| |
|
PCOS, Polycystic
Ovary Syndrome , Insulin Resistance (IR),
& Metformin: Latest Developments
Recently, there
has been much compelling research involving Polycystic
Ovary Syndrome (PCOS), highlighted by the evolving
understanding of the association between PCOS and Insulin
Resistance (IR) and the efficacy of metformin
(Glucophage®) treatment. The goal of this article
is to provide a practical review of polycystic ovarian
syndrome, IR, and metformin.
What is PCOS?
Despite continuing
research on its pathophysiology, PCOS
remains a syndrome, a heterogeneous disorder, not
a specific disease. As a syndrome, there is a group
of symptoms and signs that are recognized to be associated
with each other but are without an understood common
cause. The usual symptoms and signs identified with
PCOS
are oligo or amenorrhea, infertility,
hirsutism, obesity, polycystic ovaries, androgen excess,
IR, and elevated LH / FSH ratio . PCOS is the most common
endocrinopathy in women, occurring in about 5% of reproductive-aged
women .
The most popular definition
of PCOS is hyperandrogenic chronic oligo or anovulation.
More specifically, PCOS is defined as unexplained hyperandrogenic
chronic anovulation. Excluded by this definition of
PCOS are known causes of hyperandrogenic chronic anovulation
such as non-classic adrenal hyperplasia and rare androgen
producing ovarian tumors.
The definition of PCOS
is evolving. The NIH sponsored a conference on PCOS
in 1990 and 2001. Although both conferences affirmed
the key importance of unexplained hyperandrogenism,
the 2001 meeting de-emphasized anovulation, and placed
more importance on the polycystic appearance of the
ovaries on US (>8 follicles, 2-8 mm in diameter,
increased ovarian stroma). US evidence of polycystic
ovaries occurs in 16% of asymptomatic women.
Our studies of ovulatory
women with isolated polycystic ovaries found they demonstrate
a PCOS-like response to gonadotropin stimulation (that
is, an exaggerated response) and subtle PCOS-like lab
alterations (elevated androgens and decreased IGFBP1).
Because of findings such as these, the definition of
PCOS is evolving from unexplained hyperandrogenic chronic
anovulation to simply unexplained hyperandrogenism,
often with polycystic ovaries, ovulatory disturbance,
and IR.
How is PCOS diagnosed?
Unexplained hyperandrogenism
is the key finding. Clinical evidence of androgen excess
is provided by findings of hirsutism, androgenic alopecia,
or acne. These findings may be muted in women with less
skin sensitivity to androgens, e.g. Asian women with
PCOS. Lab evidence of hyperandrogenemia can often be
provided by measurement of serum free or total testosterone,
androstenedione, or dehydroepiandrosterone sulfate.
However, because of limitations of commercially available
tests, hyperandrogenemia may not be evident unless specialized
immunoassays or bioassays are conducted .
Exclusion of known
causes of hyperandrogenism is usually simply accomplished
by history and exam. With irregular menses, TSH and
prolactin levels should be measured. With rapidly progressive
or marked hyperandrogenism, less common conditions should
be considered. For example, non-classic adrenal hyperplasia
due to 21-hydroxylase deficiency can be excluded by
a 17-hydroxyprogesterone level less than 2 ng/mL and
rare androgen producing ovarian tumors will often be
detected by vaginal US. Furthermore, vaginal
US will identify the classic polycystic ovarian morphology;
although not mandatory for the diagnosis, it is corroboratory
evidence of polycystic ovarian
syndrome.
What is Insulin Resistance?
With PCOS defined as
unexplained hyperandrogenism and chronic anovulation,
about 40% of PCOS
women will have IR . IR refers to a state in which
for a given amount of insulin, there is a less than
normal reduction of glucose. The pancreatic beta cells
initially compensates for this resistance by producing
excess amounts of insulin. If glucose levels are maintained
within normal ranges, the person simply has IR with
high insulin levels. If however, glucose levels are
moderately high (fasting glucose = 110 or = 140 two
hours after a 75-gram glucose load) the person has Impaired
Glucose Tolerance (IGT). If glucose levels are very
high (fasting glucose = 126 or = 200 two hours after
a 75-gram glucose load) the person has type 2 diabetes.
