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The new england journal of medicine

review article

medical progress

Polycystic Ovary Syndrome

David A. Ehrmann, M.D.

i n 1935, stein and leventhal published a paper on their findings

in seven women with amenorrhea, hirsutism, obesity, and a characteristic polycys-
tic appearance to their ovaries — one of the first descriptions of a complex pheno-
type today known as the polycystic ovary syndrome.1 Insight into the pathogenesis and
treatment of the polycystic ovary syndrome has increased substantially in the decade
From the University of Chicago, Depart-
ment of Medicine, Section of Endocrinol-
ogy, Chicago. Address reprint requests to
Dr. Ehrmann at 5841 S. Maryland Ave.,
Mail Code 1027, Chicago, IL 60637, or at

since this topic was last addressed in the Journal.2 The condition is now well recognized N Engl J Med 2005;352:1223-36.
as having a major effect throughout life on the reproductive, metabolic, and cardiovas- Copyright © 2005 Massachusetts Medical Society.

cular health of affected women. This review addresses current knowledge regarding the
diagnosis, cause, and treatment of the polycystic ovary syndrome.

definition and differential diagnosis

Several factors contribute to difficulties in the diagnosis of the polycystic ovary syndrome.
Presenting signs and symptoms are heterogeneous and vary over time; in addition, a
precise and uniform definition of the syndrome has been lacking. An international con-
sensus group3 recently proposed that the syndrome can be diagnosed after the exclusion
of other medical conditions that cause irregular menstrual cycles and androgen excess
(Fig. 1 and Table 1) and the determination that at least two of the following are present:
oligoovulation or anovulation (usually manifested as oligomenorrhea or amenorrhea),
elevated levels of circulating androgens (hyperandrogenemia) or clinical manifestations
of androgen excess (hyperandrogenism), and polycystic ovaries as defined by ultraso-
nography.4 These criteria acknowledge the condition as functional: polycystic ovaries
need not be present to make a diagnosis of the polycystic ovary syndrome,5 and con-
versely, their presence alone does not establish the diagnosis.6,7
Women with the polycystic ovary syndrome almost always have some aberration in
gonadotropin secretion as compared with women who have normal menstrual cycles.8
However, since gonadotropin concentrations vary over the menstrual cycle and are re-
leased in a pulsatile fashion into the circulation, a single measurement of luteinizing
hormone and follicle-stimulating hormone provides little diagnostic sensitivity. Thus,
in routine clinical practice, abnormal gonadotropin levels (an elevated level of luteiniz-
ing hormone or an elevated ratio of luteinizing hormone to follicle-stimulating hor-
mone) need not be documented to diagnose the polycystic ovary syndrome.
Chronic anovulation most often manifests as oligomenorrhea (fewer than nine mens-
es per year) or amenorrhea. Anovulatory cycles may lead to dysfunctional uterine bleed-
ing and decreased fertility. Cutaneous manifestations of hyperandrogenemia in the poly-
cystic ovary syndrome include hirsutism, acne, and male-pattern hair loss (androgenic
alopecia), whereas acanthosis nigricans is a cutaneous marker of hyperinsulinemia.
A substantial proportion of women with the polycystic ovary syndrome are over-
weight; many are obese, some extremely so.9 Although obesity itself is not considered
the inciting event in the development of the syndrome, excess adiposity can exacerbate
associated reproductive and metabolic derangements.
The symptoms of the polycystic ovary syndrome usually begin around menarche,10

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Any 2 of the following 3 disorders confirmed: All of the following disorders ruled out:
Oligomenorrhea or amenorrhea Hyperprolactinemia
Hyperandrogenism (e.g., hirsutism, Nonclassic congenital adrenal hyperplasia
acne, alopecia) or hyperandrogenemia Cushing’s syndrome
(e.g., elevated levels of total or free Androgen-secreting neoplasm
testosterone) Acromegaly
Polycystic ovaries on ultrasonography

Polycystic ovary syndrome

Ancillary studies

Risk assessment for Risk assessment for Fasting cholesterol, HDL Risk assessment for
endometrial carcinoma glucose intolerance cholesterol, triglycerides, obstructive sleep apnea
LDL cholesterol

Endometrial biopsy Oral glucose-tolerance test Polysomnography

if risk increased if risk increased if risk increased

Figure 1. Diagnostic Algorithm for the Polycystic Ovary Syndrome.

Single measurements of serum prolactin and 17-hydroxyprogesterone are usually sufficient to rule out hyperprolactinemia and nonclassic
congenital adrenal hyperplasia due to deficiency of 21-hydroxylase. It is important to measure the 17-hydroxyprogesterone level in a blood
sample taken in the early morning, when endogenous corticotropin levels peak. As an alternate test, 17-hydroxyprogesterone can be mea-
sured in response to a single dose of exogenously administered corticotropin. Risks for glucose intolerance include an elevated body-mass
index, an increased waist circumference, a history of gestational diabetes, a family history of type 2 diabetes, and certain racial or ethnic back-
grounds (including black, Caribbean Hispanic, and Mexican American). HDL denotes high-density lipoprotein, and LDL low-density lipoprotein.

but onset after puberty may also occur as a result of hormone, the ovarian theca cell synthesizes andro-
environmental modifiers such as weight gain. Pre- gens (Fig. 2). Androgen biosynthesis is mediated by
mature pubarche, the result of early secretion of cytochrome P-450c17, an enzyme with 17a-hydrox-
adrenal steroids, may be a harbinger of the syn- ylase and 17,20-lyase activities, both of which are
drome.11 In addition, an aberrant intrauterine en- required to form androstenedione. The androgenic
vironment has been implicated in the condition’s steroid is then converted by 17b-hydroxysteroid de-
pathogenesis, particularly its metabolic compo- hydrogenase (17b-HSD) to form testosterone or is
nents.12-15 aromatized by the aromatase enzyme (cytochrome
P-450arom) to form estrone. Studies performed
pathogenesis both in vivo and in vitro (in cultured theca cells) con-
sistently suggest that ovarian theca cells in affected
No single etiologic factor fully accounts for the spec- women are more efficient at converting androgen-
trum of abnormalities in the polycystic ovary syn- ic precursors to testosterone than are normal theca
drome. In response to stimulation by luteinizing cells.16,17

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Table 1. Conditions for Exclusion in the Diagnosis of the Polycystic Ovary Syndrome.

genemia, Hyper-
androgenism, Oligomenorrhea
Condition or Both or Amenorrhea Distinguishing Features
Clinical Hormonal or Biochemical
Nonclassic congenital Yes Not often Family history of infertility, Elevated (basal) level of
adrenal hyperplasia hirsutism, or both; 17-hydroxyprogester-
due to deficiency of common in Ashkenazi one in the morning or
21-hydroxylase Jews on stimulation
Cushing’s syndrome Yes Yes Hypertension, striae, easy Elevated 24-hr urinary free
bruising cortisol level
Hyperprolactinemia or None or mild Yes Galactorrhea Elevated plasma prolactin
prolactinoma level
Primary hypothyroidism None or mild May be present Goiter may be present Elevated plasma thyrotro-
pin and subnormal
plasma thyroxine level;
prolactin level may
also be increased
Acromegaly None or mild Often Acral enlargement, coarse Increased plasma insulin-
features, prognathism like growth factor I
Premature ovarian None Yes May be associated with Elevated plasma follicle-
failure other autoimmune stimulating hormone
endocrinopathies and normal or sub-
normal estradiol level
Simple obesity Often Not often Diagnosed by exclusion None
Virilizing adrenal or Yes Yes Clitorimegaly, extreme hir- Extremely elevated plasma
ovarian neoplasm sutism, or male-pattern androgen level
Drug-related condition* Often Variably Evidence provided by None

* A drug-related condition is a condition due to the use of androgens, valproic acid, cyclosporine, or other drugs.

