Key Points
Disease summary:
Polycystic ovary syndrome (PCOS) is a highly prevalent and complex genetic disorder affecting reproductive aged women. Its characteristics include clinical and/or biochemical androgen excess, ovulatory dysfunction, and polycystic ovaries (PCOs). Women with PCOS are at increased risk for infertility, obesity, insulin resistance, glucose intolerance, type 2 diabetes mellitus (T2DM), dyslipidemia, and cardiovascular disease.
Hereditary basis:
There is an increased prevalence of PCOS among family members. Approximately 20% to 40% of first-degree female relatives of women with PCOS are affected by the condition, compared to a prevalence of 6% to 10% in the general population. A twin-family study showed 71% concordance in monozygotic twins, compared to 38% concordance in dizygotic twins and other sisters. The phenotypic components of PCOS, including hirsutism, hyperandrogenemia, oligomenorrhea, acne, and insulin resistance, are also increased in families of women with PCOS.
Differential diagnosis:
It is important to exclude thyroid dysfunction, hyperprolactinemia, nonclassical congenital adrenal hyperplasia, androgen-secreting neoplasms (ovarian and adrenal), Cushing syndrome, use of exogenous androgens, acromegaly, primary hypothalamic amenorrhea, primary ovarian failure, hyperandrogenism/insulin resistance/acanthosis nigricans (HAIRAN) syndrome (often with lipodystrophy), and syndromes characterized by insulin receptor gene mutations.
Diagnostic Criteria and Clinical Characteristics
There are currently three different definitions of PCOS.
In 1990, the National Institutes of Health (NIH)—National Institute of Child Health and Human Development Consensus Conference of PCOS recommended that the major criteria include (in order of importance) hyperandrogenism and/or hyperandrogenemia, oligo-anovulation, and the exclusion of other possible etiologies of these signs and symptoms (see Differential Diagnosis, earlier and Table 104-1).
In 2003, the Rotterdam consensus expanded the diagnostic criteria, recommending that PCOS be defined by the presence of two out of the following three features (after exclusion of other endocrinopathies): clinical and/or biochemical hyperandrogenism, oligo-anovulation, and PCO on ultrasound. This definition therefore includes all patients meeting the 1990 National Institute of Health (NIH) criteria, but in addition includes (1) ovulatory women with clinical and/or biochemical hyperandrogenism and PCO, and (2) women with PCO and ovulatory dysfunction but without androgen excess.
In 2006, the Androgen Excess-PCOS Society again emphasized hyperandrogenism, recommending that PCOS be defined principally by clinical and/or biochemical hyperandrogenism, with either oligo-anovulation or PCO, or both, after exclusion of other possible etiologies.
| Syndrome | Gene Symbol | Associated Findings |
|---|---|---|
Nonclassical congenital adrenal hyperplasia | CYP21A2 | Androgen excess, ovulatory dysfunction, PCO, elevated 17-hydroxyprogesterone level |
Type A insulin resistance | INSR | Onset in adolescence, severe hyperinsulinemia and insulin resistance, androgen excess, acanthosis nigricans, PCO, ovulatory dysfunction, normal/near-normal body mass index (BMI) |
Rabson-Mendenhall syndrome | INSR | Onset congenital, growth retardation, severe hyperinsulinemia and insulin resistance, severe androgen excess, acanthosis nigricans, PCO, ovulatory dysfunction, abnormal dentition |
Leprechaunism | INSR | Onset congenital, typically fatal in infancy, severe hyperinsulinemia and insulin resistance, severe androgen excess, acanthosis nigricans, PCO |
True cortisone reductase deficiency | HSD11B1 | Onset in adolescence or early adulthood, androgen excess, ovulatory dysfunction, bilateral adrenal enlargement, very low ratio of urinary tetrahydrocortisol to tetrahydrocortisone (typically <0.1) |
Apparent cortisone reductase deficiency | H6PD | Onset in adolescence or early adulthood, androgen excess, ovulatory dysfunction, bilateral adrenal enlargement, very low ratio of urinary tetrahydrocortisol to tetrahydrocortisone (typically <0.1) |
Glucocorticoid resistance | GR | Broad spectrum of clinical disease, from asymptomatic to severe androgen excess; ambiguous genitalia at birth, precocious adrenarche, ovulatory dysfunction, hypertension, hypokalemic alkalosis, chronic fatigue, increased urinary free cortisol |
Menstrual disorders: Women with PCOS often present with menstrual abnormalities, which can include amenorrhea, oligomenorrhea, and menorrhagia. These menstrual abnormalities reflect absent or irregular ovulation.
