Polycystic Ovary Syndrome (PCOS)

The etiology of PCOS is unclear. However, some evidence suggests that patients have a functional abnormality of cytochrome P450c17 affecting 17-hydroxylase (the rate-limiting enzyme in androgen production); as a result, androgen production increases. Pathogenesis appears to involve genes involved in the regulation of androgen biosynthesis as well as environmental factors, such as diet, nutrition, environmental toxins, and low socioeconomic status. Racial and ethnic differences are noted, particularly for metabolic issues and psychosocial issues (1).

Both metabolic hormones (insulin, growth hormones ghrelin, LEAP-2) and reproductive hormones (gonadotropin-releasing hormone [GnRH], luteinizing hormone/follicle-stimulating hormone [LH/FSH] ratio, androgens, and estrogens) are abnormal. These hormone abnormalities result in increased rates of metabolic disorders, such as diabetes and insulin resistance, having overweight and obesity, infertility, and menstrual cycle dysfunction (2, 3).

Polycystic ovaries typically contain many 2- to 6-mm follicular cysts and sometimes larger cysts containing atretic cells. Ovaries may be enlarged with smooth, thickened capsules or may be normal in size.

Polycystic ovary syndrome has several significant potential complications.

Infertility is related to ovulatory dysfunction.

Estrogen levels are elevated and are not consistently opposed by progesterone due to chronic or intermittent anovulation, increasing risk of endometrial hyperplasia and endometrial cancer.

Androgen levels are often elevated causing hirsutism. Hyperinsulinemia due to insulin resistance may be present and may contribute to increased ovarian production of androgens. Over the long term, androgen excess increases the risk of obesity, cardiovascular disorders, including hypertension, hyperlipidemia, and metabolic syndrome. Risk of androgen excess and its complications may be just as high in women who are not overweight as in those who are not.

Calcification of coronary arteries and thickening of the carotid intima media is more common among women with PCOS, suggesting possible subclinical atherosclerosis (1). This may be due to insulin resistance, obesity, or elevated androgen levels and correlates with visceral fat.

Type 2 diabetes mellitus and impaired glucose tolerance are more common, and risk of obstructive sleep apnea is increased.

Studies indicate that PCOS is associated with low-grade chronic inflammation and that women with PCOS are at increased risk of nonalcoholic fatty liver disease (2).

PCOS is associated with an increased risk of depression, anxiety, eating disorders, low self-esteem, and negative body image (3).

Symptoms of PCOS typically begin during puberty and worsen with time. Ovulatory dysfunction is usually present at puberty, sometimes resulting in primary amenorrhea. Premature adrenarche is common, caused by excess dehydroepiandrosterone sulfate (DHEAS) and often characterized by early growth of axillary hair, body odor, and microcomedonal acne.

Typical symptoms include irregular menses (oligomenorrhea or amenorrhea); fertility is impaired in many patients. Other common symptoms are mild obesity and mild hirsutism. However, in up to half of women with PCOS, weight is normal, and some women are underweight.

Body hair may grow in a male pattern (eg, on the upper lip, chin, back, thumbs, and toes; around the nipples; and along the linea alba of the lower abdomen). Some women develop acne. Virilization (clitoromegaly, deepening of the voice, increased muscle mass, male pattern baldness, breast atrophy) suggests more severe hyperandrogenism (adrenal hyperandrogenism, androgen-secreting tumor).

Areas of thickened, darkened skin (acanthosis nigricans) may appear in the axillae, on the nape of the neck, in skinfolds, and on knuckles and/or elbows; the cause is high insulin levels due to insulin resistance.

Acanthosis Nigricans in Polycystic Ovary Syndrome

Image

Images provided by Thomas Habif, MD.

Other symptoms vary across patients, and may include weight gain (sometimes seemingly out of proportion to diet and exercise), fatigue, low energy, sleep-related problems (including sleep apnea), mood swings, depression, anxiety, and headaches. Symptoms vary across patients.

• Clinical criteria

• Hormone blood tests for androgens and to exclude other endocrinologic disorders, such as measurement of serum testosterone, follicle-stimulating hormone (FSH), prolactin, and thyroid-stimulating hormone (TSH) levels

• Pelvic ultrasound

Diagnosis of PCOS is usually made based on the Rotterdam criteria, which requires at least 2 of the following 3 findings (1):

• Oligo-ovulation and/or anovulation

• Clinical and/or biochemical evidence of hyperandrogenism

• Polycystic ovaries (transvaginal ultrasound with 12 or more follicles in each ovary measuring 2 to 9 mm in diameter, and/or increased ovarian volume [>10 ml])

Blood tests include measurement of testosterone, which may be mildly elevated in PCOS; levels > 150 ng/dL suggest an ovarian or adrenal androgen-secreting tumor. Serum free testosterone is more sensitive than total testosterone but is technically more difficult to measure.

