Polycystic ovary syndrome is a common disorder that by definition affects 6-25% of women of reproductive age. Over the past 30 years, through continuous research, the understanding of the syndrome has grown from its initial relative unknown to a common medical condition. The disease affects multiple systems and requires effective treatment from a comprehensive health care perspective. The metabolic disorders and associated complications include insulin resistance, diabetes, hyperlipidemia, hypertension, fatty liver, metabolic syndrome and sleep apnea. Fertility complications include menstrual sparing/amenorrhea, low fertility, endometrial hyperplasia, and cancer.
Diagnosis
Several criteria exist for the diagnosis of polycystic ovary syndrome, and although the various diagnostic criteria vary, all rely on a combination of three main conditions to make the diagnosis: ovulatory dysfunction, hyperandrogenism (clinical or biochemical), and morphology of the ovaries. The National Institutes of Health (NIH) and the Androgen Excess Society emphasize the importance of androgen excess in the diagnosis, noting that it can help identify phenotypes at greater risk for metabolic complications.
In contrast, the Rotterdam definition includes a phenotype that does not exhibit androgen excess: i.e., anovulation and a polycystic ovary pattern, but without hirsutism. Because the name polycystic ovary syndrome focuses on a phenotype with relatively mild symptoms and is inconsistent with the fraction of the syndrome accounted for, a recent NIH workshop called for a name change for polycystic ovary syndrome.
Several nuances need to be considered in the diagnosis.
● The morphology of polycystic ovaries, as defined by the Rotterdam criteria, requires the presence of 12 or more follicles 2-9 mm in diameter per ovary on transvaginal ultrasound and/or increased ovarian volume (> 10 mL) in the absence of >10 mm dominant follicles present
Testosterone measurements are often inaccurate in normal women and in patients with polycystic ovary syndrome, and the definition of “hyperandrogenemia” is often vague.
Ovulatory dysfunction usually results in sporadic or amenorrheic menstruation, but many women with irregular ovulation have “regular” menstruation. Therefore, a history of regular menstruation does not exclude polycystic ovary syndrome.
● New diagnostic tools may hold some promise. Anti-Mullerian hormone (produced by sinusoidal follicles, of which there are many in polycystic ovaries) combined with luteinizing hormone levels have high sensitivity and specificity for the diagnosis of polycystic ovary syndrome.
Pathogenesis
The pathogenesis of polycystic ovary syndrome is unknown, and recent reviews have explored its potential etiology. Genetic and lifestyle factors combine to contribute to the development of the polycystic ovary syndrome phenotype. Some studies have evaluated potential etiologies, including abnormal gonadotropin secretion, insulin resistance, and ovarian factors.
Evaluation
Women with typical signs and symptoms of polycystic ovary syndrome almost always have polycystic ovary syndrome. Other causes of chronic anovulation and hyperandrogenemia are relatively uncommon, and the diagnosis of polycystic ovary syndrome can be made by careful history taking combined with targeted laboratory tests.
A major feature of polycystic ovary syndrome is the course of the symptoms. Symptoms are usually chronic, beginning in adolescence and progressing gradually over time. Certain events can cause an atypical pattern of symptom development. For example, weight gain can exacerbate anovulation and hirsutism, and weight loss in overweight and obese patients with polycystic ovary syndrome can increase the frequency of ovulation. Long-term use of hormonal contraceptives can prevent hyperandrogenism, and symptoms may develop after discontinuation of oral contraceptive pills (OCPs).
Other causes of sparse ovulation/anovulation and hyperandrogenemia need to be considered, even in the typical course of the disease. Hyperprolactinemia and thyroid abnormalities need to be excluded, as both can cause ovulatory disturbances (although hirsutism is rare in these conditions). Two important but less common causes of sporadic ovulation/anovulation and hirsutism include nonclassical congenital adrenocortical hyperplasia and Cushing’s syndrome.
Non-classical adrenocortical hyperplasia accounts for less than 5% of women with hyperandrogenism and can be ruled out by morning 17-hydroxyprogesterone <200 ng/dl. Cushing's syndrome may be present in >5.8% of women with symptoms of polycystic ovary syndrome. The diagnosis of these disorders is difficult to make, in part because the disease is paroxysmal or mild. Multiple tests and repeated measurements are often needed to make the diagnosis.
