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Nutritional management of chronic

female conditions
David R. Seaman, DC, MS, DABCN
Professor, Clinical Sciences

Pregnancy

NaAonal University of Health Sciences


St. Petersburg, Florida

deame@deame.com
NUHS-St Pete

Speakers Bureau

Clinical Consultant

Davis C. Self selection of diet


by newly weaned infants. Am J
Dis Chil 1928; 36(4):651-79 10.

Dr. Clara Davis studied how fifteen


infants of weaning age, i.e., from six to
eleven months, would fair if they were to
select their own diet made up of normal
whole foods.

Davis C. Results of the selfselection of diets by young


children. Can Med Assoc J
1939; (Sep):257-61

The weaning age was chosen because


these infants would have no experience
with whole foods, nor could they have
been influenced by the ideas of older
persons.
Infants were followed for 6-12 months.

Food choices included water, sweet milk, sour


(lactic) milk, sea salt, apples, bananas, orange
juice, fresh pineapple, peaches, tomatoes, beets,
carrots, peas, turnips, cauliflower, cabbage,
spinach, potatoes, lettuce, oatmeal, wheat, corn
meal, barley, Ry-krisp, beef, lamb, bone marrow,
bone jelly, chicken, sweetbreads, brains, liver,
kidneys, fish (haddock).

Despite the fact that these infants could not speak


and did not know the names of the foods they chose
to eat, all infants successfully managed their own
diets. Moreover they were described as thriving
infants with hearty appetites.

All meats, vegetables and fruits were finely cut,


mashed, or ground.

Some caught colds, which lasted for about three


days. There was one epidemic where all infants
simultaneously contracted acute glandular fever of
Pfeiffer. During convalescence from illness, all the
infants consumed large quantities of raw beef, carrots
and beets.

Most foods were cooked, although some were


provided in both the raw and cooked state.

Unlike infants who consume formulas and baby


food, the infants who selected their own diet never
experienced constipation.

At the beginning of the study, we are told that


four infants were poorly nourished and five had
rickets, two cases of which were severe. Each
infant miraculously nursed themselves back to
health without the aid of a parent or doctor.
The first infant in this study had severe rickets.
Dr. Davis placed a small glass of cod liver oil on
his tray for him to consume if he chose. He
consumed it irregularly and in varying amounts
and then suddenly stopped at the precise time
his blood calcium and phosphorus levels
normalized and x-ray signs of rickets were
gone.

Ames BN. Low micronutrient intake may accelerate the


degenerative diseases of aging through allocation of scarce
micronutrients by triage. PNAS. 2006;103(47):17589-94.

Ames presents argument for eating more fruits/


vegetables and taking key supplements:

Multivitamin/mineral
Magnesium (400-1000 mg)
Fish oil (EPA/DHA) (1000-3000 mg)
Vitamin D (2000-10,000 IU)
a-Lipoic acid & acetyl-L-carnitine (ALCAR)

Dr. Davis also assessed the acid-alkaline


balance of the diet. Davis explains that most
authorities agree that a moderate excess of
potentially alkaline foods is desirable.
In her study, one child was exactly balanced
between acid and alkaline foods. The other 14
infants ate a moderate preponderance of
alkaline foods.
The children ate salt on occasion and often
sputtered, choked and even bitterly cried;
however, they never tried to spit it out and
frequently went back for more.

Pregnancy
and
inflammation

Fiber Seaman addiAons: CoQ10, botanicals, glucosamine/


chondroiAn, probioAcs, calcium, chromium, iodine

Appreciating sub-clinical inflammation

Appreciating sub-clinical inflammation

Pathologic examination has been the gold standard


for the diagnosis of inflammation. However,
chemotactic signals must be present for the white
blood cells to migrate to the site of injury or infection.

A clear understanding of the spectrum of


inflammation is important, because there is a
common misconception in clinical medicine that
the absence of signs and symptoms, such as fever,
chills, leukocytosis, etc., makes inflammation and/
or infection unlikely.

Thus, there is a window of time in which a


molecular signature of inflammation is present
before histologic evidence is observed.
For example, analysis of the transcriptome or the
detection of inflammatory markers in body fluids (e.g.,
plasma, cerebrospinal fluid, or amniotic fluid) may
allow detection of early signs of inflammation that
may not be detectable by conventional pathology.
Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,
obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

The evidence suggests that the opposite is the


case. Most cases of histopathological
inflammation, including histological
chorioamnionitis (inflammation of the
chorioamniotic membranes), are subclinical in
nature.
Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,
obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

Pregnancy = inflammation?
Inflammation is central to reproductive success.
Ovulation, menstruation, implantation, and
parturition are all inflammatory processes.
Components of the immune system (major
histocompatability complex) have been implicated
in mate selection and spontaneous abortion.
An exaggerated inflammatory response (systemic
or localized) is a mechanism of disease in
spontaneous abortion, preterm labor, preterm
prelabor rupture of the membranes (PPROM),
preeclampsia, and other great obstetrical
syndromes.
Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,
obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

Implantation = inflammation?

Normal menstruation = inflammation?


Localized inflammation is important during
the menstrual cycle. The endometrium
contains cells of the innate immune system,
including macrophages, dendritic cells,
mast cells, and natural killer cells.
The number of cells from each population
changes during the menstrual cycle, and a
role for the innate immune system has
proposed in the mechanisms of
menstruation.
Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,
obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

Pregnancy = inflammation?

Implantation (the process by


which the blastocyst contacts,
adheres to, and penetrates the
endometrium) is also associated
with inflammatory changes,
presumably deployed to
accomplish the tissue remodeling
required for successful
placentation.

Pregnancy is also characterized by a physiologic


systemic inflammatory response.

Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,


obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,


obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

Parturition = inflammation?
Parturition has also been considered a
localized inflammatory process. The
common terminal pathway of parturition
consists of myometrial activation, cervical
ripening (dilatation and effacement), and
membrane/decidual activation.
The molecular cellular components of
inflammation have been proposed to play a
central role in each of the components of
the common terminal pathway of
parturition.
Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,
obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

The evidence in favor of this is that normal


gestation is accompanied by an increase in the
plasma concentrations of acute-phase reactants
(i.e., fibrinogen, plasminogen activator inhibitor-1,
and ceruloplasmin) and in the number of
leukocytes.
The phenotypic and metabolic characteristics of
the leukocytes (granulocytes and monocytes)
change during the course of pregnancy, and these
changes are consistent with activation.

Pregancy & increased risk of infection?


Pregnant women and animals are more susceptible
to microbial products.
This has been attributed to the activated or
primed state of granulocytes and macrophages in
normal pregnancy. This has clinical implications
because pregnant women are more likely to develop
severe complications of infection, such as acute
respiratory distress syndrome, than non-pregnant
women.
Increased production of interleukin-12 (IL-12) has
been implicated in the mechanisms responsible for
activation of the innate immune system during normal
pregnancy.
Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,
obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

Inflammation in pregnancy complications?


The leading cause of perinatal morbidity and
mortality is preterm parturition. This may occur
because of preterm labor with intact membranes or
PPROM (preterm prelabor rupture of the membranes).
Intrauterine infection and inflammation are important
mechanisms of disease in both conditions.

Pro-inflammatory cytokines in preterm labor


A solid body of evidence indicates that
cytokines play a central role in the
mechanisms of inflammation/infectioninduced preterm parturition.

Preeclampsia is a leading cause of maternal


mortality and is also characterized by an exaggerated
inflammatory response.

IL-1 was the first cytokine to be implicated


in the onset of preterm labor associated
with infection.

Intrauterine infections (bacterial and viral) can reach


the human fetus and lead to complications ranging
from congenital anomalies to cerebral palsy.

Evidence supports the role of tumor


necrosis factor alpha (TNF-a) in preterm
parturition.

Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,


obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,


obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

The following have also been implicated in the mechanisms of disease of


preterm labor and delivery:

Interleukin-10 prevents preterm parturition?

Cytokines
IL-6
IL-16
IL-18
colony stimulating factors (CSFs)
macrophage migration inhibitory factor (MIF)

IL-10 is thought to be a key cytokine for the maintenance


of pregnancy.

Chemokines
IL-8
monocyte chemotactic protein-1 (MCP-1)
epithelial cell-derived neutrophil-activating peptide
(ENA)-78
regulated on activation normal T cell expressed and
secreted (RANTES)
Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,
obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

IL-10 production is significantly reduced in the no labor


placenta at term compared with that from first- and
second-trimester tissues, suggesting that down-regulation
of IL-10 is a physiologic event that favors an inflammatory
state around the time of labor onset.
IL-10 has also been implicated in the control of preterm
parturition associated with inflammation.
IL-10 expression was reduced in placental tissues of
pregnancies complicated by preterm labor and
chorioamnionitis when compared to placental tissues
from normal controls.
Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,
obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

Interleukin-10 and pregnancy research


IL-10 inhibited COX-2 mRNA expression
in cultured placental explants from
preterm labor deliveries.
TNF-a levels and leukocyte counts were
significantly attenuated by IL-10
treatment.
The administration of IL-10 in animal
models of infection has been associated
with improved pregnancy outcome.
Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,
obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

Pregnancy complicaAons in IL-10/ mice were


associated with unexpected and robust TLR-9-
triggered acAvaAon and amplicaAon of uterine
neutrophil and macrophage subpopulaAons
followed by their migraAon to the placental zone.

A need to focus on inflammation


reduction during pregnacy

The modulation of the maternal


and fetal inflammatory
response during pregnancy
has considerable importance
for furthering understanding of
the mechanisms of disease
and reproduction.

impact on
cardiovascular and
gastrointestinal
disease

Romero R et al. Inflammation in pregnancy: its roles in reproductive physiology,


obstetrical complications, and fetal injury. Nutr Rev. Dec, 2007(II):S194-S202

Palinski W, Yamashita T, Freigang S, Napoli C. Developmental programing:


maternal hypercholesterolemia and immunity influence susceptibility to
atherosclerosis. Nutr Rev. Dec, 2007(II):S182-S187

The Fate of Early Lesions in Children


(FELIC) study, an autopsy study of 156
children aged 113 years with normal
cholesterol levels, revealed the
progression of atherosclerosis to be
markedly faster in offspring of
hypercholesterolemic mothers than in
those whose mothers had normal
cholesterol levels (Fig 1).

Palinski W, Yamashita T, Freigang S, Napoli C. Developmental programing:


maternal hypercholesterolemia and immunity influence susceptibility to
atherosclerosis. Nutr Rev. Dec, 2007(II):S182-S187

Innis SM, Jacobson K.


While fatty streaks were present in the aortas
of fetuses from normocholesterolemic
mothers, the aortas from the fetuses of
chronically hypercholesterolemic mothers,
and of mothers who developed temporary
hypercholesterolemia during pregnancy,
contained significantly more and larger
lesions, demonstrating the influence of the
maternal environment over the onset of
atherosclerosis.

Dietary lipids in early


development and intestinal
inflammatory disease.
Nutr Rev. Dec, 2007(II):S188S193

Innis SM, Jacobson K. Dietary lipids in early


development and intestinal inflammatory disease.
Nutr Rev. Dec, 2007(II):S188-S193

Innis SM, Jacobson K. Dietary lipids in early


development and intestinal inflammatory disease.
Nutr Rev. Dec, 2007(II):S188-S193

Numerous studies worldwide have shown that the


n-6 PUFA LA and the n-3 PUFA ALA and DHA contents
in human milk depend on the mothers PUFA intake.

For many years the correlation between the n-6 and


n-3 PUFA levels in human milk and the mothers
dietary fat intake was poorly appreciated, and this led
to the faulty extrapolation that the average fatty acid
composition of milk in North America is the best
model on which to base the PUFA composition of
infant formula.

It is not surprising, therefore, that the n-6 PUFA


content of human breast milk has increased
dramatically (about two-fold since the 1950s), echoing
the changes in dietary fat consumption.
At the same time, the levels of DHA in human milk in
Canada and the United States are some of the lowest
worldwide, at about 0.2 to 0.3% compared to levels of
0.8% or higher in countries where fish is widely
consumed groups.

Thus, modern infant formulas also contain 1620%


LA in the fat, representing 710% of dietary energy
intake from LA in the formula-fed infant.
Human milk in the 1950s contained closer to 4%
energy from LA.

Innis SM, Jacobson K. Dietary lipids in early


development and intestinal inflammatory disease.
Nutr Rev. Dec, 2007(II):S188-S193

Innis SM, Jacobson K. Dietary lipids in early


development and intestinal inflammatory disease.
Nutr Rev. Dec, 2007(II):S188-S193

Both swallowing of amniotic fluid and


placental transfer of fatty acid contribute to
fetal PUFA accretion, and that a maternal diet
high in n-6 and low in n-3 PUFAs can change
fetal PUFA content to favor a more
inflammatory gastrointestinal environment.

It is entirely possible that the


increased n-6 PUFA intake that has
taken place over the past 50 years has
resulted in a heightened
gastrointestinal inflammatory
response, so immune challenges that
previously would have resolved
naturally now become prolonged and
develop into IBD.

Given the low n-3 PUFA intake identified in


recent studies of pregnant women in Canada
and the United States, this is a concern.

Innis SM, Jacobson K. Dietary lipids in early


development and intestinal inflammatory disease.
Nutr Rev. Dec, 2007(II):S188-S193
Increasing dietary n-6 PUFA intakes could therefore
create a pro-inflammatory environment, while a diet low
in n-6 PUFA with a favorable n-6 to n-3 PUFA balance
should promote an environment more tolerant to
immunological challenge.
Some epidemiological evidence supports this. The
major dietary source of n-3 PUFA, EPA, and DHA is fish.
Inuit and Japanese societies with traditionally high EPA
and DHA intakes from fish or marine mammals, and low
intakes of n-6 PUFA, also tend to have low rates of IBD.
Notably, the Japanese diet is becoming increasingly
Westernized and IBD incidence is increasing.

Innis SM, Jacobson K. Dietary lipids in early


development and intestinal inflammatory disease.
Nutr Rev. Dec, 2007(II):S188-S193

Studies showing that supplementation


of the maternal diet with DHA from fish
or fish oils during gestation increases
DHA in infant plasma and red blood
cells at birth provide more specific
evidence that maternal n-3 fatty acid
nutrition is a critical determinant of
fetal n-3 fatty acid accretion.

Gluten & infertility?

Deflaming lifestyle impact on fertility


and health of
offspring

Atypical silent celiac disease


can manifest as infertility in
some women and this has been
suspected for many years
Wilson C, Eade OE, Elstein M, Wright R. Subclinical coeliac
disease and infertility. Brit Med J. 1976; 2(6029):215-16.
Collin P, Vilska S, Heinonen PK, Hallstrom 0, Pikkarainen P.
Infertility and coeliac disease. Gut. 1996;39:382-84.
Kumar A, Meena M, Begum N et al. Latent celiac disease in
reproductive performance of women. Fertil Steril. 2010 Nov 22.
[Epub ahead of print].

