Polycystic Ovary Syndrome: When to Suspect

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive-age women; the prevalence is about 5% to 10%.¹ Women with PCOS often present with irregular menses, infertility, hirsutism, and acne. Of great concern are the long-term sequelae associated with PCOS, including dyslipidemia, hypertension, glucose intolerance, and type 2 diabetes mellitus, which may put patients at increased risk for coronary artery disease. Women with PCOS are also at risk for endometrial carcinoma as a result of prolonged exposure to unopposed estrogen caused by oligoovulation.

Here we review the current diagnostic criteria for PCOS. In Polycystic Ovary Syndrome: How Best to Manage, we discuss management strategies that can reduce associated health risks.

PATHOPHYSIOLOGY

Although the basic pathophysiology of PCOS is unknown, several cardinal endocrine derangements have been identified:

•Insulin resistance and resultant hyperinsulinism.

•Dysfunctional secretion of gonadotropin-releasing hormone (GnRH).

•Increased production of androgens primarily by the ovary.

Insulin resistance and resultant hyperinsulinism are central to the pathophysiology of PCOS. Insulin acts on ovarian theca cells to promote androgen secretion both independently and synergistically with luteinizing hormone (LH). Hyperinsulinism also increases levels of bioavailable androgen by reducing the amount of sex hormone-binding globulin (SHBG) produced by the liver.²

Increased output of GnRH from the hypothalamus is thought to be responsible for the hypersecretion of LH that acts on theca cells to augment ovarian androgen production.¹ The reason for the more frequent secretion of GnRH in patients with PCOS remains unknown; it is possible that there is an intrinsic defect in the GnRH pulse generator or a lack of feedback inhibition of GnRH caused by chronically low progesterone levels.^3,4

Obesity is not a cause of the syndrome; however, it exacerbates many of the symptoms. Like hyperinsulinemia, obesity reduces SHBG production by the liver, which causes increased levels of active testosterone in the circulation. In addition, obesity worsens insulin resistance and hyperinsulinism, thereby increasing ovarian androgen production.^5,6

Obesity alone, however, does not entirely explain the degree of insulin resistance seen in women with PCOS. Obese women with PCOS have greater insulin resistance than obese women without PCOS.⁶ Similarly, lean women with PCOS are more insulin-resistant than lean women without PCOS.

CLINICAL FEATURES

In general, women with PCOS seek medical attention for the following symptoms:

•Menstrual bleeding disturbances caused by oligoovulation or anovulation. These disturbances include oligomenorrhea, amenorrhea, and dysfunctional uterine bleeding.

•Hirsutism or acne.

•Infertility.

The most common physical presentation of androgen excess in PCOS is hirsutism, followed by acne and seborrhea. Hirsutism-excessive hair in a male-pattern distribution, including the face, chest, inner thighs, and lower abdomen-predominantly involves coarse, darkly pigmented terminal hairs (Figure 1).^5,7 In contrast, hypertrichosis is a generalized increase in fine, lightly pigmented vellus hair.² Hirsutism may be formally assessed with the Ferriman-Gallwey classification system. Different anatomic sites are graded from minimal hirsutism to frank virilization; a total score of 8 or greater is abnormal.^2,8

An important consideration in the evaluation of hirsutism is the variation of hair distribution in patients of different ethnicities. Asian women are generally less likely to demonstrate hirsutism when testosterone levels are elevated than Latino and Mediterranean women, who often appear to have more hair at normal testosterone levels.^5,7,9

Acanthosis nigricans is another important physical finding that may be seen in women with PCOS. This velvety hyperpigmented thickening of skin is most often localized to the intertriginous areas (such as the axilla and neck). This skin change is associated with insulin resistance in hyperandrogenemic women.^5,10

As many as 75% of patients with PCOS are obese; however, the presence of obesity is not required for diagnosis. The pattern of fat distribution in patients with PCOS is often android and is associated with visceral adiposity.^5,11

DIAGNOSTIC CRITERIA

The clinical heterogeneity of PCOS has complicated the development of a unified definition of the syndrome. In 2003, the definition of PCOS was addressed by a consensus conference of the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine. The guidelines generated by this meeting require that 2 of the following 3 criteria be met to diagnose PCOS¹²:

•Oligoovulation or anovulation.

•Hyperandrogenism, clinical or biochemical.

•Polycystic-appearing ovaries on an ultrasonogram.

In addition, alternative causes of these symptoms have to be excluded before the diagnosis is confirmed.

In the United States, the diagnosis of PCOS has traditionally been based on the presence of oligoovulation and clinical or biochemical hyperandrogenism in the absence of other causes.^5,11 This is thought to be a sound approach that focuses on the clinical hallmarks of the condition. For instance, women with PCOS generally have a long history of irregular and, at times, heavy menses. For most patients, this pattern originates at menarche and translates to fewer than 9 spontaneous menses per year. Some women have no menses for several months.^2,5,13

PCOS in adolescents presents a unique diagnostic challenge. Because oligomenorrhea is common and self-limited in many healthy adolescents, teenagers suspected of having PCOS need to be evaluated carefully over time to prevent overdiagnosis (Box I).

Despite the recommendations of the recent international consensus conference to include ovarian ultrasonographic characteristics in the diagnosis of PCOS, this guideline remains controversial.On an ultrasonogram,polycystic ovaries appear to contain multiple subcapsular follicles, a finding often referred to as the "string of pearls" sign (Figure 2). Formally, at least 1 of the following ultrasonographic characteristics must be present to categorize ovaries as polycystic in appearance:
 

•Twelve or more follicles that measure 2 to 9 mm in diameter.

•An increased ovarian volume of greater than 10 µL.