With time, a person with IR has a tendency to progress
from high insulin levels with normal glucose levels
to abnormally high glucose levels, that is, IGT or type
2 diabetes. This is because beta cell function tends
to deteriorate. When beta cells can no longer produce
the excessive amounts of insulin needed in IR to control
glucose levels, insulin levels fall allowing abnormally
high glucose levels to develop, resulting initially
in IGT, and ultimately, if left unchecked, type 2 diabetes.
The high insulin levels
associated with IR stimulate the ovary to make excessive
amounts of androgens. Additionally, high insulin levels
decrease levels of SHBG, increasing the androgens potency.
High insulin levels may also work at the level of the
brain, causing increased LH secretion (which in turns
stimulates more ovarian androgen production) and stimulating
appetite. Increased LH secretion, high androgen levels,
and obesity disrupt ovulation. These complex and interrelated
effects lead to "unexplained hyperandrogenic chronic
anovulation" that is, PCOS. This begs the question,
what is "unexplained"? There seemingly is
an explanation for the hyperandrogenic chronic anovulation,
namely IR with high insulin levels. The answer is IR
itself is unexplained. It too is a syndrome ("syndrome
X"), a heterogeneous metabolic disorder without
a known specific cause.
How is Insulin Resistance diagnosed?
Clinically, IR is suggested
on exam by obesity (BMI >30 kg/m2), a central adipose
distribution ('apple shaped' [waist-hip ratio >0.85]
as opposed to 'pear shaped'), and acanthosis nigricans
(raised, velvety, usually hyperpigmented, nuchal and
axillary skin changes). Lab tests can provide unequivocal
proof of IR with the diagnosis of IGT or type 2 diabetes
by established criteria such as those of the WHO listed
above.
Prior to progression
to IGT or type 2 diabetes, however, there isn't a universally
agreed upon simple lab test to screen for IR. In the
research setting, detection of IR usually involves IV
infusions, multiple blood draws, and complex analysis
("clamp technique"); it is clinically impractical.
A pragmatic, clinical approach to the diagnosis of IR
is to perform a 75 gram oral glucose tolerance test,
measuring fasting and 2 hour glucose levels. By this
approach, IGT or type 2 diabetes may be revealed, proving
advanced insulin resistance. Short of this, IR may be
suggested by an elevated fasting insulin level (>20
microU/mL), a reduced fasting glucose / insulin ratio
(G/I < 4.5), or an elevated 2 hour insulin level
following a 75-gram glucose load. However, there aren't
well-established criteria or studies to validate the
use of these tests to diagnose IR. Also note, insulin
levels are notoriously difficult to measure accurately
and, of course, in the face of advanced progression,
namely, IGT or type 2 diabetes, insulin levels will
not be high because of B cell exhaustion.
IR is very common in
the general population; its prevalence is dependent
on screening method, age, and body weight. Overall,
the prevalence of IR is 2-5 times higher than that of
PCOS. Therefore, many women will have IR but not PCOS;
conversely, some women with PCOS will not be insulin
resistant. In a study of 254 women with polycystic
ovarian syndrome, almost 40% had abnormal glucose
tolerance (31% had IGT, 7.5% had previously undiagnosed
type 2 diabetes). In the non-obese women with polycystic
ovarian syndrome, 10% had IGT, 1.5% had type
2 diabetes; these rates are 3 times higher than the
non-PCOS controls .
Besides IGT and Type
2 Diabetes, what other medical problems are associated
with PCOS?
Because PCOS is associated with abnormal lipid profiles,
especially elevated LDL, there is concern that there
is an increased risk for cardiovascular events. Large,
prospective studies have yet to be conducted to prove
this. However, small cohort studies, using surrogate
endpoints for cardiovascular disease are suggestive.
For example, in one study the prevalence for subclinical
atherosclerosis in PCOS women was 10 times higher, 7.2%
compared to 0.7% in controls of similar age. This difference
was detected only in women aged 45 years or older. Women
with polycystic ovarian syndrome
are at increased risk of developing endometrial neoplasia
unless they have periodic menses resulting from progesterone
administration, birth control pills, or induction of
ovulation. Interview with Dr. Daniel Potter on PCOS
|