Mikkelsen TB, Osterdal ML, et al. Association between a


Mediterranean-type diet and risk of preterm birth among Danish
women: a prospective cohort study. Acta Obstet Gynecol Scand,
2008; 87(3): 325-30
In a prospective cohort study involving 35,530 non-smoking
women, results indicate that maternal intake of a Mediterraneantype diet may be associated with a reduced risk of preterm birth.
Mid-pregnancy diet was assessed using food frequency
questionnaires. A Mediterranean-type diet was defined by fish
intake at least twice per week, use of olive oil or rape seed oil,
intake of at least 5 fruits and vegetables per day, consumption of
meat (other than poultry and fish) at most twice per week, and at
most 2 cups of coffee per day.
Of all the participants, 1,137 women fulfilled all the
Mediterranean-type diet criteria, and 540 women met none of the
criteria. Women adhering to the Mediterranean-type diet showed
a 39% reduced risk of preterm birth and a 72% reduced risk of
early preterm birth, compared with women who did not fulfill any
of the Mediterranean-type diet criteria.

Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Diet and lifestyle in the
prevention of ovulatory disorder infertility. Obstet Gynecol. 2007;110(5):1050-58.

A validated food frequency questionnaire was used to


report how often, on average, participants consumed
certain foods, beverages, and supplements, with 9
options for frequency, from "never or less than once per
month" to "6 or more times a day.
A summary "fertility diet" score was calculated for each
woman based on variables found to predict ovulatory
disorder infertility, the highest score in the category
indicating the lowest risk.
The "fertility diet" score ranged from 8 to 40, and the
median score was 24 points.
Women were divided into 5 groups according to
quintiles.

Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Diet and
lifestyle in the prevention of ovulatory disorder infertility. Obstet
Gynecol. 2007;110(5):1050-58.

Our results suggest that a fertility diet pattern may have


favorable effects on the fertility of otherwise healthy
women and that combining this dietary strategy with body
weight control and increased physical activity may help
prevent the majority of infertility cases due to problems
with ovulation.
Because data on the potential role of specific dietary
patterns on fertility are scarce, it is important that these
findings are reproduced, preferably in large randomized
trials.
In the meantime, women trying to become pregnant could
consider following these lifestyle practices because they
are consistent with an overall healthy lifestyle and may also
help them become pregnant.

Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Diet


and lifestyle in the prevention of ovulatory disorder
infertility. Obstet Gynecol. 2007;110(5):1050-58.
Mean age of the women was 32 years, alcohol intake was
2 g/day, 22% drank 2 or more cups of coffee daily, 7% were
current smokers, and 23% were nulliparous.
During 8 years of follow-up, 25,217 pregnancies and
pregnancy attempts were accrued among the 17,544
women.
Women with a high "fertility diet" score were more likely
to consume coffee and alcohol and be physically active and
were less likely to smoke, have long menstrual cycles, and
be recent users of hormonal contraception.
Increasing adherence to the "fertility diet" was associated
with lower risk for ovulatory disorder infertility (P for trend
< .001).

Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Diet and lifestyle in the
prevention of ovulatory disorder infertility. Obstet Gynecol. 2007;110(5):1050-58.

Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Diet and lifestyle in the
prevention of ovulatory disorder infertility. Obstet Gynecol. 2007;110(5):1050-58.

Compared with women in the lowest quintile of the


"fertility diet," women in the highest quintile had a
66% lower risk for ovulatory disorder infertility and a
27% lower risk for infertility from other causes.

Age, parity, and BMI did not alter the


relationship between "fertility diet" score
and risk for ovulatory infertility.

Compared with women with a BMI between 20 and


24.9 kg/m2, women with a BMI of less than 20 kg/m2
and more than 30 kg/m2 had a higher risk for
ovulatory infertility.

The risk for ovulatory infertility was lower


for each additional low-risk lifestyle habit
followed, up to 69% lower risk for women
adhering to 5 or more habits.

Time spent in vigorous physical activity was


unrelated to infertility overall - Women with vigorous
physical activity for 30 minutes or more each day had
a slightly lower risk for ovulatory infertility.

Diet composition had a greater impact on


fertility than either BMI or vigorous physical
activity alone.

Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Diet and lifestyle in the
prevention of ovulatory disorder infertility. Obstet Gynecol. 2007;110(5):1050-58.

Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Diet and lifestyle in the
prevention of ovulatory disorder infertility. Obstet Gynecol. 2007;110(5):1050-58.

The 8 nutritional factors consider in this study:

Ratio of monounsaturated to trans fat


Animal protein (% of calories)
Vegetable protein (% of calories)
Glycemic load
Multivitamins (tablets/wk)
Iron (mg/day)
High-fat dairy (servings)
Low-fat dairy (servings)

Glycemic index

Glycemic load

Low GI = 55 or less

Low GL = 10 or less

Medium GI = 56 - 69

Medium GL = 11- 19

High GI = 70 or more

High GL = 20 or more

http://www.glycemicindex.com/

http://www.glycemicindex.com/

Zhang C. Dietary fiber intake, dietary glycemic load, and the risk for

gestational diabetes mellitus. Diabetes Care. 2006; 29(10): 2223-30

RESULTSWe documented 758 incident GDM cases


during 8 years of follow-up. After adjustment for age,
parity, prepregnancy BMI, and other covariates, dietary
total fiber and cereal and fruit fiber were strongly
associated with GDM risk.
Each 10-g/day increment in total fiber intake was
associated with 26% reduction in risk; each 5-g/day
increment in cereal or fruit fiber was associated with a
23% or 26% reduction, respectively.
Dietary glycemic load was positively related to GDM
risk. The combination of highglycemic load and low
cereal fiber diet was associated with 2.15-fold
increased risk compared with the reciprocal diet.

Qiu C et al. Dietary fiber intake in early pregnancy and risk of subsequent
preeclampsia. Am J Hypertens. 2008; 21(8): 903-9

In a study involving data from 1,538 pregnant women (residents


of Washington state), intake of dietary fiber in early pregnancy
was found to be associated with a significantly reduced risk of
preeclampsia. Subjects' diets were assessed 3 months before
pregnancy and during early pregnancy. !
Results showed that women in the highest quartile of dietary
fiber intake (at least 21.2 g/d) had a significantly reduced relative
risk of preeclampsia, compared to subjects in the lowest quartile
of dietary fiber intake (less than 11.9 g/d), after adjusting for
various potentially confounding factors. Similar associations
were found for water-soluble fiber intake and insoluble fiber
intake. !
Women consuming the most fiber had significantly lower
concentrations of triglycerides (-11.9 mg/dl) and higher
concentrations of HDL cholesterol (+2.63 mg/dl), compared to
women consuming the least (lowest quartile) dietary fiber. !

Fiber-deficiency states
Diets low in dietary fiber may
underlie or exacerbate
constipation, appendicitis,
hemorrhoids, deep vein
thrombosis, varicose veins,
diverticulitis, hiatal hernia, and
gastroesophageal reflux.
Cordain L et al. Origins and evolution of the Western diet: health implications for the 21st
century. Am J Clin Nutr. 2005; 81(2):341-54

Gestational diabetes mellitus (GDM) is among the most


common complications of pregnancy.
GDM complicates 7% of all pregnancies, resulting in
>200,000 cases annually. Recent data have shown a
substantial rise in the incidence of GDM from 1991 to 2000
and a doubling from 1994 to 2002.
Women with GDM experience increased risk for prenatal
morbidity and a considerably elevated risk for impaired
glucose tolerance and type 2 diabetes in the years
following pregnancy. Children of women with GDM are
more likely to be obese and have impaired glucose
tolerance and diabetes in early adulthood. Few modifiable
risk factors for GDM have been identified.
Obesity is the major recognized modifiable risk factor
thus far. High prepregnancy BMI has been consistently
associated with an increased risk of GDM.

Fiber issues
The fiber content (15.1 g/d) of the typical
US diet is considerably lower than
recommended values (2530 g).
Refined grains contain 400% less fiber
than do whole grains (by energy).
Fiber-rich foods: Fresh fruit typically
contains twice the amount of fiber in whole
grains, and nonstarchy vegetables contain
almost 8 times the amount of fiber in whole
grains on an energy basis.
Cordain L et al. Origins and evolution of the Western diet: health implications for the 21st
century. Am J Clin Nutr. 2005; 81(2):341-54

Morrison JA, Glueck CJ. Wang P. Dietary trans fatty


acid intake is associated with increased fetal loss.
Fertil Steril, 2007 Nov 28.
OBJECTIVE: To examine whether dietary trans fatty acids (TFAs) were
associated with fetal loss (no. of pregnancies - no. of live births). The
basis of our inquiry derives from the facts that the PPAR-gamma
receptor plays a pivotal role in placental function and that TFAs downregulate PPAR-gamma gene mRNA expression.
DESIGN: Retrospective study comparing dietary data on TFAs and total
calories from Block 98 quantitative food frequency questionnaire on 104
women with insulin data and reporting one or more pregnancies.
SETTING: Twenty-five- to 30-year follow-up as young adults (age 39.5 +/4.5 years) of schoolgirls in the Princeton School cardiovascular risk
study.
PATIENT(S): Former participants in school-based research program at
ages 6-18 years (1973-78), screened as part of follow-up study
(1998-2003).
MAIN OUTCOME MEASURE(S): Fetal loss.

Morrison JA, Glueck CJ. Wang P. Dietary trans fatty


acid intake is associated with increased fetal loss.
Fertil Steril, 2007 Nov 28.
RESULT(S): By stepwise logistic regression, with fetal loss (>/=1
vs. 0) as the dependent variable and total calories, percent
calories from TFAs (linear and squared terms), diabetes (yes/no),
serum insulin, age, race, body mass index, leisure and work
physical activity, and education as explanatory variables,
percent calories from TFAs was positively, curvilinearly,
independently associated with fetal loss.
For each 1-unit increase in the squared term of percent calories
from TFAs, the odds of having fetal loss versus no fetal loss
increased 1.106 times (odds ratio = 1.106; 95% confidence
interval 1.026-1.192).
CONCLUSION(S): Since PPAR-gamma plays a pivotal role in
placental biology and is down-regulated by TFAs, TFAs may be a
reversible risk factor for fetal loss.

Michalik L, Wahli W. Involvement of PPAR


nuclear receptors in tissue injury and wound
repair. J Clin Invest 2006; 116:598-606

Nilsen RM, Vollset SE, et al. Folic Acid and Multivitamin Supplement Use and Risk
of Placental Abruption: A Population-based Registry Study. Am J Epidemiol. 2008;
1/10

Summary: In a study involving 280,127 singleton deliveries


recorded over a 5-year period, results indicate that folic acid and
multivitamin supplementation during pregnancy may be
associated with a reduced risk of placental abruption.
Using logistic regression models adjusted for potential
confounders, any supplement use any time during pregnancy
was associated with a 26% reduced risk of placental abruption,
compared with no supplement use.
Similarly, folic acid supplementation was associated with a 19%
reduced risk of placental abruption, and multivitamin
supplementation was associated with a 28% reduced risk of
placental abruption, compared with no supplementation.
Michalik L, Wahli W. Involvement of PPAR
nuclear receptors in tissue injury and wound
repair. J Clin Invest 2006; 116:598-606

Wen, Shi Wu, Chen Xi-Kuan, et al. Folic acid supplementation in early second
trimester and the risk of preeclampsia. Am J Obs Gynecol. 2008; 198(1):
45.e1-45.e7.!

Summary: In a prospective cohort study involving


2,951 pregnant women, supplementation with
multivitamins containing folic acid was found to be
associated with a significantly reduced risk of
developing preeclampsia.
Increased serum folate (average: 10.51 micromol/L)
and decreased serum homocysteine (average: 0.39
micromol/L) were also found in women who
supplemented with multivitamins containing folic acid.
These results add further weight to the
recommendation that pregnant women supplement
with multivitamins containing folic acid.

Additionally, combined supplementation with folic acid and


multivitamins was associated with a 32% reduced risk of
placental abruption.

Chavarro JE, Willett WC, et al. Use of multivitamins, intake of B vitamins,


and risk of ovulatory infertility. Fertil Steril, 2008; 89:668-76.

In an 8-year, prospective cohort study involving 18,555 married,


premenopausal women without a history of infertility who
attempted a pregnancy or became pregnant, results indicate that
regular use of multivitamin supplements may be associated with
a reduced risk of ovulatory infertility.
During 8 years of follow-up, 438 women reported infertility
caused by ovulatory disorder.
Women taking two or less multivitamin tablets per week showed
a 12% reduced risk of ovulatory infertility, women taking three to
five multivitamin tablets per weeks showed a 31% reduced risk,
and women taking six or more multivitamin tablets per week
showed a 41% reduced risk, compared to women who did not use
multivitamin supplements.
The association between frequency of multivitamin supplement
use and risk of ovulatory infertility was partly explained by folic
acid.

10

From the vitamindcouncil.org

References

"There is growing evidence that the lack of vitamin D sufficiency


may be involved in a variety of systemic diseases, many of
which manifest later in life. Vitamin D deficiency is common
among pregnant women. Supplementation of mothers during
pregnancy and lactation with less than 1000 IU/day of vitamin D
may be inadequate in maintaining optimal levels of 25(OH)D for
both mothers and their infants (1)

1. Canadian Paediatric Society. Vitamin D


supplementation: recommendations for canadian
mothers and infants. Paediatr Child Health. 2007;12(7):
583-89.

Evidence is accumulating that autism is one sequela of maternal


vitamin D deficiency (2). Autistic damage from maternal vitamin
D deficiency will not manifest itself until several years after
birth, exposing the obstetrician to potential liability well into the
future.

3. Hollis BW. Vitamin D requirement during pregnancy


and lactation. J Bone Miner Res. 2007;22(Suppl
2):V39-44.

Recent evidence indicates pregnant and lactating women may


need as much as 7,000 IU of vitamin D per day (3). The tiny
amount of Vitamin D in prenatal vitamins is irrelevant (4).

2. Cannell JJ. Autism and vitamin D. Med Hypothesis.


2008: 70(4):750-59.

4. Bodnar LM et al. High prevalence of vitamin D


insufficiency in black and white pregnant women
residing in the northern United States and their
neonates. J Nutr. 2007;137(2):447-52.

Estimated* needs of vit D throughout lifecycle


1. Breast-fed infants (800 IU/day)
2. Formula-fed infants (400 IU/day)
3. Toddlers & young children (1000-2000 IU/day)
[when not getting adequate sun, and based on weight*]
4. Lactating women: 7,000 IU/day
5. Adolescents and adults can take between
3000-10000 IU or more depending on vitamin D levels in
blood (serum 25(OH)D: 32-100 ng/ml).
6. Pregnant or those thinking of becoming pregnant
get 25(OH)D check every 3-months (get to 40-70 ng/ml*)

PolycysAc
ovarian
syndrome

Read full text before acting: Cannell JJ, Hollis BW. Use of vitamin D(3) in
clinical practice. Alt Med Rev. 2008;13(1):6-20.

PolycysAc ovary syndrome is a disorder involving infrequent or prolonged menstrual periods


or excess male hormone (androgen) levels. The ovaries develop numerous small cysts and may
fail to release eggs.

