, insulin-stimulated glucose disposal was unchanged.73 Insulin sensitivity was also unchanged after administration of GnRH analogues for 3 months to nine women with PCOS.72 Studies using methods other than the euglycemichyperinsulinemic clamp for assessment of insulin sensitivity have also shown conicting results. Two studies using the frequently sampled intravenous glucosetolerance test to assess insulin action in women with PCOS treated with GnRH-a showed improvement in insulin sensitivity.76,77 Most studies in women with PCOS in which fasting insulin levels, HOMA-IR, or insulin responses to a glucose load were used as measures of insulin sensitivity, however, showed no effect of treatment with GnRH-a or androgen-receptor antagonists for durations of 2 weeks to 12 months.7881 The duration of treatment seems to be critical: overweight or obese PCOS women treated for 12 months with utamide showed that the improvement in insulin sensitivity increased with time, there being an additional benet at 12 months compared

with 6 months of treatment,82 suggesting that short duration of therapy may have inuenced the outcome of previous negative studies.73,83 Gambineri et al83 assessed the treatment with utamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women. They found that after 6 months, compared with placebo, utamide signicantly decreased visceral/subcutaneous fat mass, androstenedione, DHEAS, and hirsutism score, whereas metformin signicantly increased the frequency of menstruation. After 12 months, utamide maintained the effects observed after 6 months on visceral/subcutaneous fat mass and androstenedione, whereas it produced an additional signicant decrease in DHEAS and hirsutism score; metformin further improved the menstrual pattern. Panidis et al84 evaluated orlistat (120 mg, 3 times per day), combined with diet for 24 weeks, observing a signicant weight loss and improvement of insulin resistance in obese women, with or without PCOS.85 Moreover, testosterone levels were signicantly decreased in women with PCOS.85 The effects of a hypocaloric diet and a diet plus sibutramine (10 mg per day) in 59 overweight and obese PCOS women was investigated by Florakis et al.85 They found that patients who received sibutramine showed a greater weight loss and improvement in hyperandrogenemia and insulin sensitivity after 6 months of treatment. The amelioration of insulin resistance in this group could not be totally explained by weight loss, but reductions in total testosterone, FAI, and triglycerides (TG) could be a possible mechanism. Elkind-Hirsch et al86 randomized 60 overweight oligo-ovulatory PCOS women to one of three treatment groups: metformin (1000 mg twice daily), exenatide (10 mg twice daily), or their combination for 24 weeks. The authors found that the combination therapy was superior to monotherapy in improving menstrual cyclicity, ovulation rate, FAI, and insulin sensitivity measures and in reducing weight and abdominal fat. In conclusion, a marked decrease in central adiposity could partly explain the improvements in endocrine-metabolic parameters and in reproductive function observed in these overweight/obese PCOS women after weight loss. Larger trials of longer duration are warranted to assess the long-term efcacy and safety of the drugs and their combinations.

LIFESTYLE MODIFICATION INTERVENTION Dietary recommendations for PCOS include a low-fat ($30% of energy, saturated fat $10% of energy), moderate protein ($15%), and high-carbohydrate intake ($55%) and increased consumption of bers (which reduce nutrient absorption after meals and slow insulin secretion), cereals, fruit, and vegetables

