Download epidemiology, clinical manifestations, and pathophysiology

REVIEW
EPIDEMIOLOGY, CLINICAL MANIFESTATIONS, AND
PATHOPHYSIOLOGY OF POLYCYSTIC OVARY SYNDROME
—
Howard A. Zacur, MD, PhD*
ABSTRACT
Polycystic ovary syndrome (PCOS) is difficult
to diagnose and manage, in part because of its
clinical and pathophysiologic heterogeneity and
the variable manner in which it is defined. This
article discusses the epidemiology, clinical manifestations, and pathophysiology of PCOS. The
multifarious clinical manifestations of PCOS
necessitate a comprehensive approach to patient
management. Typically, women with PCOS consult physicians for infertility, menstrual irregularity, or androgen excess. Treatment strategies that
focus on short-term improvement are usually
designed to address one or more of these complaints. Whether PCOS is associated with serious
long-term sequelae remains unknown. At present, the cause of the syndrome is unknown, and
a cure does not exist.
(Adv Stud Med. 2003;3(8A):S733-S739)
*Theodore and Ingrid Baramki Professor of Reproductive
Endocrinology, and Director, Division of Reproductive
Endocrinology, Department of Gynecology-Obstetrics, Johns
Hopkins University School of Medicine, Baltimore,
Maryland.
Address correspondence to: Howard A. Zacur, MD,
PhD, Johns Hopkins Hospital, 600 N Wolfe St, Phipps Bldg
247, Baltimore, MD 21287. E-mail: [email protected].
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olycystic ovary syndrome (PCOS), characterized as a common endocrinopathy, is a
significant cause of distress to most women
affected by it.1 Reducing PCOS-associated
signs and symptoms in the individual
patient requires early recognition of the syndrome and
the adoption of preventive and ameliorative treatment
strategies tailored to the symptom profile. However,
PCOS is difficult to diagnose and manage, in part
because of its clinical and pathophysiologic heterogeneity and the variable manner in which it is defined.
This paper discusses the epidemiology, clinical manifestations, and pathophysiology of PCOS.
P
DEFINITION
A globally agreed-upon consensus definition of
PCOS has not been established. A group of experts
who were convened in 1990 by the National
Institutes of Health (NIH) defined PCOS as ovulatory dysfunction with clinical evidence of hyperandrogenism and/or hyperandrogenemia in the absence
of adrenal or thyroid diseases, including Cushing’s
syndrome, cancer, and congenital adrenal hyperplasia.2-4 A history of 6 or fewer vaginal bleeding
episodes in a calendar year coupled with either hirsutism or an elevation of androgens in the bloodstream is the criterion to be used for the diagnosis.
Thus, PCOS is a diagnosis of exclusion. This definition does not require the presence of anatomic ovarian abnormalities (eg, multifollicular ovaries
identified on pelvic ultrasonography or an elevation
in the luteinizing hormone [LH]/follicular-stimulating hormone [FSH] ratio) for diagnosis.
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In Europe, PCOS is generally defined as a polycystic ovary in the presence of at least one clinical sign of
endocrine dysfunction (eg, menstrual irregularity, hirsutism, infertility). A polycystic ovary—defined as the
presence of at least 10 subcapsular follicular cysts, each
measuring 2 to 8 mm in diameter and arranged
around or within thickened ovarian stroma—is diagnosed by pelvic ultrasonography and is not synonymous with PCOS.2,3 The European and NIH
definitions of PCOS are consistent in specifying that,
by itself, a polycystic ovary does not signify a pathologic condition. Polycystic ovaries are present in
approximately 20% of women in the general population. As many as 1 in 4 of women with a polycystic
ovary have no other known endocrine abnormalities or
clinical manifestations of the syndrome.5
PREVALENCE
The prevalence of PCOS has not been definitively
established; in part because PCOS is inconsistently
defined from study to study, prevalence estimates vary
widely. The prevalence of PCOS among women of
reproductive age in the general population has been
estimated at 4% to 12%.2 Not surprisingly, the prevalence of PCOS appears to be higher—from 37% to
90%—in women with menstrual abnormalities and
also is increased in the presence of certain diseases.6,7
The prevalence of PCOS in women with epilepsy, for
example, exceeds that in women without epilepsy.8-10
CLINICAL MANIFESTATIONS AND CORRELATES
PCOS is characterized by a remarkable spectrum of
clinical manifestations and correlates, not all of which are
present in all PCOS sufferers. Apart from the hallmark
features of hyperandrogenism and anovulation, diseases
or conditions that have been associated with PCOS
include type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, and malignancies, including
endometrial, breast, and ovarian cancer (Table).
