Polycystic Ovary Syndrome (PCOS)

Barry W. Donesky
University of Tennessee College of Medicine, Chattanooga, Tennessee, United States
Polycystic ovary syndrome is a common gynecologic dis-
order typied by the symptoms associated with chronic oligo-
or anovulation (irregular or absent menses and infertility) and
evidence of hyperandrogenism (hirsutism). It is often, but not
exclusively, associated with obesity.
HISTORY
The constellation of symptoms referred to as polycystic
ovary syndrome was rst described in 1935 when Stein
and Leventhal published a report on seven women with
amenorrhea, infertility, and hirsutism. All had enlarged
ovaries with thickened, whitish capsules containing
multiple small cysts within the cortices. In an effort to
elucidate the problem, Stein and Leventhal performed
laparotomy and bilateral ovarian wedge resections on
these women. Although the ovarian biopsies provided
no new information other than stromal hyperplasia,
surprisingly, all seven women resumed normal spontan-
eous menses and three pregnancies were conceived. For
many years subsequent to their description, the condi-
tion was referred to as Stein-Leventhal syndrome, a
term that has gradually given way to the more anatomic
polycystic ovary syndrome (PCOS). This most common
cause of amenorrhea and irregular menstruation is still
incompletely understood, but major advances have
been made. Its triad of symptoms is known to ultimately
result from an intraovarian environment where andro-
gens dominate. Attempts have been to change its name
to the more descriptive term, hyperandrogenic chronic
anovulation. However, as is often the case with well-
established names, the more common polycystic ovary
syndrome has remained.
PATHOPHYSIOLOGY
Although in reality the mechanisms are doubtless far
more complex, involving regulation from intraovarian
factors (e.g., insulin-like growth factors and their
binding proteins, transforming growth factor-b) and
extraovarian factors (e.g., gonadotropins, androgens,
insulin), a simplistic way to view the problem involves
a balance between intrafollicular production of andro-
gens and estrogens. The classic two-cell hypothesis of
estrogen production, though perhaps an oversimpli-
cation, is still very useful. The functional unit of the
ovary, the follicle, has two compartments. The inner
compartment is composed of the oocyte surrounded
by one or more layers of granulosa cells. The granu-
losa cells are, in turn, surrounded by a basement mem-
brane that excludes blood vessels, thus rendering the
inner follicular compartment avascular. Immediately
outside the basement membrane are the theca cells,
which, under the inuence of luteinizing hormone
(LH), produce androgens (testosterone and androste-
nedione) from cholesterol brought in via blood vessels.
These androgens seep their way across the basement
membrane into the inner follicular compartment,
where granulosa cells [under the inuence of follicle-
stimulating hormone (FSH)] convert the androgens
to estrogens via the enzyme aromatase. The increas-
ing estrogen content within the follicle causes follicu-
lar growth through multiplication of granulosa cells
and oocyte growth. The increasing estrogen levels
also induce more FSH receptors to appear on the
Glossary
amenorrhea The absence of menstruation.
anovulation The absence of the normal, orderly
endocrine events that lead to the growth, maturation,
and release of the oocyte.
follicle The functional unit of the ovary, consisting of
an oocyte (egg) surrounded by one or more layers of
cumulus cells encased within a basement membrane.
hyperandrogenism A condition characterized by an
excess secretion of masculinizing hormones, such as
testosterone and androstenedione. Most often the
source is the gonads, but the adrenal glands are also
frequent contributors.
oligomenorrhea Infrequent and usually irregular
menstruation.
Encyclopedia of Endocrine Diseases, Volume 4. 2004 Elsevier Inc. All rights reserved. 1
granulosa cells. More granulosa cells with FSH re-
ceptors mean further increases in granulosa cell
aromatase activity and further amplication of estro-
gen production, culminating in an LH surge and
ovulation.
The polycystic ovary is characterized by increased
intraovarian androgen concentrations. The increased
androgen content interrupts follicle development
through inhibition of FSH receptor recruitment and
aromatase activity. Estrogen production is impeded
and follicular growth stops before maturity and ovu-
lation can be achieved. A pattern of hyperandrogen-
ism and anovulation is thus established. In vitro studies
have demonstrated that granulosa cells from PCOS
ovaries function normally if adequate FSH levels are
supplied and virtually all PCOS patients can be in-
duced to ovulate, if enough exogenous FSH is sup-
plied. The problem thus is one of inadequate FSH
action at the level of the follicle and probably repre-
sents a deciency of FSH or a blockade of FSH action
by intraovarian regulators.
DIAGNOSIS
Many diagnostic criteria have been developed, but no
one item has been shown to be indispensable. Indeed,
there is still substantial discussion as to what elements
are crucial for the diagnosis. Evidence of peripheral
hyperandrogenism (hirsutism), irregular menses, and
chronic anovulation in the absence of other causes such
as hypothyroidism and hyperprolactinemia constitutes
the classic clinical presentation. Some, however, have
argued that the appearance of multiple small cysts
within the cortex of the ovary (representing incomplete
maturation of follicles) is enough to make the diagno-
sis, even in the presence of normal menstrual function.
Most authorities, however, advocate that evidence of
menstrual dysfunction and hyperandrogenism should
be present. Obesity is common, but in some studies as
many as 50% of women with PCOS are not obese.
Biochemical markers include elevated serum LH
levels, an elevated LH:FSH ratio (at least 2:1), elevated
circulating androgens (total and free testosterone,
androstenedione, dehydroepiandrosterone sulfate), de-
creased sex hormone-binding globulin, and evidence
of hyperinsulinemia.