ANDROGENS IN PCOS/GIALLAURIA ET AL

311

($1000 to 1200 kcal/day) to induce weight loss and improve insulin sensitivity as well.8789 Interestingly, new schemes, based on increasing dietary protein at the expense of carbohydrate, are also gaining popularity in treatment of obesity and polycystic ovaries.90,91 The enlargement in protein intake seems to be more useful in improvement of insulin sensitivity, weight reduction, and above all in maintenance of weight loss (probably due to the satiating effects of proteins).87,90 However, the potential detrimental effects of a high-carbohydrate diet may be attenuated through changing the glycemic index of the carbohydrate. Low glycemic index diets are associated with benecial effects on weight loss and cardiovascular risk factors in PCOS patients.87 Unfortunately, diets with severe caloric restriction, however, are notoriously difcult to maintain over the long term, and regain of weight is common. Several trials, with relatively small sample sizes, consistently show improvement in reproductive parameters with weight reduction in PCOS.92 The most frequent measure documenting restoration of reproductive function is menstrual cycling or return of ovulation. Few controlled trials are available; however, most studies demonstrate an improvement in menstrual cyclicity. Studies using severe caloric restriction demonstrate signicant improvement in both menstrual cycles and ovulation.89,9296 An improvement of cyclic menstrual function and ovulatory pattern in 80% of the women after weight reduction, including the 10 women who became pregnant, has been shown.92 Of note, the necessary weight loss of 5.6 3.4 kg (mean SD) was remarkably small. In a similar experience,95 12 of 13 women regained ovulatory cycles and 11 subjects became pregnant after a weight loss of 6.3 4.8 kg. In both studies,92,95 the achieved weight loss was similar but left 20% of the therapy group as nonresponders, suggesting that there might be a certain threshold of body weight for each individual obese patient necessary to resume normal menstrual function, which the group of nonresponders did not reach. Huber-Buchholz et al94 found that improving insulin sensitivity restored normal menstrual function and fertility in obese women with PCOS. More interestingly, by using a lifestyle program that sets realistic weight loss and exercise goals, subjects were able to sustain an improvement in carbohydrate metabolism over a 6-month period and hence improve their likelihood of pregnancy.94 Although weight loss as a percentage of body weight was small, a 70% improvement in insulin sensitivity index was obtained, and this change was associated with the return of reproductive function. In a recent study,89 our research group conducted a preliminary study comparing the effect on reproductive function of an exercise training program with a diet program in obese PCOS patients. After the interven-

tion, we found a signicant improvement in menstrual cycles and fertility in both groups, with no differences between groups. The frequency of menses and the ovulation rate were signicantly higher in the exercise group than in that in the diet group, but the increased cumulative pregnancy rate was not signicant.89 It is noteworthy to mention that signicant differences between the groups were observed in weight, BMI, waist circumference, insulin resistance indices, and in serum SHBG, androstenedione, and DHEAS levels.89 These two last parameters changed from baseline only in the diet group.89 Despite the different changes observed in insulin sensitivity indices after exercise and diet interventions, we hypothesized that in both cases, insulin sensitivity improvement itself is the pivotal factor involved in the restoration of ovarian function.89 Different mechanisms could be involved, however, in explaining the benecial effects of the two treatments on glucose/insulin homeostasis.89 In particular, a change in body weight seems to be the main mechanism by which diet ameliorates insulin sensitivity, and, thus, reproductive function.89 On the other hand, the exercise program potentially improved insulin sensitivity in two ways.89 First of all, exercise results in a large reduction of waist circumference and, thus, of visceral adipose tissue, even if related to a modest weight loss and BMI change.89 The visceral adipose tissue is more metabolically active than subcutaneous fat, and the central fat distribution (android obesity) is closely related to insulin resistance.57,97 Of note, as a result of waist circumference reduction and muscular insulin sensitivity improvement, women who ovulated under the exercise program showed better insulin resistance indices than those who ovulated under the diet program, even if they showed a smaller reduction in body weight.89 Endocrine parameters also demonstrate signicant change with lifestyle modications (diet alone or combined with exercise training). Total testosterone does not consistently decrease when studied in trials of weight reduction, but the majority of studies demonstrate a reduction in free testosterone. This result is likely related to changes in SHBG, which increases in most of the studies that report this parameter.98,99 Impact on clinical parameters such as hirsutism and acne, however, are not usually reported, so it is not clear if these important androgenic features are improved signicantly with weight reduction. A pilot study aimed at evaluating the effects of exercise and nutritional counseling (12 weeks) on hormonal, menstrual, and reproductive function showed a signicant improvement in the sum of two skinfold thickness measurements and in estimated oxygen consumption in the exercise group, with no signicant changes in the hormonal pattern.100 Recently, Thompson et al101 enrolled 94 overweight and obese women with PCOS for a longer study