Whereas luteinizing hormone regulates the Because women with the polycystic ovary syndrome
androgenic synthesis of theca cells, follicle-stim- appear to have an increased luteinizing hormone
ulating hormone is responsible for regulating the pulse frequency8 (Fig. 2), it has been inferred that
aromatase activity of granulosa cells, thereby de- the pulse frequency of GnRH must be accelerated
termining how much estrogen is synthesized from in the syndrome. It is not clear whether this accel-
androgenic precursors. When the concentration of erated pulse frequency is due to an intrinsic abnor-
luteinizing hormone increases relative to that of mality in the GnRH pulse generator or is caused by
follicle-stimulating hormone, the ovaries prefer- the relatively low levels of progesterone resulting
entially synthesize androgen. from infrequent ovulatory events. Since progestins
The frequency of the stimulus of hypothalamic slow the GnRH pulse generator, low circulating
gonadotropin-releasing hormone (GnRH) deter- progestin levels in women with the polycystic ovary
mines, in part, the relative proportion of luteiniz- syndrome may lead to an acceleration in the pulsa-
ing hormone and follicle-stimulating hormone syn- tility of GnRH,19 increased levels of luteinizing hor-
thesized within the gonadotrope (Fig. 2). Increased mone, and overproduction of ovarian androgen.
pulse frequency of hypothalamic GnRH favors tran- Insulin plays both direct and indirect roles in the
scription of the b-subunit of luteinizing hormone pathogenesis of hyperandrogenemia in the polycys-
over the b-subunit of follicle-stimulating hormone; tic ovary syndrome (Fig. 2). Insulin acts synergis-
conversely, decreased pulse frequency of GnRH fa- tically with luteinizing hormone to enhance the
vors transcription of the b-subunit of follicle-stim- androgen production of theca cells. Insulin also in-
ulating hormone, which decreases the ratio of lute- hibits hepatic synthesis of sex hormone–binding
inizing hormone to follicle-stimulating hormone.18 globulin, the key circulating protein that binds to

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Polycystic ovary syndrome ovary


scc, StAR Insulin
Pregnenolone Progesterone
Granulosa cell
Theca cell
Testosterone Aromatase

Figure 2. The Hypothalamic–Pituitary–Ovarian Axis and the Role of Insulin.

Increased ovarian androgen biosynthesis in the polycystic ovary syndrome results from abnormalities at all levels of the hypothalamic–pitu-
itary–ovarian axis. The increased frequency of luteinizing hormone (LH) pulses in the polycystic ovary syndrome appears to result from an
increased frequency of hypothalamic gonadotropin-releasing hormone (GnRH) pulses. The latter can result from an intrinsic abnormality in
the hypothalamic GnRH pulse generator, favoring the production of luteinizing hormone over follicle-stimulating hormone (FSH) in patients
with the polycystic ovary syndrome, in whom the administration of progesterone can restrain the rapid pulse frequency. By whatever mecha-
nism, the relative increase in pituitary secretion of luteinizing hormone leads to an increase in androgen production by ovarian theca cells. In-
creased efficiency in the conversion of androgenic precursors in theca cells leads to enhanced production of androstenedione, which is then
converted by 17b-hydroxysteroid dehydrogenase (17b) to form testosterone or aromatized by the aromatase enzyme to form estrone. Within
the granulosa cell, estrone is then converted into estradiol by 17b. Numerous autocrine, paracrine, and endocrine factors modulate the ef-
fects of both luteinizing hormone and insulin on the androgen production of theca cells; insulin acts synergistically with luteinizing hormone
to enhance androgen production. Insulin also inhibits hepatic synthesis of sex hormone–binding globulin, the key circulating protein that
binds to testosterone and thus increases the proportion of testosterone that circulates in the unbound, biologically available, or “free,” state.
Testosterone inhibits and estrogen stimulates hepatic synthesis of sex hormone–binding globulin. The abbreviation scc denotes side-chain
cleavage enzyme, StAR steroidogenic acute regulatory protein, and 3b-HSD 3b-hydroxysteroid dehydrogenase. Solid arrows denote a higher
degree of stimulation than dashed arrows.

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testosterone, and thus increases the proportion of obesity

testosterone that circulates in the unbound, biolog- The cause of obesity in the polycystic ovary syn-
ically available, or free, state. Because women with drome remains unknown, but obesity is present in
the polycystic ovary syndrome typically have hyper- at least 30 percent of cases; in some series, the per-
insulinemia, the concentration of free testosterone centage is as high as 75.62 Women in the United
is often elevated when the total testosterone con- States with the polycystic ovary syndrome generally
centration is at the upper range of normal or only have a higher body weight than their European
modestly elevated. counterparts.62-65 This fact has been cited as an ex-
planation for the increase in the incidence of the
polycystic ovary syndrome in the U.S. population —
the role of genetic
and environmental factors an increase that parallels the increase in obesity.66
Increased adiposity, particularly visceral adipos-
The polycystic ovary syndrome remains one of the ity that is reflected by an elevated waist circumfer-
most common hormonal disorders in women, ence (>88 cm [35 in.]) or waist-to-hip ratio, has
with a prevalence estimated between 5 and 10 per- been associated with hyperandrogenemia, insulin
cent.20-22 Variance in prevalence among popula- resistance, glucose intolerance, and dyslipidemia.60
tions may reflect the effect of ethnic origin, race, and Attenuation of insulin resistance, whether accom-
other environmental factors on the phenotype.23,24 plished by weight loss or with medication, amelio-
Several lines of evidence suggest that the poly- rates (but not necessarily normalizes) many of the
cystic ovary syndrome is heritable,25-29 and various metabolic aberrations in women with the polycystic
approaches have been initiated to attempt to define ovary syndrome.
a specific genetic cause.30,31 In rare instances, sin-
gle-gene mutations can give rise to the phenotype impaired glucose tolerance
of the syndrome.32 Current understanding of the and type 2 diabetes
pathogenesis of the syndrome suggests, however, Thirty to 40 percent of women with the polycystic
that it is a complex multigenic disorder. Candidate ovary syndrome have impaired glucose tolerance,
genes that may regulate the hypothalamic–pitu- and as many as 10 percent have type 2 diabetes by
itary–ovarian axis, as well as those responsible for their fourth decade.9,67 These prevalence rates are
insulin resistance and its sequelae, have been the among the highest known among women of simi-
principal focus of linkage and case–control studies. lar age.68 An enhanced rate of deterioration in glu-
Microarray analyses of target tissues in the polycys- cose tolerance is also evident in the polycystic ovary
tic ovary syndrome31 have been used to identify nov- syndrome.9,69 Seminal studies by Dunaif et al.70-72
el candidate genes involved in the condition, and a indicated that women with the polycystic ovary syn-
number of them appear to contribute modestly to drome are more insulin resistant than are unaffect-
the phenotype (Table 2).30,57,58 ed counterparts matched for body-mass index, fat-
free body mass, and body-fat distribution. A defect
in the insulin signaling pathway appears to be
metabolic, cardiovascular,
and other clinical components present in both the adipocyte and skeletal muscle,
the primary target tissues of insulin action.71,72
The consequences of the polycystic ovary syndrome Insulin resistance alone cannot fully account for
extend beyond the reproductive axis; women with the predisposition to and development of type 2 di-
the disorder are at substantial risk for the develop- abetes among patients with the polycystic ovary syn-
ment of metabolic and cardiovascular abnormali- drome. In patients with normal glucose tolerance,
ties similar to those that make up the metabolic syn- insulin secretion is (by definition) sufficient for the
drome.59 This finding is not surprising, since both degree of insulin resistance; when the pancreatic
the polycystic ovary syndrome and the metabolic b cell is no longer able to compensate sufficiently,
syndrome share insulin resistance as a central glucose tolerance begins to deteriorate.73,74 Most
pathogenetic feature (Fig. 2). The polycystic ovary women with the polycystic ovary syndrome are able
syndrome might thus be viewed as a sex-specific to compensate fully for their insulin resistance, but
form of the metabolic syndrome,60 and the term a substantial proportion (particularly those with a
“syndrome XX” has been suggested as an apt term first-degree relative with type 2 diabetes27) have a
to underscore this association.61 disordered and insufficient b-cell response to meals

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hypertension and vascular dysfunction

