Clinical Review

Polycystic ovary syndrome: Where we stand with diagnosis and treatment and where we’re going

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PCOS is one of the most common reproductive endocrine disorders of women—and one of the most impenetrable to understand and difficult to manage. Two experts tackle a long list of questions that your clinician–colleagues have been posing.



Polycystic ovary syndrome, or PCOS, is a condition characterized by hyperandrogenism and chronic anovulation—the most common endocrinopathy in women of reproductive age, affecting at least 1 in every 15. Associated metabolic and health complications are significant and serious, and include obesity, insulin resistance, dyslipidemia, pancreatic ß-cell dysfunction, type-2 diabetes, cardiovascular disease, endometrial cancer, sleep apnea, inflammation, and infertility. To the frustration of the medical community and patients, the exact cause (or causes) of PCOS remains largely unknown; making the diagnosis means, essentially, excluding disorders that mimic PCOS—including congenital adrenal hyperplasia, hyperprolactinemia, and thyroid disease. PCOS is an enigma, in that it is a heterogeneous disorder, with the severity of clinical hyperandrogenism (hirsutism, acne, alopecia), obesity, and menstrual disturbance being considerably variable.

Furthermore, as many as 40% of women who have PCOS do not express classic signs of hyperandrogenism, making the diagnosis exceedingly challenging, particularly in the case of a patient of the lean (i.e., physical appearance) phenotype.

The picture is further confused. The appearance of polycystic-appearing ovaries (multiple tiny cysts) on ultrasonography (US) is noted in as many as 20% of women who have polycystic ovaries without evidence of androgen excess. The significance of this as an isolated finding on imaging in an otherwise normal woman is unclear. Some experts have described the presence of this finding as, again, signaling a cryptic or unexpressed form of PCOS or a prelude to the manifestation of signs of PCOS later.

The four parts of this article that will be posted here on the OBG Management Web site over coming months address questions that are often asked by clinicians about this challenging clinical entity. [Editor’s note: Those four installments will, as they are published, be collected on a single Web page for ease of access.]

Historical perspective

I’m confused. Going back to medical school, we were always taught that PCOS was an anatomic abnormality in which the ovary 1) produced excess androgens and 2) had a thickened covering, thus preventing ovulation. Today, PCOS has evolved into a seemingly complex entity. How did that transformation happen?

In its original description in the medical literature in the 1800s, PCOS was called cystic oophoritis.1,2 However, it wasn’t until the early 1930s that Stein and Leventhal first diagnosed what was initially coined Stein-Leventhal syndrome, reporting their findings in 1935.3 Later, the condition was referred to as polycystic ovarian disease.

In 1945, Stein published a follow-up report in which he added excessive male-pattern hair growth and obesity to the list of described symptoms. Although other associated symptoms have been noted in women who have the syndrome, the four principal ones established by Stein and Leventhal between 1935 and 1945 are irregular menstruation, infertility, obesity, and hirsutism.

Evolution as a disorder. PCOS was, initially, thought to be an anatomic disorder that specifically involved the ovaries and their thickened capsules. By the 1960s, with the advent of the radioimmunoassay, researchers could measure hormone levels in women who had the disorder. Studies confirmed that PCOS was associated with 1) increased androgen production from the ovaries and 2) abnormal gonadotropin secretion. Specifically, luteinizing hormone (LH) stimulated excess ovarian androgen production. From a historical perspective, then, the view of PCOS changed from anatomic disorder to, primarily, an endocrine disorder.

By the 1980s, clinical observations suggested a strong relationship between hyperinsulinemia and hyperandrogenism. The constellation of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) was then called HAIR-AN syndrome. Dunaif described how insulin, acting through ovarian insulin growth-factor receptors as mediators in ovarian dysfunction, led to hyperandrogenism.4 Two mechanisms appeared to account for HAIR-AN syndrome:

  • hyperinsulinemia induced by insulin resistance causes hyperandrogenism
  • hyperandrogenism causes insulin resistance and hyperinsulinemia (acanthosis nigricans is considered to be an epiphenomenon caused by hyperinsulinemia).

In the late 1980s, Reaven theorized that central obesity (male-type, or apple-shaped, obesity), diabetes, and hypertension have a common cause in insulin resistance (IR) and impaired glucose tolerance (IGT).5 This constellation of symptoms, at first called syndrome X, is known today as metabolic syndrome and is an object of extensive scientific inquiry—especially because the combination of findings strongly predisposes an affected person to cardiovascular disease.

By 2000, PCOS was viewed more as a metabolic disorder, with an array of cardiac and metabolic risk factors (insulin resistance and glucose intolerance; hypertension; dyslipidemia; and dysfibrinolysis) that have been linked to a number of health disorders, including type-2 diabetes and atherosclerotic cardiovascular and cerebrovascular disease. Today, diagnostic criteria for metabolic syndrome are at least three of these five findings:

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