Gordon
Kuttner, MD Board Certified Reproductive Endocrinologist
History-
In the 1930s, Stein and Leventhal first described a
complex of symptoms associated with ovulation dysfunction
and hyperandrogenism (clinical hirsutism or elevated
testosterone and androstenedione levels) now known as
polycystic ovarian syndrome (PCOS). PCOS affects approximately
5 to 7% of reproductive age women. Research has revealed
that these clinical manifestations are due to persistent
ovulation dysfunction resulting from numerous causes
that now include insulin resistance, hyperinsulinemia,
and hyperandrogenism.
Clinicians have seen familial patterns
of PCOS suggesting a genetic component. Research has
demonstrated a possible X-linked dominant transmission
and autosomal dominant mode of inheritance. A germline
mutation in the insulin receptor gene has been implicated
as an etiology of insulin resistance in some cases.
Over the last several years, the association between
insulin resistance and PCOS has become more evident
and is one of the most important relationships uncovered
regarding this condition affecting both obese and thin
women.
Insulin resistance (IR) is defined as a
reduced glucose response to a given amount of insulin.
There are several clinical and laboratory criteria clinicians
use to define insulin resistance, but no one is accepted
by all. Such criteria include the MRI > 27 kg/M2,
a waist/hip ratio > 0.85, the presence of acanthosis
nigricans, an elevated fasting insulin concentration,
and decreased glucose/insulin ratio. Resistance to insulin-stimulated
glucose uptake is relatively common, often referred
to as Syndrome X. Not all women who are insulin resistant
are hyperandrogenic or have impaired glucose tolerance.
There are several mechanisms described for insulin resistance:
peripheral target tissue resistance, decreased hepatic
clearance, or increased pancreatic sensitivity.
Hyperinsulinemia
contributes to the increased risk of cardiovascular
disease by means of a direct atherogenic action and
indirectly by adversely affecting the lipoprotein profile.
There is a direct relationship between hyperinsulinemia
and hypertension although not evidenced until the post
reproductive years. In addition, there is also an association
with increased production of plasminogen activator inhibitor
type 1 (PIA-1) that has been linked to increased risk
of coronary and vascular disease due to the decrease
in the fibrinolytic activity.
is defined as having a BMI 25-30 kg/M2; obesity is defined
as having a BMI > 30 kg/M2. Ovulation dysfunction
occurs with a BMI > 25 kg/M2. Generally speaking,
all obese women are insulin resistant and most overweight
women are insulin resistant. Obese, anovulatory women
with hyperandrogenism have a characteristic distribution
of body fat known as android (central body) obesity,
similar to seen in older men, pear shaped body habitus.
This fat distribution is associated with hyperinsulinemia,
impaired glucose tolerance, diabetes mellitus, and an
increase in androgen production resulting in decreased
levels of sex hormone-binding globulin (SHBG) and increased
levels of free testosterone and estradiol. Android obesity
is also associated with cardiovascular risk factors.
Research
supports hyperinsulinemia produces hyperandrogenism
in PCOS patients: (1) the administration of insulin
to woman with PCOS increases androgen levels, (2) the
administration of glucose to hyperandrogenic women increases
levels of both insulin and androgens, (3) weight loss
decreases levels of both insulin and androgens, and
increases the level of insulin-like growth factor binding
protein-1 (IGFBP-1), (4) in vitro, insulin stimulates
theca cell androgen production, (5) reduction of insulin
levels in women reduces androgen levels in women with
PCOS, but not in normal women, (6) after normalization
of androgens with GnRH agonist treatment, the hyperinsulin
response to glucose tolerance testing remains abnormal
in obese woman with PCOS.
Hyperinsulinemia
produces hyperandrogenism when there are a reduced number
of functional insulin receptors or they are blocked.
Circulating insulin then binds to IGF receptors, which
are structurally similar to the insulin receptor and
results in androgen produced by theca cells. In addition,
Hyperinsulinemia inhibits hepatic synthesis of SHBG
and hepatic production of IGFBP-1. Lower levels of SHBG
allows for increased circulating levels of androgens
and estrogens. Lower levels of circulating IGFBP-1 increases
IGF activity resulting in increased theca cell androgen
production. Lastly, insulin may directly increase the
LH secretion in obese, anovulatory women.
By the age of 40, up to 40 % of PCOS patients
develop impaired glucose tolerance or clinical diabetes.
During the reproductive years, these women are more
likely to experience spontaneous abortions and develop
gestational diabetes. Those who develop gestational
diabetes are at increased risk of developing hyperandrogenism
and hyperinsulinemia later in life.
Both thin and obese women with
ovulatory dysfunction, hyperandrogenism and polycystic
ovaries can be hyperinsulinemic. It is more common and
severe in obese women. Not all hyperandrogenic women
(lean and obese) have elevated insulin levels. Thin
women with hyperinsulinemia are less likely than obese
women to develop early-onset diabetes mellitus. Ideally,
all obese patients should be tested for hyperinsulinemia.
One criterion is to test women with a waist circumference
> 35 inches, which is predictive of abnormal endocrine
and metabolic function and associated with an increased
risk of cardiovascular disease. Adolescents who present
with premature adrenarche and those with early ovulatory
dysfunction should also be tested. Many of these adolescents
will develop all of the long and short-term complications
associated with chronic anovulation.