Table 2. Representative Candidate Genes with Evidence of Linkage,
Association, or Both, with the Polycystic Ovary Syndrome (PCOS).
Hypertension develops in some women with the
polycystic ovary syndrome during their reproduc-
Pathway and Protein (Gene) Comments tive years,59,80 and sustained hypertension may de-
Insulin secretion and action velop in later life in women with the disorder.81,82
Insulin receptor (INSR) region D19S884, an anonymous marker 1 cM centro- Reduced vascular compliance83 and vascular endo-
meric to INSR; evidence for linkage and thelial dysfunction were noted in most,83-86 but not
association with PCOS26,33 all,87 studies of women with the polycystic ovary
Insulin variable-number tan- Region involved in transcriptional regulation syndrome. Furthermore, the degree of impairment
dem repeats (VNTR) of insulin gene; evidence for linkage and
association with class III allele34-36 in vascular reactivity is significantly greater than can
Insulin receptor substrate 1 Post-receptor molecule in insulin signaling
be explained by obesity alone.83 Insulin-lowering
(IRS-1) pathway; association with PCOS37,38 therapies appear to improve the vascular endothe-
Insulin receptor substrate 2 Post-receptor molecule in insulin signaling lial dysfunction in patients with the polycystic ovary
(IRS-2) pathway; association with PCOS 37,38 syndrome.85
Calpain 10 (CAPN10) Cysteine protease with effect on insulin action
and secretion; linkage and association coronary and other vascular disease
with type 2 diabetes39,40
A predisposition to macrovascular disease and
Peroxisome-proliferator–acti- The Pro12Ala polymorphism in the PPARg
vated receptor g (PPARg) gene is a modifier of insulin resistance in
thrombosis88,89 in women with the polycystic ovary
PCOS41-43 syndrome has also been described. A recent study
Protein phosphatase 1 regula- Variant of regulatory subunit of the glycogen- of premenopausal women showed that those with
tory subunit (PPP1R3) associated form of protein phosphatase-1 the polycystic ovary syndrome had a higher preva-
derived from skeletal muscle; associated lence of coronary-artery calcification as detected by
with insulin resistance44
electron-beam computed tomography.90 Increased
Gonadotropin secretion
and action levels of plasminogen-activator inhibitor type 1 may
Follistatin (FST) Acts to inhibit ovarian follicular maturation
contribute to this risk.91-93 Levels of plasminogen-
and androgen production; enhances folli- activator inhibitor type 1 in patients with the poly-
cle-stimulating hormone and insulin cystic ovary syndrome may exceed those typically
seen in type 2 diabetes.91 A reduction in insulin lev-
Androgen biosynthesis, els91 decreases levels and activity of plasminogen-
secretion, transport,
and metabolism activator inhibitor type 1.
Androgen receptor (AR) Number of CAG repeats associated with an- Hypertriglyceridemia, increased levels of very-
drogen levels in PCOS46 low-density lipoprotein and low-density lipoprotein
Sex hormone–binding Association of the pentanucleotide (TAAAA)n cholesterol, and decreased levels of high-density
globulin (SHBG) repeat polymorphism with PCOS47,48 lipoprotein cholesterol94 also predispose patients to
Cytochrome P-450c17 (CYP17) Possible association with PCOS49-53 vascular disease in the polycystic ovary syndrome.
Cytochrome P-45011a Early analyses revealed association with hy- Both insulin resistance and hyperandrogenemia
(CYP11a) perandrogenemia and PCOS54,55; more contribute to this atherogenic lipid profile. Testos-
recently, strength of association has been
questioned56 terone decreases lipoprotein lipase activity in ab-
11b-Hydroxysteroid dehydro- Mutations in both 11b-HSD and H6PD in
dominal fat cells, and insulin resistance impairs the
genase (11b-HSD) and a triallelic digenic model of inheritance ability of insulin to exert its antilipolytic effects. Al-
hexose-6-phosphate de- result in low 11b-HSD expression and though these abnormalities would be expected to
hydrogenase (H6PD) NADPH generation with loss of 11b-HSD
1 oxo-reductase activity32
increase the morbidity and mortality from coronary
artery disease and other vascular disorders in wom-
en with the polycystic ovary syndrome, this has been
difficult to establish.95-97
or a glucose challenge.27,75-78 Before the develop-
ment of frank glucose intolerance, defects in insu- obstructive sleep apnea
lin secretion may be latent and revealed only in cir- Recent studies indicate that the prevalence of ob-
cumstances that augment insulin resistance, as with structive sleep apnea in the polycystic ovary syn-
the development of gestational diabetes in preg- drome is higher than expected and cannot be ex-
nancy79 or glucose intolerance associated with glu- plained by obesity alone.98-100 In two studies,98,100
cocorticoid administration.77 the severity of sleep apnea did not correlate with

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body-mass index; in a third study,99 even after con- since most progestins also possess variable andro-
trolling for body-mass index, the risk of sleep-dis- genic effects. Norgestimate and desogestrel are vir-
ordered breathing was increased by a factor of 30. tually nonandrogenic progestins.103 Drospirenone,
Insulin resistance appears to be a stronger predic- an analogue of spironolactone with unique antimin-
tor of sleep-disordered breathing than is age, body- eralocorticoid and antiandrogenic activities,104 has
mass index, or the circulating testosterone concen- been approved for use in combination with ethinyl
tration.98 estradiol; thus, it is potentially ideal for the treat-
ment of women with the polycystic ovary syn-
association with cancer drome.105
There is an increased prevalence of endometrial hy- Controversy persists regarding the use of oral
perplasia and carcinoma in women with the poly- contraceptives as first-line therapy in women with
cystic ovary syndrome.101,102 This increase has been the polycystic ovary syndrome.106 These agents
attributed largely to the persistent stimulation of clearly improve hirsutism and acne and protect
endometrial tissue by estrogen (mainly estrone) against unopposed estrogenic stimulation of the
without the progesterone-induced inhibition of endometrium, but their potential adverse effects on
proliferation and differentiation to secretory en- insulin resistance, glucose tolerance, vascular re-
dometrium that occurs after ovulation. Endometrial activity, and coagulability are a concern, particular-
carcinoma has also been associated with obesity and ly since insulin-lowering agents are now available
type 2 diabetes, both of which are common in the (see below).
polycystic ovary syndrome.
Breast and ovarian cancer have been variably as- Antiandrogens
sociated with the polycystic ovary syndrome102; The antiandrogen cyproterone acetate competitive-
obesity, anovulation, infertility, and the hormonal ly inhibits the binding of testosterone and its more
treatment of infertility are so frequent in the poly- potent conversion product, 5a-dihydrotestosterone,
cystic ovary syndrome that the condition is difficult to the androgen receptor. Although not available in
to isolate as an independent risk factor for these the United States, cyproterone acetate effectively
types of cancer. treats hirsutism and acne107 and is used throughout
Canada, Mexico, and Europe.
treatment Spironolactone, typically used as an antiminer-
alocorticoid, possesses moderate antiandrogenic
cutaneous manifestations of androgen effects when administered in large doses (100 to
excess: hirsutism and acne 200 mg daily).108 Adverse effects seem to be mini-
Medical treatment of hirsutism and acne in the poly- mal, with the exception of occasional vaginal bleed-
cystic ovary syndrome generally aims to reduce an- ing resulting from progestin-like properties at a
drogen levels, attenuate their effects by lowering high dose. Spironolactone and oral contraceptives
androgen production, augment androgen binding appear to be synergistic. For these reasons, and be-
to specific plasma-binding proteins, and block an- cause antiandrogens should not be administered to
drogen action at the level of the target tissue. women desiring pregnancy, a combination of estro-
gen and progestin is often prescribed in conjunction
Oral Contraceptives with spironolactone.
Estrogen–progestin combination therapy (with the Flutamide is a potent nonsteroidal antiandrogen
use of the combination oral-contraceptive pill) re- that is effective in the treatment of hirsutism.109-111
mains the predominant treatment for hirsutism and Concern about inducing hepatocellular dysfunction,
acne in the polycystic ovary syndrome. The estro- however, has limited its use.
genic component of the oral contraceptive sup-
presses luteinizing hormone and thus ovarian an- Glucocorticoids
drogen production. Estrogen also enhances hepatic Some women with the polycystic ovary syndrome
production of sex hormone–binding globulin (Fig. have elevated adrenal androgen levels,5,112 though
2), thereby reducing the free, or unbound, fraction the contribution to ovulatory dysfunction appears
of plasma testosterone available to occupy the an- modest.113 Unless a woman with the polycystic ova-
drogen receptor. ry syndrome has marked adrenal androgen excess,
The choice of oral contraceptive is important, prolonged use of glucocorticoids is not advised.

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Other Agents to be advantageous in this patient population. How-

