Polycystic ovary syndrome (PCOS): clinical approach

Polycystic ovary syndrome, commonly known as PCOS, is the predominant endocrine disorder among women of reproductive age. It manifests through a trio of anovulation, clinical or biochemical signs of hyperandrogenism, and the presence of numerous small ovarian cysts. Many individuals with PCOS also experience various metabolic issues, including insulin resistance. Symptoms such as amenorrhea, abnormal uterine bleeding, and infertility typically arise from anovulation and hyperandrogenism, directing the focus of PCOS management towards the specific needs of each patient, whether it be infertility, hyperandrogenism, or insulin resistance.

When assessing a patient with potential symptoms of PCOS, the initial approach involves a detailed history and physical examination. It is crucial to inquire about menstrual irregularities, specifically the duration of their cycles without hormonal contraception. Commonly, these individuals will describe irregular menstrual cycles, either notably short (less than 21 days) or long (more than 35 days).

Patients often present with secondary amenorrhea, defined as the absence of menstrual periods for three or more months after the onset of menstruation. Such ovulatory dysfunction can lead to concerns about fertility, often the primary worry of the patient. Reports of increasing coarse, dark hair growth in areas sensitive to androgens, like the face, chest, back, and abdomen, are indicative of hirsutism associated with PCOS.

During the physical examination, signs of hyperandrogenism such as hirsutism, acne, and possibly androgenic alopecia might be observable. Signs of insulin resistance might include a body mass index (BMI) over 25, a waist circumference exceeding 35 inches, and acanthosis nigricans—brown, velvety plaques typically found in the neck, axillae, or groin. Hypertension may also be present, although a pelvic examination usually appears normal.

Given the commonality of irregular menstruation or amenorrhea in these patients, the first diagnostic step is to exclude pregnancy through an hCG test. If positive, the patient should be advised to start prenatal care. If negative, PCOS remains a probable diagnosis, and further tests should be conducted.

Laboratory tests should be performed between days 3 and 5 of the menstrual cycle to confirm biochemical hyperandrogenemia and rule out other causes of the symptoms. These tests should include levels of total testosterone, sex hormone-binding globulin (SHBG)—which helps estimate free testosterone levels—dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), thyroid-stimulating hormone (TSH), prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol. A day 20 or 21 progesterone level is also valuable for assessing ovulatory function. Additionally, a pelvic ultrasound should be ordered.

In PCOS, elevated free and total testosterone, and/or DHEAS levels are typical. However, markedly high levels could suggest the presence of ovarian or adrenal androgen-secreting tumors. Normal 17-OHP levels are expected in PCOS, but an increase might indicate nonclassical congenital adrenal hyperplasia, which mimics PCOS. Normal levels of TSH and prolactin are usual, but any elevation might indicate thyroid or prolactin imbalances, contributing to ovulatory dysfunction.

Luteinizing hormone (LH) levels may be slightly raised, particularly in relation to follicle-stimulating hormone (FSH). The presence of normal FSH and estradiol levels excludes ovarian failure as a cause of amenorrhea. Furthermore, a progesterone measurement less than 4 ng/mL on days 20 or 21 of the cycle indicates anovulation.

In addition, a pelvic ultrasound might reveal a polycystic ovarian morphology, characterized by either 20 or more follicles per ovary or an ovarian volume exceeding 10 mL on either side. The follicles should range from 2 to 9 mm in size, with an absence of corpus luteum, cysts, or dominant follicles.

A clinical tip: There are currently two criteria for diagnosing polycystic ovarian morphology via ultrasound in adults. One criterion identifies a lower threshold of 12 follicles located peripherally on the ovarian cortex, while another criterion requires at least 20 follicles, depending on the ultrasound machine’s resolution capabilities.

A thickened endometrium may also be observed, a result of prolonged exposure to unopposed estrogen, which is common in cases of anovulation.

An important point to note is that patients with PCOS who experience anovulation are at a heightened risk of developing endometrial cancer due to prolonged estrogen exposure without progesterone. However, endometrial thickness measurement is not a reliable method for detecting endometrial cancer in premenopausal women; endometrial sampling through biopsy is the preferred diagnostic method.

To diagnose PCOS, a patient must meet two of the three following Rotterdam criteria: ovulatory dysfunction, clinical or biochemical hyperandrogenism, and polycystic ovarian morphology on ultrasound. It is also essential to rule out other potential causes of the patient's symptoms.