TREATMENT
The initial treatment of Stein and Leventhal, that of
bilateral ovarian wedge resection, was the only avail-
able treatment for polycystic ovary syndrome until the
1960s. That procedure is theorized to produce a
sudden decrease in the concentration of intraovarian
androgens through the removal of ovarian stromal
tissue. The lower levels of intraovarian androgens
release the follicle from interference with FSH action
and follicle development and thus ovulation can occur.
Due to concerns about postoperative adhesion forma-
tion and subsequent impairment of fertility, coupled
with the introduction of effective medical treatments,
the procedure is rarely performed anymore. Instead,
treatment varies considerably depending on the indi-
vidual patients desires and most troubling symptoms.
For many years, PCOS was regarded by many as a
nuisance disease with inconvenient symptoms, but
presenting no major health consequences. As a result,
treatment was directed at managing the most bother-
some symptoms, such as irregular menstrual bleeding,
hirsutism, and infertility. In women whose only con-
cern was their irregular menstrual cycles, progestins
were supplied to make up their deciency of the hor-
mone progesterone in the anovulatory state. In those
who wished pregnancy, ovulation was induced with
medications such as clomiphene citrate or injections
of FSH. Those presenting with hirsutism and other
signs of peripheral hyperandrogenism, such as acne,
were given oral contraceptives and agents that blocked
androgen action at the level of the hair follicle. As the
relationship between hyperinsulinemia and PCOS
began to be noted, a viewof PCOS as a systemic disease
with long-term health consequences, including in-
creased cardiovascular risk and development of dia-
betes, emerged. It has become common for women
with PCOS to routinely undergo screening for glucose
intolerance and insulin resistance. Where these condi-
tions are present, treatment with insulin-sensitizing
agents, such as metformin, is often instituted.
NEW DEVELOPMENTSTHE
INSULIN CONNECTION
For some time, it has been observed that women with
polycystic ovary syndrome have a higher incidence of
long-term health problems than do normally menstru-
ating women. The incidence of non-insulin-dependent
diabetes mellitus is increased as is cardiovascular dis-
ease. Increasing attention has been given to the obser-
vation of insulin resistance in a large proportion of
women with PCOS (up to 80% by some estimates).
The elevated levels of insulin in these women that
are necessary to maintain normal serum glucose
levels cause direct stimulation of androgen production
in the ovary, thus leading to the hyperandrogenism
2 Polycystic Ovary Syndrome (PCOS)
characteristic of polycystic ovary syndrome. As insulin
promotes fat storage and inhibits fat release from
adipose tissue, these elevated insulin levels may play a
role in promoting obesity, which, in turn, promotes
further insulin resistance.
Findings of primary defects in the insulin receptor
may explain much of the familial clustering of polycystic
ovaries. Observed abnormalities of the insulin receptor
in PCOS include excessive autophosphorylation of
serine residues rather than threonine residues as is the
case with normal insulin receptor function. Excessive
serine autophosphorylation inhibits insulin receptor
action by interfering with the translocation of intracel-
lular glucose transporters to the cell surface, thus de-
creasing glucose uptake in those cells. Administration
of medications designed to increase insulin sensitiv-
ity, such as metformin, have proven very useful in
improving the hormonal and metabolic abnormalities
of the syndrome and are rapidly becoming a primary
treatment modality for PCOS.
See Also the Following Articles
Hyperandrogenism, Functional
.
Hyperandrogenism,
Hyperinsulinemic
.
Hypothalamic Anovulation, Functional
.
Infertility, Overview
.
Menstrual Cycle: An Integrative
View
.
Ovarian Androgen-Producing Tumors
.
Ovarian
Hyperstimulation Syndrome
.
Polycystic Ovary Syndrome:
Implications for Cardiovascular, Endometrial, and Breast
Disease
Further Reading
Almahbobi, G., Anderiesz, C., Hutchinson, P., et al. (1996). Func-
tional integrity of granulosa cells from polycystic ovaries. Clin.
Endocrinol. 44, 571580.
Barbieri, R. L., Makris, A., Randall, R. W., et al. (1986). Insulin
stimulated androgen accumulation in incubations of ovarian
stroma obtained from women with hyperandrogenism. J. Clin.
Endocrinol. Metab. 62, 904.
Dunaif, A. (1997). Insulin resistance and the polycystic ovary syn-
drome: Mechanism and implications for pathogenesis. Endocr.
Rev. 18, 774800.
Nestler, J. E., Clore, J. N., and Blackard, W. G. (1989). The central
role of obesity (hyperinsulinemia) in the pathogenesis of the
polycystic ovary syndrome. Am. J. Obstet. Gynecol. 161, 1095
1089.
Nestler, J. E., Jakubowicz, D. J., Evans, W. S., and Pasquali, R.
(1998). Effects of metformin on spontaneous and clomiphene-
induced ovulation in the polycystic ovary syndrome. N. Engl.
J. Med. 338, 18761880.
Stein, I. F., and Leventhal, M. L. (1935). Amenorrhea associated with
bilateral polycystic ovaries. Am. J. Obstet. Gynecol. 29, 181191.
Yen, S. S. C. (1999). Polycystic ovary syndrome (hyperandrogenic
chronic anovulation). In Reproductive Endocrinology: Physi-
ology, Pathophysiology, and Clinical Management (S. S. C.
Yen, R. B. Jaffe, and R. L. Barbieri, eds.), 4th ed., pp. 436476.
W. B. Saunders, Philadelphia, PA.
Polycystic Ovary Syndrome (PCOS) 3