Hypothalamic amenorrhea is another condition to consider when evaluating symptoms of polycystic ovary syndrome. Both can present with amenorrhea and some degree of hirsutism. In hypothalamic amenorrhea, the secretion of gonadotropin-releasing hormone suppresses the central nervous system resulting in low levels of follicle stimulating hormone, luteinizing hormone and estrogen. This is in contrast to polycystic ovary syndrome, in which none of these hormones are suppressed.
Laboratory tests can show the difference between the two. However, OCP is often used in both conditions and it is challenging to differentiate the diagnosis of these two disorders in the context of hormone use. In both cases, OCP use can result in low gonadotropin and estrogen levels. Clues suggesting hypothalamic amenorrhea include a history of excessive exercise, life stress, or eating disorders.
Management
Polycystic ovary syndrome is a heterogeneous syndrome and one of the key challenges is to support patients in self-management to achieve a reduction in its incidence. In previous book chapters, we introduced the “My Polycystic Ovary Syndrome” approach to organize the multisystemic management of women with polycystic ovary syndrome. The elements are shown in Table 3, and each element is described below.
Metabolism (M in Metabolic-MY PCOS)
An important reason to diagnose polycystic ovary syndrome is to take early preventive and therapeutic measures for women affected by the disease. A variety of metabolic problems have been identified, including early diabetes, obesity, hypertension, dyslipidemia, and fatty liver.
The results of several studies that summarize the risk of developing these complications. Metabolic screening includes.
● Oral glucose tolerance test. This test is particularly important for women with other risk factors for diabetes or a body mass index >30. However, several studies have shown that a large proportion of women with polycystic ovary syndrome with prediabetes or diabetes and no other risk factors suggest that all women with polycystic ovary syndrome should undergo an oral glucose tolerance test.
Glycosylated hemoglobin can be used to screen for diabetes, but it is not sensitive to prediabetes.
● Lipid profile
● Transaminases. Patients may be screened for transaminases if they have other risk factors, such as metabolic syndrome associated with fatty liver.
Lifestyle modifications such as weight loss (if overweight), a healthy diet and regular exercise are the first-line treatment options for polycystic ovary syndrome. Even without weight loss, moderate intensity exercise can improve the metabolic status of polycystic ovary syndrome. Bariatric surgery may also be an effective method of weight loss, but should be used in patients who are unable to obtain their weight loss goals through lifestyle modification therapy.
Treatment with metformin may be considered for those patients with prediabetes or diabetes, especially in those who are unable to achieve their treatment goals with lifestyle interventions. In such cases, if tolerated and not contraindicated, metformin may be used as first-line drug therapy. The use of metformin to treat insulin resistance alone (without prediabetes or diabetes) is theoretically useful, but studies evaluating clinical efficacy do not support this view.
Studies have shown that thiazolidinediones can slow the progression of prediabetes to diabetes, but cost, safety issues, and possible adverse effects on the fetus limit their use. Statins may be considered for the treatment of dyslipidemia in patients meeting the indications (refer to the Adult Treatment Panel-III or the American College of Cardiology/American Heart Association guidelines). Recent studies have shown that statins can inhibit follicular membrane cell growth and decrease ovarian androgen production.
However, further studies are needed to evaluate the role of statins in the treatment of polycystic ovary syndrome before they can be recommended for use in conditions other than dyslipidemia. Other relatively benign treatments such as fish oil or psyllium fiber may be useful in some patients. Interestingly, a small study using 4 g/day of omega-3 fatty acids in women with polycystic ovary syndrome showed that it improved triglycerides, blood pressure and liver fat content.
Menstrual cycle adjustment (Cycle Control – Y in MY PCOS)
Women with polycystic ovary syndrome have many established risk factors for endometrial cancer and its precursor, endometrial hyperplasia, including irregular menstruation, progesterone deficiency, anti-estrogen exposure, obesity, insulin resistance, and diabetes. The risk of endometrial cancer appears to be increased to 3-fold in women with polycystic ovary syndrome (2.70, 95% confidence interval (CI): 1.0-7.29). Routine ultrasound screening to measure endometrial thickness is not recommended, but the menstrual cycle should be adjusted to include menstruation at least once every 3 months (unless amenorrhea is intentionally induced).
A variety of methods can be used to adjust the menstrual cycle. The first-line treatment option is hormonal contraceptives, the risks and benefits of which are discussed below (“Cosmetic issues” section). Because metformin can increase ovulation rates, it may be considered as a second-line treatment for cycle modification. However, it remains unknown whether the increase in ovulation rate is sufficient to prevent endometrial hyperplasia.