PolycysAc
ovarian
syndrome
PolycysAc ovaries have been called
oyster ovaries because they are
enlarged and sclerocysAc with
smooth, pearl-white surfaces w/o
indentaAons. Many small uid-lled
follicle cysts lie beneath the thickened
brous surface of the cortex.
Tzadik M et al. Benign disorders of the ovaries and oviducts. In p.
654-661. In Decherney AH et al. Current Diagnosis and Treatment.
Obstetrics and gynecology. 10th ed. New York: McGraw Hill; 2007

11

PCOS basics:

Imaging for polycysAc ovarian syndrome

ManifestaAons: persistent anovulaAon can lead to enlarged


polycysAc ovaries, secondary amenorrhea or
oligomenorrhea, and inferAlity

Ovarian ultrasonography, preferably accomplished by using


a transvaginal approach, can be performed to assess
ovarian morphology.

Prevalence: 5-10% with variances among races and


ethniciAes

Polycystic ovaries are defined as 12 or more follicles in at


least 1 ovary measuring 2-9 mm in diameter or a total
ovarian volume of >10 cm3.

50% of paAents are hirsute


30-75% are obese
Most paAents with PCOS seek treatment for hirsuAsm or
inferAlity
As liale as 2-7% reducAon in body weight improves
ovulatory funcAon in PCOS
Tzadik M et al. Benign disorders of the ovaries and oviducts. In p.654-661. In Decherney AH
et al. Current Diagnosis and Treatment. Obstetrics and gynecology. 10th ed. New York:
McGraw Hill; 2007

hap://emedicine.medscape.com/arAcle/256806-workup#a0720

Metabolic syndrome and PCOS


Metabolic syndrome is a growing health epidemic, currently
aecAng nearly 25% of all women in the USA.
Central obesity has the strongest correlaAon with metabolic
syndrome. Metabolic syndrome is present in 28% of overweight
and 50% of obese women; furthermore, in women with abdominal
obesity (dened as a waist circumference >35), 43% develop
metabolic syndrome within 5 years.
The presence of metabolic syndrome ranging from 33% to 46% of
women with a diagnosis of PCOS

Trends Endocrinol Metab. 2011;22(3):103-9.


Cardozo E et al. Metabolic syndrome and oocyte quality. Trends Endocrinol Metab. 2011;22(3):103-9.

But what about normal weight women


with syndrome X?

33.4% of women with PCOS in a study also had undiagnosed


metabolic syndrome, with obesity having an independent eect on
the development of metabolic syndrome
InteresAngly, none of the women with PCOS who had a BMI of
<27.0 met the criteria for metabolic syndrome
Cardozo E et al. Metabolic syndrome and oocyte quality. Trends Endocrinol Metab. 2011;22(3):103-9.

Metabolic syndrome and obese animal models


Altered mitochondrial acAvity has been proposed as a
mechanism for compromised oocyte quality and poor
reproducAve outcomes in obese females.
Oocytes of obese mice have increased inner
mitochondrial membrane potenAal, uneven distribuAon of
mitochrondria throughout the ooplasm, increased
generaAon of reacAve oxygen species, and a more oxidized
redox state.

St-Onge MP, Janssen I, Heymsfield SB. Metabolic syndrome in normal-weight


Americans; new definition of the metabolically obese, normal weight individual.
Diabetes Care 2004;27: 2222-28.

The oocytes of these mice demonstrated decreased


ability to develop to the blastocyst stage compared with
those of non-obese mice, indicaAng the importance of
correct mitochondrial funcAon for normal embryonic
development.
Cardozo E et al. Metabolic syndrome and oocyte quality. Trends Endocrinol Metab. 2011;22(3):103-9.

12

In humans: Follicular inammaAon idenAed


A study exploring dierences in the pre-ovulatory follicular
environment of obese women, by analyzing aspirated follicular
uid at oocyte retrieval, found that women with higher BMI
had increased levels of insulin, lactate, triglycerides and C-
reacAve protein (CRP) in the follicular uid, and had decreased
levels of steroid hormone-binding globulin, indicaAng that the
maternal metabolic environment has a direct eect on the
ovarian follicular microenvironment.
The increased level of CRP in the follicular uid of obese
women is of parAcular concern, because it might indicate
inammaAon and increased oxidaAve stress, which has been
associated with decreased developmental potenAal in the
oocyte.
Cardozo E et al. Metabolic syndrome and oocyte quality. Trends Endocrinol Metab. 2011;22(3):103-9.

PolycysAc ovary syndrome (PCOS) is characterized by


hyperandrogenism and anovulaAon and aects 510% of
women of reproducAve age. Insulin resistance is a common
nding, and has been linked with the pathogenesis of
PCOS. Women with PCOS are more likely to develop type 2
diabetes, and there is some evidence to support an
increase in cardiovascular disease (CVD) risk.
Cross-secAonal data showed that a greater plasma n6
PUFA concentraAon and n6:n3 PUFA raAo were
associated with higher circulaAng androgens.
Phelan N et al. Hormonal and metabolic eects of polyunsaturated faay acids in young
women with polycysAc ovary syndrome: results from a cross-secAonal analysis and a
randomized, placebo-controlled, crossover trial. Am J Clin Nutr. 2011;93(3):652-62.

PCOS basics:
ManifestaAons: persistent anovulaAon can lead to enlarged polycysAc ovaries, secondary amenorrhea
or oligomenorrhea, and inferAlity
Prevalence: 5-10% with variances among races and ethniciAes
50% of paAents are hirsute
30-75% are obese
Most paAents with PCOS seek treatment for hirsuAsm or inferAlity

As liale as 2-7% reducAon


in body weight improves
ovulatory funcAon in PCOS
Tzadik M et al. Benign disorders of the ovaries and oviducts. In p.654-661. In Decherney AH
et al. Current Diagnosis and Treatment. Obstetrics and gynecology. 10th ed. New York:
McGraw Hill; 2007

Ames BN. Low micronutrient intake may accelerate the


degenerative diseases of aging through allocation of scarce
micronutrients by triage. PNAS. 2006;103(47):17589-94.

Ames presents argument for eating more fruits/


vegetables and taking key supplements:

Multivitamin/mineral
Magnesium
Fish oil (EPA/DHA)
Vitamin D
a-Lipoic acid & acetyl-L-carnitine (ALCAR)
Fiber

(Seaman additions: CoQ10, anti-inflammatory botantical,


glucosamine/chondroitin, hydroxyapatite calcium,
proteolytic enzymes, chromium, vitamin K2, iodine)

Supplements for glycemic regulaAon:

Magnesium
Vitamin D
Chromium
Lipoic acid
Gymnema sylvestre
Cinnamon
Vanadium

Not in notes

Pimental M Dig Dis Sci. 2010;55:1085-89.

13

PLOS One. 2013;8(7):e67531

RNA Sequencing of the Human Milk Fat Layer


Transcriptome Reveals Distinct Gene Expression Profiles
at Three Stages of Lactation
Danielle G. Lemay1, Olivia A. Ballard2,3, Maria A. Hughes2, Ardythe L. Morrow2,3, Nelson D. Horseman3,
Laurie A. Nommsen-Rivers2,3*
1 Genome Center, University of California Davis, Davis, California, United States of America, 2 Department of Pediatrics, Cincinnati Childrens Hospital Medical Center,
Cincinnati, Ohio, United States of America, 3 College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America

Abstract
Aware of the important benefits of human milk, most U.S. women initiate breastfeeding but difficulties with milk supply
lead some to quit earlier than intended. Yet, the contribution of maternal physiology to lactation difficulties remains poorly
understood. Human milk fat globules, by enveloping cell contents during their secretion into milk, are a rich source of
mammary cell RNA. Here, we pair this non-invasive mRNA source with RNA-sequencing to probe the milk fat layer
transcriptome during three stages of lactation: colostral, transitional, and mature milk production. The resulting
transcriptomes paint an exquisite portrait of human lactation. The resulting transcriptional profiles cluster not by
postpartum day, but by milk Na:K ratio, indicating that women sampled during similar postpartum time frames could be at
markedly different stages of gene expression. Each stage of lactation is characterized by a dynamic range (105-fold) in
transcript abundances not previously observed with microarray technology. We discovered that transcripts for isoferritins
and cathepsins are strikingly abundant during colostrum production, highlighting the potential importance of these
proteins for neonatal health. Two transcripts, encoding b-casein (CSN2) and a-lactalbumin (LALBA), make up 45% of the
total pool of mRNA in mature lactation. Genes significantly expressed across all stages of lactation are associated with
making, modifying, transporting, and packaging milk proteins. Stage-specific transcripts are associated with immune
defense during the colostral stage, up-regulation of the machinery needed for milk protein synthesis during the transitional
stage, and the production of lipids during mature lactation. We observed strong modulation of key genes involved in
lactose synthesis and insulin signaling. In particular, protein tyrosine phosphatase, receptor type, F (PTPRF) may serve as a
biomarker linking insulin resistance with insufficient milk supply. This study provides the methodology and reference data
set to enable future targeted research on the physiological contributors of sub-optimal lactation in humans.
Citation: Lemay DG, Ballard OA, Hughes MA, Morrow AL, Horseman ND, et al. (2013) RNA Sequencing of the Human Milk Fat Layer Transcriptome Reveals
Distinct Gene Expression Profiles at Three Stages of Lactation. PLoS ONE 8(7): e67531. doi:10.1371/journal.pone.0067531
Editor: Kartik Shankar, University of Arkansas for Medical Sciences, United States of America
Received January 7, 2013; Accepted May 20, 2013; Published July 5, 2013
Copyright: ! 2013 Lemay et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by the Cincinnati Childrens Hospital Perinatal Institute (http://www.cincinnatichildrens.org/service/p/perinatal/default/);
Cincinnati Diabetes and Obesity Center (http://diabetes.uc.edu/Research/Overview.aspx); National Center for Research Resources (NCRR) (P51RR000169-49S1); the
National Center for Advancing Translational Sciences (NIH 8 UL1 TR000077-04); and National Institutes of Health (NIH) HD13021. The content is solely the
responsibility of the authors and does not necessarily represent the official views of the NCRR or NIH. The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript.

We observed strong modulation of key genes


involved inlactose synthesis and insulin signaling.
In particular, protein tyrosine phosphatase,
receptor type, F (PTPRF) may serve as a biomarker
linking insulin resistance with insufficient milk
supply.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: laurie.nommsen-rivers@cchmc.org

systematic samples of mammary tissue from lactating woman.


However, there is an intriguing workaroundhuman milk secreted
during lactation is a rich source of mammary epithelial cell RNA.
As lipid droplets exit the mammary epithelial cell, they are
enveloped by cell membrane and secreted into milk as membranebound globules of fat. About 38% of human milk fat globules
contain mammary epithelial cell cytoplasmic remnants, including
RNA, captured during milk fat globule formation and secretion
[9]. Maningat et al. demonstrated that the microarray-generated
human milk fat layer transcriptome includes genes uniquely
expressed in the lactating mammary epithelial cell [10]. Their
ground-breaking work established the human milk fat layer as a
potential window into mammary epithelial cell gene expression
during lactation without invasive tissue biopsy.
With the advent of RNA sequencing (RNA-Seq) it is now
possible to characterize the gene expression of milk-producing cells

Introduction

Diabetes Care.
2011;34:1669-75.

Premenstrual syndrome!

Breastfeeding provides numerous benefits for both mother and


infant [13]. The U.S. Surgeon General [4], Institute of Medicine
[5], and American Academy of Pediatrics [6] all recommend that
infants be exclusively breastfed for the first 6 months with
continued breastfeeding for at least 1 year. Most new mothers in
the U.S. initiate breastfeeding in an attempt to follow these
recommendationsbut there is wide variation in lactation success
with 50% of mothers failing to achieve their personal breastfeeding
goals [7]. While there has been progress in recognizing how
hospital and workplace barriers may undermine breastfeeding [8],
the contribution of maternal physiology to lactation difficulties
remains poorly characterized.
Research into the biology of human lactation has been seriously
impeded by the impracticality and ethical concerns of obtaining

PLOS ONE | www.plosone.org

July 2013 | Volume 8 | Issue 7 | e67531

Premenstrual syndrome (PMS)


Psychoneuroendocrine disorder with biologic,
psychologic, and social parameters
Extremely prevalent: 75% experience some
PMS symptoms; 20-40% are mentally or
physically incapacitated to some degree; 5%
experience severe distress
Highest incidence: later 20s to early 30s
Decherney AH, Goodwin TM. Current diagnosis & treatment: obstetrics and gynecology.
10th ed. McGraw-Hill: NY; 2007

Symptoms of PMS

Diagnosis of Premenstrual Dysphoric Disorder

Headache, breast tenderness, pelvic pain,


bloaAng
More severe symptoms: irritability, dysphoria
(anxiety, depression, and restlessness,
dissaAsfacAon), mood liability (intense mood
swings)
*when disrupt daily funcAoning = (PMDD)
premenstrual dysphoric disorder
Decherney AH, Goodwin TM. Current diagnosis & treatment: obstetrics and gynecology.
10th ed. McGraw-Hill: NY; 2007

Treat with anA-depressants: SSRIs

14

EAology of PMS
Unknown, but the following have been
historically proposed: estrogen-progesterone
imbalance, excess aldosterone, hypoglycemia,
hyperprolacAnemia, psychogenic factors
Recent consensus: physiologic ovulaAon is
trigger (medical or surgical inhibiAon of ovulaAon
eliminates symptoms); with estrogen/
progesterone and serotonin being viewed as
parAcipants
Decherney AH, Goodwin TM. Current diagnosis & treatment: obstetrics and gynecology.
10th ed. McGraw-Hill: NY; 2007

Diagnosis of PMS
A. Based on paAent history
B. Laboratory TesAng
1. No physiological or hormonal tests conrm PMS/
PMDD
2. Laboratory tests may be in order to rule out
alternaAve diagnoses.
- This includes such condiAons as anemia,
autoimmune disorders, endocrine and thyroid
disorders (hyperprolacAnemia, hypothyroidism,
diabetes mellitus), chronic faAgue syndrome,
endometriosis, and psychiatric disorders
hap://www.medscape.com/viewarAcle/551199_2

Physical EvaluaAon
A.Vital signs
B. Weight
C. Thyroid examinaAon
D.Breast, abdominal, and pelvic examinaAon
if indicated as part of rouAne reproducAve
health care
E. AddiAonal physical examinaAon
components as indicated by history
F. Assessment of aect
hap://www.medscape.com/viewarAcle/551199_2

Premenstrual syndrome can be diagnosed if the paAent reports at


least one of the following aecAve and somaAc symptoms during the
5 days before menses in each of the three prior menstrual cycles:
AecAve
- depression
- angry outbursts
- irritability (hallmark symptoms)
- anxiety
- confusion
- social withdrawal

SomaAc
- breast tenderness
- abdominal bloaAng
- headache
- swelling of extremiAes