HYPERANDROGENISM
Hyperandrogenism, a cardinal feature of PCOS,
can be detected by measuring the serum concentration
of androgens, including testosterone, androstenedione, and the androgen precursor dehydroepiandrosterone sulfate. It is suggested by clinical signs, such as
acne and hirsutism.1 The etiology of hyperandro-
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genism in PCOS is unknown but has been hypothesized to be attributed to abnormalities such as
inborn defects in ovarian steroidogenesis, hyperinsulinemia-stimulated excessive steroidogenesis by the
ovaries, and LH stimulation of excessive steroidogenesis by the ovaries.
Several findings are consistent with a central role
for persistent LH stimulation in the etiology of hyperandrogenism in PCOS.11 First, serum LH levels relative to FSH levels are elevated in 30% to 90% of
women with PCOS. In addition, women with PCOS
who are administered gonadotropin-releasing hormone (which, when endogenously released from the
hypothalamus, stimulates LH secretion) show
enhanced LH secretion compared with women without PCOS. Finally, women with PCOS do not show
the normal waxing and waning in frequency of LH
pulse secretions across the menstrual cycle. Rather,
women with PCOS demonstrate rapid, consistent
pulses of LH secretion throughout the menstrual
cycle. The reasons for these LH abnormalities in
women with PCOS are unknown but are hypothesized
to result from abnormalities in gonadotropin-releasing
hormone secretion from the hypothalamus. The
abnormal gonadotropin-releasing hormone secretion
could be attributed to a primary defect in the hypothalamus or could be secondary to abnormal circulating levels of estrogen, androgens, or insulin in PCOS.
MENSTRUAL IRREGULARITY AND INFERTILITY
Consistent with these abnormalities in ovarian hormonal function, anovulation—usually chronic and
often first manifested as oligomenorrhea or amenorrhea around the time of onset of menstruation—is
Table. Conditions Associated with PCOS
Insulin resistance
Type 2 diabetes
Hypertension
Dyslipidemia
Cardiovascular disease
Cancer (endometrial, breast, ovarian)
PCOS = polycystic ovary syndrome.
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present in most women with PCOS.12 This aspect of
PCOS has been difficult to characterize because of
reliance on patients’ self-reports and inconsistencies
between studies in the means of assessing and defining
anovulation. Although most conceptualizations of
PCOS include anovulation as a defining characteristic,
it would be more accurate to state that women with
PCOS are oligo-ovulatory, because women with
PCOS will ovulate on occasion.
OBESITY
Obesity is often described as a characteristic of
PCOS. However, obesity is not observed in all women
with PCOS.1 The prevalence of obesity in women with
PCOS ranges from 1% to 80% across studies and
varies with the definition of obesity as well as with
women’s race and cultural group. In the general population, the prevalence of overweight and obesity
exceeds 50%.13 The degree to which obesity and its
metabolic correlates exacerbate PCOS and/or contribute to its development is being actively researched.
TYPE 2 DIABETES AND INSULIN RESISTANCE
An association between PCOS and insulin resistance and type 2 diabetes has been observed independent of obesity, but the effect of a family history of
diabetes has not been fully explored.14,15 The prevalence
of type 2 diabetes has been reported to be higher among
women with PCOS (15% to 33% across studies) compared with women without PCOS (2% to 24%), but
the magnitude of this difference depends upon the criteria used to make the diagnosis. If elevated fasting
blood glucose is used as the sole criterion, the prevalence
of type 2 diabetes in women with PCOS is close to that
in women without PCOS. If abnormal 2-hour glucose
with normal fasting glucose following a 75-g glucose
challenge is used as the criterion, then the prevalence of
type 2 diabetes in women with PCOS is much higher
than in women without PCOS.
Insulin resistance in PCOS is important in the
pathogenesis of hyperandrogenemia and anovulation. Both hyperandrogenemia and polycystic
ovaries cluster in families, a finding that suggests a
genetic component to these disorders. In a study of
217 sisters of PCOS sufferers compared with 47
women with normal reproductive function who
were not sisters of PCOS sufferers, regardless of
whether they had PCOS or hyperandrogenism, the
sisters of PCOS sufferers had significantly reduced
Advanced Studies in Medicine
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glucose/insulin ratios and elevated total cholesterol
and low-density lipoprotein (LDL) cholesterol levels.16 The authors concluded that both insulin resistance and elevated LDL levels cluster in families
with PCOS, a finding that suggests that these traits
have a genetic component.