CARES
obtains a fasting glucose (FG) and fasting insulin (FI)
on thin and obese women with ovulation dysfunction regardless
of clinical manifestations of hyperandrogenism. If the
ratio of FG/FI < 4.5, the patient is diagnosed with
insulin resistance. Those women who meet this criterion
are offered metformin treatment. Concurrently, we order
a 2-hour glucose level after 75 g glucose load. Normal
glucose tolerance is < 140 mg/dl, impaired 140-199
mg/dl, and non insulin-dependent diabetes mellitus >
200 mg/dl. Those women who demonstrate impaired glucose
tolerance or insulin-dependent diabetes mellitus are
referred to their primary care providers.
If hyperinsulinemia, due to insulin resistance, truly
produces the clinical short and long-term manifestations
of PCOS, then treatments that decrease insulin resistance
should also decrease hyperandrogenism and restore cyclic
menses, alleviating the major cause of infertility associated
with PCOS. Treatment objectives are (1) reduce the production
and circulating levels of androgens, (2) avoid the long
term effects of hyperinsulinemia, the risk of cardiovascular
disease and diabetes mellitus, (3) protect the endometrium
from the effect of unopposed estrogen, (4) lifestyle
changes to achieve normal body weight, (5) induction
of ovulation to achieve pregnancy (6) decrease spontaneous
abortion rates and (7) decrease gestational diabetes
and its resultant effects.
The best therapy is lifestyle modification with weight
loss. Weight reduction, improved nutrition, and exercise
are behavioral modifications that should be encouraged
as first-line therapy for obese PCOS patients. If diet
and exercise fail, then medications may be introduced
to improve peripheral insulin sensitivity and achieve
a reduction in insulin secretion. Some of the oral insulin
sensitizing medications approved by the FDA for the
treatment of Type II diabetes are metformin (Glucophage)
and thiazolidinediones such as rosiglitazone (Avandia)
and pioglitazone (Actos). Thiazolidinediones are briefly
discussed in the expanded web version.
Metformin reduces insulin resistance of peripheral tissue and
allows muscle and adipose cells to utilize glucose at
normal insulin levels. The drug improves insulin sensitivity
by reducing intestinal absorption of glucose and significantly
decreases hepatic glucose production, without causing
hypoglycemia in either normal or patients with Type
II diabetes. Medical treatment with 500 mg t.i.d. or
850 mg b.i.d. reduces hyperinsulinemia, basal and stimulated
LH levels, free testosterone concentrations, and PAI-1
levels in obese PCO patients. Metformin is rapidly absorbed
from the small intestine with peak plasma levels occurring
two hours after ingestion unless taken with food, which
delays both. The plasma half-life is approximate 6 hours
and is cleared through the renal system. Metformin is
available in 500 mg, 850 mg, and 1000 mg tablets. An
extended release form is available in 500 mg tablets.
Clinical results are usually observed at doses between
1500 mg and 2550 mg daily. Resumption of cycle regularity
is dependent on the length of treatment with metformin.
Most individuals require 4-6 months of metformin treatment
before ovulatory menses occur.
There is overwhelming evidence from at least three well
performed randomized controlled trials and several cohort
studies indicating that when taken with clomiphene citrate,
metformin enhances the probability of ovulation and
pregnancy. There is controversy over the mechanism of
action. Some suggest that these outcomes were due to
the weight loss that results when using metformin. Only
a few studies have shown that metformin has no or minimal
effect on insulin resistance and these studies were
in morbidly obese PCO patients or when there was no
weight loss. Numerous studies have shown that metformin
is effective in both obese and thin women correcting
insulin metabolism, endocrine parameters or both. Some
studies on the effects of metformin have revealed positive
trends without achieving statistical significances.
This may imply there are subsets of PCOS patients that
may not benefit from metformin use.
Metformin also improves clomiphene resistant anovulation
in women treated with follicle-stimulating hormone.
Use of metformin significantly reduced the rate of cycle
cancellation and ovarian hyperstimulation syndrome in
comparison to gonadotropins alone. Research has shown
PCOS patients undergoing IVF develop a greater number
of poor quality oocytes demonstrated by lower fertilization
and pregnancy rates probably due to higher levels of
intrafollicular androgens. In one prospective study,
patients undergoing IVF treated with FSH and metformin
had a significant increase in the number of mature oocytes
retrieved, fertilization rates, and number of embryos
produced.
Use of Metformin (FDA pregnancy Category
B) has not been linked to birth defects in animals or
humans. Metformin has been used off-label to achieve
pregnancy and throughout the first trimester in order
to reduce the risk of spontaneous abortion. Insulin
sensitized medications have no risk of causing multiple
pregnancies. Although Metformin is not approved for
use during pregnancy, it is being used more commonly
off-label through the first trimester since it has been
postulated, but not proven by randomized prospective
trials, that its use may reduce the risk of early pregnancy
miscarriages and reduce the risk of gestational diabetes
with its sequela.
Metformin has been shown in clinical
trials to have equal or superior results in comparison
to low-calorie diet alone or FDA approved weigh loss
medications.
As
with all medication, refer to the manufacture's product
information regarding FDA approved indications, risks,
benefits, dosages, and side effects.
Through
clinical observation, diagnostic testing, and implementing
lifestyle and medical therapy, reproductive health care
providers may be able to have a short-term and long-term
impact on the lives of thin and obese women who been
diagnosed with ovarian dysfunction, hyperinsulinemia,
insulin resistance, hyperandrogenemia commonly called
polycystic ovarian syndrome. An expanded, in-depth review
of this subject can be found at www.caresmed.com under
Newsletter-Conception.
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