Relieved within 4 days of menses onset, w/o recurrence unAl at least


cycle day 13
Present in the absence of any pharmacologic therapy, hormone ingesAon,
or drug/ROH abuse
Occur reproducibly during two cycles of prospecAve recording
Suers from idenAable dysfuncAon in social or economic performance
hap://www.medscape.com/viewarAcle/551199_2

15

NON-pharmacologic Rx

Pharmacologic Rx
A. Non-steroidal anA-inammatory drugs (NSAIDs)
alleviate most physical symptoms.
B. Spironolactone
1. EecAve for breast tenderness and bloaAng
2. The recommended dose is 50 mg twice daily to
begin 2 to 3 days before the anAcipated symptoms
unAl menses.
3. Potassium levels should be monitored. Why?
4. Avoid use in those with impaired renal funcAon.
C. Combined oral contracepAves (COC)

A 2- to 3-month trial of non-prescripAon therapies, nutriAonal


intervenAons, and lifestyle changes iniAally should be employed while the
paAent records her symptoms in her calendar/diary:
a. SupplementaAon of calcium carbonate in a dosage of 1000-1200 mg per
day for three menstrual cycles
b. ReducAon of sodium, sugar, alcohol, and caeine can minimize somaAc
symptoms and bloaAng
c. Regular aerobic exercise 20 to 30 minutes 3 days a week, relaxaAon,
stress management, and yoga may enhance general well being
d. EaAng frequent and smaller porAons of foods high in complex
carbohydrates
e. AddiAonal supplements (including vitamin B6 (200 mg/d), magnesium
(200-360/d), vitamin E, chaste tree berry (20 mg/d of Vitex agnus-castus),
primrose oil) have conicAng reports of eecAveness, as well as limited,
substanAated research through random placebo- controlled trials.
hap://www.medscape.com/viewarAcle/551199_2

hap://www.medscape.com/viewarAcle/551199_2

Hypocapnia/respiratory alkalosis is not described in typical diagnostic texts, so


if we did not know about clinical papers, we would be left with acid-base books
as our resource. Acid-base books suggest that hypocapnia is not a common
clinical encounter. pH problems manifest as metabolic alkalosis, metabolic
acidosis, respiratory acidosis, and respiratory alkalosis. Causes of respiratory alkalosis:
Non-hypoxic causes:
1. Lung disease
- pneumonia
- pulmonary embolism
- interstitial lung disease
- fumes
2. Drugs and hormones
- salicylates
- progesterone
3. CNS disease
- trauma
- tumor
- hemorrhage
- infarction
- infection
4. Heat stroke/exhaustion

5. Liver failure
6. Others
- mechanical ventilation
- post-metabolic acidosis
- psychogenic
Hypoxic causes:
1. Low O2 content
- altitude
- lung disease
- anemia
- CO poisoning
2. Impaired perfusion
- hypovolemia
- septic shock
- cardiogenic shock

Thomson WST et al. Clinical acid-base balance. New York: Oxford U Press; 1997

http://emedicine.medscape.com/article/807277

Current thinking suggests


that the syndrome might
better be termed
behavioral breathlessness.

16

Example of symptoms caused by hypocapnia:

apprehension
faintness
fatigue
headache
impaired concentration
giddiness
irritability
seizure
weakness
visual disturbances
diaphoresis
perioral numbness
dyspnea
1.
2.

palpations
tachycardia
abdominal discomfort
chest pain
air swallowing
breathlessness
yawning and/or sighing
dry mouth
tetany
muscle tightening &
stiffness
distal paresthesias

Duncan S, Raffin T. Handling hyperventilation syndrome. Hosp Med. 1992;28:58-67.


Rice RL. Symptom patterns of the hyperventilation syndrome. Am J Med.
1950;8:691-700.

Mechanism
by which
symptoms
develop?
IMPORTANT #s to embrace!

Normal arterial CO2


(PaCO2) is:

35-45 mmHg

Duncan S, Raffin T. Handling


hyperventilation syndrome. Hosp
Med. 1992;28:58-67.

Most reports suggest an


incidence of 6% to 11%,
although a few studies estimate
that HVS may contribute to
some 40% of symptoms in the
general medical clinic.

What is the mechanism


of symptom generation?

Thomson WST et al. Clinical acid-base balance. New York: Oxford U Press; 1997

Neurological symptoms are principally


attributable to vasospastic reduction of
cerebral blood flood:

Cerebral blood flow falls 20%


when PaCO2 reaches 34 mmHG.
Cerebral blood flow falls by
more than 50% when PaCO2
reaches 20 mmHg.

17

Low CO2 = alkalosis = vasoconstriction

Thomson WST et al. Clinical acid-base balance. New York: Oxford U Press; 1997

Most of the symptoms are caused by


hypocapnic-induced vasospasm, but
alkalosis-induced changes in protein
binding of calcium and shifts of sodium,
potassium, and hydrogen ions across cell
membranes are also though to have a roll.
Hypocalcemia typically results, due to an alkalosisinduced increase in albumin bound calcium and may
lead, in the extreme cases to tetany and a positive
Chvostek or Trousseau sign. Such calcium binding
leads to an increase in sodium conductance and
neuronal hyperexcitability.

Thomson WST et al. Clinical acid-base balance. New York: Oxford U Press; 1997

Vasospasm reduces skin blood flow and


may account for:
paresthesias in limbs
circumoral numbness
** Skeletal muscle cramps, exaggerated
tendon reflexes, and carpopedal spasms
may be due to:
Increased membrane excitability due to a
combination of reduced ionized calcium and
movement of sodium, potassium, and
hydrogen ions across excitable membranes.

McSwiney BA, Newton WH. Reaction of smooth muscle to the h-ion


concentration. J Physiol. 1927;63(1):51-60.

Thomson WST et al. Clinical acid-base balance. New York: Oxford U Press; 1997

Neurological symptoms are principally


attributable to vasospastic reduction of
cerebral blood flood:

light-headedness
impaired intellectual functions
confusion
syncope
seizures

Thomson WST et al. Clinical acid-base balance. New York: Oxford U Press; 1997

Chest pain: attributed to coronary artery


spasm and may be dull and aching but is
often left-sided, sharp, and piercing.
It may be indistinguishable from classical
angina or the pain of MI.
ECG: QT prolongation, T-wave flattening
and marked ST depression. With exception
of ST depression, the others can be
initiated by voluntary hyperventilation.

18

Thomson WST et al. Clinical acid-base balance. New York: Oxford U Press; 1997

Gastrointestinal
symptoms - such as
nausea, lack of appetite,
and vomitingare all
attributable to cerebral
hypoxia.

Example of symptoms caused by hypocapnia =


respiratory alkalosis:
palpations
apprehension
tachycardia
faintness
abdominal discomfort
fatigue
chest pain
headache
air swallowing
impaired concentration
breathlessness
giddiness
yawning and/or sighing
irritability
dry mouth
seizure
tetany
weakness
muscle tightening &
visual disturbances
stiffness
diaphoresis
distal paresthesias
perioral numbness
dyspnea
1.
2.

Dysmenorrhea!

Duncan S, Raffin T. Handling hyperventilation syndrome. Hosp Med. 1992;28:58-67.


Rice RL. Symptom patterns of the hyperventilation syndrome. Am J Med.
1950;8:691-700.

Dysmenorrhea!
One of most common complaints of gynecologic paAents
Many suer with mild discomfort; dysmenorrhea is reserved
for those whose pain prevents normal acAvity and requires
medicaAon
Three types of dysmenorrhea:
1. Primary (no organic cause)
2. Secondary (pathologic cause)
a. endometriosis, adenomyosis, pelvic inammatory
disease, cervical stenosis, broids, and endometrial
polyps
3. Membranous (cast of endometrial cavity she as single
enAty through undilated cervix)
4. Cramping due to intrauterine device
Decherney AH, Goodwin TM. Current diagnosis & treatment: obstetrics and gynecology. 10th
ed. McGraw-Hill: NY; 2007

Pain during menstruaAon has been


aaributed to:

Prostaglandin acAvity
Leukotriene acAvity

Prostaglandins & Leukotrienes


Current evidence suggests that the pathogenesis of primary dysmenorrhea is
due to prostaglandin F2alpha (PGF2alpha), a potent myometrial sAmulant and
vasoconstrictor. The response to prostaglandin inhibitors in paAents with
dysmenorrhea supports the asserAon that dysmenorrhea is prostaglandin
mediated. SubstanAal evidence aaributes dysmenorrhea to prolonged uterine
contracAons and decreased blood ow to the myometrium. Elevated
prostaglandin levels were found in the endometrial uid of women with
dysmenorrhea and correlated well with the degree of pain.
A 3-fold increase in endometrial prostaglandins occurs from the follicular phase
to the luteal phase, with a further increase occurring during menstruaAon.[12]
The increase in prostaglandins in the endometrium following the fall in
progesterone in the late luteal phase results in increased myometrial tone and
excessive uterine contracAon.
Leukotrienes have been postulated to heighten the sensiAvity of pain bers in
the uterus. Signicant amounts of leukotrienes have been demonstrated in the
endometrium of women with primary dysmenorrhea that does not respond to
treatment with prostaglandin antagonists.

Decherney AH, Goodwin TM. Current diagnosis & treatment: obstetrics and gynecology. 10th
ed. McGraw-Hill: NY; 2007: p.572

hap://emedicine.medscape.com/arAcle/253812

19

Dysmenorrhea is OSTEOARTHRITIS of
the dysmenorrhea anatomy

Eicosanoid synthesis - made ridiculously simple


Planted seed omega-3-desaturase

(LA) n-6 FA

(ALA) n-3 FA
Green veg,
chia, flax,
hemp

Fish, n3
meat, wild
game, n3
eggs

GLA
J Am Diet Assoc.
2008;108:1178-1185.

Inhib: Glucagon, EPA

PGE1

TXA1

Anti-inflammatory
2004 Dr. David Seaman.

J Alt Complement Med. 2009;15(2):129-32.

PGE2

air
gul
Sin

AID

NS

Arachidonic
acid
irin

Stim: Insulin & Statins

Asp

DGLA

LTB4
TXA2
Pro-inflammatory

DHA

EPA

Resolvins
Neuroprotectins
Docosatrienes

PGE3 LTB5
TXA3
Anti-inflammatory

Breast cancer
and syndrome
X connecAon

Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome
among US adults: findings from the Third National Health and Nutrition
Examination Survey. JAMA 2002;287:3569.

20

A beneficial effect of metformin in breast


cancer appears to be biologically plausible.
By inhibiting transcription of key
gluconeogenesis genes in the liver and
increasing glucose uptake in skeletal
muscle, metformin reduces levels of
circulating glucose, increases insulin
sensitivity, and reduces the
hyperinsulinemia associated with insulin
resistance, 5 all of which are factors
associated with breast cancer
prognosis.
Goodwin PJ et al. Mezormin in breast cancer: Ame for acAon. J Clin Oncol.
2009;27(20):3271-73.

If patients have three or more of the


following risk factors, they are said to be
suffering from syndrome X:
1. Fasting glucose of 100 mg/dL
2. Triglycerides of 150 mg/dL
3. HDL cholesterol <40 mg/dL for men
and <50 mg/dL for women
4. Blood pressure of 130/85 mmHg
5. Waist circumference of >40 inches for
men and >35 inches for women
Wilson PW, Grundy SM. The metabolic syndrome: practical guide to
origins and treatment: Part I. Circulation. 2003; 108:1422-24

Goodwin PJ et al. Mezormin in breast cancer: Ame for acAon. J Clin Oncol.
2009;27(20):3271-73.

Barclay AW, Petocz P et al. Glycemic index, glycemic load, and chronic disease
risk--a meta-analysis of observational studies. Am J Clin Nutr. 2008; 87(3): 627-37!

These results suggest that adherence to a low


glycemic index or low glycemic load diet may be
associated with a reduced risk of certain chronic
diseases.!
The authors point out that the reduced risk of
type 2 diabetes and heart disease associated with
these diets is comparable to the reduced risk
associated with whole grain consumption and high
fiber intakes. !
The authors conclude, the findings support the
hypothesis that higher postprandial glycemia is a
universal mechanism for disease progression.!

Cowey S, Hardy RW. The


metabolic syndrome: A highrisk state for cancer? Am J
Pathol. 2006; 169(5):1505-22

Blaha M, Elasy TA. Clinical use of the


metabolic syndrome: why the confusion?
Clin Diabetes. 2006; 24(3):125-31.

21

Cowey S, Hardy RW. The metabolic syndrome: A high-risk state for cancer? Am J
Pathol. 2006; 169(5):1505-22

Diabetes mellitus is correlated with liver,


endometrial, pancreaAc, cervical, and breast
cancer incidence or mortality.

Increased fasAng insulin levels in


nondiabeAc paAents are signicantly and
independently associated with development
of colorectal, breast, endometrial, and
prostate cancers.
Suppressed HDLc and elevated triglycerides
in paAents are also risk factors for colon,
breast, and prostate cancers.

Cowey S, Hardy RW. The metabolic syndrome: A high-risk state for cancer? Am J
Pathol. 2006; 169(5):1505-22

Cowey S, Hardy RW. The metabolic syndrome: A high-risk state for cancer? Am J
Pathol. 2006; 169(5):1505-22

Epidemiological studies indicate that increased


waist circumference and/or BMI is posiAvely
correlated with the development of cancers of the
colon, breast (postmenopausal), endometrium,
esophagus, liver, gallbladder, gastric, and kidney.
A large prospecAve study demonstrated that
increasing BMI is associated with increased
mortality from many types of cancer. The authors
suggest that increased BMI (25 kg/m2) contributes
to 90,000 cancer-related deaths per year in the US.

Breast cancer promoting foods

Increased fasAng insulin levels in nondiabeAc


paAents are signicantly and independently
associated with development of colorectal,
breast, endometrial, and prostate cancers.
Hyperglycemia, diabetes mellitus, and
hyperinsulinemia can be risk factors for cancer
development and underscore the importance of
insulin and glucose regulaAon for suppressing
aberrant cell proliferaAon.

BRCA is a tumor
suppressor

van der Groep P et al. Pathology of hereditary breast cancer. Cell Oncol. 2011;
34(2): 7188.

BRCA1, symbol for a breast cancer gene. (BRCA2 [similar


function])
A healthy BRCA1 gene produces a protein that protects
against unwanted cell growth. The protein is packaged by
the cell's Golgi apparatus into secretory vesicles, which
release their contents on the cell's surface. The protein
circulates in the intracellular space, attaching itself to
neighboring cell receptors. The receptors signal the cell
nuclei to stop growing. When the gene is defective, it
produces a faulty protein that is unable to prevent
proliferation of abnormal cells as they evolve into
potentially deadly breast cancer. BRCA1 may also
normally inhibit ovarian cancer.
Mosby's Medical Dictionary, 8th edition. 2009, Elsevier.