BLOOD LIPID ABNORMALITIES
Women with PCOS have higher levels of total cholesterol, LDL cholesterol, very-low density lipoprotein
cholesterol, and triglycerides, as well as lower levels of
high-density lipoprotein (HDL) and HDL2 compared
with healthy women.17 The effect of obesity independent of PCOS on these lipid abnormalities remains to
be determined.
CARDIOVASCULAR DISEASE
Most of the clinical abnormalities in women with
PCOS constitute risk factors for cardiovascular disease.16 Dyslipidemia, type 2 diabetes, obesity, and
hypertension are established risk factors for cardiovascular disease. Chronic anovulation, hyperandrogenemia, and insulin resistance are also associated with
increased cardiovascular risk.
In an epidemiologic case-control study of coronary
heart disease risk factors in women with PCOS
(defined as chronic anovulation with clinical and/or
biochemical evidence of androgen excess), women
with PCOS, when compared with age-, race-, and
neighborhood-matched controls, had: significantly
higher body mass indexes (BMIs) and waist-hip ratios;
poorer lipid profiles, including higher levels of total
cholesterol, LDL cholesterol, and triglycerides and
lower levels of HDL and HDL2; thicker carotid arteries as measured by carotid artery ultrasonography
assessment of intima-media thickness, which is a preclinical measure of atherosclerosis (observed in women
≥45 years of age); and more extensive coronary artery
calcification as measured by electron beam computed
tomography (coronary calcification, which occurs in
the presence of atherosclerosis, predicts the occurrence
of cardiovascular events).18
Although these converging lines of evidence support
the hypothesis that PCOS increases cardiovascular risk,
women with PCOS have not been shown to experience a
higher incidence of cardiovascular events compared with
women without PCOS. Results of a United Kingdom
study, which followed women diagnosed with PCOS
between 1939 and 1979, showed that death rates or cir-
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culatory-disease death rates in the women with PCOS
did not differ from expected death rates (using standardized UK mortality ratios).19 The odds of coronary heart
disease were not significantly different between women
with PCOS and those without PCOS in a follow-up
assessment of a sample of women from this study.
However, the odds of cerebrovascular disease were higher
for women with PCOS compared with those without
PCOS. The discrepancy between the cardiovascular mortality data and the data showing heightened cardiovascular risk in women with PCOS highlights the need for
prospective studies to evaluate the incidence of cardiovascular events in women with PCOS.
CANCER
Several studies have suggested a link between
PCOS and cancer (eg, endometrial, breast, and ovarian
cancers), but these studies were generally small, retrospective, and did not employ adequate controls.8
Although an association between PCOS and endometrial cancer has been reported in these studies, use of
progestins and/or oral contraceptive pills by the women
was not determined. The hypothesized links between
PCOS and breast and ovarian cancer have not been
consistently supported by studies conducted to date.8
ETIOLOGY
Although the etiology of PCOS has not been determined, it is thought to be multifactorial and to include
endocrine, metabolic, genetic, neurologic, and environmental factors. Endocrine abnormalities thought
to cause PCOS include increased LH/FSH ratio,
increased insulin concentrations, and/or increased 17hydroxyprogesterone levels in thecal cells.3 All of these
abnormalities result in the androgen excess that may
underlie many of the clinical manifestations of PCOS.
For example, elevated insulin concentrations resulting
from insulin resistance may stimulate the ovaries to
overproduce androgens and lead to lipid abnormalities. Insulin resistance decreases the release of sex hormone–binding globulin in the liver with a resultant
increase in free androgen levels.
Obesity or marked weight gain may cause or exacerbate PCOS by inducing insulin resistance.9 In addition to a hypothesized indirect effect on androgen
production by inducing insulin resistance, obesity can
contribute to hyperandrogenism by stimulating
steroid production by adipose tissue. Although obesity
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is thought to be an important contributor to reproductive endocrine abnormalities in women with
PCOS, hyperandrogenism and PCOS also occur in
lean women.
Environmental factors have also been implicated in
causing or exacerbating PCOS independent from the
endocrine and metabolic factors. Medications, such as
antiepileptic drugs, have been postulated to lead to a
condition mimicking PCOS.9,10 In particular, the anticonvulsant valproate, which is used to treat bipolar
disorder as well as epilepsy, has been suggested to create a PCOS-like condition, primarily on the basis of
several studies conducted by Isojärvi and colleagues in
the mid-1990s.9,10,20 More recent data and assessments
of the evidence suggest the prevalence of PCOS is no
greater with valproate compared with other antiepileptic drugs.