Finasteride, a 4-aza steroid and competitive inhibi- ever, several recent studies designed to address this
tor of type 2 5a-reductase,114 has been reported issue have not shown a distinct benefit from calo-
to treat hirsutism.115 However, the prominence of rie-restricted diets limiting carbohydrates rather
type 1 5a-reductase in the pilosebaceous unit makes than fat.123,124
it unlikely to be an optimal treatment for the andro- A reduction in insulin levels pharmacologically
gen-related cutaneous manifestations associated ameliorates sequelae of both hyperinsulinemia and
with the condition. hyperandrogenemia. The place of insulin-reduction
Eflornithine hydrochloride, an inhibitor of the therapies in treating the polycystic ovary syndrome
enzyme ornithine decarboxylase in human skin, has is evolving and should be viewed in context with all
been approved for topical use in treating facial hir- available therapies (Table 3). These therapies can ef-
sutism. The inhibition of hair growth is its primary fectively manage the established metabolic derange-
action, but clinical data are too limited to recom- ments in the polycystic ovary syndrome, but whether
mend its routine use. they can prevent them is not yet established.
Both metformin (a biguanide) and the thiazo-
management of oligomenorrhea lidinediones pioglitazone and rosiglitazone have
and amenorrhea been used to reduce insulin resistance. Although
Chronic anovulation is associated with an increased metformin appears to influence ovarian steroido-
risk of endometrial hyperplasia and carcinoma, as genesis directly,125,126 this effect does not appear to
discussed. Thus, it is prudent to consider endome- be primarily responsible for the attenuation of ovar-
trial biopsy in patients with the polycystic ovary syn- ian androgen production in women with the poly-
drome who have not had menstrual bleeding for a cystic ovary syndrome. Rather, metformin inhibits
year or longer. Some investigators have advocated the output of hepatic glucose, necessitating a lower
the use of ultrasonography to determine endome- insulin concentration and thereby probably reduc-
trial thickness in deciding whether to biopsy the ing the androgen production of theca cells.
endometrium.102 Endometrial proliferation can be Subject characteristics and control measures for
inhibited by administering either cyclic progestin effects of weight change, dose of metformin, and
or oral contraceptives with a combination of estro- outcome vary widely among published studies of
gen and progestin. The latter approach, which also metformin in the polycystic ovary syndrome. A re-
reduces ovarian androgen production, may be par- cent meta-analysis of 13 studies in which metfor-
ticularly beneficial in this setting. min was administered to 543 participants127 report-
The induction of ovulation is a complex issue in ed that patients taking metformin had an odds ratio
the polycystic ovary syndrome that is beyond the for ovulation of 3.88 (95 percent confidence inter-
scope of this review but has been discussed else- val, 2.25 to 6.69) as compared with placebo and an
where.116-119 It is important to note, however, that odds ratio for ovulation of 4.41 (95 percent confi-
modest reductions in body weight (2 to 7 percent) dence interval, 2.37 to 8.22) for metformin plus
through lifestyle modification have been associated clomiphene as compared with clomiphene alone.
with reductions in androgen levels and improved Metformin also improved fasting insulin levels,
ovulatory function in patients with the polycystic blood pressure, and levels of low-density lipopro-
ovary syndrome.120,121 In addition, numerous stud- tein cholesterol. These effects were judged to be in-
ies have shown that the lowering of insulin levels dependent of any changes in weight that were as-
may increase ovulatory events, potentially restoring sociated with metformin, but controversy persists
cyclic menses and fertility.122,123 The long-term out- as to whether the beneficial effects of metformin
comes of pregnancies associated with the use of in- are entirely independent of the weight loss128 that is
sulin-lowering medications remain unknown. typically seen early in the course of therapy. Finally,
the rates of spontaneous miscarriage and gestation-
insulin resistance and glucose intolerance al diabetes are reportedly lower among women with
Weight reduction is important in treating over- the polycystic ovary syndrome who conceive while
weight patients with the polycystic ovary syndrome. taking metformin.129-132 The long-term effects of
No unique weight-loss regimen targets excess adi- metformin in pregnancy are unknown.
posity specific to the syndrome. Restricting carbo- The thiazolidinediones improve the action of in-
hydrates as compared with fats is generally perceived sulin in the liver, skeletal muscle, and adipose tissue

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Table 3. Drug Treatments.*

Agent Mechanism of Action Advantages or Disadvantages Examples Uses

Hirsutism, Oligomenorrhea Ovulation Insulin
Acne or Amenorrhea Induction Lowering
Combinations of estrogen Increase SHBG, suppress LH Cyclic exposure of endometrium to Ethinyl estradiol and X X
and progestin and FSH, suppress ovari- estrogen and progestin; effective norgestimate (Ortho-
an androgen production; for hirsutism and acne; may in- Cyclen); ethinyl estra-
progestin can act as an crease risk of thrombosis and diol and desogestrel
antiandrogen metabolic abnormalities; bene- (Orthocept); ethinyl
ficial antiandrogenic effects of estradiol and dros-
drospirenone pirenone (Yasmin)
Antiandrogens Inhibit androgens from Effective for hirsutism and acne; Cyproterone acetate, X
binding to the androgen risk of hyperkalemia (spirono- spironolactone,
receptor lactone) or hepatitis (flutamide) flutamide
Glucocorticoids Suppress corticotropin and Attenuate adrenal component of an- Prednisone, dexametha- X X X

n engl j med 352;12

thus adrenal androgen drogen excess; long-term risks of sone
production glucose intolerance, insulin re-
sistance, osteopenia, weight gain
5a-Reductase inhibitors Inhibit 5a-reductase Do not specifically target the iso- Finasteride (Propecia) X
enzyme of 5a-reductase in the
pilosebaceous unit

Ornithine decarboxylase Inhibit ornithine decarboxy- Minimal documented efficacy; used Eflornithine hydrochlo- X
medical progress

inhibitors lase topically ride (Vaniqa)

Antiestrogen Induces rise in FSH, LH Moderately effective as monother- Clomiphene citrate X
apy, less effective in obese pa-
tients; may be useful in conjunc-

The New England Journal of Medicine

tion with insulin-lowering

march 24, 2005

Biguanide Reduces hepatic glucose pro- Substantial efficacy in restoration of Metformin (Glucophage, X X X X
duction, secondarily low- menstrual cycling, less effective Glucophage XR)
ering insulin levels; may for hirsutism; usually associated

Copyright © 2005 Massachusetts Medical Society. All rights reserved.

have direct effects on with initial weight loss; may have
ovarian steroidogenesis untoward gastrointestinal effects
Thiazolidinediones Enhance insulin action at tar- Extremely effective at lowering levels Pioglitazone (Actos), X X X X
get-tissue level (adipo- of insulin and androgens, mod- rosiglitazone
cyte, muscle); may have est effects on hirsutism; associ- (Avandia)
direct effects on ovarian ated with weight gain

* SHBG denotes sex hormone–binding globulin, LH luteinizing hormone, and FSH follicle-stimulating hormone.

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and have only a modest effect on hepatic glucose only a subgroup of women with the polycystic ova-
output. As with metformin,125,126 the thiazolidine- ry syndrome go on to have glucose intolerance, just
diones are reported to affect ovarian steroid synthe- that high-risk subgroup should be screened. Factors
sis directly,133 although most evidence indicates that that augment the risk are increased body weight
the reduction in insulin levels is responsible for de- (particularly if body fat is distributed in an android
creased concentrations of circulating androgen. pattern), a history of gestational diabetes, type 2 di-
Obese women with the polycystic ovary syn- abetes in a first-degree relative, and Caribbean-His-
drome who took troglitazone had consistent im- panic,141 Mexican-American,23 or African-Ameri-
provements in insulin resistance, hyperandro- can39 heritage.
genemia, and glucose tolerance.91,134 In addition, Integral to this issue is whether the measurement
troglitazone treatment was associated with a rela- of fasting glucose, with or without simultaneous
tive improvement in pancreatic b-cell function and measurement of fasting insulin, is sufficient to as-
a reduction in levels of the prothrombotic factor sess the risk of glucose intolerance. Although a su-
plasminogen-activator inhibitor type 1.91 These pranormal fasting glucose concentration increases
findings led to a double-blind, randomized, place- the likelihood that a patient will have an abnormally
bo-controlled study of troglitazone in the polycys- elevated glucose concentration at two hours during
tic ovary syndrome.62 Ovulation was significantly a formal oral glucose-tolerance test, a normal fast-
greater for women who received troglitazone than ing glucose concentration does not necessarily pre-
for those who received placebo; free testosterone dict normal glucose tolerance and is insufficient to
levels decreased, and levels of sex hormone–binding distinguish between women who have normal glu-
globulin increased in a dose-dependent fashion. cose tolerance and those who have impaired glucose
Nearly all glycemic measures showed dose-related tolerance.9,62,67 Thus, if the goal is to detect im-
decreases with troglitazone treatment. Although paired glucose tolerance for the purpose of interven-
troglitazone is no longer available, subsequent ing to reduce the risk of conversion from impaired
studies using rosiglitazone135,136 and pioglita- glucose tolerance to type 2 diabetes, an oral glucose-
zone137 have had similar results. Because of con- tolerance test should be performed.
cern about using thiazolidinediones in pregnancy, Although insulin resistance is virtually inherent
the drugs have been less readily adopted for routine in the phenotype of the polycystic ovary syndrome,
clinical use. there is little to support its formal assessment out-
side the context of a clinical study. First, insulin re-
controversies sistance is not a diagnostic criterion, nor is it rec-
ommended as a factor to be used in determining
Several unresolved controversies persist regarding treatment3 in the polycystic ovary syndrome. These
the evaluation and treatment of women with the recommendations relate to the observation that the
polycystic ovary syndrome. One issue surrounds the clinical response to insulin-lowering therapies does
question of whether all women with the polycystic not appear to be related to the magnitude of insulin
ovary syndrome should be screened for glucose in- resistance. Insulin resistance is virtually universal
tolerance, insulin resistance, or both. Screening is and maximal once the body-mass index (the weight
supported by evidence that the combined prevalence in kilograms divided by the square of the height in
of impaired glucose tolerance and type 2 diabetes meters) exceeds 3073; thus, there appears to be little
approaches 45 percent by the fourth decade,9,67 value gained by formal measurement of insulin sen-
that both impaired glucose tolerance and type 2 di- sitivity in obese patients. Finally, it is important to
abetes are associated with significant morbidity, and note that the simple and readily available methods
that there is a substantial rate of conversion from proposed as tests to quantify insulin resistance —
impaired glucose tolerance to diabetes in the ab- the ratio of fasting glucose to insulin142 or the
sence of intervention among women with the poly- homeostatic model assessment index143 — may
cystic ovary syndrome9,69 and those without the con- be misleading, since both have been shown to
dition.138,139 The American Diabetes Association lack precision when compared with the gold-stan-
recognizes the polycystic ovary syndrome as a risk dard method for quantifying whole-body insulin
factor that justifies screening for type 2 diabetes.140 resistance (i.e., the hyperinsulinemic–euglycemic
On the other hand, it may be argued that since clamp).144

