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Pb41-polycystic.qxd.pdf

PRACTICE
BULLETIN
OBSTETRICIAN–GYNECOLOGISTSNUMBER 41, DECEMBER 2002 Polycystic Ovary
Syndrome

This Practice Bulletin wasdeveloped by the ACOG Com- Polycystic ovary syndrome (PCOS) is a condition of unexplained hyperandro- genic chronic anovulation that most likely represents a heterogenous disorder. Its etiology remains unknown, and treatment is largely symptom based and empirical. Recent findings suggest PCOS has substantial metabolic sequelae, including risk of diabetes and possibly cardiovascular disease, and that pri- practitioners in making deci-sions about appropriate obstet- mary treatment should focus on metabolic sequelae. The purpose of this docu- ment is to examine the best available evidence on the diagnosis and clinical strued as dictating an exclusivecourse of treatment or proce-dure. Variations in practice may Background
be warranted based on theneeds of the individual patient, Incidence, Definition, and Diagnostic Criteria
Although there is no universally accepted definition of PCOS, diagnostic criteria established by the National Institutes of Health in 1990 define it as hyperandro- genism and chronic anovulation in cases in which secondary causes (such asadult-onset congenital adrenal hyperplasia, hyperprolactinemia, and androgen-secreting neoplasms) have been excluded (1). Insulin resistance has been notedconsistently among many women with unexplained hyperandrogenic chronicanovulation, but it is not included in the diagnostic criteria (2). Ultrasonograms ofwomen with unexplained hyperandrogenic chronic anovulation frequently showovaries that appear polycystic (3); however, polycystic ovaries are a nonspecificfinding and also are frequently noted in women with no endocrine or metabolicabnormalities. Hyperandrogenic chronic anovulation occurs in approximately4–6% of women, with no significant differences in the prevalence of hirsutism orelevated circulating androgen levels between white and black women (4).
Hyperandrogenism can be established on the basis of clinical findings (eg, hirsutism or acne) or hormone measurement or both. However, not all womenwith hirsutism will have androgen excess, and not all women with androgen excess will have hirsutism (5). In the largest clinical trial cardiovascular disease [male younger than 55 years and to date of women with PCOS, 50–60% of the 400 women female younger than 65 years]) is important. Lifestyle fac- prospectively identified as having hyperandrogenic tors, such as smoking, alcohol consumption, diet, and chronic anovulation had no evidence of hirsutism (6). exercise, are particularly important in these women.
The physical examination should include an evalua- Etiology
tion of balding, acne, clitoromegaly, and body hair dis-tribution, as well as a pelvic examination to look for No gene or specific environmental substance has been ovarian enlargement. The presence and severity of acne identified as causing PCOS. Selective insulin resistance should be noted. Signs of insulin resistance, such as may be central to the etiology of the syndrome: skeletal obesity, centripetal fat distribution, and the presence of muscle is profoundly resistant, and other tissues (hypo- acanthosis nigricans, should be recorded. Acanthosis thalamus, adrenal, ovary) remain sensitive to the effects of nigricans is a dermatologic condition marked by velvety, insulin (7). Thus, compensatory hyperinsulinemia may mossy, verrucous, hyperpigmented skin. It has been result in decreased levels of sex hormone binding globulin noted on the back of the neck, in the axillae, underneath (SHBG) and serve as a trophic stimulus to androgen pro- the breasts, and even on the vulva. The presence of acan- duction in the adrenal gland and ovary. Insulin also may thosis nigricans appears to be more a sign of insulin have direct hypothalamic effects, such as abnormally stim- resistance than a distinct disease unto itself. Other patho- ulating appetite and gonadotropin secretion. logic conditions associated with acanthosis nigricansshould be considered, such as insulinoma and malignant Clinical Manifestations
disease, especially adenocarcinoma of the stomach. Women with PCOS commonly present with infertility or Because Cushing’s syndrome is extremely rare (1 in menstrual disorders. For this reason, much attention has 1,000,000) and screening tests are not 100% sensitive or been focused on the risks of ovulation induction among specific (16), routine screening for Cushing’s syndrome women with PCOS because they are at increased risk for in all women with hyperandrogenic chronic anovulation ovarian hyperstimulation syndrome, multiple pregnancy, is not indicated. Those who have co-existing signs of and first-trimester pregnancy loss. In addition, women Cushing’s syndrome, including a moon facies, buffalo with PCOS appear to be at increased risk for complica- hump, abdominal striae, centripetal fat distribution, or tions of pregnancy, including gestational diabetes and hypertension, should be screened. Proximal myopathies hypertensive disorders (8–10); the risk of these compli- and easy bruising, not present in women with PCOS, also cations is further exacerbated by multiple pregnancy.
may help identify patients with Cushing’s syndrome.