22

In fact, among those variables that have been shown to bear


a causal relationship with breast cancer, the highest
increased risk, after age, is a positive family history of breast
cancer.
With the knowledge of today, only in about 5% of all the
breast cancer cases, the disease will occur as part of a
hereditary cancer susceptibility syndrome, caused by
mutations in high penetrance susceptibility genes.
A substantial proportion of hereditary breast cancers, about
16%, can be attributed to germline mutations in either of the
BRCA (breast cancer 1 and 2) early onset genes. Since the
identification of the BRCA1 and BRCA2 genes in 1994,
several studies have been undertaken to find other high
penetrance breast cancer susceptibility genes than BRCA1
and BRCA2, with less spectacular results so far.
van der Groep P et al. Pathology of hereditary breast cancer. Cell Oncol. 2011;
34(2): 7188.

Highly penetrant alleles, and highly heritable symptoms, are easier to


demonstrate, because if the allele is present, the phenotype is generally
expressed. Mendelian genetic concepts such as recessiveness, dominance, and
co-dominance are fairly simple additions to this principle.

Complete penetrance: The allele is said to have complete


penetrance if all individuals who have the disease-causing
mutation have clinical symptoms of the disease.
Highly penetrant: If an allele is highly penetrant, then the trait it
produces will almost always be apparent in an individual
carrying the allele.
Incomplete penetrance or reduced penetrance: Penetrance is
said to be reduced or incomplete when some individuals fail to
express the trait, even though they carry the allele.
Low penetrance: An allele with low penetrance will only
sometimes produce the symptom or trait with which it has been
associated at a detectable level. In cases of low penetrance, it is
difficult to distinguish environmental from genetic factors.

Breast cancer promoting foods

Allele:
Any of several forms of a gene, usually
arising through mutation, that are
responsible for hereditary variation.

Origin:
193035; < German Allel, apparently as
shortening of German equivalents of
allelomorph or allelomorphic gene;
allelo- < Greek alllo-, combining form
of allln of/to one another, reciprocally

http://efaeducation.nih.gov/sig/eicosa3.html

LA sources: grains; oils:


corn, safflower,
sunflower, cottonseed,
peanut, soybean
Linoleic acid

AA sources:
Grain-fed animals,
(FR tilapia, catfish,
bronzini)
Arachidonic acid
COX/LOX
PGE2, TXA2, LTB4

Excessive signaling by omega-6 eicosanoids promotes vigorous


autacoid signaling that sometimes goes beyond the normal self-healing
process and creates pathology. These disorders are often treated with
aspirin-like drugs to slow the excessive omega-6 actions and permit
normal tissue functions.

Modern diet - source of calories


10% dairy products
1-2% alcohol
20% refined grains/pasta/bread/cereal
20% refined sugars
20% refined vegetable oils
15-20% obese meat
<10% vegetables, fruit
Cordain L et al. Origins and evolution of the Western diet: health implications for
the 21st century. Am J Clin Nutr. 2005; 81(2):341-54.

23

Eicosanoid synthesis - made ridiculously simple


Planted seed omega-3-desaturase

(LA) n-6 FA

(ALA) n-3 FA
Green veg,
chia, flax,
hemp

Fish, n3
meat, wild
game, n3
eggs

GLA
J Am Diet Assoc.
2008;108:1178-1185.

Inhib: Glucagon, EPA

PGE1

TXA1

Anti-inflammatory
2004 Dr. David Seaman.

PGE2

air
gul
Sin

AID

NS

Arachidonic
acid
irin

Stim: Insulin & Statins

Asp

DGLA

LTB4
TXA2
Pro-inflammatory

DHA

EPA

Resolvins
Neuroprotectins
Docosatrienes

PGE3 LTB5
TXA3
Anti-inflammatory

Bulun SE et al. Aromatase excess in cancers of breast, endometrium


and ovary. J Steroid Biochem Mol Biol. 2007;106(1-5):81-96

Bulun SE et al. Aromatase excess in cancers of breast, endometrium


and ovary. J Steroid Biochem Mol Biol. 2007;106(1-5):81-96
Origins of estrogen in postmenopausal breast cancer
This gure exemplies the important pathologic roles of extraovarian
(peripheral) and local estrogen biosynthesis in an estrogen-dependent disease
in postmenopausal women. The estrogen precursor androstenedione (A)
originates primarily from the adrenal in the postmenopausal woman.
Aromatase expression and enzyme acAvity in extraovarian Assues such as fat
increases with advancing age. The aromatase acAvity in skin and subcutaneous
adipose broblasts gives rise to formaAon of systemically available estrone (E1)
and to a smaller extent estradiol (E2).
The conversion of circulaAng A to E1 in undierenAated breast adipose
broblasts compacted around malignant epithelial cells and subsequent
conversion of E1 to E2 in malignant epithelial cells provide high Assue
concentraAons of E2 for tumor growth. The clinical relevance of these ndings
is exemplied by the successful use of aromatase inhibitors to treat breast
cancer.

Bulun SE, Simpson ER. Aromatase expression in womens


cancers. Adv Exp Med Biol. 2008;630:112-32.
Estrogen has been posiAvely linked to the pathogenesis and
growth of three common women's cancers (breast,
endometrium and ovary). A single gene encodes the key
enzyme for estrogen biosynthesis named aromatase, inhibiAon
of which eecAvely eliminates estrogen producAon in the
enAre body.
Aromatase inhibitors successfully treat breast cancer, whereas
their roles in endometrial and ovarian cancers are less dear.
Ovary, tesAs, adipose Assue, skin, hypothalamus and placenta
express aromatase normally, whereas breast, endometrial and
ovarian cancers overexpress aromatase and produce local
estrogen exerAng paracrine and intracrine eects.

Bulun SE, Simpson ER. Aromatase expression in womens


cancers. Adv Exp Med Biol. 2008;630:112-32.

Bulun SE et al. RegulaAon of aromatase expression in breast


cancer Assue. Ann NY Acad Sci. 2009;115:121-31.

Tissue specic promoters distributed over a 93 kilobase regulatory


region upstream of a common coding region alternaAvely control
aromatase expression. A disAnct set of transcripAon factors
regulates each promoter in a signaling pathway- and Assue-specic
manner. In cancers of breast, endometrium and ovary, aromatase
expression is primarly regulated by increased acAvity of the
proximally located promoter 1.3/II region.
Promoters I.3 and II lie 215 bp from each other and are coordinately
sAmulated by PGE2 via a cAMP-PKA-dependent pathway.
In breast adipose broblasts exposed to PGE2 secreted by malignant
epithelial cells, acAvaAon of PKC potenAates cAMP-PKA-dependent
inducAon of aromatase. Thus, inammatory substances such as
PGE2 may play important roles in inducing local producAon of
estrogen that promotes tumor growth.

24

Bulun SE et al. RegulaAon of aromatase expression in breast


cancer Assue. Ann NY Acad Sci. 2009;115:121-31.

We and others previously found that the majority of


estrogen producAon in breast cancer Assue was accounted
for by the aberrant acAvaAon of the proximal promoter I.3/
II region.
PGE2 that is secreted in large amounts by malignant breast
epithelial cells is the most potent known natural inducer of
this promoter region in breast adipose broblasts.
Signaling eectors/transcripAonal regulators that mediate
PGE2 acAon include the acAvator pathways p38/CREB-ATF
and JNK/jun and the inhibitory factor BRCA1 in breast
adipose broblasts.

Ronco AL et al. Hormonal and metabolic modulaAon through


nutriAon: towards a primary prevenAon of breast cancer. Breast.
2010;19:322-32.

Muri HJ et al. Dietary polyunsaturated faay acids and breast


cancer risk in chinease women: a prospecAve cohort study. Int J
Cancer. 2011;128(6):1434-41.
Breast cancer is the most common cancer in women. Controversy exists regarding the role
of dietary fat in breast cancer eAology.
Dietary faay acid intake was determined using food frequency quesAonnaires.
We found no associaAon of breast cancer risk to dietary intake of linoleic acid, arachidonic
acid, -linolenic acid or marine-derived n-3 PUFA.
We found a staAsAcally signicant interacAon between n-6 PUFA intake, marine-derived
n-3 PUFA intake and breast cancer risk (p = 0.008). Women with lower intake (the lowest
terAle) of marine-derived n-3 PUFA and higher intake (the highest terAle) of n-6 PUFA had
an increase risk for breast cancer (RR = 2.06; 95% CI = 1.27-3.34) compared to women with
higher intake (the highest terAle) of marine-derived n-3 PUFAs and lower intake (the
lowest terAle) of n-6 PUFAs aer adjusAng for potenAal confounders.

The relaAve amounts of n-6 PUFA to marine-derived n-3 PUFAs may


be more important for breast cancer risk than individual dietary
amounts of these faay acids.

Erickson KL, Hubbard NE.Faay acids and breast cancer: the role of stem cells. Prostaglandins
Leukot Essent Faay Acids. 2010;82(4-6):237-41.

Studies with animal models in vivo as well as with animal and human
tumor cells in vitro suggest that specic faay acids could reduce breast
tumorigenesis.
The most striking dietary faay acid studies in animal models that show
promise for reducAon of breast cancer risk in humans are with
conjugated linoleic acids (CLA) and n-3 faay acids. The specic target of
those faay acids is not yet known.
The isomers, cis9, trans11-CLA and trans10, cis12-CLA, and the n-3 faay
acids, docosahexaenoic and eicosapentaenoic, reduced the proliferaAon
of, and had increased toxicity towards, mammary tumor iniAaAng cells.
One mechanism involved in the eect of n-3 faay acids may be due to
alteraAon of the prole of prostaglandins. These results indicate that
select faay acids may be useful for prevenAng or reducing the risk of
breast cancer as they may target the tumor iniAaAng cell.

Holick MF. Deficiency of sunlight and vitamin D. BMJ 2008:336;1318-1319

25

Eskin BA. Iodine and mammary cancer. Adv Exp Med


Biol. 1977;91:293-304.
From laboratory studies presented, iodine appears to be a requisite for the
normalcy of breast Assue in higher vertebrates. When lacking, the parenchyma in
rodents and humans show atypia, dysplasia, and even neoplasia.
Iodine-decient breast Assues are also more suscepAble to carcinogen acAon and
promote lesions earlier and in greater profusion. Metabolically, iodine-decient
breasts show changes in RNA/DNA raAos, estrogen receptor proteins, and cytosol
iodine levels.

Recent studies have shown that toxicity doesn't occur until the serum level is 200
ng/ml or above.

http://www.grassrootshealth.org/

Clinically, radionuclide studies have shown that breast atypia and malignancy have
increased radioacAve iodine uptakes. Imaging of the breasts in high-risk women has
localized breast tumors. The potenAal use of breast iodine determinaAon to
determine estrogen dependence of breast cancer has been considered and the role
of iodide therapy discussed.
In conclusion, iodine appears to be a compulsory element for the breast Assue
growth and development. It presents great potenAal for its use in research directed
toward the prevenAon, diagnosis, and treatment of breast cancer.

Grtner R. The role of iodine and -iodolactone in growth


and apoptosis of malignant thyroid epithelial cells and
breast cancer cells. Hormones. 2010, 9(1):60-66

Wine (red wine)

32% (23-41)

Food
choices for
Dark chocolate
21%
(14-27)
disease
prevention
Vegetables & Fruit (potatoes) 21%
(14-27)
and health
Garlic (all spices)
25% (21-27)
promotion.
Fish (n-3 meat, chicken, eggs) 14% (8-19)

Almonds (all raw nuts)

12.5% (10.5-13.5)

Combine effect

76% (63-84)

Franco OH et al. The Polymeal: a more natural, safer, and probably tastier (than
the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ.
2004; 329:1447-50

Iodine

Patrick L. Iodine: defiency and therapeutic considerations. Alt Med Rev.


2008;13(2):116-27.

26

Iodine from the gut

Patrick L. Iodine: defiency and therapeutic considerations. Alt Med Rev. 2008;13(2):116-27.

Iodine enters the human body in a variety of


forms, but most is broken down to iodide (I-). From
there, its main fates are concentration by the
thyroid and excretion by the kidney.
Small amounts are also concentrated by the
salivary glands, choroid plexus, and mammary
gland.
The metabolism of molecular iodine (I2) may differ
somewhat from that of iodide (I-), with less uptake
by the thyroid and more to fatty tissues, including
the mammary gland.
Dunn JT. Iodine. In Shils ME et al. Eds. Modern nutrition in health and
disease. Lippincott Williams & Wilkins: Baltimore; 2006, p.300-311.

Patrick L. Iodine: defiency and therapeutic considerations. Alt Med Rev. 2008;13(2):116-27.

1. Iodine, in the form of iodide, is absorbed in the thyroid


follicle through the sodium/iodine symported protein (NIS)
found in the basolateral membrane of the follicular cell. The
activity of NIS is up-regulated by the binding of TSH to the
TSH receptors on the follicular cells (TSH-R). This allows
the absorption and concentration of iodine inside the cell to
levels 20-40 times greater than that found in the blood.

Iodine benefits - Japan


Japanese iodine intake from seaweed is linked
to health benefits not seen in cultures with
dissimilar diets.

2. Iodide is then organified (oxidized) to iodine by thyroid


peroxidase (TPO) and incorporatedinto the thyroglobulin
molecule (Tg). Thyroid hormones (T3 and T4) are then
secreted into the bloodstream from the follicular cell.

Knowing how much iodine the Japanese


consume daily is beneficial for people who
wish to consume equivalent amounts of iodine
or seaweed supplements while avoiding
excessive amounts that may adversely affect
health. Estimated intake is 1000-3000 mcg/d.
Zava TT, Zava DT. Assessment of Japanese iodine intake based on
seaweed consumption in Japan: a literature-based analysis. Thyroid
Research 2011, 4:14
http://www.thyroidresearchjournal.com/content/4/1/14

United States recommended daily intake (RDI)

150 mcg/d

Adults

220 mcg/d

Pregnacy

270 mcg/d

Lactation

Patrick L. Iodine: defiency and therapeutic considerations. Alt Med Rev.


2008;13(2):116-27.

Above 1000 mcg of iodine

Iodine intake over this limit


has been shown to
potentially contribute to an
underlying thyroid pathology
in those with Hashimotos
thyroiditis or Graves
disease.
Patrick L. Iodine: defiency and therapeutic considerations. Alt Med Rev.
2008;13(2):116-27.

27

Iodine upper limit (UL) recs

Iodine deficiency concerns

1. Burgi H. Iodine excess. Best Pract Res Clin Endocrinol Metab.


2010;24:107-110.

Stadel has postulated that given the


geographical associations of iodine
deficiency, prevalence of goiter, and
incidence of reproductive cancers,
there is a direct association with
iodine deficiency and increased risk
for prostate, endometrial, ovarian, and
breast cancers.

2. Zava TT, Zava DT. Assessment of Japanese iodine intake based on


seaweed consumption in Japan: a literature-based analysis. Thyroid
Research 2011, 4:14.

Patrick L. Iodine: defiency and therapeutic considerations. Alt Med Rev.


2008;13(2):116-27.

600 mcg/d

European Union (1)

1000 mcg/d

United States (1)

3000 mcg/d

Japan (2)

Aceves C et al. Is iodine a gatekeeper of the integrity of the


mammary gland? J Mammary Gland Biol Neoplasia.
2005;10(2):189-96.