312

SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 27, NUMBER 4

2009

period (20 weeks). PCOS women were randomized to diet only (n 30), diet and aerobic exercise (n 31), or diet and combined aerobic-resistance exercise (n 33). All interventions reduced weight with no difference between treatments. Fat mass decreased more (3 kg) and fat-free mass decreased less (2 kg) in the exercising groups compared with that in the diet-alone group. A reduction in blood pressure and an improvement in lipid and glucose metabolism were also achieved. Interestingly, improvements in testosterone, FAI, SHBG, and reproductive function occurred in all groups, with no difference between treatments. Moreover, exercise training programs have also shown benecial effects on cardiopulmonary functional capacity and autonomic function, insulin sensitivity parameters, and a signicant reduction in BMI in PCOS women.102,103 Finally, exercise training programs also provide the benecial effect of decreasing C-reactive protein, thus ameliorating the subclinical inammatory status typical of this syndrome.5,14,103,104

5.

6.

7.

8.

9.

10.

11.

CONCLUSIONS Clinical studies have shown that hyperandrogenism is linked with insulin resistance/metabolic syndrome in PCOS women.104 There are several potential mechanisms for the association of androgen excess with insulin resistance, including both direct and indirect actions of androgens on insulin target tissues. Studies to dene the molecular mechanisms whereby androgens interact with insulin effects on glucose metabolism in target tissues, as well as the regulation of local androgen production in the adipose tissue and its role in metabolism, are required. Exercise training and diet efciently decrease fasting insulin levels and also improve hyperandrogenism by increasing SHBG and decreasing androgen levels. Whether in conjunction with pharmacotherapy or as a stand-alone treatment, lifestyle modications (diet and exercise training) certainly represent a fundamental strategy for the treatment of women with PCOS.

12.

13.

14.

15.

16.

17.

REFERENCES
1. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:12231236 2. Azziz R, Marin C, Hoq L, Badamgarav E, Song P. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. J Clin Endocrinol Metab 2005;90:46504658 3. Diamanti-Kandarakis E. Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. Expert Rev Mol Med 2008;10:e3 4. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related 18.

19.

20.

to polycystic ovary syndrome. Fertil Steril 2004;81: 1925 Giallauria F, Orio F, Palomba S, Lombardi G, Colao A, Vigorito C. Cardiovascular risk in women with polycystic ovary syndrome. J Cardiovasc Med (Hagerstown) 2008;9: 987992 Hoffman LK, Ehrmann DA. Cardiometabolic features of polycystic ovary syndrome. Nat Clin Pract Endocrinol Metab 2008;4:215222 Diamanti-Kandarakis E. Role of obesity and adiposity in polycystic ovary syndrome. Int J Obes (Lond) 2007; 31(Suppl 2):S8S13; discussion S31S32 Schroder AK, Tauchert S, Ortmann O, Diedrich K, Weiss JM. Insulin resistance in patients with polycystic ovary syndrome. Ann Med 2004;36:426439 Chen MJ, Yang WS, Yang JH, Chen CL, Ho HN, Yang YS. Relationship between androgen levels and blood pressure in young women with polycystic ovary syndrome. Hypertension 2007;49:14421447 Orio F Jr, Giallauria F, Palomba S, et al. Cardiopulmonary impairment in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:29672971 Orio F Jr, Palomba S, Giallauria F, Colao A, Vigorito C. Impaired cardiopulmonary parameters in young women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2007;66:152153 Giallauria F, Palomba S, Manguso F, et al. Abnormal heart rate recovery after maximal cardiopulmonary exercise stress testing in young overweight women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2008;68:8893 Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JM, Sattar N. Low grade chronic inammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2001; 86:24532455 Giallauria F, Orio F, Lombardi G, et al. Relationship between heart rate recovery and inammatory markers in patients with polycystic ovary syndrome: a cross-sectional study. J Ovarian Res 2009;2:3 Rossi B, Sukalich S, Droz J, et al. Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:47804786 Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 1986;62:904 910 Nestler JE, Powers LP, Matt DW, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1991;72:8389 Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 1998;83:20012005 Codner E, Inguez G, Villarroel C, et al. Hormonal prole in women with polycystic ovarian syndrome with or without type 1 diabetes mellitus. J Clin Endocrinol Metab 2007;92: 47424746 Codner E, Escobar-Morreale HF. Clinical review: hyperandrogenism and polycystic ovary syndrome in women with