Chronic anovulation (11), obesity (12), hyperinsu- Androgen-secreting tumors of the ovary or adrenal linemia (13), and decreased levels of SHBG (14) are all gland are invariably accompanied by elevated circulating associated with endometrial cancer. Insulin resistance androgen levels. However, there is no absolute level that and its associated conditions, such as acanthosis nigri- is pathognomonic for a tumor, just as there is no mini- cans, centripetal fat distribution, obesity, and obesity-related sleep disorders (15), are all common with PCOS.
In turn, all of these conditions are risk factors for long-term metabolic sequelae, such as type 2 diabetes and car-diovascular disease. Factors to Consider in the Differential Diagnosis of
Polycystic Ovary Syndrome
Differential Diagnosis
The differential diagnosis of PCOS includes other causes of androgen excess (see box “Factors to Consider in the Differential Diagnosis of Polycystic Ovary Syndrome”).
Nonclassical congenital adrenal hyperplasia Essential components of the history and physical examina- tion are necessary to diagnose the underlying cause of oli-goovulation (see box “Suggested Diagnostic Evaluation for Polycystic Ovary Syndrome”). The history should focus on the onset and duration of the various signs of androgen excess, the menstrual history, and concomitant medications, including the use of exogenous androgens. A family history of diabetes and cardiovascular disease(especially first-degree relatives with premature onset of mum androgen level that excludes a tumor. In the past, Suggested Diagnostic Evaluation
testosterone levels greater than 2 ng/mL and dehy- for Polycystic Ovary Syndrome
droepiandrosterone sulfate (DHEAS) levels greater than700 µg/dL were regarded as suspicious for a tumor of, Physical
respectively, ovarian and adrenal etiology, but these cut- off levels have poor sensitivity and specificity (17).
• Body mass index (weight in kg divided by height in m2) The best measurement of circulating androgens to document unexplained androgen excess is uncertain.
Evaluation of testosterone or bioavailable testosterone is • Waist–hip ratio to determine body fat distribution useful for documenting ovarian hyperandrogenism.
Evaluation of DHEAS levels may be useful in cases of rapid virilization (as a marker of adrenal origin), but its • Presence of stigmata of hyperandrogenism or insulin utility in assessing common hirsutism is questionable.
Both the adrenal glands and ovaries contribute to the ■ Acne, hirsutism, androgenic alopecia, acanthosis circulating androgen pool in women. The adrenal gland preferentially secretes weak androgens, such as dehy- Laboratory
droepiandrosterone (DHEA) or DHEAS (up to 90% of • Documentation of biochemical hyperandrogenemia adrenal origin). These hormones, in addition to ■ Total testosterone and/or bioavailable or free testos- androstenedione, may serve as prohormones for more potent androgens, such as testosterone or dihydrotestos- • Exclusion of other causes of hyperandrogenism terone. The ovary is the preferential source of testosterone, ■ Thyroid-stimulating hormone levels (thyroid dysfunction) and it is estimated that 75% of circulating testosterone originates from the ovary (mainly through peripheral con- version of prohormones by liver, fat, and skin, but also ■ 17-Hydroxyprogesterone (nonclassical congenital adre- through direct secretion). Androstenedione, largely of nal hyperplasia caused by 21-hydroxylase deficiency):random normal level <4 ng/mL or morning fasting ovarian origin, is the only circulating androgen that is higher in premenopausal women than men, yet its andro- ■ Consider screening for Cushing’s syndrome and other genic potency is only 10% of testosterone. Dihydro- testosterone is the most potent androgen, although it • Evaluation for metabolic abnormalities circulates in negligible quantities and results primarily ■ 2-hour oral glucose tolerance test (fasting glucose from the intracellular 5-α-reduction of testosterone.
<110 mg/dL = normal, 110–125 mg/dL = impaired, Mild elevations in prolactin are common in women >126 mg/dL = type 2 diabetes) followed by 75-g with PCOS (18). A prolactin level can identify prolactin- oral glucose ingestion and then 2-hour glucose omas that secrete large amounts of prolactin and that level (<140 mg/dL = normal glucose tolerance, may stimulate ovarian androgen production, but this is 140–199 mg/dL = impaired glucose tolerance, an extremely rare cause of hyperandrogenic chronic anovulation. Evaluating serum levels of thyroid-stimu- • Fasting lipid and lipoprotein level (total cholesterol, high- lating hormone also is useful given the protean manifes- density lipoprotein, triglycerides, [low-density lipoproteinusually calculated by Friedewald equation]) tations and frequency of thyroid disease in women.
Optional Tests to Consider
• Ultrasound examination of ovaries for baseline evaluation
and morphology before ovulation induction or in cases of Clinical Considerations and
virilization or rapid conversion to an androgen excess state Recommendations
• Gonadotropin determinations to determine cause of • Fasting insulin levels in younger women, those with severe Who should be screened for nonclassical
stigmata of insulin resistance and hyperandrogenism, or congenital adrenal hyperplasia, and how
should screening be performed?
