AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

In 1935, Stein and Leventhal first described the association of polycystic ovaries, amenorrhea, hirsutism, and obesity.¹ However, the key features necessary for the diagnosis of polycystic ovarian syndrome (PCOS) were not detailed until 1990 at a conference convened by the National Institutes of Health (NIH). These key features included hyperandrogenism, menstrual dysfunction, and exclusion of other causes of hyperandrogenism (eg, congenital adrenal hyperplasia, androgen-secreting tumors, hyperprolactinemia). Probable criteria included insulin resistance, perimenarchal onset, elevated luteinizing hormone (LH)–to–follicle-stimulating hormone (FSH) ratio, and polycystic ovaries identified using ultrasonography.

The hyperandrogenic effects observed in PCOS most commonly include hirsutism, acne, and androgen-dependent alopecia. Obesity is also common. Endocrine abnormalities include elevated serum concentrations of androgens, particularly testosterone and androstenedione, as well as increased LH levels and normal or decreased FSH levels. PCOS is also associated with insulin resistance and changes in lipid metabolism. The acronym for the clinical association of hyperandrogenism, insulin resistance, and acanthosis nigricans is the HAIR-AN syndrome.

Beyond the NIH criteria of hyperandrogenism and menstrual dysfunction, other manifestations vary; PCOS is a clinically, histologically, and biochemically heterogeneous condition. For example, many women with the syndrome do not have evidence of polycystic ovaries. Although earlier descriptions of the syndrome were based on ovarian morphology, approximately 20% of regularly ovulating normal women have polycystic ovaries; therefore, ovarian morphology is no longer an essential requirement for diagnosis.

Pathophysiology

Major features of PCOS include menstrual dysfunction, anovulation, and signs of hyperandrogenism. Although the exact etiology is not clear, PCOS is an abnormality of the hypothalamic-pituitary-ovarian system. A characteristic of the syndrome is inappropriate gonadotropin secretion, which is more likely a result of, rather than a cause of, ovarian dysfunction. LH is tonically elevated throughout the menstrual cycle, FSH levels are within the reference range or low, the LH-to-FSH ratio is often greater than 3, and an exaggerated response of LH to gonadotropin-releasing hormone (GnRH) is observed.

Androgens such as testosterone, free testosterone, and dehydroepiandrosterone sulfate (DHEAS), may or may not be measurably elevated in the peripheral circulation, yet these hormones and their metabolites account for the physical characteristics of the syndrome. The source of androgens may be from the ovaries, adrenals, or both. Other contributing factors to androgen excess in women with PCOS (compared with women without PCOS) include an elevated serum level of androstenedione, which is converted within adipose tissue to testosterone, and a greater percentage of unbound active testosterone.

In the early phase of the menstrual cycle, circulating estradiol levels in women with PCOS are equal to those of normal women. However, mid-cycle elevations of estrogen and progesterone that normally occur after ovulation are absent. Because of the lack of cyclical progesterone secretion, the action of estradiol on both the hypothalamic-pituitary axis and the endometrium is unopposed. Both progesterone deficiency and acyclic estrogen production contribute to increased secretion of LH. The effects of unopposed estrogen on the endometrium may cause it to become hyperplastic, which may cause intermittent and heavy uterine bleeding and increase the long-term risk of endometrial cancer. These effects may be compounded, especially in patients who are obese, by increased levels of estrone converted from androstenedione in adipose tissue.

Frequency

United States

PCOS affects approximately 5-7% of premenopausal women

Mortality/Morbidity

Because of prolonged unopposed estrogen stimulation of the endometrium, patients have an increased risk of endometrial cancer. Approximately 40% of patients have insulin resistance that is independent of body weight. These women are at increased risk for adult-onset diabetes mellitus and consequent cardiovascular complications compared to healthy women. Women with hyperandrogenism also have elevated lipoproteins similar to men, which may increase the risk of cardiovascular disease.

Race

A great deal of ethnic variability in hirsutism is observed. For instance, Asian women have less hirsutism given the same serum androgen values as white women. On the other hand, southern Mediterranean women more often are hirsute.

Sex

PCOS affects females of reproductive age. Studies of family members with PCOS indicate that an autosomal dominant mode of inheritance with premature male pattern baldness as the male phenotype may occur.