•A single ovary meeting either of the above criteria is sufficient for diagnosis.¹⁴

The poor specificity of ultrasonography is the main limitation to its use in the diagnosis of PCOS. Polycystic ovaries are found in up to 75% of women with oligoovulation, including many who do not have PCOS. Furthermore, up to 25% of healthy women with no diagnosed uterine problems have polycystic-appearing ovaries on an ultrasonogram.⁵ Based on these limitations, we recommend focusing the diagnosis on signs of oligoovulation and hyperandrogenism. If ultrasonography is used, alternative diagnoses must be rigorously sought and excluded.

DIFFERENTIAL DIAGNOSIS

The most important conditions in the differential diagnosis of PCOS include those that also cause oligomenorrhea and hyperandrogenism. While rare, adult-onset congenital adrenal hyperplasia (CAH) has many features in common with PCOS and should be excluded, especially in certain ethnic groups (Slavic, Latina, and Ashkenazi Jewish women).^2,7,15

Cushing syndrome is even less common than CAH; however, women with this condition can present with oligomenorrhea, hirsutism, acne, and obesity. In contrast to PCOS, Cushing syndrome is associated with the presence of moon facies, a buffalo hump, abdominal striae, and muscle wasting. Given the rarity of this condition, we suggest screening only those who present with these associated symptoms.^11,16

In women with signs of virilization-male pattern baldness, clitoromegaly, voice deepening-instead of hirsutism, rule out a testosterone-producing tumor of the ovary or adrenal gland. In women who present with secondary amenorrhea after a long history of regular cycles, especially in the absence of hyperandrogenism, rule out endocrine abnormalities, such as thyroid disease, hyperprolactinemia, and dysfunction of the hypothalamic-pituitary-gonadal axis.^2,5

LABORATORY EVALUATION

Many practitioners view PCOS primarily as a clinical diagnosis and order laboratory tests to confirm PCOS in women without overt hyperandrogenism or to rule out other conditions.^5,10,11 Thus, although a source of debate, laboratory evaluation does have a role in the diagnosis of PCOS. The tests listed in Box II are used to rule out alternative diagnoses with features similar to those of PCOS.

Expert agreement on a cutoff testosterone level that defines biochemical hyperandrogenism has been a challenge. It has been argued that testosterone thresholds traditionally considered abnormal were improperly derived and that true biochemical hyperandrogenism exists at lower testosterone levels than reported by many laboratories. Nevertheless, a value of 60 ng/dL or greater is considered abnormal, since this value is 2 standard deviations above the mean testosterone level in women with normal menstrual cycles.⁵ In addition, a testosterone level of 200 ng/dL or greater (particularly in the setting of virilization) is an unequivocal indication to search for a testosterone-producing neoplasm.^2,5

The utility of free testosterone measurements (as opposed to the total testosterone levels described above) has been debated among practitioners and experts. A free testosterone measurement determines the fraction of the hormone that is active and not bound to protein in the circulation. Theoretically, the free testosterone level should be a highly accurate marker of PCOS and superior to the total testosterone level. However, in practice, the test has been unreliable and expensive.⁵ We believe that a free testosterone measurement is rarely needed; if assessed, it should be measured in conjunction with, rather than instead of, total testosterone. Free testosterone measurements are probably best suited for the evaluation of women with anovulation who lack clinical hyperandrogenism.

References:

REFERENCES:1.Michelmore KF, Balen AH, Dunger DB, Vessey MP. Polycystic ovaries and associated clinical and biochemical features in young women. Clin Endocrinol. 1999;51:779-786.
2.Speroff L, Glass RH, Kase NG, eds. Clinical Gynecologic Endocrinology and Infertility. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 1999.
3.Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352:1223-1236.
4.Waldstreicher J, Santoro NF, Hall JE, et al. Hyperfunction of the hypothalamic-pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab. 1988;66:165-172.
5.Guzick DS. Polycystic ovary syndrome [Published correction in Obstet Gynecol. 2004;103:799]. Obstet Gynecol. 2004;103:181-193.
6.Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165-1174.
7.Azziz R. The evaluation and management of hirsutism. Obstet Gynecol. 2003;101:995-1007.
8. Moncada E. Familial study of hirsutism. J Clin Endocrinol Metab. 1970;31:556-564.
9.Carmina E, Koyama T, Chang L, et al. Does eth-nicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol. 1992;167: 1807-1812.
10.Driscoll DA. Polycystic ovary syndrome in adolescence. Ann N Y Acad Sci. 2003;997:49-55.
11.Chang RJ. A practical approach to the diagnosis of polycystic ovary syndrome. Am J Obstet Gynecol. 2004;191:713-717.
12.Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19-25.
13.Franks S. Polycystic ovary syndrome [Published correction in N Engl J Med. 1995;333:1435]. N Engl J Med. 1995;333:853-861.
14.Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment of the polycystic ovary: international consensus definitions. Hum Reprod Update. 2003;9:505-514.
15.Azziz R, Dewailly D, Owerbach D. Clinical review 56: Nonclassic adrenal hyperplasia: current concepts. J Clin Endocrinol Metab. 1994;78:810-815.
16. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical Manage-ment Guidelines for Obstetrician-Gynecologists: number 41, December 2002. Obstet Gynecol. 2002; 100:1389-1402.
17.Salmi DJ, Zisser HC, Jovanovic L. Screening forand treatment of polycystic ovary syndrome in teenagers. Exp Biol Med (Maywood). 2004;229:369-377.

Evidence-Based Medicine

• Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome.

Diabetes.

1989;38:1165-1174.
• Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome.

Cochrane Database Syst Rev.

2003;(3):CD003053.

Guidelines

• American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists: number 41, December 2002. Obstet Gynecol. 2002;100:1389-1402.

• Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19-25.