• 24-hour urine test for urinary free cortisol with late onset of polycystic ovary syndrome symptoms or stigmata of Nonclassical congenital adrenal hyperplasia, often referred to as late-onset congenital adrenal hyperplasia,can present in adult women with anovulation and hir- sutism and is almost exclusively caused by genetic women with PCOS. Women with PCOS should be defects in the steroidogenic enzyme, 21-hydroxylase screened for type 2 diabetes and impaired glucose toler- (CYP21). In Europe and the United States, congenital ance with a fasting glucose level followed by a 2-hour adrenal hyperplasia occurs with the highest frequency glucose level after a 75-g glucose load (27). This finding among Ashkenazi Jews, followed by Hispanics, has taken on new significance with the findings of the Yugoslavs, Native American Inuits in Alaska, and Italians Diabetes Prevention program that both lifestyle interven- tions and metformin significantly reduce the risk of To screen for nonclassical congenital adrenal hyper- developing diabetes in women with impaired glucose tol- plasia caused by CYP21 mutations, a fasting level of 17- hydroxyprogesterone should be obtained in the morning.
A value less than 2 ng/mL is considered normal. If the Does PCOS have a long-term impact on the
sample is obtained in the morning and during the follicu- development of cardiovascular disease?
lar phase, some investigators have proposed cutoffs ashigh as 4 ng/mL (20). Specificity decreases if the sample No prospective studies have documented an increased is obtained in the luteal phase. High levels of 17-hydroxy- risk of cardiovascular events in women with PCOS.
progesterone should prompt an adrenocorticotropic hor- However, a number of studies using surrogate endpoints for cardiovascular disease risk have suggested womenwith PCOS are at increased risk (29, 30). A recent cohort Does PCOS increase the risk of developing
study found an increased prevalence of subclinical ather- type 2 diabetes?
osclerosis in those with PCOS (7.2%) when comparedwith controls of similar ages (0.7%) (31). This difference Retrospective studies of women with PCOS have noted a was detected only in women aged 45 years or older. twofold to fivefold increased risk of diabetes in women Women with PCOS display a number of well-recog- with PCOS when compared with a control population nized risk factors for both diabetes and cardiovascular (21, 22). In a prospective, cohort study, 11.9% of women disease, such as obesity and impaired glucose tolerance older than 30 years with PCOS had a physician’s diagno- (32). Dyslipidemia is a common metabolic abnormality sis of type 2 diabetes, compared with only 1.4% of con- among women with PCOS. The prevalence of borderline trols (23). Recent studies have suggested as many as 40% or high lipid levels according to National Cholesterol of women with PCOS demonstrate glucose intolerance Education Program guidelines (33) approaches 70% in when the less stringent World Health Organization crite- women with PCOS (34). Low-density lipoprotein (LDL) ria are applied (2-hour glucose levels ≥140 mg/dL) (24).
levels are disproportionately elevated in women with Undiagnosed diabetes approaches 10% in these PCOS PCOS (34–36) when compared with other insulin-resist- cohorts. The risk factors associated with glucose intoler- ance in women with PCOS—age, high body mass index Insulin resistance has been associated with other dis- (BMI), high waist–hip ratios, and family history of dia- tinct patterns of dyslipidemia, including decreased levels betes—are identical to those in other populations (25).
of high-density lipoprotein (HDL); increased levels of Currently, the American Diabetes Association does small, dense LDL; and elevated levels of triglycerides. A not recommend screening for insulin resistance with large cohort study looked at the effect of aging on the pat- measures of insulin or other markers of the insulin resist- tern of dyslipidemia in women with PCOS (35). Subjects ance syndrome (26). Although insulin sensitivity can be were first evaluated in their 30s and underwent repeat much more precisely quantified by direct measurement lipid phenotyping over time (36). Later evaluations of insulin effects on glucose metabolism in target tissues, showed persistent lipid abnormalities in women with both in vivo and in vitro, dynamic tests such as the eug- PCOS, but these abnormalities tended to persist and lycemic glucose clamp or frequently sampled intra- plateau, whereas in the control population, lipid abnor- venous glucose tolerance test are too intensive and unwieldy to have widespread clinical utility. Thus, rou- All women with PCOS should be screened for car- tine screening for insulin resistance is not useful in the diovascular risk by determination of BMI and waist–hip larger population of women with PCOS. However, it may ratio and measurement of fasting lipid and lipoprotein be useful to screen selected women with PCOS for levels (total cholesterol, HDL cholesterol, and triglyc- hyperinsulinemia—for example, those with severe hyper- erides). Regular exercise and weight control are proven androgenism and acanthosis nigricans, younger women, methods to reduce cardiovascular morbidity and mortal- or those undergoing ovulation induction. Fasting glucose ity. These modalities should be considered before pre- levels are poor predictors of glucose intolerance risk in In a woman with PCOS who is not attempting
vary. There are class differences, for example, biguanides to conceive, what is the best medical mainte-
tend to decrease weight and thiazolidinediones to nance therapy to treat anovulation and
increase weight. Within a class there also can be signifi- amenorrhea?