Psychological (P in Psychosocial-MY PCOS)
Although the studies assessing psychological problems are small, the prevalence of depression in women with polycystic ovary syndrome appears to be three times higher than in normal controls (35% vs. 11%, P < 0.001). Eating disorders are also seen more often in women with polycystic ovary syndrome, especially binge eating (12.6% in patients with polycystic ovaries versus 1.9% in controls, P < 0.01).
Therefore, it is important to screen women with polycystic ovary syndrome for depression and eating disorders. Depression can be effectively screened for by asking two simple questions about mood and lack of pleasure. In our experience, many women with polycystic ovary syndrome have the experience of not feeling that their diagnosis and associated symptoms are seen as a significant medical problem. Therefore providing non-judgmental support, valuing positive information about healthy behaviors and self-care, and confirming that polycystic ovary syndrome and its associated complications are important for diagnosis and treatment are all important aspects of the clinical process.
Cosmetic issues (the C in Cosmetic-MY PCOS)
The prevalence of hirsutism in women with polycystic ovary syndrome is over 75%. Acne and androgenetic alopecia (male pattern baldness) are other manifestations of hyperandrogenemia. Hormone therapy can significantly improve hirsutism and acne. Estrogen-containing OCPs inhibit gonadotropin secretion, thereby decreasing ovarian androgen production, and the estrogen component of OCPs increases sex hormone-binding globulin and decreases androgen bioavailability.
Small studies have been conducted to explore the effects of different formulations of OCPs in women with polycystic ovary syndrome. However, there is no consensus on the drug of choice. Formulations using low doses of ethinyl estradiol may minimize the effects of adverse estrogen reactions. The choice of progestin is more complex. Some of the newer progestins (including desogestrel, norethindrone, and drospirenone) have the advantage of low androgenic activity compared to the older progestin levonorgestrel. However, they also increase the risk of venous thromboembolism (although still very low).
The significance of this increased risk in polycystic ovary syndrome remains unclear, although it is estimated that 2000 women on OCPs containing these newer progestins would need to switch to OCPs containing levonorgestrel to prevent 1 case of venous thromboembolism in 1 year. This population may itself be at a higher risk of venous thromboembolism than women without the disease. Therefore, the choice of OCP must be individualized based on the patient’s symptoms, previous experience with OCP, and other metabolic risk factors.
Antiandrogenic drugs are often used beyond their indications for the treatment of hirsutism and acne. They are potentially teratogenic and may cause pseudohermaphroditism in male fetuses. Reliable contraception is essential. Spironolactone is the most commonly used anti-androgen drug in the United States. Doses of 50-200 mg per day block androgen receptors in hair follicles.
Finasteride (2.55 mg daily) inhibits 5-alpha reductase, the enzyme that converts testosterone to the more active dihydrotestosterone, with the same effect as spironolactone. Flutamide is an equally effective androgen receptor blocker, but its use is limited by severe hepatotoxicity. Although cyproterone acetate, an effective androgen receptor blocker, is not available in the United States, it is effective and generally well tolerated for the treatment of hirsutism and acne.
Other treatments for hirsutism include laser, electrolysis, manual removal (waxing, shaving, patching), bleaching, and hair removal creams. Lasers and electrolysis are two methods that result in permanent hair reduction, but often require regular maintenance treatments. The effectiveness of laser depends on the difference between skin tone and hair pigmentation, making it effective for light-skinned women with black terminal hair growth. However, it is not effective on fine (“downy”) hairs.
Patients with dark skin and tan skin require higher energy pulses, which increase the risk of burns and therefore require specialized lasers with cooling devices and adjustable energy levels for treatment. Electrolysis, which requires the insertion of an electrode to individual hair follicles to destroy them, can be an option for patients with localized areas requiring treatment. Eflornithine hydrochloride cream (Vaniqa®) improved facial hirsutism in 58% of women with unwanted hair growth and significantly improved facial hirsutism in 32% of this population, compared to 8% in the placebo group.
Hormone therapy with estrogen-containing oral contraceptives and/or anti-androgen drugs as described above can be effective in treating acne. In addition, topical agents, retinoids, antibacterial agents, benzoyl peroxide and salicylic acid used to treat acne are also effective. Topical minoxidil (2% or 5%) can be used to treat male pattern baldness.
Ovulation and Fertility (O in MY PCOS)
There are only few data on the rate of spontaneous ovulation in patients with polycystic ovary syndrome. However, in the placebo group of a relatively large randomized clinical trial of women with polycystic ovary syndrome, spontaneous ovulation occurred in 32% of menstrual cycles. In addition to reduced ovulation, changes in the endometrium associated with insulin resistance, reduced implantation and increased miscarriage rates may all contribute to poor fertility.