Age

PCOS affects premenopausal women, and the age of onset is most often perimenarchal.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• Family history
• • Hirsutism
  • Adrenal enzyme deficiencies
  • Menstrual disorders
  • Polycystic ovarian syndrome (PCOS)
  • Diabetes
  • Infertility
• Menstrual disturbance
• • The patient usually has a history of menstrual disturbance dating back to menarche. Irregular menses during the initial 2 years after menarche are most often physiologic, requiring no special evaluation. Persistent clinical symptoms beyond this time, especially in the presence of other signs of PCOS, warrant further evaluation.
  • Because of anovulation or oligo-ovulation, patients may present with amenorrhea, oligomenorrhea, dysfunctional uterine bleeding, or infertility. Menarche may be delayed, and primary amenorrhea, although uncommon, does occur.
• Hyperandrogenism
• • Hyperandrogenism presents as hirsutism, acne, and male pattern alopecia.
  • Rapid progression of virilization is characteristic of adrenal or ovarian androgen-producing tumors.
  • Other signs of hyperandrogenism (eg, clitoromegaly, increased muscle mass, voice deepening) are more characteristic of an extreme form of PCOS termed hyperthecosis. These signs and symptoms could also be consistent with androgen-producing tumors, exogenous androgen administration, or virilizing congenital adrenal hyperplasia.
  • Premature adrenarche is a common occurrence and, in some cases, may represent a precursor to PCOS. Both hirsutism and obesity may be present in premenarchal adolescent girls with PCOS.
• Acanthosis nigricans
• • Another cutaneous manifestation is acanthosis nigricans.
  • Patients may have a dark and thickened area of skin behind the neck and in skin folds. Acanthosis nigricans is staged according to the scoring system below. Among sites where severity is taken into consideration, the neck showed the highest agreement and the least variation between a pediatric endocrinologist's examination (the gold standard) and individual observers, and between the individual observers themselves.
  • Staging acanthosis (neck severity)
  • • Absent (0): Not detectable on close inspection
    • Present (1): Clearly present on close visual inspection, not visible to the casual observer, extent not measurable
    • Mild (2): Limited to the base of the skull, usually does not extend to the lateral margins of the neck
• Obesity
• • Obesity, although common, is not universal.
  • Obesity is not usually the presenting complaint.

Physical

• Hirsutism: The modified Ferriman-Gallwey score grades 11 body areas (ie, upper lip, chin, chest, upper and lower abdomen, thighs, upper and lower back, arm, forearm, buttocks) from 0 (no hair) to 4 (frankly virile) and sums the score. A total score of 8 or more is considered abnormal for an adult Caucasian woman, with a score of 44 being the most severe.
• Other cutaneous findings
• • Acne
  • Acanthosis nigricans (marker for insulin resistance)
• Other possible physical examination findings
• • Increased upper body mass
  • Obesity (increased body mass index >85%)
  • Male pattern baldness
  • Clitoromegaly
  • Enlarged ovaries (not always present): Evaluate for ovarian mass.
  • Elevated prolactin levels and galactorrhea
  • Endometrial hyperplasia

Causes

• Enzyme abnormality
• • The cause is unknown, although some evidence suggests that patients have a functional abnormality of cytochrome P450c17, the 17-hydroxylase, which is the rate-limiting enzyme in androgen biosynthesis.²
  • Cytochrome P450c17 is active in the adrenals and ovaries, and excess activity of this enzyme could explain the increased androgen production from both sources in PCOS.
• Genetic causes
• • PCOS is, in some cases, a familial disorder, but the genetic basis of the syndrome remains unclear. One study revealed evidence of an autosomal dominant mode of inheritance.³
  • Full expression of the syndrome may require an insulin abnormality and a defect in androgen biosynthesis, but no gene (or genes) has been identified.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Patients with menstrual disturbances and signs of hyperandrogenism
Idiopathic hirsutism
Late-onset congenital adrenal hyperplasia
Familial hirsutism
Masculinizing tumors of the adrenal or ovary (rapid onset of signs of virilization)
Cushing syndrome (low K+, striae, central obesity, high cortisol; high androgens in adrenal carcinoma)
Hyperprolactinemia
Exogenous anabolic steroid use
Medications
Stromal hyperthecosis (valproic acid)

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

The goal is to assess the severity and source of androgen excess and to rule out an adrenal or ovarian tumor. A karyotype usually excludes mosaic Turner syndrome as a cause of the primary amenorrhea.