cant differences in the risk–benefit ratio, for instance aknown increased risk of hepatotoxicity with troglitazone(no longer available) compared with the minimal risk Combination Oral Contraceptives
with rosiglitazone. These differences should discourage Oral contraceptives have been the mainstay of long-term aggregating all of these agents into a single category management of PCOS. They offer benefit through a vari- when considering their use. Nonetheless, improving in- ety of mechanisms, including suppression of pituitary sulin sensitivity is associated with a decrease in circulat- luteinizing hormone secretion, suppression of ovarian ing androgen levels, improved ovulation rate, and androgen secretion, and increased circulating SHBG.
improved glucose tolerance. It is difficult to separate the Individual preparations may have different doses and effects of improving insulin sensitivity from those of drug combinations and thus have varying risk–benefit lowering serum androgens, as any “pure” improvement ratios. For instance, various progestins have been shown in insulin sensitivity can increase SHBG and, thus, de- to have different effects on circulating SHBG levels (38), crease bioavailable androgen. None of the agents noted but whether that translates into a clinical benefit is uncer- are currently approved by the U.S. Food and Drug Ad- tain. The “best” oral contraceptive for women with PCOS ministration (FDA) for treatment of PCOS. Despite en- is not known. Oral contraceptives also are associated couraging preliminary results, troglitazone was removed with a significant reduction in the risk for endometrial from the world wide market because of hepatotoxicity.
cancer (38), but the magnitude of the effect in women Small studies of 3–6 months’ duration with met- formin in women with PCOS suggested improvement inovulatory function in about one half of those studied Progestin
(45–47). Circulating androgen levels also appear todecrease with long-term treatment. There are no studies Both depot and intermittent oral medroxyprogesterone of treatment for 1 year or more with a thiazolidinedione acetate (10 mg for 10 days) have been shown to suppress in women with PCOS. The effects of either metformin or pituitary gonadotropins and circulating androgens in thiazolidinediones on preventing endometrial hyperplasia women with PCOS (39). No studies have addressed the or neoplasia in women with PCOS are unknown.
long-term use of these compounds to treat hirsutism. Theregimen of cyclic oral progestin therapy that most effec- In a woman with PCOS who is not attempting
tively prevents endometrial cancer in women with PCOS to conceive, what is the best medical mainte-
is unknown. However use of medroxyprogesterone nance therapy to prevent cardiovascular dis-
acetate has been associated with decreases in SHBG inwomen with PCOS (40). Progestin-only oral contracep- ease and diabetes?
tives are an alternative for endometrial protection, butthey are associated with a high incidence of breakthrough Combination Oral Contraceptives and
Progestins
In the general population, oral contraceptive use has not Insulin-Sensitizing Agents
been associated with an increased risk of developing type Drugs initially developed to treat type 2 diabetes also 2 diabetes (48). There is no convincing evidence that the have been used to treat PCOS. Most studies have focused use of oral contraceptives contributes to the risk of dia- on agents that improve peripheral insulin sensitivity by betes in women with PCOS. However, suppression of decreasing circulating insulin levels. These agents androgens with oral contraceptives is associated with a include biguanides (metformin) (42, 43), thiazolidine- significant elevation in circulating triglycerides as well as diones (troglitazone, pioglitazone, and rosiglitazone), in HDL levels, as demonstrated in a large, 3-year study of and an experimental insulin sensitizer drug known as D- women with PCOS (49). Most of these effects were chiro-inositol (44). They do not increase insulin secre- achieved at 12 months, with little change in circulating tion, as do sulfonylureas, and are, thus, rarely associated lipid values between 12 months and 36 months (49).
with hypoglycemia, a risk for those who are normo- Other studies with fewer participants or of shorter dura- glycemic when fasting (as are most women with PCOS).
tion showed similar or no effects on circulating lipids These drugs often are referred to as insulin-sensitizing (50). There is no evidence to suggest that women with agents, but their individual effects and risk–benefit ratios PCOS experience more cardiovascular events than the general population when they use oral contraceptives.
Table 1. Pregnancy Categories of Common Medications
The effect of progestins alone on metabolic risk factors Used in the Treatment of Polycystic Ovary Syndrome
Pregnancy
Insulin-Sensitizing Agents
Category
A National Institutes of Health sponsored trial demon- strated that metformin can prevent the development of diabetes in high-risk populations (eg, those with impaired glucose tolerance) (28). The use of troglitazone in this trial was terminated because of its hepatotoxicity. Among women with PCOS who use metformin, glucose toler- ance improves or stays steady over time (46). Metformin also may be associated with weight loss, but results are inconsistent. Currently, data are insufficient to warrant use of insulin-sensitizing agents prophylactically to pre- vent diabetes in women with PCOS. However, results ofongoing prevention trials may favor more aggressive man- agement of impaired glucose tolerance to prevent diabetes.