In animal and human studies, molecular iodine (I2)


supplementation exerts a suppressive effect on the
development and size of both benign and cancer
neoplasias. This effect is accompanied by a
significant reduction in cellular lipoperoxidation.

Breast J. 2004;10(4) 328-36

Iodine, in addition to its incorporation into thyroid


hormones, is bound into antiproliferative iodolipids in
the thyroid called iodolactones, which may also play
a role in the proliferative control of mammary gland.
We propose that an I2 supplement should be
considered as an adjuvant in breast cancer therapy.

A randomized, double-blind, placebo-controlled,


multicenter clinical trial was conducted with 111
otherwise healthy euthyroid women with a history of
breast pain.
Patients had to document moderate or severe breast
pain by recording a score 5 on a visual analog scale
(VAS) of pain for 6 days per cycle and had to present
with fibrosis involving at least 25% of both breast
surfaces.
Subjects could not be effectively treated with more
conservative measures such as local heat or
nonprescription analgesics. There was not a
statistically significant difference in the dropout rate
for patients on placebo (11.8%), 1.5 mg /day (31.3%),
3.0 mg /day (18.4%), or 6.0 mg/day (25%) of molecular
iodine for 6 months.

The active study drug (IoGen) is a novel iodine formulation based


on sodium iodide and sodium iodate; these two food additives are
generally regarded as safe for general consumption.

Physicians assessed breast pain, tenderness, and nodularity


each cycle; patients assessed breast pain and tenderness with
the Lewin breast pain scale at 3-month intervals and with a VAS
at each cycle. A statistically significant improvement (p < 0.01)
associated with dose was observed in the Lewin overall pain
scale for all treated groups compared to placebo.
Reductions in all three physician assessments were observed in
patients after 5 months of therapy in the 3.0 mg/day (7/28; 25%)
and 6.0 mg/day (15/27; 18.5%) treatment groups, but not the 1.5
mg/day or placebo group.
Patients recorded statistically significant decreases in pain by
month 3 in the 3.0 and 6.0 mg /day treatment groups, but not the
1.5 mg /day or placebo group; more than 50% of the 6.0 mg /day
treatment group recorded a clinically significant reduction in
overall pain.
All doses were associated with an acceptable safety profile. No
dose-related increase in any adverse event was observed.

28

Ames BN. Low micronutrient intake may accelerate the


degenerative diseases of aging through allocation of scarce
micronutrients by triage. PNAS. 2006;103(47):17589-94.

Ames presents argument for eating more fruits/


vegetables and taking key supplements:

Multivitamin/mineral
Magnesium (400-1000 mg)
Fish oil (EPA/DHA) (1000-3000 mg)
Vitamin D (2000-10,000 IU)
a-Lipoic acid & acetyl-L-carnitine (ALCAR)
Fiber

Seaman addiAons: CoQ10, spices, glucosamine/chondroiAn,


probioAcs, calcium, vitamin C, iodine, peppermint oil, oil of
oregano.

From NIH report: http://kidney.niddk.nih.gov/kudiseases/


pubs/interstitialcystitis/

IntersAAal
cysAsis

Recurring discomfort or pain in the bladder and the


surrounding pelvic region.
The symptoms vary from case to case and even in the
same individual:
mild discomfort, pressure, tenderness, or intense pain
in the bladder and pelvic area
urgent need to urinate
a frequent need to urinate
pain may change in intensity as the bladder fills with
urine or as it empties
womens symptoms often get worse during
menstruation
may sometimes experience pain during vaginal
intercourse

From NIH report: http://kidney.niddk.nih.gov/kudiseases/


pubs/interstitialcystitis/
The diagnosis (dx of exclusion) of IC/PBS (painful bladder
syndrome) in the general population is based on:

The presence of pain related to the bladder,


usually accompanied by frequency and urgency
of urination absence of other diseases that
could cause the symptoms.
Diagnostic tests that help rule out other
diseases include urinalysis, urine culture,
cystoscopy, biopsy of the bladder wall and
urethra, and distention of the bladder under
anesthesia.

In summary, this study provides preliminary data to


support the hypothesis that SIBO may be associated
with IC. If excess bacteria in the small intestine were
the trigger for the immune activation and visceral
hypersensitivity seen in IC, then management of this
vexing disorder could be dramatically improved by
directing the diagnostic and treatment efforts toward
SIBO. A randomized, double-blind, placebo-controlled
study is currently underway to test this hypothesis.

29

Shorter B et al. Effect of comestibles on


symptoms of interstitial cystitis. 2007; 178:145-52.

Klumpp DJ, Rudick CN. Summation model of pelvic pain in interstitial cystitis.
Nature Clin Pract. 2008;5(9):494-500.

The most frequently reported and


most bothersome comestibles were:
1.
2.
3.
4.
5.
6.
7.

coffee
tea
soda
alcoholic beverages
citrus fruits and juices
artificial sweeteners
hot pepper

Klumpp DJ, Rudick CN. Summation model of pelvic pain in interstitial cystitis.
Nature Clin Pract. 2008;5(9):494-500.

Many patients with interstitial cystitis (IC) find that


particular foods exacerbate disease symptoms.
These patients may modify their diet to manage
symptoms, but the mechanism by which dietary
modification benefits patients with IC is unclear.

Endometriosis

We hypothesize that integration of neural signals


from pelvic organs mediates the effects of diet on
symptoms of IC. In animal models, pelvic
inflammation is subject to crosstalk, so an
inflammatory stimulus in one pelvic organ evokes a
response in an independent organ.

Endometriosis

http://emedicine.medscape.com/article/271899-overview#a0156

Endometriosis occurs in 7-10% of US


women in the general population, and
approximately 4 per 1000 women are
hospitalized with this condition each
year.
The exact incidence in the general
population is unknown, because the
definitive diagnosis requires biopsy or
visualization of the endometriotic
implants at laparoscopy or laparotomy.

Endometriosis

http://emedicine.medscape.com/article/271899-overview#a0156

Endometriosis is an estrogen-dependent disease and,


thus, usually affects reproductive-aged women. This
condition has a prevalence rate of 20-50% in infertile
women, but it can be as high as 80% in women with
chronic pelvic pain.
In a large series involving adolescent females with
chronic pelvic pain, 45% were found to have
endometriosis at laparoscopy. Of note, only 25% had a
normal pelvis. In that series, the rate of endometriosis
was found to increase with age from 12% in females
aged 11-13 years to 45% in females aged 20-21 years.
In an earlier study, evidence of endometriosis was
found during laparoscopy in 20-50% of asymptomatic
women.

30

A recent survey of women in the US


general population indicated that
women with endometriosis are
significantly more likely to suffer with
proinflammatory conditions including
fibromyalgia, chronic fatigue
syndrome, autoimmune diseases,
endocrine disorders, allergies, and
asthma.
Sinaii N et al. High rates of autoimmune and endocrine disorders,
fibromyalgia, chronic fatigue syndrome and atopic diseases among women
with endometriosis: a survey analysis. Hum Repro 2002; 17:2715-24

Olive DL,
Schwartz LB.
Endometriosis.
NEJM. 1993;
328:1759-69

What causes endometriosis? The most


well-accepted theory is that retrograde
menstruation results in the leakage of
endometrial tissue into the pelvic
peritoneum.
While this process happens to all women,
a certain percentage are unable to
effectively clear the menstrual efflux,
resulting in the proliferation of endometrial
tissue in extra-uterine sites.
Bulun SE et al. Estrogen biosynthesis in endometriosis: molecular
basis and clinical relevance. J Molecular Endocrinol 2000; 25:35-42

A consistent abnormality found in those with


endometriosis is an abnormal expression of the
enzyme
"aromatase,"
which
converts
androstenedione to estrone (another enzyme
converts estrone to estradiol).

Panel B, an axial T1-weighted image of the same patient, reveals multiple


high-signal-intensity adnexal masses consistent with endometriomas
(straight arrows). There is also tethering of the rectum (curved arrow),
which indicates that adhesions are present.

Aromatase drives endometriosis,


by stimulating estrogen synthesis.

Normal endometrium has no aromatase activity;


while dysfunctional endometrium has extremely
high levels, the outcome being increased
production of estrogen, which is potent driver of
endometriosis.
Bulun SE et al. Estrogen biosynthesis in endometriosis: molecular
basis and clinical relevance. J Molecular Endocrinol 2000; 25:35-42

Origin of estrogen in
endometrioAc lesions

PGE-2 is the substance that


stimulates aromatase. The resultant
production of estrogen adds fuel to
the fire by acting as an inducer of
the COX-2 enzyme that drives PGE2
synthesis. Bulun SE et al. Estrogen biosynthesis in
endometriosis: molecular basis and clinical
relevance. J Molecular Endocrinol 2000; 25:35-42

Bulun SE et al. Estrogen production and


metabolism in endometriosis. 2002; 955:75-85

31

Origin of estrogen
in endometrioAc
lesions?

COX2

Bulun SE et al. Estrogen production and metabolism in


endometriosis. Ann NY Acad Sci. 2002; 955:75-85

Origin of estrogen
in endometrioAc
lesions?

COX2

Bulun SE et al. Estrogen production and metabolism in


endometriosis. Ann NY Acad Sci. 2002; 955:75-85

Origin of estrogen in endometrioAc lesions - 1


Estradiol in an endometriotic lesion arises from several
body sites. In an ovulatory woman, estradiol is secreted
directly from the ovary in a cyclic fashion.
In the early follicular phase and after menopause,
peripheral tissues (adipose and skin) are the most
important sources to account for the circulating estradiol.
Estradiol is also produced locally in the endometriotic
implant itself in both ovulatory and postmenopausal
women.
Although total fat consumpAon was not associated with endometriosis risk, those women in
the highest h of long-chain omega-3 faay acid consumpAon were 22% less likely to be
diagnosed with endometriosis compared with those with the lowest h of intake. In
addiAon, those in the highest quinAle of trans-unsaturated fat intake were 48% more likely to
be diagnosed with endometriosis.

The most important precursor, androstenedione of adrenal


origin, becomes converted to estrone, which in turn is
reduced to estradiol in the peripheral tissues and
endometriotic implants.
Bulun SE et al. Estrogen production and metabolism in endometriosis. Ann NY
Acad Sci. 2002; 955:75-85

Origin of estrogen in endometrioAc lesions - 2


We demonstrated significant levels of 17-HSD
type 1 expression in endometriosis, which
catalyzes the conversion of estrone to estradiol.

FerAlity Sterility. 2010;94(6):1985-94.

Estradiol both directly and indirectly (through


cytokines) induces prostaglandin synthase-2
(cyclooxygenase-2), which gives rise to elevated
concentrations of PGE2 in endometriosis.
PGE2, in turn, is the most potent known stimulator
of aromatase in endometriotic stromal cells. This
establishes a positive feedback loop in favor of
continuous estrogen formation in endometriosis.
Bulun SE et al. Estrogen production and metabolism in endometriosis. Ann NY
Acad Sci. 2002; 955:75-85

32

FibrinolyAc
Balance

M
PL
AS

Fibrin

IN

Thrombin
Fibrinogen

ProteolyAc
Enzymes

Plasminogen
acAvator (PA)

Plasminogen

Plasminogen acAvator inhibitor


(PAI)

1. Prophylaxis is best; initiate supplementation


immediately after injury

Can be taken 200-2000 mg per day for long term


without effects - he did not specify long term.

2. Ingest 2-8 tablets 3-5xs daily on empty stomach


(water best)

Can be therapeutic at 160 mg/d, but best results occur


when starting at 750 mg day.

3. Enteric coating preferred; not needed for bromelain

Maurer HR. Bromelain: biochemistry, pharmacology, and medical use. Cell M ol


Sci. 2001; 58:1234-45
!

4. Multiple proteases preferred (combo bromelain,


trypsin, chymotrypsin, papain)
5. Continue supplementation for 1 week or until
improvement is notice

RA patients took 3 measuring spoons/ day for 12 months =


- 900 mg bromelain

* Usually improvement is seen within week. Can


maintain low dose maintenance of 2 per day or so
Bucci L. Nutrition Applied to Injury Rehabilitation and Sports Medicine. Boca
Raton: CRC Press; 1995: p.167-76.!

Menopause

- 3000 mg pancreatin

- 1800 mg papain

- 720 mg trypsin

- 30 mg chymotrypsin

Leipner J, Iten F, Saller R. Therapy with proteolytic enzymes in rheumatic


disorders. Biodrugs. 2001; 15(12):779-89
!

The decline in ovarian function with menopause is


associated with spontaneous increases in
proinflammatory cytokines (IL-1, IL-6, and TNF-a).
Exact mechanisms by which estrogen interferes with
cytokine activity may include interactions of the estrogen
receptor with other transcription factors, modulation of
nitric oxide activity, antioxidative effects, plasma
membrane actions, and changes in immune cell function.
Experimental and clinical studies strongly support a link
between the increased state of proinflammatory cytokine
activity and postmenopausal bone loss.
Preliminary evidence suggests that these changes also
might be relevant to vascular homeostasis and the
development of atherosclerosis.
Pfeilschifter J et al. Changes in Proinflammatory Cytokine Activity after Menopause. Endocrine Reviews 2002; 23 (1): 90-119

33

Schematic presentation of the potential actions of


estrogen on proinflammatory cytokine activity.

The activated Estrogen Receptor directly inhibits IL-6
and TNF-a gene expression via NF-kB and AP-1dependent mechanisms.
Estrogen also modulates the activity of NO via eNOS and
iNOS, exerts direct and indirect antioxidative actions, and
interferes with the activity of the hypothalamic-pituitaryadrenal (HPA)-axis and lymphocyte function.
Membrane ERs may also be involved in cytokine
regulation. Cytokines that have been shown to be directly
and/or indirectly modulated by estrogen include IL-1, IL-6,
TNF-a, M-CSF, GM-CSF, OPG, and TGF-.
Pfeilschifter J, Kditz R, Pfohl M, Schatz H. Changes in proinflammatory
cytokine activity after menopause. Endocrine Reviews 2002; 23(1):90-119

Pfeilschifter J et al. Changes in Proinflammatory Cytokine Activity after Menopause. Endo Rev 2002; 23 (1): 90-119

Wine (red wine)

32% (23-41)

Food
choices for
Dark chocolate
21%
(14-27)
disease
prevention
Vegetables & Fruit (potatoes) 21%
(14-27)
and health
Garlic (all spices)
25% (21-27)
promotion.
Fish (n-3 meat, chicken, eggs) 14% (8-19)

Pfeilschifter J et al. Changes in Proinflammatory Cytokine Activity after Menopause. Endo


Rev 2002; 23 (1): 90-119

Ames BN. Low micronutrient intake may accelerate the


degenerative diseases of aging through allocation of scarce
micronutrients by triage. PNAS. 2006;103(47):17589-94.