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pathogenesis of insulin resistance that is associat-

ed with complications of the polycystic ovary syn-
The polycystic ovary syndrome is one of the most drome has led to novel therapies — chiefly insulin-
common hormonal disorders affecting women. As lowering medications. Research that is focused on
a syndrome, it has multiple components — repro- the genetic and environmental determinants of the
ductive, metabolic, and cardiovascular — with polycystic ovary syndrome may provide the basis for
health implications across the life span. Androgen new treatment methods and possible prevention of
excess and insulin resistance, both of which have the syndrome and its sequelae.
strong genetic components, underlie much of the Supported in part by grants from the National Institutes of
clinical presentation. The insulin resistance of the Health (M01-RR00055, K08-DK002315, R01-HL075079, and
polycystic ovary syndrome appears to impart an in- P60-DK20595), the American Diabetes Association, and the Blum-
Kovler Foundation.
creased risk of glucose intolerance, diabetes, and Dr. Ehrmann reports having received a consulting fee from Merck
lipid abnormalities and may enhance the develop- and lecture and grant support from Takeda.
ment of macrovascular disease. Obstructive sleep I am indebted to the patients and nursing staff at the University
of Chicago General Clinical Research Center and to Drs. Kenneth
apnea is emerging as important in the polycystic S. Polonsky, Graeme I. Bell, Robert L. Rosenfield, and Andrea E.
ovary syndrome. A better understanding of the Dunaif.

1. Stein IF, Leventhal ML. Amenorrhea as- precocious pubarche: ontogeny of the low- that flutamide restores sensitivity of the
sociated with bilateral polycystic ovaries. birthweight effect. Clin Endocrinol (Oxf ) gonadotropin-releasing hormone pulse gen-
Am J Obstet Gynecol 1935;29:181-91. 2001;55:667-72. erator to inhibition by estradiol and proges-
2. Franks S. Polycystic ovary syndrome. 12. Eisner JR, Dumesic DA, Kemnitz JW, terone. J Clin Endocrinol Metab 2000;85:
N Engl J Med 1995;333:853-61. [Erratum, Abbott DH. Timing of prenatal androgen 4047-52.
N Engl J Med 1995;333:1435.] excess determines differential impairment 20. Knochenhauer E, Key TJ, Kahsar-Miller
3. Revised 2003 consensus on diagnostic in insulin secretion and action in adult fe- M, Waggoner W, Boots LR, Azziz R. Preva-
criteria and long-term health risks related to male rhesus monkeys. J Clin Endocrinol lence of the polycystic ovary syndrome in
polycystic ovary syndrome (PCOS). Hum Metab 2000;85:1206-10. unselected black and white women of the
Reprod 2004;19:41-7. 13. Eisner JR, Dumesic DA, Kemnitz JW, southeastern United States: a prospective
4. Adams J, Polson DW, Franks S. Preva- Colman RJ, Abbott DH. Increased adiposity study. J Clin Endocrinol Metab 1998;83:
lence of polycystic ovaries in women with in female rhesus monkeys exposed to an- 3078-82.
anovulation and idiopathic hirsutism. Br drogen excess during early gestation. Obes 21. Diamanti-Kandarakis E, Kouli CR, Ber-
Med J (Clin Res Ed) 1986;293:355-9. Res 2003;11:279-86. giele AT, et al. A survey of the polycystic ova-
5. Ehrmann D, Rosenfield R, Barnes RB, 14. Eisner JR, Barnett MA, Dumesic DA, Ab- ry syndrome in the Greek island of Lesbos:
Brigell DF, Sheikh Z. Detection of functional bott DH. Ovarian hyperandrogenism in hormonal and metabolic profile. J Clin En-
ovarian hyperandrogenism in women with adult female rhesus monkeys exposed to docrinol Metab 1999;84:4006-11.
androgen excess. N Engl J Med 1992;327: prenatal androgen excess. Fertil Steril 2002; 22. Asuncion M, Calvo RM, San Millan JL,
157-62. 77:167-72. Sancho J, Avila S, Escobar-Morreale HF.
6. Polson DW, Adams J, Wadsworth J, 15. Abbott DH, Dumesic DA, Franks S. De- A prospective study of the prevalence of the
Franks S. Polycystic ovaries — a common velopmental origin of polycystic ovary syn- polycystic ovary syndrome in unselected
finding in normal women. Lancet 1988;1: drome — a hypothesis. J Endocrinol 2002; Caucasian women from Spain. J Clin Endo-
870-2. 174:1-5. crinol Metab 2000;85:2434-8.
7. Michelmore KF, Balen AH, Dunger DB, 16. Nelson VL, Legro RS, Strauss JF III, 23. Kauffman RP, Baker VM, DiMarino P,
Vessey MP. Polycystic ovaries and associated McAllister JM. Augmented androgen pro- Gimpel T, Castracane VD. Polycystic ovarian
clinical and biochemical features in young duction is a stable steroidogenic phenotype syndrome and insulin resistance in white
women. Clin Endocrinol (Oxf ) 1999;51: of propagated theca cells from polycystic and Mexican American women: a compari-
779-86. ovaries. Mol Endocrinol 1999;13:946-57. son of two distinct populations. Am J Obstet
8. Waldstreicher J, Santoro NF, Hall JE, Fil- 17. Nelson VL, Qin KN, Rosenfield RL, et al. Gynecol 2002;187:1362-9.
icori M, Crowley WF Jr. Hyperfunction of the The biochemical basis for increased testos- 24. Williamson K, Gunn A, Johnson N, Mil-
hypothalamic-pituitary axis in women with terone production in theca cells propagated som SR. The impact of ethnicity on the pre-
polycystic ovarian disease: indirect evidence from patients with polycystic ovary syn- sentation of polycystic ovarian syndrome.
for partial gonadotroph desensitization. drome. J Clin Endocrinol Metab 2001;86: Aust N Z J Obstet Gynaecol 2001;41:202-6.
J Clin Endocrinol Metab 1988;66:165-72. 5925-33. 25. Azziz R, Kashar-Miller MD. Family his-
9. Ehrmann DA, Barnes RB, Rosenfield 18. Haisenleder DJ, Dalkin AC, Ortolano tory as a risk factor for the polycystic ovary
RL, Cavaghan MK, Imperial J. Prevalence of GA, Marshall JC, Shupnik MA. A pulsatile syndrome. J Pediatr Endocrinol Metab 2000;
impaired glucose tolerance and diabetes in gonadotropin-releasing hormone stimulus 13:1303-6.
women with polycystic ovary syndrome. Di- is required to increase transcription of the 26. Urbanek M, Legro R, Driscoll DA, et al.
abetes Care 1999;22:141-6. gonadotropin subunit genes: evidence for Thirty-seven candidate genes for polycystic
10. Franks S. Adult polycystic ovary syn- differential regulation of transcription by ovary syndrome: strongest evidence for link-
drome begins in childhood. Best Pract Res pulse frequency in vivo. Endocrinology age is with follistatin. Proc Natl Acad Sci
Clin Endocrinol Metab 2002;16:263-72. 1991;128:509-17. U S A 1999;96:8573-8.
11. Ibanez L, Valls C, Potau N, Marcos MV, 19. Eagleson CA, Gingrich MB, Pastor CL, 27. Ehrmann DA, Sturis J, Byrne MM, Karri-
de Zegher F. Polycystic ovary syndrome after et al. Polycystic ovarian syndrome: evidence son T, Rosenfield RL, Polonsky KS. Insulin