Androgen excess: Signs and symptoms of androgen excess are common in women with PCOS. These include hirsutism (present in 60%) (development of coarse facial and body hair in a male-type pattern), acne (present in 15%-25%), androgenic alopecia (present in up to 5%), oily skin, and excessive sweating. Circulating androgen levels (total and free testosterone, and dehydroepiandrosterone sulfate [DHEAS]) are elevated in 50%-75% of these women.
Obesity: Obesity is common in PCOS, particularly centripetal obesity. However, obesity per se is not intrinsic to PCOS, as up to 40% to 50% of women with PCOS are not obese.
Metabolic sequelae: Women with PCOS are at increased risk for insulin resistance and its associated conditions, including metabolic syndrome, nonalcoholic fatty liver disease, acanthosis nigricans, and obesity-related disorders such as sleep apnea. Insulin resistance occurs in 50% to 70% of PCOS women, and the degree of insulin resistance is typically beyond that predicted by BMI. Insulin resistance often leads to compensatory hyperinsulinemia and impaired glucose tolerance. These conditions increase the risk of long-term metabolic consequences, including T2DM and cardiovascular disease. Of note, hyperinsulinemia plays a key role in many of the phenotypic features of PCOS.
Hypertension: Women with PCOS have an increased risk of both hypertension and prehypertension. Hyperandrogenemia and/or the insulin resistance syndrome may contribute to elevated systolic and diastolic blood pressure.
Dyslipidemia: Abnormalities in the lipid profile occur in approximately 70% of women with PCOS in the United States. The most common abnormalities are hypertriglyceridemia, decreased high-density lipoprotein (HDL), and increased low-density lipoprotein (LDL) cholesterol levels. These changes, combined with the other metabolic abnormalities, promote an inflammatory atherothrombotic state, with impaired endothelial function and vasoreactivity, and increased atherosclerosis. Women with PCOS thus have an increased risk of cardiovascular events and cerebrovascular accidents when compared to women without PCOS.
Polycystic ovaries: Ovarian hyperandrogenism, hyperinsulinemia, and altered intraovarian paracrine signaling are thought to disrupt proper follicular development in polycystic ovaries. This leads to arrested follicular growth and the accumulation of small follicles within the periphery of the ovaries, which appear polycystic in morphology. In women with PCOS, there is an alteration in the normal progression from the recruitment of a group of smaller follicles to the selection of a follicle that becomes dominant and undergoes ovulation.
Gonadotropin abnormalities: About 70% of women with PCOS have hypersecretion of luteinizing hormone (LH). Elevated LH pulse amplitude and frequency leads to LH levels that are abnormally high in comparison to follicle stimulating hormone (FSH) levels (LH:FSH ratio of two to three). This occurs due to reduced steroid hormone negative feedback from the ovaries because of ovarian androgen excess. Obesity reduces the LH:FSH ratio.
Infertility: Subfertility in PCOS is primarily caused by oligo-anovulation. In addition, some women with PCOS have impaired oocyte development and increased risk of miscarriage, thought to be secondary to higher degrees of hyperandrogenism and hyperinsulinemia. With the use of ovulation induction agents, women with PCOS have increased risks of ovarian hyperstimulation syndrome and multifetal pregnancy.
Obstetric morbidity: PCOS in pregnancy increases the risk of pre-eclampsia, pregnancy-induced hypertension, gestational T2DM, and possibly preterm delivery. These complications lead to a greater risk of perinatal mortality and a higher rate of admission to the neonatal intensive care unit.
Malignancy: Women with PCOS are at increased risk for endometrial cancer, given the high prevalence of risk factors including chronic oligo-anovulation (resulting in unopposed estrogen), obesity, and T2DM. These women may also be at increased risk for ovarian and breast cancer, however, these risks are not well documented.