Ames presents argument for eating more fruits/


vegetables and taking key supplements:

Almonds (all raw nuts)

12.5% (10.5-13.5)

Combine effect

76% (63-84)

Franco OH et al. The Polymeal: a more natural, safer, and probably tastier (than
the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ.
2004; 329:1447-50

Vaginitis

Multivitamin/mineral
Magnesium (400-1000 mg)
Fish oil (EPA/DHA) (1000-3000 mg)
Vitamin D (2000-10,000 IU)
a-Lipoic acid & acetyl-L-carnitine (ALCAR)
Fiber

Seaman addiAons: CoQ10, spices, glucosamine/


chondroiAn, probioAcs, calcium, vitamin C, iodine

34

Urogenital infecAons: Which bugs cause the trouble?

VaginiAs Bacterial vaginosis and vulvovaginal candidiasis

Recurrent UTI:
dominant organisms are the uropathogens,
generally Escherichia coli
Recurrent bacterial vaginosis:
anaerobic Gram negaAve rods, Gardnerella
vaginalis
Recurrent yeast vaginiAs:
mostly Candida albicans
Reid G, Bruce AW. Urogenital infecAons in women: can probioAcs help?
Postgrad Med J. 2003;79:428-32.

VaginiAs Bacterial vaginosis and vulvovaginal candidiasis


VaginiAs (infecAon of the vagina) is the most
common gynecologic condiAon encountered in
the oce. VaginiAs is dened as the spectrum of
condiAons that cause vulvovaginal symptoms
such as itching, burning, irritaAon, and abnormal
discharge.
The most common causes of vaginiAs in
symptomaAc women are bacterial vaginosis
(40-45%), vulvovaginal candidiasis (20-25%), and
trichomoniasis (15-20%); yet, 7-72% of women
with vaginiAs may remain undiagnosed.
hap://emedicine.medscape.com/arAcle/257141

VaginiAs Bacterial vaginosis and vulvovaginal candidiasis


The normal postmenarchal and premenopausal
vaginal pH is 3.8-4.2. At this pH, growth of pathogenic
organisms usually is inhibited. Disturbance of the
normal vaginal pH can alter the vaginal ora, leading
to overgrowth of pathogens.
Vaginal pH is typically 4.5 or greater with BV and 4.5
or less with VVC.
Factors that alter vaginal environment include
feminine hygiene products, contracepAves, vaginal
medicaAons, anAbioAcs, sexually transmiaed diseases
(STDs), sexual intercourse, and stress.
hap://emedicine.medscape.com/arAcle/257141

35

InserAon of probioAcs into vagina for implantaAon

Reid G, Millsap K, Bruce, AW. ImplantaAon of


Lactobacillus casei var. rhamnosus into the
vagina. Lancet 1994;344, 1229.
Reid G, Bruce AW, Taylor M. InsAllaAon of
Lactobacillus and sAmulaAon of indigenous
organisms to prevent recurrence of urinary
tract infecAons. Microecol Ther.
1995;23;32-45.

Vulvovaginal candidiasis exam ndings


Erythema and swelling of the labia and vulva with
satellite lesions (discrete pustulopapular lesions)
Vaginal erythema with adherent thick, coaage
cheese like vaginal discharge (the cervix usually
appears normal)

Vulvovaginal
candidiasis

Vulvovaginal candidiasis causes


Candida species (C albicans, C tropicalis, and C glabrata)
are airborne fungi that are natural inhabitants of the
vagina in as many as 50% of women, and vaginal
candidiasis is the second most common cause of vaginiAs.
In 85-90%, it is caused by candida albicans and in 5-10%,
it is caused by C glabrata and C parapsilosis.
Risk factors include oral contracepAve use, IUD use,
young age at rst intercourse, increased frequency of
intercourse, recepAve cunnilingus, diabetes, HIV or other
immunocompromised states, chronic anAbioAc use, and
pregnancy.

hap://emedicine.medscape.com/arAcle/257141

hap://emedicine.medscape.com/arAcle/257141

Promoters of vulvovaginal candidiasis:

Treatment for vulvovaginal candidiasis:

Candidal vulvovaginiAs may develop


into chronic or recurrent candidal
infecAon related to the following:

Butoconazole 2% cream 5g intravaginally for 3 days Butoconazole 2% cream 5g


(butoconazole 1 sustained release) single intravaginal applicaAon
Clotrimazole 1% cream 5 g intravaginally for 7-14 days
Clotrimazole 100 mg vaginal tablet for 7 days
Clotrimazole 100 mg vaginal tablet, 2 tablets for 3 days

Diabetes mellitus**
Oral contracepAve (OCP)
AnAbioAc use
Immunodeciency
Tight-ng undergarments
hap://emedicine.medscape.com/arAcle/797497

Miconazole 2% cream 5 g intravaginally for 7 days


Miconazole 100 mg vaginal suppository, 1 suppository for 7 days
Miconazole 200 mg vaginal suppository, 1 suppository for 3 days
Miconazole 1200 mg vaginal suppository, 1 suppository for 1 day
NystaAn 100,000 unit vaginal tablet, 1 tablet for 14 days
Terconazole 80 mg vaginal suppository, 1 suppository for 3 days
hap://emedicine.medscape.com/arAcle/257141

36

Complimentary
treatments for
vaginitis

Oral probioAcs colonize the vagina?

Reid G, Bruce AW. Urogenital infecAons in women: can probioAcs help? Postgrad
Med J. 2003;79:428-32.

We report the rst clinical evidence that probioAc lactobacilli


can be delivered to the vagina following oral intake.
In 10 women with a history of recurrent yeast vaginiAs,
bacterial vaginosis (BV) and urinary tract infecAons, strains
Lactobacillus rhamnosus GR-1 and Lactobacillus fermentum
RC-14 suspended in skim milk and given twice daily for 14
days, were recovered from the vagina and idenAed by
morphology and molecular typing within 1 week of
commencement of therapy.
In six cases of asymptomaAc BV or intermediate BV (based
upon Nugent scoring) was resolved within 1 week of therapy.
Reid G et al. Oral probioAcs can resolve urogenital infecAons. FEMS Immunol Med Microbiol.
2001;30:49-52..

For BV and VVC

37

Oral probioAcs: possible mechanism of acAon


Daily oral intake of probioAc strains Lactobacillus rhamnosus GR-1
and Lactobacillus fermentum RC-14 (reuteri), resulted in some
asymptomaCc bacterial vaginosis paAents reverAng to a normal
lactobacilli dominated vaginal microora The mode of acAon has
not been elucidated but might comprise:
(1) Increased ascension of probioAc and/or indigenous lactobacilli
from the rectal skin to the vagina.
(2) Reduced ascension of pathogens from the rectal skin to the
vagina.
(3) Enhancement of the intesAnal mucosal immunity which aects
vaginal immunity rendering the environment less recepAve to
bacterial vaginosis organisms.
Reid G, Bruce AW. Urogenital infecAons in women: can probioAcs help?
Postgrad Med J. 2003;79:428-32.

Reid G et al. Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum


RC-14 signicantly alters vaginal fora: randomized, placebo-controlled trial in
64 healthy women. FEMS Immunol Med Microbiol. 2003;35:131-34.

3. Lactobacilli were detected in more women in the lactobacilli-


treated group than in the placebo group at 28 day (P = 0.08) and
60 day (P = 0.05) test points. Culture ndings conrmed a
signicant increase in vaginal lactobacilli at day 28 and 60, a
signicant depleAon in yeast at day 28 and a signicant
reducAon in coliforms at day 28, 60 and 90 for lactobacilli-
treated subjects versus controls.
4. The combinaAon of probioAc L. rhamnosus GR-1 and L.
fermentum RC-14 is not only safe for daily use in healthy
women, but it can reduce colonizaAon of the vagina by
potenAal pathogenic bacteria and yeast.

Reid G et al. Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum


RC-14 signicantly alters vaginal fora: randomized, placebo-controlled trial in
64 healthy women. FEMS Immunol Med Microbiol. 2003;35:131-34.

1. Urogenital infecAons aict an esAmated one billion people


each year. The size of this problem and the increased
prevalence of mulAdrug resistant pathogens make it imperaAve
that alternaAve remedies be found.
2. A randomized, placebo-controlled trial of 64 healthy women
given daily oral capsules of Lactobacillus rhamnosus GR-1 and
Lactobacillus fermentum RC-14 for 60 days showed no adverse
eects. Microscopy analysis showed restoraAon from
asymptomaAc bacterial vaginosis microora to a normal
lactobacilli colonized microora in 37% women during
lactobacilli treatment compared to 13% on placebo (P =0.02).

Bacterial vaginosis (BV) is the most prevalent vaginal infecAon


worldwide and is characterized by depleAon of the indigenous
lactobacilli. AnAmicrobial therapy is oen ineecAve.
Sixty-four Brazilian women diagnosed with BV were randomly
assigned to receive a single dose of Anidazole (2 g) supplemented
with either 2 placebo capsules or 2 capsules containing L. rhamnosus
GR-1 and L. reuteri RC-14 every morning for the following 4 weeks.
At the end of treatment (day 28), the probioAc group had a
signicantly higher cure rate of BV (87.5%) than the placebo group
(50.0%) (p = 0.001). In addiAon, according to the Gram-stain Nugent
score, more women were assessed with "normal" vaginal microbiota
in the probioAc group (75.0% vs. 34.4% in the placebo group; p =
0.011).
MarAnez RC et al. Improved cure of bacterial vaginosis with single dose of Anidazole (2 g),
Lactobacillus rhamnosus GR-1, and Lactobacillus reuteri RC-14: a randomized, double-blind,
placebo-controlled trial.Can J Microbiol. 2009;55(2):133-8.

Vitamin D deficiency & bacterial vaginosis

CD4

469 pregnant women; first trimester of pregnancy;


pelvic examination and provided blood samples. 4
Approximately 57% of the women with serum
25(OH)D concentrations <8 ng/mL had BV compared
with 23% of women with serum 25(OH)D
concentrations >32 ng/mL.
After adjusting for confounders, compared to women
with serum 25(OH)D levels of 30 ng/mL:
1. 8 ng/mL showed a 65% increased risk of BV
2. 20 ng/mL showed a 26% increased risk of BV
Bodnar LM et al. Maternal Vitamin D Deficiency Is Associated with
Bacterial Vaginosis in the First Trimester of Pregnancy. J Nutr. 2009
apr 8 [Epub ahead of print].

T helper cells

TH1

Cytokines are proinflammatory [i.e., IFNg] - [IL-1, TNF].


Perpetuate
autoimmunity and
lead to uncontrolled
damage and must be
balanced by TH2 and
T-reg.

TH2

T-reg

IL-4, 5, 13,
Maintenance
which are
of selfassociated with
tolerance
IGE responses,
and IL-10 which
is anti-inflammatory.
Berger A. Science commentary: Th1 and
Th2 responses: what are they. BMJ 2000;
321: p.424

38

Vitamin D3 and immunoregulation


Cell

Effect of Vit D3

Th1

decreased number
suppress function

Th2

increase number/function
suppress function

T reg increase function


increase number
DC

inhibit maturation
inhibit Th1 induction
increase Th2 induction

Cantorna MT, Mahon BD. Mounting evidence for vitamin D as an environmental


factor affecting autoimmune disease prevalence. Exp Biol Med. 2004; 229:1136-42

IFN-g --> IL-1,


IL-6, TNF

Cantorna MT, Mahon BD.


Mounting evidence for vitamin D as an
environmental factor affecting autoimmune
disease prevalence.
Exp Biol Med. 2004; 229:1136-42

Estimated* needs of vit D throughout lifecycle


1. Breast-fed infants (800 IU/day)
2. Formula-fed infants (400 IU/day)

Self tolerance

IL-10

IFN-g --> IL-1, IL-6, TNF

Self tolerance
IL-10

3. Toddlers & young children (1000-2000 IU/day)


[when not getting adequate sun, and based on weight*]
4. Lactating women: 7,000 IU/day
5. Adolescents and adults can take between
3000-10000 IU or more depending on vitamin D levels in
blood (serum 25(OH)D: 32-100 ng/ml).
6. Pregnant or those thinking of becoming pregnant
get 25(OH)D check every 3-months (get to 40-70 ng/ml*)
Read full text before acting: Cannell JJ, Hollis BW. Use of vitamin D(3) in
clinical practice. Alt Med Rev. 2008;13(1):6-20.

Probiotics

39

Probiotics

Kaptchuk TJ et al.
Sham device v inert pill:
randomised controlled trial of
two placebo treatments.
BMJ. 2006; 332:391-97

Nocebo eects of sham treatments


The types of side eects were totally dierent in
the two study groups and clearly mimicked the
informaAon given at informed consent.
At two weeks, a quarter of the parAcipants
receiving the sham device reported one or more
side eects compared with nearly a third in the pill
group (P = 0.30).
No reported eect was serious even though three
parAcipants withdrew from the placebo pill group
because of faAgue or dry mouth.

40

Diet and the intestinal microbiota:

A pro-inammatory dietary paaern of rened carbohydrate and


lipid creates a pro-inammatory shi in the character of the gut
bacterial ora. The outcome is an increase in circulaAng endotoxin
levels, and associated inammaAon, and a greater energy harvest
from consumed carbohydrates, both of which lead to an increase
in fat mass [1-3]. This shi to an increase in energy harvest refers
to the ability of the transformed microbiota to more eciently
extract calories from consumed carbohydrate that leads to an
increased gain in adiposity without a substanAal increase in
consumed calories.

1. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI: An obesity-
associated gut microbiome with increased capacity for energy harvest. Nature 2006,
44:1027-31.

2. DeBaise JK, Zhang H, Crowell MD, Krajmalnik-Brown R, Decker GA, Riamann BE: Gut
microbiota and its relaAonship with obesity. Mayo Clin Proc 2008, 83:460-69.
3. Musso G, Gambino R, Cassader M: Obesity, diabetes, and gut microbiota. Diabetes Care
2010, 33:2277-84.

Diabetes Care 34:392397, 2011

Maes M et al. The gut-brain barrier in major depression: intesAnal mucosal


dysfuncAon with an increased translocaAon of LPS from gram negaAve
enterobacteria (leaky gut) plays a role in the inammatory pathophysiology
of depression. Neuroendocrinol Lea. 2008;29:117-24.

Pussinen PJ et al. Endotoxemia is assoicated with an increased risk of


incident diabetes. Diabetes Care. 2011;34:392-97.

41

History of probiotics
The concept of probioAcs probably dates back to 1908,
when Noble Prize winner Eli Metchniko suggested that
the long life of Bulgarian peasants resulted from their
consumpAon of fermented milk products.
The term "probioAc" was rst used in 1965, by Lilly and
SAllwell for describing substances secreted by one
organism which sAmulate the growth of another.
Marteau et al , in 2002 dened them as "microbial
preparaAons or components of microbial cells that have a
benecial eect on health and well being.
Gupta V, Garg R. ProbioAcs. Indian J Med Microbiol. 2009;27(3):202-209.