n engl j med 352;12 www.nejm.org march 24, 2005 1233

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secretory defects in polycystic ovary syn- clinical profile of polycystic ovary patients. genic states. Clin Endocrinol (Oxf ) 1997;
drome: relationship to insulin sensitivity J Clin Endocrinol Metab 2003;88:5529-36. 46:131-4.
and family history of non-insulin-depen- 41. Orio F Jr, Matarese G, Di Biase S, et al. 53. Diamanti-Kandarakis E, Bartzis MI,
dent diabetes mellitus. J Clin Invest 1995; Exon 6 and 2 peroxisome proliferator-acti- Zapanti ED, et al. Polymorphism T˚C (-34
96:520-7. vated receptor-gamma polymorphisms in bp) of gene CYP17 promoter in Greek pa-
28. Legro RS, Driscoll D, Strauss JF III, Fox polycystic ovary syndrome. J Clin Endo- tients with polycystic ovary syndrome. Fertil
J, Dunaif A. Evidence for a genetic basis for crinol Metab 2003;88:5887-92. Steril 1999;71:431-5.
hyperandrogenemia in polycystic ovary syn- 42. Korhonen S, Heinonen S, Hiltunen M, 54. Gharani N, Waterworth DM, Batty S, et
drome. Proc Natl Acad Sci U S A 1998;95: et al. Polymorphism in the peroxisome pro- al. Association of the steroid synthesis gene
14956-60. liferator-activated receptor-gamma gene in CYP11a with polycystic ovary syndrome and
29. Kahsar-Miller MD, Nixon C, Boots LR, women with polycystic ovary syndrome. hyperandrogenism. Hum Mol Genet 1997;
Go RC, Azziz R. Prevalence of polycystic Hum Reprod 2003;18:540-3. 6:397-402.
ovary syndrome (PCOS) in first-degree rela- 43. San Millan JL, Corton M, Villuendas G, 55. Diamanti-Kandarakis E, Bartzis MI,
tives of patients with PCOS. Fertil Steril Sancho J, Peral B, Escobar-Morreale HF. As- Bergiele AT, Tsianateli TC, Kouli CR. Micro-
2001;75:53-8. sociation of the polycystic ovary syndrome satellite polymorphism (tttta)(n) at -528
30. Urbanek M, Spielman R. Genetic analy- with genomic variants related to insulin re- base pairs of gene CYP11alpha influences
sis of candidate genes for the polycystic ova- sistance, type 2 diabetes mellitus, and obesi- hyperandrogenemia in patients with poly-
ry syndrome. Curr Opin Endocrinol Diabe- ty. J Clin Endocrinol Metab 2004;89:2640-6. cystic ovary syndrome. Fertil Steril 2000;73:
tes 2002;9:492-501. 44. Alcoser SY, Hara M, Bell GI, Ehrmann 735-41.
31. Wood JR, Nelson VL, Ho C, et al. The DA. Association of the (AU)AT-rich element 56. Gaasenbeek M, Powell BL, Sovio U, et
molecular phenotype of polycystic ovary polymorphism in PPP1R3 with hormonal al. Large-scale analysis of the relationship
syndrome (PCOS) theca cells and new can- and metabolic features of polycystic ovary between CYP11A promoter variation, poly-
didate PCOS genes defined by microarray syndrome. J Clin Endocrinol Metab 2004; cystic ovarian syndrome, and serum testos-
analysis. J Biol Chem 2003;278:26380-90. 89:2973-6. terone. J Clin Endocrinol Metab 2004;89:
32. Draper N, Walker EA, Bujalska IJ, et al. 45. Urbanek M, Wu X, Vickery KR, et al. Al- 2408-13.
Mutations in the genes encoding 11beta- lelic variants of the follistatin gene in poly- 57. Roldan B, San Millan JL, Escobar-Morre-
hydroxysteroid dehydrogenase type 1 and cystic ovary syndrome. J Clin Endocrinol ale HF. Genetic basis of metabolic abnormal-
hexose-6-phosphate dehydrogenase inter- Metab 2000;85:4455-61. ities in polycystic ovary syndrome: implica-
act to cause cortisone reductase deficiency. 46. Hickey T, Chandy A, Norman RJ. The tions for therapy. Am J Pharmacogenomics
Nat Genet 2003;34:434-9. androgen receptor CAG repeat polymor- 2004;4:93-107.
33. Tucci S, Futterweit W, Concepcion ES, et phism and X-chromosome inactivation in 58. Carmina E. Genetic and environmental
al. Evidence for association of polycystic Australian Caucasian women with infertility aspect of polycystic ovary syndrome. J Endo-
ovary syndrome in caucasian women with a related to polycystic ovary syndrome. J Clin crinol Invest 2003;26:1151-9.
marker at the insulin receptor gene locus. Endocrinol Metab 2002;87:161-5. 59. Glueck CJ, Papanna R, Wang P, Golden-
J Clin Endocrinol Metab 2001;86:446-9. 47. Cousin P, Calemard-Michel L, Lejeune berg N, Sieve-Smith L. Incidence and treat-
34. Waterworth DM, Bennett ST, Gharani H, et al. Influence of SHBG gene pentanu- ment of metabolic syndrome in newly re-
N, et al. Linkage and association of insulin cleotide TAAAA repeat and D327N poly- ferred women with confirmed polycystic
gene VNTR regulatory polymorphism with morphism on serum sex hormone-binding ovarian syndrome. Metabolism 2003;52:
polycystic ovary syndrome. Lancet 1997; globulin concentration in hirsute women. 908-15.
349:986-90. J Clin Endocrinol Metab 2004;89:917-24. 60. National Cholesterol Education Pro-
35. Vankova M, Vrbikova J, Hill M, Cinek O, 48. Xita N, Tsatsoulis A, Chatzikyriakidou gram (NCEP) Expert Panel on Detection,
Bendlova B. Association of insulin gene A, Georgiou I. Association of the (TAAAA)n Evaluation, and Treatment of High Blood
VNTR polymorphism with polycystic ovary repeat polymorphism in the sex hormone- Cholesterol in Adults (Adult Treatment Pan-
syndrome. Ann N Y Acad Sci 2002;967:558- binding globulin (SHBG) gene with poly- el III). Third Report of the National Choles-
65. cystic ovary syndrome and relation to SHBG terol Education Program (NCEP) Expert
36. Michelmore K, Ong K, Mason S, et al. serum levels. J Clin Endocrinol Metab 2003; Panel on Detection, Evaluation, and Treat-
Clinical features in women with polycystic 88:5976-80. ment of High Blood Cholesterol in Adults
ovaries: relationships to insulin sensitivity, 49. Carey AH, Waterworth D, Patel K, et al. (Adult Treatment Panel III): final report. Cir-
insulin gene VNTR and birth weight. Clin Polycystic ovaries and premature male pat- culation 2002;106:3143-421.
Endocrinol (Oxf ) 2001;55:439-46. tern baldness are associated with one allele 61. Sam S, Dunaif A. Polycystic ovary syn-
37. Ehrmann DA, Tang X, Yoshiuchi I, Cox of the steroid metabolism gene CYP17. drome: syndrome XX? Trends Endocrinol
NJ, Bell GI. Relationship of insulin receptor Hum Mol Genet 1994;3:1873-6. Metab 2003;14:365-70.
substrate-1 and -2 genotypes to phenotypic 50. Franks S, White D, Gilling-Smith C, 62. Azziz R, Ehrmann D, Legro RS, et al.
features of polycystic ovary syndrome. J Clin Carey A, Waterworth D, Williamson R. Hy- Troglitazone improves ovulation and hirsut-
Endocrinol Metab 2002;87:4297-300. persecretion of androgens by polycystic ova- ism in the polycystic ovary syndrome: a mul-
38. El Mkadem SA, Lautier C, Macari F, et al. ries: the role of genetic factors in the regula- ticenter, double blind, placebo-controlled
Role of allelic variants Gly972Arg of IRS-1 tion of cytochrome P450c17 alpha. Baillieres trial. J Clin Endocrinol Metab 2001;86:
and Gly1057Asp of IRS-2 in moderate-to- Clin Endocrinol Metab 1996;10:193-203. 1626-32.
severe insulin resistance of women with 51. Liovic M, Prezelj J, Kocijancic A, Majdic 63. Franks S. Polycystic ovary syndrome:
polycystic ovary syndrome. Diabetes 2001; G, Komel R. CYP17 gene analysis in hyper- a changing perspective. Clin Endocrinol
50:2164-8. androgenised women with and without ex- (Oxf ) 1989;31:87-120.
39. Ehrmann DA, Schwarz PE, Hara M, et aggerated 17-hydroxyprogesterone response 64. Conway GS, Honour JW, Jacobs HS.
al. Relationship of calpain-10 genotype to to ovarian stimulation. J Endocrinol Invest Heterogeneity of the polycystic ovary syn-
phenotypic features of polycystic ovary syn- 1997;20:189-93. drome: clinical, endocrine and ultrasound
drome. J Clin Endocrinol Metab 2002;87: 52. Techatraisak K, Conway GS, Rumsby G. features in 556 patients. Clin Endocrinol
1669-73. Frequency of a polymorphism in the regula- (Oxf ) 1989;30:459-70.
40. Gonzalez A, Abril E, Roca A, et al. Spe- tory region of the 17 alpha-hydroxylase- 65. Carmina E, Legro RS, Stamets K, Lowell
cific CAPN10 gene haplotypes influence the 17,20-lyase (CYP17) gene in hyperandro- J, Lobo RA. Difference in body weight be-