Multiple studies have documented improvement with the use of insulin-sensitizing agents in the cardio- vascular risk profile of patients with diabetes or insulin resistance syndrome, but the role of these agents in pri- mary or secondary prevention of cardiovascular disease is uncertain (51). However, similar improvements in lipid profiles have not been noted consistently in women with PCOS. The cardioprotective effects of insulin-sensitizing agents in women with PCOS are still unknown. Anotherarea where there is theoretic appeal, but little data toguide therapy, is the use of statins to prevent cardiovas- will occur within the first six ovulatory cycles. Increasing cular disease in young women with PCOS or the meta- the duration of treatment adds little to the pregnancy rate.
A recent meta-analysis showed clomiphene citrate to beeffective in women with ovulatory dysfunction and estro- In women with PCOS who are attempting to
gen production (55). There are no clear prognostic factors conceive, which methods of ovulation induc-
for response, although increased weight is associated tion are effective?
with a larger dose requirement and a greater likelihood offailure (56).
There is no evidence-based schema to guide the initial Alternative clomiphene regimens have been devel- and subsequent choices of ovulation induction methods oped, including prolonging the period of administration in women with PCOS. Treatment should begin with a (57) and adding dexamethasone. Dexamethasone as regimen of regular exercise and weight control and then adjunctive therapy with clomiphene citrate has been proceed to other methods if necessary (52). The preg- shown to increase ovulation rates in women with PCOS nancy classification of common medications used to treat with higher DHEAS levels (>2000 ng/mL) (57, 58). Gonadotropins frequently are used to induce ovula- Clomiphene Citrate or Gonadotropins
tion in women with PCOS for whom clomiphene treat-ment has failed (59). In a large trial of gonadotropins in Clomiphene citrate has traditionally been the first-line women with PCOS, women were randomized to either an treatment agent for anovulatory women, including those aggressive or low-dose follicle-stimulating hormone pro- with PCOS. Up to 80% of women with PCOS will ovu- tocol. Higher pregnancy rates (40% versus 20%, respec- late in response to clomiphene treatment, and 50% of tively) and less multifollicular ovulation (27% versus these women will conceive (53). One half of all women 74%) were achieved with the low-dose protocol (60).
who are going to conceive using clomiphene will do so There were fewer cases of multiple pregnancy, ovarian with the 50-mg starting dose, and another 20% will do so hyperstimulation, and multifollicular ovulation (74% with the 100-mg per day dosage (54). Most pregnancies versus 27%) (60). Low-dose therapy with gonadotropins offers a higher rate of monofollicular development (ap- nancy (73). Some clinicians advocate its use during early proximately 50% or greater) with a significantly lower pregnancy to reduce the miscarriage rate, but the docu- risk of ovarian hyperstimulation syndrome (20–25%) that results in cycle cancellation or more serious seque-lae (60, 61). Thiazolidinediones
Thiazolidinediones are peroxisome proliferator activat- Ovarian Drilling
ing receptor (PPAR-γ) agonists and are thought to The value of laparoscopic ovarian drilling with laser or improve insulin sensitivity through a postreceptor mech- diathermy as a primary treatment for subfertile women anism. In a large, randomized, controlled, multicenter with anovulation and PCOS is undetermined (62).
trial, troglitazone demonstrated a dose-response effect in Neither drilling by laser nor diathermy has any obvious improving ovulation and hirsutism (6). These benefits advantages, and there is insufficient evidence to suggest appeared to be mediated through decreases in hyperinsu- a difference in ovulation or pregnancy rates when linemia and decreases in free testosterone levels (with drilling is compared with gonadotropin therapy as a sec- corresponding increases in SHBG). Newer thiazolidine- ondary treatment for women who do not respond to diones, such as rosiglitazone and pioglitazone, appear to clomiphene (62). A recent randomized trial found no dif- be safer in terms of hepatotoxicity but also have been ference in pregnancy or miscarriage rates between ovar- associated with embryotoxicity in animal studies, and ian surgery or 3 months of ovulation induction with little has been published on their effects in women with gonadotropins (63). Multiple pregnancy rates are reduced in those women who conceive after laparoscop- ic drilling. In some cases, the fertility benefits of ovarian In obese women with PCOS, does weight loss
drilling may be temporary (64), and drilling does not improve ovarian function?
appear to improve metabolic abnormalities in womenwith PCOS (65). Obesity contributes substantially to reproductive andmetabolic abnormalities in women with PCOS. Multiple Insulin-Sensitizing Agents
studies have shown that weight loss can improve the fun-damental aspects of the endocrine syndrome of PCOS by Metformin
decreasing circulating androgen levels and causing spon- Most randomized trials using metformin have shown that taneous resumption of menses (75, 76). These changes it improves ovulatory frequency in women with PCOS have been reported with weight loss as little as 5% of the (43, 45, 46, 66, 67), although several have not shown a initial weight (77). Other benefits include decreased cir- benefit (68–70). The dosage most frequently used has culating insulin levels (75, 77). The decrease in unbound been 1,500 mg per day, and more recent studies have testosterone levels after weight loss may be largely used 2,000 mg per day in divided doses. Metformin also mediated through increases in SHBG (77). There also has been used successfully as an adjunctive agent with may be decreases in circulating luteinizing hormone lev- both clomiphene citrate (43) and gonadotropins (67, 71).