For patients with hirsutism or virilization, other etiologies of hyperandrogenism should be excluded by measuring other serum androgens including

• Early-morning serum 17-hydroxyprogesterone to exclude adrenal hyperandrogenism

• DHEAS; high levels (> 800 mcg/dL) suggest an adrenal androgen-secreting tumor

Testing includes pregnancy testing and measurement of FSH, prolactin, and TSH to exclude other possible causes of symptoms. Also, serum cortisol is measured to exclude Cushing syndrome, which may cause oligomenorrhea, hirsutism, and obesity.

Transvaginal ultrasound is done to detect polycystic ovaries and exclude other possible causes of symptoms. However, transvaginal ultrasound is not done in adolescent girls.

• Usually estrogen/progestin contraceptives or progestins

• Sometimes metformin or other Sometimes metformin or otherinsulin sensitizers

• Management of hirsutism and, in adult women, long-term risks of hormonal abnormalities

• Infertility treatments in women who desire pregnancy

Treatment of PCOS aims to:

• Manage hormonal and metabolic abnormalities and thus reduce risks of estrogen excess (eg, endometrial hyperplasia) and androgen excess (eg, diabetes, cardiovascular disorders)

• Relieve symptoms (irregular menses, acne, excess facial and body hair)

• Treat infertility

Hormonal medications are used to cause regular shedding of the endometrium and/or to provide progestins to oppose the proliferative effect of estrogens on the endometrium. This reduces the risk of endometrial hyperplasia and cancer. Estrogen-progestin contraceptives are often first-line, and result in regular menses, reduce acne and hirsutism, and provide contraception. These treatments also reduce circulating androgens, which may decrease acne and hirsutism. Other options include cyclic oral progestins (eg, medroxyprogesterone 5 to 10 mg orally once a day for 10 to 14 days every 1 to 2 months) or a levonorgestrel intrauterine device is also an option. Antiandrogenic progestins include drosperinone and dienogest. Estrogen-progestin contraceptives are often first-line, and result in regular menses, reduce acne and hirsutism, and provide contraception. These treatments also reduce circulating androgens, which may decrease acne and hirsutism. Other options include cyclic oral progestins (eg, medroxyprogesterone 5 to 10 mg orally once a day for 10 to 14 days every 1 to 2 months) or a levonorgestrel intrauterine device is also an option. Antiandrogenic progestins include drosperinone and dienogest.

Lifestyle changes and pharmacologic approaches are used to manage insulin insensitivity. If obesity is present, weight loss and regular exercise are encouraged. These measures may help induce ovulation (which makes menstrual cycles more regular and many improve fertility), increase insulin sensitivity, and reduce acanthosis nigricans and hirsutism. Weight loss may also help improve fertility. Bariatric surgery may be an option for some women with PCOS (1). However, weight loss is unlikely to benefit women with PCOS who do not have obesity.

Metformin 500 to 1000 mg twice a day may be used to help increase Metformin 500 to 1000 mg twice a day may be used to help increaseinsulin sensitivity in women with PCOS, if lifestyle modifications are ineffective or if they cannot take or cannot tolerate hormonal medications. Metformin can also reduce free sensitivity in women with PCOS, if lifestyle modifications are ineffective or if they cannot take or cannot tolerate hormonal medications. Metformin can also reduce freetestosterone levels. When metformin is used, serum glucose should be measured, and kidney and liver function tests should be done periodically. Metformin helps correct metabolic and glycemic abnormalities and makes menstrual cycles more regular, but it has little or no beneficial effect on hirsutism, acne, or infertility. Because metformin may induce ovulation, contraception is needed if pregnancy is not desired. levels. When metformin is used, serum glucose should be measured, and kidney and liver function tests should be done periodically. Metformin helps correct metabolic and glycemic abnormalities and makes menstrual cycles more regular, but it has little or no beneficial effect on hirsutism, acne, or infertility. Because metformin may induce ovulation, contraception is needed if pregnancy is not desired.

Insulin sensitizers (eg, glucagon-like peptide-1 receptor agonists or thiazolidinediones) combined with metformin are being studied (-like peptide-1 receptor agonists or thiazolidinediones) combined with metformin are being studied (2). A study of PCOS patients with obesity (n = 27) treated with semaglutide for 6 months found that almost 80% had at least a 5% decrease in body weight, which was often associated with normalization of menstrual cycles (). A study of PCOS patients with obesity (n = 27) treated with semaglutide for 6 months found that almost 80% had at least a 5% decrease in body weight, which was often associated with normalization of menstrual cycles (3). Other studies are evaluating the role of microbiota treatments for PCOS (4).

The following is a list of professional medical society or government clinical practice guidelines regarding this medical issue (this is not a comprehensive list):

• American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin. Polycystic Ovary Syndrome. 2018 (reaffirmed 2022).

• Endocrine Society Clinical Practice Guideline. Evaluation and Treatment of Hirsutism in Premenopausal Women. 2018.

The following English-language resources may be useful. Please note that The Manual is not responsible for the content of these resources.

1. Legro RS, Arslanian SA, Ehrmann DA. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline [published correction appears in J Clin Endocrinol Metab. 2021 May 13;106(6):e2462. doi: 10.1210/clinem/dgab248.]. J Clin Endocrinol Metab. 2013;98(12):4565-4592. doi:10.1210/jc.2013-2350