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tween American and Italian women with with a history of gestational diabetes. Clin Lapidus L, Lindstedt G, Tengborn L. Hemo-
polycystic ovary syndrome: influence of the Endocrinol (Oxf ) 2000;53:501-7. static and metabolic variables in women
diet. Hum Reprod 2003;18:2289-93. 80. Zimmermann S, Phillips RA, Dunaif A, with polycystic ovary syndrome. Fertil Steril
66. Mokdad AH, Ford ES, Bowman BA, et et al. Polycystic ovary syndrome: lack of hy- 1994;61:455-60.
al. Prevalence of obesity, diabetes, and obe- pertension despite profound insulin resis- 93. Atiomo WU, Bates SA, Condon JE, Shaw
sity-related health risk factors, 2001. JAMA tance. J Clin Endocrinol Metab 1992;75: S, West JH, Prentice AG. The plasminogen
2003;289:76-9. 508-13. activator system in women with polycystic
67. Legro RS, Kunselman AR, Dodson WC, 81. Dahlgren E, Janson PO, Johansson S, ovary syndrome. Fertil Steril 1998;69:236-
Dunaif A. Prevalence and predictors of risk Lapidus L, Oden A. Polycystic ovary syn- 41.
for type 2 diabetes mellitus and impaired drome and risk for myocardial infarction: 94. Talbott E, Guzick D, Clerici A, et al. Cor-
glucose tolerance in polycystic ovary syn- evaluated from a risk factor model based on a onary heart disease risk factors in women
drome: a prospective, controlled study in prospective population study of women. Acta with polycystic ovary syndrome. Arterioscler
254 affected women. J Clin Endocrinol Obstet Gynecol Scand 1992;71:599-604. Thromb Vasc Biol 1995;15:821-6.
Metab 1999;84:165-9. 82. Dahlgren E, Johansson PO, Lindstedt G, 95. Wild S, Pierpoint T, Jacobs H, McKeigue
68. Krosnick A. The diabetes and obesity et al. Women with polycystic ovary syn- P. Long-term consequences of polycystic
epidemic among the Pima Indians. N J Med drome wedge resected in 1956 to 1965: ovary syndrome: results of a 31 year follow-
2000;97:31-7. a long-term follow-up focusing on natural up study. Hum Fertil (Camb) 2000;3:101-5.
69. Norman RJ, Masters L, Milner CR, history and circulating hormones. Fertil 96. Talbott EO, Zborowskii JV, Boudraux
Wang JX, Davies MJ. Relative risk of conver- Steril 1992;57:505-13. MY. Do women with polycystic ovary syn-
sion from normoglycaemia to impaired glu- 83. Kelly CJG, Speirs A, Gould GW, Petrie drome have an increased risk of cardiovas-
cose tolerance or non-insulin dependent JR, Lyall H, Connell JMC. Altered vascular cular disease? Review of the evidence. Min-
diabetes mellitus in polycystic ovarian syn- function in young women with polycystic erva Ginecol 2004;56:27-39.
drome. Hum Reprod 2001;16:1995-8. ovary syndrome. J Clin Endocrinol Metab 97. Legro RS. Polycystic ovary syndrome
70. Dunaif A, Segal KR, Futterweit W, 2002;87:742-6. and cardiovascular disease: a premature as-
Dobrjansky A. Profound peripheral insulin 84. Paradisi G, Steinberg HO, Hempfling A, sociation? Endocr Rev 2003;24:302-12.
resistance, independent of obesity, in poly- et al. Polycystic ovary syndrome is associat- 98. Vgontzas AN, Legro RS, Bixler EO,
cystic ovary syndrome. Diabetes 1989;38: ed with endothelial dysfunction. Circulation Grayev A, Kales A, Chrousos GP. Polycystic
1165-74. 2001;103:1410-5. ovary syndrome is associated with obstruc-
71. Dunaif A. Insulin resistance and the 85. Paradisi G, Steinberg HO, Shepard MK, tive sleep apnea and daytime sleepiness: role
polycystic ovary syndrome: mechanism and Hook G, Baron AD. Troglitazone therapy of insulin resistance. J Clin Endocrinol
implications for pathogenesis. Endocr Rev improves endothelial function to near nor- Metab 2001;86:517-20.
1997;18:774-800. mal levels in women with polycystic ovary 99. Fogel RB, Malhotra A, Pillar G, Pittman
72. Dunaif A, Wu X, Lee A, Diamanti-Kan- syndrome. J Clin Endocrinol Metab 2003; SD, Dunaif A, White DP. Increased preva-
darakis E. Defects in insulin receptor signal- 88:576-80. lence of obstructive sleep apnea syndrome
ing in vivo in the polycystic ovary syndrome 86. Orio F Jr, Palomba S, Cascella T, et al. in obese women with polycystic ovary syn-
(PCOS). Am J Physiol Endocrinol Metab Early impairment of endothelial structure drome. J Clin Endocrinol Metab 2001;86:
2001;281:E392-E399. and function in young normal-weight wom- 1175-80.
73. Kahn SE, Prigeon RL, McCulloch DK, et en with polycystic ovary syndrome. J Clin 100. Gopal M, Duntley S, Uhles M, Attarian
al. Quantification of the relationship be- Endocrinol Metab 2004;89:4588-93. H. The role of obesity in the increased prev-
tween insulin sensitivity and B-cell function 87. Mather KJ, Verma S, Corenblum B, alence of obstructive sleep apnea syndrome
in human subjects: evidence for a hyperbolic Anderson TJ. Normal endothelial function in patients with polycystic ovary syndrome.
function. Diabetes 1993;42:1663-72. despite insulin resistance in healthy women Sleep Med 2002;3:401-4.
74. Polonsky KS, Sturis J, Bell GI. Non- with the polycystic ovary syndrome. J Clin 101. Hardiman P, Pillay OC, Atiomo W.
insulin-dependent diabetes mellitus — Endocrinol Metab 2000;85:1851-6. Polycystic ovary syndrome and endometrial
a genetically programmed failure of the beta 88. Yildiz BO, Haznedaroglu IC, Kirazli S, carcinoma. Lancet 2003;361:1810-2. [Erra-
cell to compensate for insulin resistance. Bayraktar M. Global fibrinolytic capacity is tum, Lancet 2003;362:1082.]
N Engl J Med 1996;334:777-83. decreased in polycystic ovary syndrome, 102. Balen A. Polycystic ovary syndrome
75. O’Meara NM, Blackman JD, Ehrmann suggesting a prothrombotic state. J Clin En- and cancer. Hum Reprod Update 2001;7:
DA, et al. Defects in beta-cell function in docrinol Metab 2002;87:3871-5. 522-5.
functional ovarian hyperandrogenism. J Clin 89. Orio F Jr, Palomba S, Spinelli L, et al. 103. Kuhl H. Comparative pharmacology of
Endocrinol Metab 1993;76:1241-7. The cardiovascular risk of young women newer progestogens. Drugs 1996;51:188-
76. Ehrmann DA, Breda E, Cavaghan MK, et with polycystic ovary syndrome: an observa- 215.
al. Insulin secretory responses to rising and tional, analytical, prospective case-control 104. Krattenmacher R. Drospirenone: phar-
falling glucose concentrations are delayed study. J Clin Endocrinol Metab 2004;89: macology and pharmacokinetics of a unique
in subjects with impaired glucose tolerance. 3696-701. progestogen. Contraception 2000;62:29-38.
Diabetologia 2002;45:509-17. 90. Christian RC, Dumesic DA, Behrenbeck 105. Guido M, Romualdi D, Giuliani M, et
77. Ehrmann DA, Breda E, Corcoran MC, T, Oberg AL, Sheedy PF II, Fitzpatrick LA. al. Drospirenone for the treatment of hirsute
et al. Impaired beta-cell compensation to Prevalence and predictors of coronary artery women with polycystic ovary syndrome:
dexamethasone-induced hyperglycemia in calcification in women with polycystic ovary a clinical, endocrinological, metabolic pi-
women with polycystic ovary syndrome. syndrome. J Clin Endocrinol Metab 2003; lot study. J Clin Endocrinol Metab 2004;89:
Am J Physiol Endocrinol Metab 2004;287: 88:2562-8. 2817-23.
E241-E246. 91. Ehrmann D, Schneider DJ, Sobel BE, et 106. Diamanti-Kandarakis E, Baillargeon
78. Dunaif A, Finegood DT. b-cell dysfunc- al. Troglitazone improves defects in insulin J-P, Iuorno MJ, Jakubowicz DJ, Nestler JE.
tion independent of obesity and glucose in- action, insulin secretion, ovarian steroido- A modern medical quandary: polycystic ova-
tolerance in the polycystic ovary syndrome. genesis, and fibrinolysis in women with ry syndrome, insulin resistance, and oral
J Clin Endocrinol Metab 1996;81:942-7. polycystic ovary syndrome. J Clin Endo- contraceptive pills. J Clin Endocrinol Metab
79. Kousta E, Cela E, Lawrence N, et al. The crinol Metab 1997;82:2108-16. 2003;88:1927-32.
prevalence of polycystic ovaries in women 92. Dahlgren E, Janson PO, Johansson S, 107. Golland IM, Elstein ME. Results of an