ANDROGENS IN PCOS/GIALLAURIA ET AL

313

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32. 33.

34.

35.

36.

type 1 diabetes mellitus. J Clin Endocrinol Metab 2007;92: 12091216 Diamanti-Kandarakis E, Argyrakopoulou G, Economou F, Kandaraki E, Koutsilieris M. Defects in insulin signaling pathways in ovarian steroidogenesis and other tissues in polycystic ovary syndrome (PCOS). J Steroid Biochem Mol Biol 2008;109:242246 Legro RS, Gnatuk CL, Kunselman AR, Dunaif A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. J Clin Endocrinol Metab 2005;90:32363242 Zawadski J, Dunaif A. Diagnostic criteria for polycystic ovary syndrome. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, eds. Polycystic Ovary Syndrome. Boston, MA: Blackwell Scientic; 1992:377384 Azziz R, Carmina E, Dewailly D, et al; Androgen Excess Society. Positions statement: criteria for dening polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006;91:42374245 Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab 2006;91:781785 Auchus RJ, Rainey WE. Adrenarche - physiology, biochemistry and human disease. Clin Endocrinol (Oxf) 2004;60: 288296 Fluck CE, Miller WL, Auchus RJ. The 17, 20-lyase activity of cytochrome p450c17 from human fetal testis favors the delta5 steroidogenic pathway. J Clin Endocrinol Metab 2003;88:37623766 Doi SA, Al-Zaid M, Towers PA, Scott CJ, Al-Shoumer KA. Steroidogenic alterations and adrenal androgen excess in PCOS. Steroids 2006;71:751759 Nakajin S, Shively JE, Yuan PM, Hall PF. Microsomal cytochrome P-450 from neonatal pig testis: two enzymatic activities (17 alpha-hydroxylase and c17,20-lyase) associated with one protein. Biochemistry 1981;20:40374042 Lin D, Harikrishna JA, Moore CC, Jones KL, Miller WL. Missense mutation serine106proline causes 17 alphahydroxylase deciency. J Biol Chem 1991;266:1599215998 Zuber MX, Simpson ER, Waterman MR. Expression of bovine 17 alpha-hydroxylase cytochrome P-450 cDNA in nonsteroidogenic (COS 1) cells. Science 1986;234:1258 1261 Penning TM. Molecular endocrinology of hydroxysteroid dehydrogenases. Endocr Rev 1997;18:281305 Nelson VL, Qin KN, Roseneld RL, et al. The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2001;86:59255933 Carbunaru G, Prasad P, Scoccia B, et al. The hormonal phenotype of Nonclassic 3 beta-hydroxysteroid dehydrogenase (HSD3B) deciency in hyperandrogenic females is associated with insulin-resistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deciency. J Clin Endocrinol Metab 2004;89:783794 Loughlin T, Cunningham S, Moore A, Culliton M, Smyth PP, McKenna TJ. Adrenal abnormalities in polycystic ovary syndrome. J Clin Endocrinol Metab 1986;62:142147 Kumar A, Woods KS, Bartolucci AA, Azziz R. Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2005;62:644 649