els (76), although not uniformly (78). Changes in body In a small study, metformin significantly improved the weight have been associated with improved ovulation pregnancy rate in clomiphene-resistant women with and pregnancy rates. Longer-term effects from improve- PCOS when compared with placebo (72). Studies have ment in ovarian function also have been reported. In one been hampered by small numbers, inconsistent use of a study, hirsutism improved in approximately 50% of placebo, selection bias (primarily women who are clomi- phene-resistant), and lack of a dose-ranging study. Although there is much interest in the therapeutic Metformin carries a small risk of lactic acidosis, effects of a high protein diet for women with PCOS, few most commonly among women with poorly controlled studies support the benefits. Further, there are theoretic diabetes and impaired renal function. Gastrointestinal concerns about the adverse effects of high protein on symptoms (diarrhea, nausea, vomiting, abdominal bloat- renal function in a population at high risk for diabetes, as ing, flatulence, and anorexia) are the most common well as the adverse effects of the increased fat composi- adverse reactions and may be ameliorated by starting at tion of such diets on dyslipidemia. Only limited studies a small dose and gradually increasing the dose or by on the effects of exercise on PCOS have been performed using the sustained-release version now available in the (80). It is reasonable to assume that exercise would have the same beneficial effects in women with PCOS as Metformin has no known human teratogenic risk or women with type 2 diabetes, which exist even with no embryonic lethality in humans and appears safe in preg- In the general population, weight loss can result in Spironolactone
significant improvement in the risk for diabetes and car- Spironolactone, a diuretic and aldosterone antagonist, diovascular disease (82). These data support the utility of also binds to the androgen receptor as an antagonist (90).
lifestyle modification, ie, improved diet and increased It has other mechanisms of action, including inhibition exercise, as primary treatments for all obese women with of ovarian and adrenal steroidogenesis, competition for androgen receptors in hair follicles, and direct inhibition of 5-α-reductase activity. The usual dosage is 25–100 mg How effective are the various medical agents
twice per day, and the dosage is titrated to balance effi- in treating hirsutism in women with PCOS?
cacy while avoiding side effects. A full clinical effect Most medical methods, while improving hirsutism, do may take 6 months or more. Approximately 20% of not produce the dramatic results women desire, and women using spironolactone will experience increased treatment often is palliative rather than curative. In gen- menstrual frequency (91). Because it can cause and eral, combination therapies appear to produce better exacerbate hyperkalemia, spironolactone should be used results than single-agent approaches (83–85); however, cautiously in women with renal impairment. Rarely, randomized trials have not established a primary treat- exposure has resulted in ambiguous genitalia in male infants. Although spironolactone has had long and exten-sive use as an antiandrogen and multiple clinical trials Oral Contraceptives
have shown a benefit, the overall quality of the trials andsmall numbers enrolled have limited the ability of a No oral contraceptive has been approved by the FDA for meta-analysis to document its benefit in the treatment of the treatment of hirsutism. A number of observational or nonrandomized studies have noted improvement in hir-sutism in women with PCOS who use oral contracep- Flutamide
tives (86), but there are no definitive data to confirm theirbenefit in improving hirsutism in PCOS. Few studies Flutamide, an androgen-receptor agonist, is another non- have compared outcomes of different types of oral con- steroidal antiandrogen that has been shown to be effec- traceptives, and no one type of pill has been shown to be tive against hirsutism in observational trials (93, 94). The superior in treating hirsutism in women with PCOS (87).
most common side effect is dry skin, but its use has been A number of studies have found additive benefit when associated with hepatitis in rare cases. The common oral contraceptives are combined with other treatment dosage is 250 mg per day. The risk of teratogenicity with modalities, such as flutamide (83). If a woman is taking this compound is significant, and contraception should an oral contraceptive that contains drospirenone, it may be used. Administration of flutamide to a population of be necessary to reduce her dose of spironolactone and women with PCOS resulted in significantly decreased Antiandrogens
Finasteride
None of the antiandrogen agents were developed to treat Finasteride inhibits both forms of the enzyme 5-α-reduc- hyperandrogenism in women or are approved by the tase (type I, predominantly found in the skin, and type II, FDA for that indication. They have been used empirical- predominantly found in the prostate and reproductive tis- ly in women with PCOS. These compounds primarily sues). It is available as a 5-mg tablet for the treatment of antagonize the binding of testosterone and other andro- prostate cancer and a 1-mg tablet for the treatment of gens to the androgen receptor. Androgen antagonism male alopecia. It has been found to be effective for the may result in improvements in other metabolic variables, treatment of hirsutism (95, 96). Finasteride is better tol- such as circulating lipid levels (88). Randomized trials erated than other antiandrogens, with minimal hepatic have found that spironolactone, flutamide, and finas- and renal toxicity; however, it has well-documented risk teride all have similar efficacy in improving hirsutism for teratogenicity in male fetuses, and adequate contra- (89). All appear to offer some benefit, although the best choice for hirsutism in PCOS is unknown. As a class,antiandrogens are teratogenic and pose a risk of femi- Insulin-Sensitizing Agents
nization of the external genitalia in a male fetus Insulin sensitizers may treat hirsutism by improving both (ambiguous genitalia) if the patient conceives. There- hyperinsulinemia and hyperandrogenemia concurrently.