• FSH and LH
• • FSH levels are within the reference range or low.
  • LH levels are elevated for Tanner stage, gender, and age.
  • The LH-to-FSH ratio is usually greater than 3.
  • Stimulation testing with a long-acting GnRH agonist induces a characteristic rise in ovarian-derived 17-hydroxyprogesterone after 24 hours. This is thought to be a result of excessive 17-hydroxylase activity.
• Prolactin: A small percentage of patients have elevated prolactin levels (typically >25 mg/dL).
• Thyroid-stimulating hormone (TSH) and free thyroxine
• • Thyroid dysfunction may cause amenorrhea and hirsutism.
  • Thyroid function tests are within the reference range in patients with polycystic ovarian syndrome (PCOS).
  • Long-standing primary hypothyroidism can be associated with markedly elevated circulating TSH level. Elevated alpha subunit delivery (from one half of the dimeric TSH molecule) can then crossreact with FSH and LH receptors on breast tissue, leading to premature thelarche and, on ovarian tissue, leading to a PCOS-like picture. These physical findings of the van Wyk-Grumbach syndrome resolve upon thyroxine replacement therapy.
• Total and free testosterone
• • Total testosterone is elevated in women with PCOS; however, total testosterone levels greater than 200 ng/dL is suggestive of an androgen-producing tumor of the ovary or adrenal gland.
  • Free testosterone levels are sensitive for ovarian hyperandrogenism and are elevated in patients with PCOS.
  • Sex hormone-binding globulin (SHBG) is concomitantly low.
• Dehydroepiandrosterone
• • DHEAS is a marker of adrenal androgen production.
  • DHEAS levels greater than 700 mcg/dL are suggestive of a tumor. DHEAS is elevated in women with PCOS but not at such high levels.
  • Androstenedione levels are also elevated. This androgen precursor is 60% ovarian and 40% adrenal in derivation.
• Fasting cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, insulin, glucose, hemoglobin A1C: Some women with PCOS have insulin resistance and an abnormal lipid profile (cholesterol >200 mg/dL; LDL >160 mg/dL).
• Adrenocorticotropic hormone stimulation test
• • In female patients with signs of virilization that include clitoromegaly, premature pubarche, and high serum 17-hydroxyprogesterone (eg, >200 ng/dL in an 8-am sample), suspect late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
  • Further evaluation of adrenal function is required. An adrenocorticotropic hormone (ACTH) stimulation test can be used to check for late-onset congenital adrenal hyperplasia.
• Dexamethasone suppression test: History and physical examination usually exclude Cushing syndrome, but further tests, including 24-hour urine collection for free cortisol and 17-ketosteroids, a dexamethasone suppression test, and corticotropin-releasing hormone (CRH) stimulation tests, may be needed.

Imaging Studies

• Ultrasonography
• • Perform ultrasonography if pelvic examination is inadequate, the patient has abdominal pain, or if testosterone levels are unusually high (eg, >200 ng/dL).
  • Criteria for polycystic ovaries include bilateral ovarian enlargement (>9 cm in diameter), 10 or more follicles 2-10 mm in diameter per ovary, and increased density of the stroma.
• CT scan or MRI: If a tumor is suspected, obtain a CT scan or MRI to visualize the adrenals and ovaries.

Histologic Findings

• Histological changes of the ovary include enlarged, sclerotic, multiple cystic follicles.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

Medical therapy is used to treat menstrual dysfunction, manifestations of hyperandrogenism, infertility, and insulin resistance. The Endocrine Society published its clinical practice guideline in April 2008.⁴