37. Carmina E, Lobo RA. Pituitary-adrenal responses to ovine corticotropin-releasing factor in polycystic ovary syndrome and in other hyperandrogenic patients. Gynecol Endocrinol 1990;4:225232 38. Gonzalez F. Adrenal involvement in polycystic ovary syndrome. Semin Reprod Endocrinol 1997;15:137157 39. Carmina E, Gonzalez F, Chang L, Lobo RA. Reassessment of adrenal androgen secretion in women with polycystic ovary syndrome. Obstet Gynecol 1995;85:971976 40. Matteri RK, Stanczyk FZ, Cassidenti DL, Paulson RJ, Lobo RA. The ovarian contribution to peripherally derived serum C19 conjugates. J Clin Endocrinol Metab 1992;75: 768772 41. Gonzalez F, Hatala DA, Speroff L. Adrenal and ovarian steroid hormone responses to gonadotropin-releasing hormone agonist treatment in polycystic ovary syndrome. Am J Obstet Gynecol 1991;165:535545 42. Kahsar-Miller M, Boots LR, Bartolucci A, Azziz R. Role of a CYP17 polymorphism in the regulation of circulating dehydroepiandrosterone sulfate levels in women with polycystic ovary syndrome. Fertil Steril 2004;82:973975 43. Witchel SF, Kahsar-Miller M, Aston CE, White C, Azziz R. Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess. Fertil Steril 2005;83:371375 44. Guido M, Romualdi D, Suriano R, et al. Effect of pioglitazone treatment on the adrenal androgen response to corticotrophin in obese patients with polycystic ovary syndrome. Hum Reprod 2004;19:534539 45. Corbould A. Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome? Diabetes Metab Res Rev 2008;24: 520532 46. Arner P. Effects of testosterone on fat cell lipolysis. Species differences and possible role in polycystic ovarian syndrome. Biochimie 2005;87:3943 47. Pasquali R. Obesity and androgens: facts and perspectives. Fertil Steril 2006;85:13191340 48. Kapoor D, Malkin CJ, Channer KS, Jones TH. Androgens, insulin resistance and vascular disease in men. Clin Endocrinol (Oxf) 2005;63:239250 49. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006;295:1288 1299 50. Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 1981; 53:5868 51. Pugeat M, Crave JC, Elmidani M, et al. Pathophysiology of sex hormone binding globulin (SHBG): relation to insulin. J Steroid Biochem Mol Biol 1991;40:841849 52. Khosla S. Editorial: sex hormone binding globulin: inhibitor or facilitator (or both) of sex steroid action? J Clin Endocrinol Metab 2006;91:47644766 53. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab 2007;92:405413 54. Liu Y, Ding J, Bush TL, et al. Relative androgen excess and increased cardiovascular risk after menopause: a hypothesized relation. Am J Epidemiol 2001;154:489494