fore, they are frequently used in combination with oral In a 12-month study, only the highest dose of troglita- zone was found to significantly—although modestly— improve hirsutism in women with PCOS (6). In small (101). The success of laser treatment is operator-depend- studies with metformin, hirsutism was unchanged (50, ent, and concomitant medical management generally is 97) or showed only slight improvement (47, 98). Studies of longer duration are needed to detect differencesbetween classes of insulin-sensitizing agents and theirlong-term benefits.
Summary of
Eflornithine
Recommendations
An inhibitor of the enzyme ornithine decarboxylase, top- The following recommendations are based on
ical eflornithine has been approved by the FDA for treat- good and consistent scientific evidence (Level A):
ing hirsutism. It appears to be well tolerated, and may have notable benefit after 6 months of use. A variety of All women with PCOS should be screened for glu- adverse skin conditions have been reported in a small cose intolerance with a 2-hour glucose level after a percentage of patients. Any additional benefit or de- creased efficacy in women with PCOS is unknown at All women with PCOS should be screened for dys- lipidemia with a fasting lipoprotein profile, includ- ing total cholesterol, LDL, HDL, and triglyceride Is there a role for adjuvant cosmetic man-
agement of hirsutism?
Interventions that improve insulin sensitivity, Mechanical hair removal (shaving, plucking, waxing, including weight loss, use of metformin, and use of depilatory creams, electrolysis, and laser vaporization) thiazolidinediones, are useful in improving ovula- often is the front line of treatment used by women (99).
There is no evidence that shaving can increase hair folli- Use of clomiphene citrate is appropriate because it cle density or size of the hair shaft (100). Judicious effectively results in pregnancy in women with plucking can be helpful if tolerated, but care must be taken to avoid folliculitis, pigmentation, and scarring. In electrolysis, a direct current is passed down a nee- The following recommendations are based on lim-
dle inserted into the hair follicle, destroying the follicle.
ited or inconsistent scientific evidence (Level B):
Unlike mechanical and chemical depilatory methods, electrolysis can permanently reduce hirsutism by Improvements in insulin sensitivity, by weight loss destroying the follicle. Electrolysis satisfactorily or by the use of insulin-sensitizing agents, may removes hair from women and men with hypertrichosis favorably improve many risk factors for diabetes (generalized increased hair distribution). However, elec- and cardiovascular disease in women with PCOS.
trolysis is tedious, its success is highly operator-depend- When using gonadotropins to induce ovulation, ent, and it may be impractical for treating large numbers low-dose therapy is recommended because it offers of hairs. The regulation of electrology practice varies a high rate of monofollicular development and a sig- among states. Concomitant medical management direct- nificantly lower risk of ovarian hyperstimulation in ed at decreasing androgen levels usually is recommend- ed for excess androgen states, otherwise new vellus hairs will differentiate into terminal hairs, causing recurrence The benefit and role of surgical therapy in ovulation induction in women with PCOS is uncertain.
Laser treatment removes hair because follicular melanin absorbs the laser wavelengths of light, which The following recommendations are based primar-
selectively thermally damage the target without damag- ily on consensus and expert opinion (Level C):
ing surrounding tissue. Women with dark hair and light Although eflornithine hydrochloride cream has been skin are ideal candidates, and the approach appears to be effective in treating facial hirsutism in women, addi- most effective during anagen. Because of the skew of tional benefits or risks for women with PCOS are hair follicles among varying segments of the hair growth cycle, multiple treatments may be necessary. Most stud- ies have been observational, nonrandomized studies with All women with a suspected diagnosis of PCOS no specific focus on women with PCOS. Randomized should be screened with a 17-hydroxyprogesterone studies have demonstrated a benefit over control areas value for nonclassical congenital adrenal hyperplasia. Combining medical interventions may be the most 8. Urman B, Sarac E, Dogan L, Gurgan T. Pregnancy in effective way to treat hirsutism. Combined therapy infertile PCOD patients. Complications and outcome. J with an ovarian suppression agent and an antiandro- gen appears effective in treating hirsutism in women 9. Anttila L, Karjala K, Penttila RA, Ruutiainen K, Ekblad with PCOS. The best pill or antiandrogen is U. Polycystic ovaries in women with gestational diabetes.