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open one-year study with Diane-35 in wom- sensitivity and luteinizing hormone. J Clin Sieve-Smith L, Wang P. Continuing metfor-
en with polycystic ovarian syndrome. Ann Endocrinol Metab 1999;84:1470-4. min throughout pregnancy in women with
N Y Acad Sci 1993;687:263-71. 121. Hoeger KM, Kochman L, Wixom N, polycystic ovary syndrome appears to safely
108. Spritzer PM, Lisboa KO, Mattiello S, Craig K, Miller RK, Guzick DS. A random- reduce first-trimester spontaneous abortion:
Lhullier F. Spironolactone as a single agent ized, 48-week, placebo-controlled trial of a pilot study. Fertil Steril 2001;75:46-52.
for long-term therapy of hirsute patients. intensive lifestyle modification and/or met- 133. Mitwally MF, Witchel SF, Casper RF.
Clin Endocrinol (Oxf ) 2000;52:587-94. formin therapy in overweight women with Troglitazone: a possible modulator of ovari-
109. Muderris II, Bayram F, Guven M. Treat- polycystic ovary syndrome: a pilot study. an steroidogenesis. J Soc Gynecol Investig
ment of hirsutism with lowest-dose fluta- Fertil Steril 2004;82:421-9. 2002;9:163-7.
mide (62.5 mg/day). Gynecol Endocrinol 122. Nestler JE, Jakubowicz DJ, Evans WS, 134. Dunaif A, Scott D, Finegood D, Quin-
2000;14:38-41. Pasquali R. Effects of metformin on sponta- tana B, Whitcomb R. The insulin-sensitiz-
110. Moghetti P, Tosi F, Tosti A, et al. Com- neous and clomiphene-induced ovulation in ing agent troglitazone improves metabolic
parison of spironolactone, flutamide, and the polycystic ovary syndrome. N Engl J Med and reproductive abnormalities in the poly-
finasteride efficacy in the treatment of hir- 1998;338:1876-80. cystic ovary syndrome. J Clin Endocrinol
sutism: a randomized, double blind, place- 123. Moran LJ, Noakes M, Clifton PM, Metab 1996;81:3299-306.
bo-controlled trial. J Clin Endocrinol Metab Tomlinson L, Galletly C, Norman RJ. Di- 135. Ghazeeri G, Kutteh WH, Bryer-Ash
2000;85:89-94. etary composition in restoring reproductive M, Haas D, Ke RW. Effect of rosiglitazone
111. Gambineri A, Pelusi C, Genghini S, et and metabolic physiology in overweight on spontaneous and clomiphene citrate-
al. Effect of flutamide and metformin ad- women with polycystic ovary syndrome. induced ovulation in women with polycystic
ministered alone or in combination in diet- J Clin Endocrinol Metab 2003;88:812-9. ovary syndrome. Fertil Steril 2003;79:562-6.
ing obese women with polycystic ovary 124. Stamets K, Taylor DS, Kunselman A, 136. Belli SH, Graffigna MN, Oneto A, Ote-
syndrome. Clin Endocrinol (Oxf ) 2004;60: Demers LM, Pelkman CL, Legro RS. A ran- ro P, Schurman L, Levalle OA. Effect of
241-9. domized trial of the effects of two types of rosiglitazone on insulin resistance, growth
112. Azziz R, Black V, Hines GA, Fox LM, short-term hypocaloric diets on weight loss factors, and reproductive disturbances in
Boots LR. Adrenal androgen excess in the in women with polycystic ovary syndrome. women with polycystic ovary syndrome.
polycystic ovary syndrome: sensitivity and Fertil Steril 2004;81:630-7. Fertil Steril 2004;81:624-9.
responsivity of the hypothalamic-pituitary- 125. Mansfield R, Galea R, Brincat M, Hole 137. Romualdi D, Guido M, Ciampelli M, et
adrenal axis. J Clin Endocrinol Metab 1998; D, Mason H. Metformin has direct effects on al. Selective effects of pioglitazone on insu-
83:2317-23. human ovarian steroidogenesis. Fertil Steril lin and androgen abnormalities in normo-
113. Azziz R, Black VY, Knochenhauer ES, 2003;79:956-62. and hyperinsulinaemic obese patients with
Hines GA, Boots LR. Ovulation after gluco- 126. Attia GR, Rainey WE, Carr BR. Met- polycystic ovary syndrome. Hum Reprod
corticoid suppression of adrenal androgens formin directly inhibits androgen produc- 2003;18:1210-8.
in the polycystic ovary syndrome is not pre- tion in human thecal cells. Fertil Steril 2001; 138. Knowler WC, Barrett-Connor E, Fowl-
dicted by the basal dehydroepiandrosterone 76:517-24. er SE, et al. Reduction in the incidence of
sulfate level. J Clin Endocrinol Metab 1999; 127. Lord JM, Flight IHK, Norman RJ. In- type 2 diabetes with lifestyle intervention or
84:946-50. sulin-sensitising drugs (metformin, trogli- metformin. N Engl J Med 2002;346:393-
114. Liang T, Heiss CE, Ostrove S, Rasmus- tazone, rosiglitazone, pioglitazone, D-chi- 403.
son GH, Cheung A. Binding of a 4-methyl- ro-inositol) for polycystic ovary syndrome. 139. Tuomilehto J, Lindstrom J, Eriksson
4-aza-steroid to 5 alpha-reductase of rat liv- Cochrane Database Syst Rev 2003;3: JG, et al. Prevention of type 2 diabetes melli-
er and prostate microsomes. Endocrinology CD003053. tus by changes in lifestyle among subjects
1983;112:1460-8. 128. Crave JC, Fimbel S, Lejeune H, Cug- with impaired glucose tolerance. N Engl J
115. Falsetti L, Gambera A, Legrenzi L, Ia- nardey N, Dechaud H, Pugeat M. Effects of Med 2001;344:1343-50.
cobello C, Bugari G. Comparison of finas- diet and metformin administration on sex 140. American Diabetes Association.
teride versus flutamide in the treatment of hormone-binding globulin, androgens, and Screening for type 2 diabetes. Diabetes Care
hirsutism. Eur J Endocrinol 1999;141:361- insulin in hirsute and obese women. J Clin 2004;27:Suppl 1:S11-S14.
7. Endocrinol Metab 1995;80:2057-62. 141. Dunaif A, Sorbara L, Delson R, Green
116. Yildiz BO, Chang W, Azziz R. Polycys- 129. Glueck CJ, Goldenberg N, Pranikoff J, G. Ethnicity and polycystic ovary syndrome
tic ovary syndrome and ovulation induction. Loftspring M, Sieve L, Wang P. Height, are associated with independent and additive
Minerva Ginecol 2003;55:425-39. weight, and motor-social development dur- decreases in insulin action in Caribbean-
117. Barbieri RL, Gargiulo AR. Metformin ing the first 18 months of life in 126 infants Hispanic women. Diabetes 1993;42:1462-8.
for the treatment of the polycystic ovary born to 109 mothers with polycystic ovary 142. Legro RS, Finegood D, Dunaif A.
syndrome. Minerva Ginecol 2004;56:63- syndrome who conceived on and continued A fasting glucose to insulin ratio is a useful
79. metformin through pregnancy. Hum Re- measure of insulin sensitivity in women
118. Franks S. Assessment and manage- prod 2004;19:1323-30. with polycystic ovary syndrome. J Clin Endo-
ment of anovulatory infertility in polycystic 130. Glueck CJ, Wang P, Kobayashi S, Phil- crinol Metab 1998;83:2694-8.
ovary syndrome. Endocrinol Metab Clin lips H, Sieve-Smith L. Metformin therapy 143. Legro RS, Castracane VD, Kauffman
North Am 2003;32:639-51. throughout pregnancy reduces the develop- RP. Detecting insulin resistance in polycys-
119. Nestler JE, Stovall D, Akhter N, Iuorno ment of gestational diabetes in women with tic ovary syndrome: purposes and pitfalls.
MJ, Jakubowicz DJ. Strategies for the use of polycystic ovary syndrome. Fertil Steril Obstet Gynecol Surv 2004;59:141-54.
insulin-sensitizing drugs to treat infertility 2002;77:520-5. 144. Diamanti-Kandarakis E, Kouli C, Alex-
in women with polycystic ovary syndrome. 131. Glueck CJ, Wang P, Goldenberg N, andraki K, Spina G. Failure of mathematical
Fertil Steril 2002;77:209-15. Sieve-Smith L. Pregnancy outcomes among indices to accurately assess insulin resis-
120. Huber-Buchholz MM, Carey DG, Nor- women with polycystic ovary syndrome tance in lean, overweight, or obese women
man RJ. Restoration of reproductive po- treated with metformin. Hum Reprod 2002; with polycystic ovary syndrome. J Clin Endo-
tential by lifestyle modification in obese 17:2858-64. crinol Metab 2004;89:1273-6.
polycystic ovary syndrome: role of insulin 132. Glueck CJ, Phillips H, Cameron D, Copyright © 2005 Massachusetts Medical Society.

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