314

SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 27, NUMBER 4

2009

55. Reinecke H, Bogdanski J, Woltering A, et al. Relation of serum levels of sex hormone binding globulin to coronary heart disease in postmenopausal women. Am J Cardiol 2002;90:364368 56. Bernini GP, Sgro M, Moretti A, et al. Endogenous androgens and carotid intimal-medial thickness in women. J Clin Endocrinol Metab 1999;84:20082012 57. Cascella T, Palomba S, De Sio I, et al. Visceral fat is associated with cardiovascular risk in women with polycystic ovary syndrome. Hum Reprod 2008;23:153159 58. Shpakov AO, Pertseva MN. Structural and functional characterization of insulin receptor substrate proteins and the molecular mechanisms of their interaction with insulin superfamily tyrosine kinase receptors and effector proteins. Membr Cell Biol 2000;13:455484 59. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 1981; 30:10001007 60. Abel ED, Peroni O, Kim JK, et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 2001;409:729733 61. Mahajan DK. Polycystic ovarian disease: animal models. Endocrinol Metab Clin North Am 1988;17:705732 62. Manneras L, Cajander S, Holmang A, et al. A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology 2007;148: 37813791 63. Holmang A, Svedberg J, Jennische E, Bjorntorp P. Effects of testosterone on muscle insulin sensitivity and morphology in female rats. Am J Physiol 1990;259(4 Pt 1):E555E560 64. Holmang A, Larsson B-M, Brzezinska Z, Bjorntorp P. Effects of short-term testosterone exposure on insulin sensitivity of muscles in female rats. Am J Physiol 1992; 262(6 Pt 1):E851E855 65. Holmang A, Niklasson M, Rippe B, Lonnroth P. Insulin insensitivity and delayed transcapillary delivery of insulin in oophorectomized rats treated with testosterone. Acta Physiol Scand 2001;171:427438 m 66. Rincon J, Holmang A, Wahlstro EO, et al. Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment. Diabetes 1996;45:615621 67. Bolduc C, Larose M, Yoshioka M, et al. Effects of dihydrotestosterone on adipose tissue measured by serial analysis of gene expression. J Mol Endocrinol 2004;33:429 444 68. Pedersen SB, Fuglsig S, Sjgren P, Richelsen B. Identication of steroid receptors in human adipose tissue. Eur J Clin Invest 1996;26:10511056 69. Dieudonne MN, Pecquery R, Boumediene A, Leneveu MC, Giudicelli Y. Androgen receptors in human preadipocytes and adipocytes: regional specicities and regulation by sex steroids. Am J Physiol 1998;274(6 Pt 1):C1645C1652 70. Joyner J, Hutley L, Cameron D. Intrinsic regional differences in androgen receptors and dihydrotestosterone metabolism in human preadipocytes. Horm Metab Res 2002;34:223228 71. Moghetti P, Tosi F, Castello R, et al. The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab 1996;81: 952960

72. Dunaif A, Green G, Futterweit W, Dobrjansky A. Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1990;70:699704 73. Diamanti-Kandarakis E, Mitrakou A, Raptis S, Tolis G, Duleba AJ. The effect of a pure antiandrogen receptor blocker, utamide, on the lipid prole in the polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:26992705 74. Dahlgren E, Landin K, Krotkiewski M, Holm G, Janson PO. Effects of two antiandrogen treatments on hirsutism and insulin sensitivity in women with polycystic ovary syndrome. Hum Reprod 1998;13:27062711 75. Krotkiewski M, Landin K, Dahlgren E, Janson PO, Holm G. Effect of two modes of antiandrogen treatment on insulin sensitivity and serum leptin in women with PCOS. Gynecol Obstet Invest 2003;55:8895 76. Elkind-Hirsch KE, Valdes CT, Malinak LR. Insulin resistance improves in hyperandrogenic women treated with Lupron. Fertil Steril 1993;60:634641 77. Cagnacci A, Paoletti AM, Arangino S, Melis GB, Volpe A. Effect of ovarian suppression on glucose metabolism of young lean women with and without ovarian hyperandrogenism. Hum Reprod 1999;14:893897 78. Lanzone A, Fulghesu AM, Andreani CL, et al. Insulin secretion in polycystic ovarian disease: effect of ovarian suppression by GnRH agonist. Hum Reprod 1990;5:143 149 79. Gadir AA, Khatim MS, Mowa RS, Alnaser HM, Alzaid HG, Shaw RW. Hormonal changes in patients with polycystic ovarian disease after ovarian electrocautery or pituitary desensitization. Clin Endocrinol (Oxf) 1990;32: 749754 80. Tropeano G, Liberale I, Vuolo IP, et al. Effects of ovary suppression by a long-acting GnRH-agonist on circulating GH, insulin-like growth factor I and insulin levels in women with polycystic ovary syndrome. J Endocrinol Invest 1997;20:220224 81. Zulian E, Sartorato P, Benedini S, et al. Spironolactone in the treatment of polycystic ovary syndrome: effects on clinical features, insulin sensitivity and lipid prole. J Endocrinol Invest 2005;28:4953 82. Gambineri A, Patton L, Vaccina A, et al. Treatment with utamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study. J Clin Endocrinol Metab 2006;91:39703980 83. Gambineri A, Pelusi C, Genghini S, et al. Effect of utamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2004;60:241249 84. Panidis D, Farmakiotis D, Rousso D, Kourtis A, Katsikis I, Krassas G. Obesity, weight loss, and the polycystic ovary syndrome: effect of treatment with diet and orlistat for 24 weeks on insulin resistance and androgen levels. Fertil Steril 2008;89:899906 85. Florakis D, Diamanti-Kandarakis E, Katsikis I, et al. Effect of hypocaloric diet plus sibutramine treatment on hormonal and metabolic features in overweight and obese women with polycystic ovary syndrome: a randomized, 24-week study. Int J Obes (Lond) 2008;32:692699 86. Elkind-Hirsch K, Marrioneaux O, Bhushan M, Vernor D, Bhushan R. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in