• First-line medical therapy usually consists of an oral contraceptive to suppress ovarian androgen production and induce regular menses. If symptoms such as hirsutism are not sufficiently alleviated, an androgen-blocking agent may be added (see Medications).
• Recently, metformin has been successfully used in clinical trials; however, data are insufficient as yet to recommend this agent to all women with polycystic ovarian syndrome (PCOS).
• If the patient has concomitant adrenal hyperandrogenism, treatment with low dose prednisone or dexamethasone may be considered.
• Depot leuprolide acetate (Lupron) is effective in suppressing ovarian hormone production, which effectively induces menopause; therefore, this drug must be accompanied by hormone replacement therapy. This treatment approach has not gained widespread favor.
• Several medications, including benzoyl peroxide, Retin-A, and topical and oral antibiotics, are effective for acne treatment.
• If the patient develops type 2 diabetes mellitus, consider treatment with oral antihyperglycemic drugs, such as metformin. Clinical trials have recently shown that metformin can effectively reduce androgens, improve insulin sensitivity, and facilitate weight loss in patients with PCOS as early as adolescence.^{5, 6}
• The patient may desire mechanical removal of excess hair. Options include electrolysis, waxing, bleaching, tweezing, depilatories, shaving, and laser removal.
• Clomiphene citrate is used to stimulate ovulation when fertility is desired. Other approaches use GnRH analogues in combination with pulsatile luteinizing hormone-releasing hormone (LHRH) treatment.

Surgical Care

• Ovarian wedge resection was formerly considered an effective treatment for PCOS. Since the advent of hormonal therapies, this treatment is not often used but may be effective in alleviating ovarian dysfunction. Laparoscopic "ovarian drilling" is now performed.
• If desired, clitoromegaly may be corrected with surgery.

Consultations

Consultation with an endocrinologist is necessary for performing an ACTH stimulation test or for other causes of menstrual irregularity such as thyroid disease or pituitary adenoma.

Diet

• Nutritional counseling that addresses obesity and dyslipidemia is an important aspect of medical management.
• Weight loss may help to decrease insulin resistance and also may decrease adverse long-term cardiovascular effects.

Activity

Discourage smoking because of increased risk of cardiovascular disease.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Drug Category: Low-dose combination oral contraceptive pills (OCPs)

OCPs are the mainstay of treatment for women with PCOS who are not actively trying to conceive. OCPs suppress LH production, which suppresses ovarian production of androgens and decreases the level of free testosterone by increasing the level of SHBG circulating in the blood. OCPs also decrease adrenal androgen production and 5-alpha-reductase activity. OCPs improve acne and hirsutism. Restoration of regular menstrual cycles prevents endometrial hyperplasia associated with anovulation. Improvements of hyperandrogenic effects are seen in 60-100% of women but usually require a minimum of 6-12 months of use. A pregnancy test should be performed before initiating therapy. If the woman has had no menstrual period for 3 months, withdrawal bleeding should be induced by administration of 5-10 mg of medroxyprogesterone acetate (Provera) daily for 10 days; then, therapy is begun with OCPs.

Drug Category: Antiandrogens

These agents block active androgen production. Cyproterone acetate is a progestin with antiandrogen activity used to treat hirsutism but has not been approved for use in the United States. In Europe, it is offered as the progestin component of an OCP.

Drug Category: Progesterones

These agents are used to treat secondary amenorrhea.

Drug Category: Antidiabetic agents

These agents are used to treat insulin resistance and overt diabetes mellitus.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• The only indication for inpatient care is menorrhagia with severe anemia.

Further Outpatient Care

• Monitor OCP use.
• Monitor for adverse effects of medications.
• Monitor for insulin resistance and development of diabetes.
• Monitor lipid profile.
• Encourage exercise and a healthy diet.

Complications

• Type 2 diabetes mellitus
• Cardiovascular disease
• Endometrial carcinoma
• Infertility

Prognosis

• Prognosis is good.

Patient Education

• Encourage a sensible exercise program, a healthy diet, and maintenance of ideal body weight.
• Discourage cigarette smoking.
• When prescribing OCPs for sexually active women, stress condom use for protection against sexually transmitted diseases.
• Make patients aware of the possible long-term complications of PCOS and encourage the necessity of medical follow-up care.
• Internet sites for patients include the following:
• • Polycystic Ovarian Syndrome Association
  • The Cysterhood - Putting Faces to PCOS
• For excellent patient education resources, visit eMedicine's Women's Health Center. Also, see eMedicine's patient education articles Ovarian Cysts, Amenorrhea, and Female Sexual Problems.
• Also, see patient education articles and find a local endocrinologist via The Hormone Foundation.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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Article Last Updated: Jul 10, 2008