If less than two of these criteria are met, alternative diagnoses should be considered based on the patient’s symptoms. For instance, genital infections could cause abnormal vaginal bleeding, or androgenic medications might exacerbate acne. Additionally, some facial hair patterns may be familial or genetic rather than indicative of a disorder. Diagnosis of PCOS is confirmed when two or three criteria are met, and other potential causes have been excluded.

The next steps involve determining the patient’s desire for pregnancy and screening for associated conditions such as dyslipidemia, insulin resistance, type 2 diabetes, and metabolic syndrome.

Testing for diabetes and impaired glucose tolerance should include a fasting glucose test followed by a 2-hour glucose test after a 75-gram glucose challenge. Cardiovascular risk can also be evaluated by measuring BMI, fasting lipid levels, and identifying factors related to metabolic syndrome.

If the patient wishes to conceive, dietary modifications and exercise recommendations should be discussed, and weight loss encouraged if necessary. A weight reduction of 5 to 10 percent in overweight individuals can significantly decrease circulating androgen levels, restore regular menstrual cycles, and enhance fertility rates.

For those with existing conditions like diabetes or hypertension, optimizing these conditions before conception is crucial to improve pregnancy outcomes. In cases of infertility due to anovulation, ovulation induction with letrozole (used off-label) or clomiphene citrate, possibly combined with metformin for obese patients, is recommended.

Here’s a clinical insight: PCOS increases the risk of gestational diabetes and hypertensive disorders during pregnancy, with the risk further heightened by multiple gestations often resulting from ovulation induction treatments.

For patients not seeking pregnancy, it’s crucial to focus on cardiovascular health through recommended diet and exercise programs, which may also aid in weight reduction if needed. Losing weight can enhance menstrual regularity, lessen hirsutism, and reduce cardiovascular risk factors such as dyslipidemia and impaired glucose tolerance.

Hormonal contraceptives are beneficial for regulating menstrual cycles and reducing the risk of endometrial cancer, thanks to the protective effects of progestins. Low-dose combination oral contraceptives are typically preferred as they suppress LH production, reduce ovarian androgen secretion, and elevate levels of sex hormone-binding globulin, thus decreasing bioavailable free testosterone. Progestin-containing intrauterine devices (IUDs) serve as another option for both contraception and endometrial protection.

Hirsutism, a prevalent and often distressing issue for those with PCOS, can be managed initially through mechanical hair removal methods such as shaving, waxing, electrolysis, and laser treatments. While medical treatments may provide some reduction in terminal hair growth, the results can be underwhelming. The use of combined oral contraceptives, particularly when combined with spironolactone—a potassium-sparing diuretic that acts as an androgen receptor antagonist—may improve outcomes. Topical eflornithine is another treatment option, effectively reducing facial hirsutism in about one-third of patients. A combination of oral contraceptives or topical eflornithine is recommended to help prevent hair regrowth.

For patients with dyslipidemia, insulin resistance, diabetes, or metabolic syndrome, management should include insulin-sensitizing agents such as metformin, a first-line treatment, or myo-inositol, an alternative for those who cannot tolerate metformin.

A critical point to remember is that while combined oral contraceptives are effective for preventing pregnancy and managing PCOS symptoms, they also carry a risk of thromboembolism, particularly if the patient is over 35, has additional risk factors like hypertension or smoking, or has a personal or family history of thromboembolism.

To summarize, PCOS is diagnosed when two of the three Rotterdam criteria—ovulatory dysfunction, clinical or biochemical hyperandrogenism, and polycystic ovarian morphology—are met, and other conditions have been excluded. Management strategies are tailored based on whether the patient desires pregnancy. Treatment options include lifestyle modifications, weight management, and various therapeutic approaches aimed at addressing specific symptoms and risk factors.

Ref:

"ACOG Practice Bulletin No. 194: Polycystic Ovary syndrome" Obstet Gynecol (2018)

"Recommendations from the international evidence-based guidelines for the assessment and management of polycystic ovary syndrome" Hum Reprod (2018)

"The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report" Fertil Steril (2009)

"Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS)" Hum Reprod (2003)

"Clinical practice: Polycystic ovary syndrome" N Engl J Med (2016)

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