PCOS AND ANTIEPILEPTIC DRUGS
Data suggesting a link between valproate and
PCOS evolved from 3 nonrandomized, observational
studies, 2 of which were retrospective analyses.9,10,20 In
the first study, which included 238 women with
epilepsy and 51 healthy untreated controls, menstrual
disturbances were reported by 45% of 29 women
receiving valproate, 19% of 120 women receiving carbamazepine, 25% of 12 women receiving a combination of carbamazepine and valproate, 13% of 62
women receiving other medications, and 0% of the
untreated women.10 Vaginal ultrasonography performed on the 98 women with epilepsy and a history
of menstrual abnormalities revealed polycystic ovaries
in 43% of valproate-treated patients, 22% of carbamazepine-treated patients, and 50% of patients treated with both drugs.
In a second, similar study of 22 women taking valproate monotherapy and 43 women taking carbamazepine monotherapy, polycystic ovaries and/or
hyperandrogenism were present in 64% of valproatetreated women, 21% of carbamazepine-treated
women, and 19% of a control group of healthy
women.9 Fasting insulin levels were slightly higher in
the valproate-treated group (16.9 ± 10.5) compared
with the carbamazepine group (15.4 ± 10.5) and the
control group (9.6 ± 5.1), and half of the valproatetreated women had marked, progressive weight gain
(mean, 21.0 kg) associated with hyperinsulinemia and
low serum levels of insulin-like growth factor protein I.
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In a third study, switching 12 obese patients from valproate to lamotrigine improved serum insulin, testosterone, and HDL concentrations with a concomitant
reduction in BMI.20
Very recently, Morrell and colleagues reported on
the results of a multicenter study that included
women without epilepsy (controls; n = 23), women
with localization-related epilepsy (n = 59), and women
with idiopathic (primary) generalized epilepsy.21
Subjects were not randomized to different drug treatments because they were already undergoing treatment
with either a cytochrome p450 enzyme–inducing
antiepileptic drug (carbamazepine, phenytoin, or phenobarbital), a cytochrome p450 enzyme–inhibiting
drug (valproate), or an antiepileptic drug with a mechanism of action that does not affect p450 enzymes
(lamotrigine or gabapentin). Women were to have
been on monotherapy for 6 months or longer before
being studied for 3 menstrual cycles. Anovulatory
cycles were observed in 10.9% of cycles in control
patients, in 14.3% of cycles in women with localization-related epilepsy, and in 27.1% of cycles in women
with idiopathic generalized epilepsy. Of women who
were currently taking valproate or who had taken the
drug in the preceding 3 years, 38.1% had at least 1
anovulatory cycle, in contrast to 10.7% of women
not taking valproate within the preceding 3 years.
Women who had taken valproate or lamotrigine had
a significantly higher BMI.
In the study by Morrell et al, it was clear that valproate was the most commonly prescribed neuroleptic
drug for women with idiopathic generalized epilepsy.
What remained unclear was whether the condition of
idiopathic generalized epilepsy was more likely to cause
anovulatory cycles in the untreated state.21 In a study by
Herzog et al, which included 50 women with temporal lobe epilepsy, 20 women did not receive treatment,
and 30 women received treatment.22 Of the untreated
women, 60% had menstrual disturbances compared
with 53% of the treated women. Polycystic ovaries or
hyperandrogenism were diagnosed in 30% of the
untreated women and 13% of the treated women.
Studies of menstrual cycle disturbances in epileptic women using antiseizure medication have not
been controlled, especially for BMI, and patients
have not been randomized to treatment groups; use
of the NIH criteria for defining PCOS does not
often occur. It is therefore difficult to draw conclusions about the data, and several subsequent investi-
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gations have produced conflicting results. In a
prospective cohort analysis of 93 women with epilepsy and PCOS defined by NIH criteria, PCOS was present in 2 of 18 valproate-treated patients (11%), 2 of
20 carbamazepine-treated patients (10%), none (0%)
of the patients on antiepileptic polytherapy, and 11%
of an untreated control group over a 6-month followup period (Figure).23 The authors concluded that the
results suggest that manifestations of PCOS in patients
with focal epilepsy are not related to the administration of either valproate or carbamazepine.
Reproductive endocrine disorders, including
PCOS, were not associated with the use of any
antiepileptic drugs or with type of epileptic syndrome
in a study of 50 women with epilepsy who underwent
clinical endocrinologic evaluation, hormonal assessment, and ovarian ultrasonography.24 One third (32%)
of women experienced reproductive endocrine disorders, most commonly PCOS (n = 13) followed by
hypothalamic amenorrhea (n = 2) and luteal-phase
deficiency (n = 1). Valproate also was not associated
with an excess risk of PCOS relative to other
antiepileptic drugs in another sample of 43 women
with epilepsy who had received treatment for at least 2
Figure. Incidence of PCOS in Women Treated or Not
Treated with Antiepileptic Drugs Over a 6-month
Follow-up Period
PCOS = polycystic ovary syndrome.