A common misconception is that probiotics


colonize in the gut to create a healthy
favorable microflora that directly combat the
pathogenic bacteria.
Research suggests that probioAcs funcAon in three general
ways; they have luminal, mucosal and submucosal
funcAons. None of these funcAons involve permanent
colonizaAon by the supplemental bacteria; however, as
probioAcs move through the gastrointesAnal tract, they
can transiently bind to epithelial cells and prevent the
binding and replicaAon of pathogenic bacteria.
Sherman PM, Ossa JC, Johnson-Henry K. Unraveling mechanisms of acAon of
probioAcs. Nutr Clin Pract. 2009;24:10-14.

Mucosal functions

The mucosal eects of probioAcs involve their


interacAon with mucosal cells of the gut:

Luminal functions
The luminal eects involve the ability of the
probioAcs to alter the biochemical environment of
the lumen:
1. ProbioAcs lower the gut pH and release
anAbacterial products called bacteriocins, which
prevent pathogenic bacteria from binding to
epithelial cells.
2. ProbioAcs appear to alter gene expression in
pathogenic bacteria and reduce their virulence.
Sherman PM, Ossa JC, Johnson-Henry K. Unraveling mechanisms of acAon of
probioAcs. Nutr Clin Pract. 2009;24:10-14.

Submucosal functions
The submucosal eects of probioAcs involve anA-
inammatory adapAve immune responses:

ProbioAcs sAmulate mucosal cells to release of


mucin and defensins (innate immune molecules).
Mucin (goblet cells) is an anAbacterial shield that
prevents the mucosal binding of enteric pathogens,
while defensins (Paneth cells) are anAbacterial
pepAdes.

Humoral immune B cells dierenAate into plasma


cells that release secretory IgA (sIgA) producAon,
which binds enteric pathogens; prevents their
translocaAon.

ProbioAcs also reduce gut permeability by


enhancing the integrity of epithelial Aght juncAons.

Inhibit NF-kB = less pro-inammatory cytokines and


eicosanoid producAon.

Sherman PM, Ossa JC, Johnson-Henry K. Unraveling mechanisms of acAon of


probioAcs. Nutr Clin Pract. 2009;24:10-14.

Sherman PM, Ossa JC, Johnson-Henry K. Unraveling mechanisms of acAon of


probioAcs. Nutr Clin Pract. 2009;24:10-14.

Increase adapAve immune T-regulatory cell release


of interleukin-10 (IL-10) (anA-inammatory)

42

The gut immune system should


not only protect the mucosa
against pathogens, but also
avoid hypersensitivity reactions
to food proteins and normal
microflora.

These luminal, mucosal and


submucosal effects of probiotics
can be broadly characterized as
anti-inflammatory in nature, as they
promote both host tissue and
commensal bacteria homeostasis.
Sherman PM, Ossa JC, Johnson-Henry K. Unraveling mechanisms of acAon of
probioAcs. Nutr Clin Pract. 2009;24:10-14.
Isolauri E et al. ProbioAcs: a role in the treatment of intesAnal infecAon and
inammaAon? Gut 2002;50(Suppl III):iii54-iii59.

Mengheri E. Health, probioAcs, and inammaAon. J Clin Gastroenterol.


2008;42:S177-78.

Mengheri E. Health, probioAcs, and inammaAon. J Clin Gastroenterol.


2008;42:S177-78.

The gut changes as we age???


The localized inammatory process that is present in the
intesAne of the elderly may be caused by an abnormally
acAvated response to commensal bacteria due to (1) an
abrogated mucosal immune tolerance, changes of the
microbiota composiAon, (2) expression of virulence
factors by bacteria or (3) some basic defect in the
mucosal barrier.
Outcome of 1-3: an overwhelming sAmulaAon of
immune cells by nonpathogenic bacterial products.
Sartor RB. Bacteria in Crohn's Disease: Mechanisms of Inflammation and
Therapeutic Implications. J Clin Gastroenterol. 2007; 41(Suppl 1):S37-S43.
Guigoz Y, Dore J, Schirin EJ. The inammatory status of old age can be nurtured from the
intesAnal environment. Curr Opin Clin Nutr Metab Care. 2008,11:1320.

Signicant structural changes occur in the microbiota with aging,


and this was especially evident with respect to putaAvely
protecAve bidobacteria. ReducAons in these organisms in the
large bowel may be related to increased disease risk in the
elderly.
Studies with dogs showed that ora of the young contained large
numbers of bacterioides, bidobacteria, lactobacilli, and
anaerobic cocci, while older animals harbored greater numbers of
clostria and enteroccoi. Shis also occur in humans.

Microora abnormaliAes (dysbiosis) is associated


with various diseases
Irritable bowel syndrome (1-3)
Inflammatory bowel disease (4)
Systemic complaints such rheumatoid
arthritis (5)

1. Lin HC. Small intesAnal bacterial overgrowth: a framework for understanding irritable bowel
syndrome. J Am Med Assoc. 2004;292: 852-858
2. Peralta S, Coaone C, Doveri T, Almasio PL, Craxi A. Small intesAne bacterial overgrowth and irritable
bowel syndrome-related symptoms: experience with Rifaximin. World J Gastroenterol 2009; 15(21):
2628-31.

In this study, one subject skewed the results a bit because he was
unusually healthy and t and had very high counts.

3. Jimenez MB. Treatment of irritable bowel syndrome with probioAcs. An eAopathogenic approach at
last? Rev Esp Enferm Dig. 2009; 101(8):553-64.

Consider supplemental decient elderly with pre and probioAcs

4. Packey CD, Sartor RB. Commensal bacteria, tradiAonal and opportunisAc pathogens,
dysbiosis and bacterial killing in inammatory bowel diseases. Curr Opin Infect Dis. 2009; 22(3):
292-301.

Hopkins MJ et al. Age and disease related changes in intesAnal bacterial


populaAons assessed by cell culture, 16s rRNA abundance, and community
cellular faay acid proles. Gut 2001; 48:198-205

5. Hvatum M, Kanerud L, Hallgren R, Brandtzaeg P. The gutjoint axis: cross reacAve food anAbodies in
rheumatoid arthriAs. Gut 2006;55:1240-47.

43

More general health issue


Diet is known to be a key factor that modulates the intesAnal microora
(1,2). An excessive consumpAon of rened carbohydrates, which
characterizes the average Americans diet, seems to be a primary culprit
(3,4).
Not surprisingly, when paAents with IBS consume a very low carbohydrate
diet, their IBS symptoms improve (4), supporAng the view that paAents
with intesAnal dysbiosis need to adopt a diet that does not feed the
dysbioAc state. That is, rened carbohydrates (sugar, our) promote
bacterial overgrowth and fermentaAon.
1. De Filippo C, Cavalieri D, Di Paola M et al. Impact of diet in shaping gut microbiota revealed by a comparaAve study
in children from Europe and rural Africa. Proc Natl Acad Sci. 2010; 107(33):14691-96.
2. Mai V, M McCrary QM, Sinha R, Glei M. AssociaAons between dietary habits and body mass index with gut
microbiota composiAon and fecal water genotoxicity: an observaAonal study in African American and Caucasian
American volunteers. NutriAon Journal. 2009, 8:49
3. Kruis W, Forstmaier G, Scheurlen C, Stellaard F. Eect of diets low and high in rened sugars on gut transit, bile acid
metabolism, and bacterial fermentaAon. Gut. 1991;32:367-71.
4. AusAn GL, Dalton CB, Hu Y et al. A very low-carbohydrate diet improves symptoms and quality of life in diarrhea-
predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2009;7(6):706-708.

Commonality of dysbiosis sufferers:


Approximately 12-20% of the adult populaAon suers from IBS (1),
which suggests that up to 1 in 5 adults are compromised by
dysbioAc gastrointesAnal symptoms such as pain, bloaAng,
consApaAon, and diarrhea. From a musculoskeletal perspecAve, a
substanAal number of paAents with bromyalgia are also thought
to suer with intesAnal dysbiosis (2), and women with two or more
gastrointesAnal complaints are more likely to suer with low back
pain (3).
1. Peralta S, Coaone C, Doveri T, Almasio PL, Craxi A. Small intesAne bacterial
overgrowth and irritable bowel syndrome-related symptoms: experience with
Rifaximin. World J Gastroenterol 2009; 15(21): 2628-31.
2. Pimentel M, Wallace D, Hallegua D et al. A link between irritable bowel syndrome
and bromyalgia may be related to ndings on lactulose breath tesAng. Ann Rheum Dis
2004;63:450452.
3. Smith MD, Russell A, Hodges PW. How common is back pain in women with
gastrointesAnal problems? Clin J Pain. 2008;24:199-203.

Lin HC. Small intestinal bacterial overgrowth: a framework for


understanding irritable bowel syndrome. JAMA. 2004;292:852-58

Triggers of zonulin release


Among the several potenAal intesAnal luminal
sAmuli that can trigger zonulin release, we idenAed
small intesAnal exposure to bacteria and gluten as the
two more powerful triggers.

The immune response to bacterial


antigens is known to lead to sickness
behavior including flu-like symptoms
of fatigue, anxiety, depression, and
impaired cognition.
Lin HC. Small intestinal bacterial overgrowth: a framework for
understanding irritable bowel syndrome. JAMA. 2004;292:852-58

Enteric infecAons have been implicated in the


pathogenesis of several pathological condiAons,
including allergic, autoimmune, and inammatory
diseases, by causing impairment of the intesAnal
barrier.
We have generated evidence that small intesAnes
exposed to enteric bacteria secreted zonulin.
Fasano A. Zonulin and its regulation of intestinal barrier function: the biological
door to inflammation, autoimmunity, and cancer. Phys Rev. 2011;91:151-75.

44

Fasano A. Zonulin and its reg of intest barrier functionPhys Rev. 2011;91:151-75.

Fasano A. Zonulin and its reg of intest barrier functionPhys Rev. 2011;91:151-75.

Fasano A. Zonulin and its regulation of intestinal barrier function: the biological
door to inflammation, autoimmunity, and cancer. Phys Rev. 2011;91:151-75.

O'Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO reports. 2006;
7:688-93

45

O'Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO reports. 2006;
7:688-93

O'Hara AM, Shanahan F.


The gut flora as a
forgotten organ. EMBO
reports. 2006; 7:688-93

Functions of the
intestinal flora.

(A) Bacteria density increases in the jejunum/ileum from the


stomach and duodenum, and in the large intestine, colonresiding bacteria achieve the highest cell densities recorded
for any ecosystem. The most common anaerobic and aerobic
genera are listed.
(B) Commensal bacteria exert a miscellany of protective,
structural and metabolic effects on the intestinal mucosa.

Immunosensory detection of intestinal bacteria.

Surface enterocytes secrete


many immune mediators in
response to antigens,
including antibacterial
peptides, immunoglobulin A
(IgA) and chemokines.
Specialized epithelial cells, termed M cells, transport and
deliver antigens to antigen-presenting cells, which
subsequently process antigens and present them to nave T
cells.

O'Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO reports. 2006;
7:688-93

Schematic illustration of the


mechanisms by which some
commensal bacteria limit pathogeninduced nuclear factor NF-kB
signalling.
Pathogenic bacteria such as
Salmonella typhimurium trigger IB
kinase activation, IB degradation and
nuclear translocation of p50/p65 NFkB subunits.

O'Hara AM, Shanahan F.


The gut flora as a forgotten
organ. EMBO Reports.
2006; 7:688-93

Some commensal bacteria offset


these affects by promoting the
nuclear export of activated p65
through associations with peroxisome
proliferator-activated receptor (PPAR),
thereby terminating promoter
activation.
Other commensal bacteria inhibit IkB
degradation.

Antigen-presenting dendritic cells (DCs) also survey and


sample the mucosal microenvironment. Pattern recognition
receptors (PRRs) expressed by DCs and enterocytes mediate
the detection of bacterial antigens, and DCs modulate
immune responsiveness or tolerance by promoting either
effector or regulatory T cells.

Safety of probiotics - 1

The safety prole of probioAcs is excellent.


Dierent studies have shown that the use of
probioAcs in healthy subjects and even in
immunocompromised paAents, involves a very low
risk of bacterial complicaAons, although over 80
cases of bacteremia have been reported in Finland,
associated with severe prior comorbidiAes or
surgery.
Jimenez MB. Treatment of irritable bowel syndrome with probioAcs. An eAopathogenic
approach at last? Rev Esp Enferm Dig. 2009; 101(8):553-64.

46

Diverse eects of probioAcs

Safety of probiotics - 2
Results: In total, 1966 arAcles were idenAed, of which 72 fullled
the inclusion criteria.
There were 20 case reports of adverse events in 32 paAents, all of which
were infecAons due to Lactobacillus rhamnosus GG or Saccharomyces
boulardii; the risk factors included central venous catheters and disorders
associated with increased bacterial translocaAon.
There were 52 arAcles reporAng 53 trials in which 4131 paAents received
probioAcs. Most trials showed either no eect or a posiAve eect on
outcomes related to safety (eg, mortality and infecAons).
Only 3 trials showed increased complicaAons, which were largely
noninfecAous in nature and in specic paAent groups (eg, transplant and
pancreaAAs). In 2 of these trials, the probioAc was administered through a
postpyloric tube.
Whelan K, Myers CE. Safety of probioAcs in paAents receiving nutriAonal support: a systemaAc
review of case reports, randomized controlled trials, and nonrandomized trials. Am J Clin Nutr.
2010;91(3):687-703.

Supplemental probioAcs have also demonstrated a clinical benet in


paAents suering with irritable bowel syndrome, inammatory
bowel disease, diverAcular disease, hypertension, chronic faAgue,
and anxiety in paAents with chronic faAgue.

Aragon G, Graham DB, Borum M, Doman DB. ProbioAc therapy for irritable bowel
syndrome. Gastroenterol Hepatol. 2010;6(1)39-44.

Packey CD, Sartor RB. Commensal bacteria, tradiAonal and opportunisAc pathogens,
dysbiosis and bacterial killing in inammatory bowel diseases. Curr Opin Infect Dis. 2009;
22(3): 292-301.
Beckham H, Whitlow CB. The medical and nonoperaAve treatment of diverAculiAs. Clin
Colon Rectal Surg. 2009;22(3):156-60.
Lye HS Kuan CY, Ewe JA, Fung WY, Liong MT. The improvement of hypertension by
probioAcs: eects on cholesterol, diabetes, renin, and phytoestrogens. Int J Mol Sci.
2009:10:3755-75.
Sullivan A, Nord CE, Evengrd B. Eect of supplement with lacAc-acid producing bacteria
on faAgue and physical acAvity in paAents with chronic faAgue syndrome. NutriAon
Journal. 2009, 8:4.
Rao AV et al. A randomized, double-blind, placebo-controlled pilot study of a probioAc in
emoAonal symptoms of chronic faAgue syndrome. Gut Pathogens. 2009;1:6.

Shanahan F. Gut
microbes: from bugs to
drugs. Am J
Gastroenterol.
2010;105:275-79.

The microbiota is inuenced by diet and lifestyle factors, and has become a target for
drug therapy in various disorders. However, it also oers new opportuniAes as a
repository of bioacAves from which novel drugs may be mined.

47

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