ANDROGENS IN PCOS/GIALLAURIA ET AL

315

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:26702678 Moran L, Norman RJ. Understanding and managing disturbances in insulin metabolism and body weight in women with polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 2004;18:719736 Moran LJ, Brinkworth GD, Norman RJ. Dietary therapy in polycystic ovary syndrome. Semin Reprod Med 2008;26: 8592 Palomba S, Giallauria F, Falbo A, et al. Structured exercise training programme versus hypocaloric hyperproteic diet in obese polycystic ovary syndrome patients with anovulatory infertility: a 24-week pilot study. Hum Reprod 2008;23: 642650 Moran LJ, Noakes M, Clifton PM, Tomlinson L, Galletly C, Norman RJ. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88:812819 Norman RJ, Davies MJ, Lord J, Moran LJ. The role of lifestyle modication in polycystic ovary syndrome. Trends Endocrinol Metab 2002;13:251257 Hollmann M, Runnebaum B, Gerhard I. Effects of weight loss on the hormonal prole in obese, infertile women. Hum Reprod 1996;11:18841891 Guzick DS, Wing R, Smith D, Berga SL, Winters SJ. Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 1994;61:598 604 Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modication in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999;84: 14701474 Clark AM, Ledger W, Galletly C, et al. Weight loss results in signicant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod 1995;10:2705 2712 Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ. Weight loss in obese infertile women results in

97.

98.

99.

100.

101.

102.

103.

104.

improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 1998;13:15021505 Lord J, Thomas R, Fox B, Acharya U, Wilkin T. The central issue? Visceral fat mass is a good marker of insulin resistance and metabolic disturbance in women with polycystic ovary syndrome BJOG 2006;113:1203 1209 Kiddy DS, Hamilton-Fairley D, Bush A, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992;36:105111 Hamilton-Fairley D, Kiddy D, Anyaoku V, Koistinen R, Seppala M, Franks S. Response of sex hormone binding globulin and insulin-like growth factor binding protein-1 to an oral glucose tolerance test in obese women with polycystic ovary syndrome before and after calorie restriction. Clin Endocrinol (Oxf) 1993;39:363367 Bruner B, Chad K, Chizen D. Effects of exercise and nutritional counseling in women with polycystic ovary syndrome. Appl Physiol Nutr Metab 2006;31:384391 Thomson RL, Buckley JD, Noakes M, Clifton PM, Norman RJ, Brinkworth GD. The effect of a hypocaloric diet with and without exercise training on body composition, cardiometabolic risk prole, and reproductive function in overweight and obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:3373 3380 Vigorito C, Giallauria F, Palomba S, et al. Benecial effects of a three-month structured exercise training program on cardiopulmonary functional capacity in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92:13791384 Giallauria F, Palomba S, Maresca L, et al. Exercise training improves autonomic function and inammatory pattern in women with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2008;69:792798 Orio F, Giallauria F, Palomba S, et al. Metabolic and cardiopulmonary effects of detraining after a structured exercise training programme in young PCOS women. Clin Endocrinol (Oxf) 2008;68:976981