Data from Bauer et al.23
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years25 or in a sample of 105 women with epilepsy who
had received valproate monotherapy (n = 52) or carbamazepine monotherapy (n = 53) for at least 2
years.26 Thus, although a high percentage of patients
with epilepsy experienced reproductive endocrine
abnormalities in some studies, these abnormalities
were not more likely to be associated with valproate
than with any other antiepileptic drug.
The high incidence of reproductive endocrine
abnormalities in patients with epilepsy is consistent
with a possible role of epilepsy in the development of
PCOS. It is hypothesized that epileptic discharges
involving the amygdala and hippocampus may alter
release of gonadotropin-releasing hormone, which in
turn alters release of FSH and LH to cause the hyperandrogenism characteristic of PCOS.5 Alternatively,
the pathophysiologic substrate of PCOS could be the
same as that of epilepsy. Most studies of epileptic
women taking valproate have reported increased
weight gain or BMI coupled with hyperinsulinemia
believed to be secondary to the weight gain. Weight
loss with lowered fasting insulin levels was also reported when women with epilepsy who were taking valproate were switched to lamotrigine.9
Findings in patients with bipolar disorder treated
with antiepileptic drugs do not support a role of the
drugs in causing PCOS. In a study of 22 outpatients
with bipolar disorder, none of the 10 women receiving
divalproex, 10 women receiving lithium, or 2 women
receiving both divalproex and lithium for a mean
duration of 12 months developed clinical or
endocrinologic symptoms associated with PCOS.27
Ultrasound revealed an increased number of ovarian
follicles in 1 patient taking lithium and in none of the
patients taking divalproex. Women’s self-reports
revealed a high incidence of menstrual disturbances
regardless of which antiepileptic medication was used,
a finding that the authors suggested might be attributed to a dysfunctional hypothalamic-pituitarygonadal axis in women with bipolar disorder.
A high incidence of menstrual disturbances among
women with bipolar disorder was also found in a study
of 32 women (17 received valproate and 15 did not
receive valproate).28 Menstrual abnormalities were
reported by significantly more women receiving valproate (47%) than women not receiving valproate
(13%) compared with a control group of women (n =
22) with no psychiatric disorder. PCOS was determined to be present in all of the 7 women in the val-
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proate group who reported current menstrual problems and who were assessed for PCOS. Because this
study was an observational study and patients were not
randomized, it is difficult to draw conclusions from
the results. In addition, the incidence of PCOS was
assessed only among the subset of patients who were
using valproate and who reported current menstrual
problems. The incidence of PCOS in the women with
bipolar disorder not receiving valproate and in the
healthy control subjects was not determined.
Considered in aggregate, the findings to date on
the relationship between antiepileptic drugs and
PCOS provide conflicting data on valproate use and
the development of PCOS, although patients with
epilepsy may be more likely to have PCOS compared
with those without epilepsy. Studies suggesting an
association between antiepileptic drug use and epilepsy are often small, and are retrospective and poorly
controlled. To date, there are no data that contraindicate the use of valproate in women with epilepsy or
bipolar disorder, but additional study is warranted.
The relationship between use of valproate and weight
gain is deserving of further study. Monitoring body
weight during treatment, with institution of weightloss methods if excessive weight gain occurs, seems to
be a practical recommendation, as has been previously
recommended.29
CONCLUSIONS AND IMPLICATIONS
FOR CARE OF PATIENTS
The multifarious clinical manifestations of PCOS
necessitate a comprehensive approach to patient management. The clustering of cardiovascular and metabolic risk factors in women with PCOS underscores
the importance of managing PCOS as a chronic disease. Women with PCOS typically consult physicians
for infertility, menstrual irregularity, or androgen
excess. Treatment strategies, focusing on short-term
improvement, are usually targeted at addressing one or
more of these complaints. However, the syndrome also
needs to be conceptualized and managed as a chronic
condition. Reduction of insulin resistance constitutes
a key component of long-term treatment strategies.
Nonpharmacologic measures, when appropriate,
include diet, exercise, and weight reduction.
Pharmacologic measures include insulin sensitizers,
oral contraceptives, antiandrogen medications, and
glucocorticoids.
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