If fertility is required, methods to increase the frequency of ovulation should be discussed. If the patient is obese, weight loss is recommended. Although there are no long-term controlled trials of the effect of weight loss on pregnancy and live birth rates, several small studies of women with polycystic ovary syndrome have reported that weight loss improves menstrual cycles and ovulation. Therefore, considering the role of diet, exercise and weight loss in overweight and obese individuals, healthy lifestyle modification is recommended.
Clomiphene
Clomiphene (CC) is the first-line agent for ovulation in women with polycystic ovary syndrome. The anti-estrogenic effect blocks the negative feedback of endogenous estrogen to the hypothalamus and pituitary gland. This increases follicle stimulating hormone and eventually ovulation. Ovulation occurs in 60-85% of patients, with a pregnancy rate of 30-50% after six ovulatory cycles.
Metformin
Metformin improves ovulation rates in women with polycystic ovary syndrome. However, the largest randomized controlled trial including 626 infertile women with polycystic ovary syndrome demonstrated that better live birth rates were achieved with CC alone (22.5%) or in combination (CC plus metformin) (26.8%) than with metformin alone (7.2%, metformin alone versus CC alone and combination therapy: P < 0.001). There was no benefit of the combination compared to CC alone. In addition, a recent Cochrane systematic review reported no benefit with metformin compared with placebo for live birth rates and no benefit with metformin in combination with CC compared with CC alone.
The use of metformin to prevent miscarriage and/or pregnancy complications has also been studied. Compared to placebo, metformin by itself did not affect miscarriage rates (OR 0.36, 95% CI 0.09-1.47). In addition, the combination of metformin and CC did not significantly increase the miscarriage rate compared to CC alone (OR 1.61, 95% CI 1.00-2.60). Therefore, despite initial reports of metformin reducing the risk of miscarriage and preventing miscarriage, it is not currently an indication for metformin use in women with polycystic ovary syndrome.
Women with polycystic ovary syndrome are at high risk for gestational diabetes, gestational hypertension, preeclampsia, and preterm delivery. [29] Although initial studies showed that metformin reduced complications of pregnancy in women with polycystic ovary syndrome, a subsequent larger multicenter randomized controlled trial of metformin versus placebo found no significant differences between the two groups in the primary outcomes: preeclampsia (7.4% in the metformin group versus 3.7% in the placebo group, P = 0.18), preterm delivery (3.7% in the metformin group versus 8.2% in the metformin group, P = 0.12), gestational diabetes (17.6% in the metformin group and 16.9% in the placebo group, P = 0.87), or a combination of the three outcomes (25.9% in the metformin group and 24.4% in the placebo group, P = 0.78). [30] Thus, metformin does not appear to prevent pregnancy complications in women with polycystic ovary syndrome.
Sleep apnea (S in Sleep apnea-MY PCOS)
Obstructive sleep apnea is associated with insulin resistance and type 2 diabetes mellitus as well as polycystic ovary syndrome. A retrospective study showed an increased incidence of sleep apnea (17.0% vs. 0.6%, P < 0.001) and excessive daytime sleepiness (80.4% vs. 27.0%, P < 0.001) in 53 patients with polycystic ovary syndrome relative to 452 premenopausal controls. The risk and severity of obstructive sleep apnea in patients with polycystic ovary syndrome were strongly associated with insulin resistance.
Continuous positive airway pressure treatment for at least 4 hours per night improves insulin sensitivity, reduces norepinephrine levels and diastolic blood pressure, and decreases sympathetic activity in the heart. Therefore, it is important to screen patients with polycystic ovary syndrome for symptoms of sleep apnea (daytime sleepiness, snoring, witnessing apnea episodes, morning headache) and provide sleep study if symptoms are found. The addition of continuous positive airway pressure therapy improved the metabolic parameters in these patients.
Conclusion
Recognizing that women with polycystic ovary syndrome present with sporadic ovulation and hyperandrogenism is important to begin a lifelong discussion of prevention and treatment for this disease that has a multisystemic impact on patients. Identifying this disorder provides an opportunity for physicians and patients to discuss the prevention and early treatment of metabolic disorders. Discussions can also address menstrual cycle adjustment and prevention of endometrial hyperplasia, with attention to mood, diet and body image, as well as cosmetic, fertility and sleep concerns. Each of these is important for the health and quality of life of patients with this common disorder.