Obstet Gynecol 1998;92:13–6. (Level II-2) 10. Holte J, Gennarelli G, Wide L, Lithell H, Berne C. High The ideal choice of ablative procedures for long- prevalence of polycystic ovaries and associated clinical, term management of hirsutism in women with endocrine, and metabolic features in women with previ- ous gestational diabetes mellitus. J Clin Endocrinol Metab The optimal progestin, duration, and frequency of 11. Ho SP, Tan KT, Pang MW, Ho TH. Endometrial hyper- treatment to prevent endometrial cancer in women plasia and the risk of endometrial carcinoma. Singapore The effects of insulin-sensitizing agents on early 12. Dahlgren E, Friberg LG, Johansson S, Lindstrom B, Oden A, Samsioe G, et al. Endometrial carcinoma; ovarian dys- pregnancy are unknown; metformin appears safe, function—a risk factor in young women. Eur J Obstet but any additional effect at reducing pregnancy loss Gynecol Reprod Biol 1991;41:143–50. (Level II-3) 13. Troisi R, Potischman N, Hoover RN, Siiteri P, Brinton The best or initial treatment for hirsutism, ovulation LA. Insulin and endometrial cancer. Am J Epidemiol1997;146:476–82. (Level II-2) induction, or prevention of long-term metabolicsequelae for women with PCOS is unknown. All of 14. Potischman N, Hoover RN, Brinton LA, Siiteri P, Dorgan JF, Swanson CA, et al. Case-control study of endogenous these conditions may benefit from lifestyle modifi- steroid hormones and endometrial cancer. J Nat Cancer 15. Vgontzas AN, Legro RS, Bixler EO, Grayev A, Kales A, Chrousos GP. Polycystic ovary syndrome is associated References
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LR. Leuprolide and estrogen versus oral contraceptive J Clin Endocrinol Metab 1994;79:831–5. (Level II-2) pills for the treatment of hirsutism: a prospective ran- 97. Morin-Papunen LC, Koivunen RM, Ruokonen A, domized study. J Clin Endocrinol Metab 1995;80: Martikainen HK. Metformin therapy improves the men- strual pattern with minimal endocrine and metabolic 85. De Leo V, Fulghesu AM, la Marca A, Morgante G, Pasqui effects in women with polycystic ovary syndrome. Fertil L, Talluri B, et al. Hormonal and clinical effects of GnRH agonist alone, or in combination with a combined oral 98. Ibanez L, Valls C, Potau N, Marcos MV, de Zegher F.
contraceptive or flutamide in women with severe hir- Sensitization to insulin in adolescent girls to normalize sutism. Gynecol Endrocrinol 2000;14:411–6. (Level I) hirsutism, hyperandrogenism, oligomenorrhea, dyslipi- 86. Falsetti L, Gambera A, Tisi G. Efficacy of the combina- demia, and hyperinsulinism after precocious pubarche. J tion ethinyl oestradiol and cyproterone acetate on Clin Endocrinol Metab 2000;85:3526–30. (Level II-2) 99. Richards RN, Uy M, Meharg G. Temporary hair removal in patients with hirsutism: a clinical study. Cutis 1990; The MEDLINE database, the Cochrane Library, and ACOG’s own internal resources and documents were used 100. Peereboom-Wynia JD. Effect of various methods of to conduct a literature search to locate relevant articles pub- depilation on density of hairgrowth in women with idio- lished between January 1985 and January 2001. The search pathic hirsutism. Arch Dermatol Forsch 1972;243: was restricted to articles published in the English language.
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and scientific conferences were not considered adequate for inclusion in this document. Guidelines published by organi-zations or institutions such as the National Institutes ofHealth and the American College of Obstetricians and Gy-necologists were reviewed, and additional studies werelocated by reviewing bibliographies of identified articles.
When reliable research was not available, expert opinionsfrom obstetrician–gynecologists were used.
Studies were reviewed and evaluated for quality accordingto the method outlined by the U.S. Preventive Services TaskForce: Evidence obtained from at least one properly de-signed randomized controlled trial.
II-1 Evidence obtained from well-designed controlled II-2 Evidence obtained from well-designed cohort or case–control analytic studies, preferably from morethan one center or research group.
II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncon-trolled experiments could also be regarded as thistype of evidence.
Opinions of respected authorities, based on clinicalexperience, descriptive studies, or reports of expertcommittees.
Based on the highest level of evidence found in the data,recommendations are provided and graded according to thefollowing categories: Level A—Recommendations are based on good and consis-tent scientific evidence.
Level B—Recommendations are based on limited or incon-sistent scientific evidence.
Level C—Recommendations are based primarily on con-sensus and expert opinion.
Copyright December 2002 by the American College of Obstetriciansand Gynecologists. All rights reserved. No part of this publication maybe reproduced, stored in a retrieval system, or transmitted, in any formor by any means, electronic, mechanical, photocopying, recording, orotherwise, without prior written permission from the publisher.
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Polycystic ovary syndrome. ACOG Practice Bulletin No. 41. AmericanCollege of Obstetricians and Gynecologists. Obstet Gynecol 2002;100:1389–402.

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Induction Rate Doubles as ACOG Issues New GuidelinesMisoprostol should not be used for inducing labor in women with a history of uterine surgery or a priorcesarean delivery, according to new guidelines issued by the American College of Obstetricians andGynecologists (ACOG). Action Points Explain to interested patients that a number of clinical conditions affecting the mother or fetus orboth m

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