pcos presentation

TRACY WILLIAMS, MD, RAMI MORTADA, MD, AND SAMUEL PORTER, MD

A more recent article on polycystic ovary syndrome is available.

Am Fam Physician. 2016;94(2):106-113

Author disclosure: No relevant financial affiliations.

Polycystic ovary syndrome is the most common endocrinopathy among reproductive-aged women in the United States, affecting approximately 7% of female patients. Although the pathophysiology of the syndrome is complex and there is no single defect from which it is known to result, it is hypothesized that insulin resistance is a key factor. Metabolic syndrome is twice as common in patients with polycystic ovary syndrome compared with the general population, and patients with polycystic ovary syndrome are four times more likely than the general population to develop type 2 diabetes mellitus. Patient presentation is variable, ranging from asymptomatic to having multiple gynecologic, dermatologic, or metabolic manifestations. Guidelines from the Endocrine Society recommend using the Rotterdam criteria for diagnosis, which mandate the presence of two of the following three findings—hyperandrogenism, ovulatory dysfunction, and polycystic ovaries—plus the exclusion of other diagnoses that could result in hyperandrogenism or ovulatory dysfunction. It is reasonable to delay evaluation for polycystic ovary syndrome in adolescent patients until two years after menarche. For this age group, it is also recommended that all three Rotterdam criteria be met before the diagnosis is made. Patients who have marked virilization or rapid onset of symptoms require immediate evaluation for a potential androgen-secreting tumor. Treatment of polycystic ovary syndrome is individualized based on the patient's presentation and desire for pregnancy. For patients who are overweight, weight loss is recommended. Clomiphene and letrozole are first-line medications for infertility. Metformin is the first-line medication for metabolic manifestations, such as hyperglycemia. Hormonal contraceptives are first-line therapy for irregular menses and dermatologic manifestations.

Polycystic ovary syndrome (PCOS) is a complex condition that is most often diagnosed by the presence of two of the three following criteria: hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. Because these findings may have multiple causes other than PCOS, a careful, targeted history and physical examination are required to ensure appropriate diagnosis and treatment. This article provides an algorithmic approach to the care of patients with suspected or known PCOS.

WHAT IS NEW ON THIS TOPIC: POLYCYSTIC OVARY SYNDROME

Recent studies suggest that letrozole (Femara) is associated with higher live-birth and ovulation rates compared with clomiphene in patients with polycystic ovary syndrome.

A 2012 Cochrane review concluded that metformin does not improve fertility in patients with polycystic ovary syndrome.

Epidemiology and Pathophysiology

PCOS is the most common endocrinopathy among reproductive-aged women in the United States, affecting approximately 7% of female patients. 1 Although its exact etiology is unclear, PCOS is currently thought to emerge from a complex interaction of genetic and environmental traits. Evidence from one twin-family study indicates that there is a strong correlation between familial factors and the presence of PCOS. 2

The pathogenesis of PCOS has been linked to altered luteinizing hormone (LH) action, insulin resistance, and a possible predisposition to hyperandrogenism. 3 – 7 One theory maintains that underlying insulin resistance exacerbates hyperandrogenism by suppressing synthesis of sex hormone–binding globulin and increasing adrenal and ovarian synthesis of androgens, thereby increasing androgen levels. These androgens then lead to irregular menses and physical manifestations of hyperandrogenism. 8

Common Comorbidities

PCOS is associated with multiple metabolic defects, including metabolic syndrome. Twice as many women with PCOS have metabolic syndrome as in the general population, and about one-half of women with PCOS are obese. 1 , 9 The presence of PCOS is also associated with a fourfold increase in the risk of type 2 diabetes mellitus. 10 There is an increased prevalence of nonalcoholic fatty liver disease, 11 , 12 sleep apnea, 13 and dyslipidemia 14 in patients with PCOS, even when controlled for body mass index. Rates of cardiovascular disease are higher in patients with PCOS, but increased cardiovascular mortality has not been consistently demonstrated. 15 , 16 Finally, there is evidence to suggest an increased risk of mood disorders among patients with PCOS. 17 , 18

Given the conditions associated with PCOS, the Endocrine Society, the Androgen Excess and PCOS Society, and the American College of Obstetricians and Gynecologists recommend that clinicians evaluate patients' blood pressure at every visit and lipid levels at the time of diagnosis, and screen for type 2 diabetes with a two-hour oral glucose tolerance test regardless of a patient's body mass index. Patients should have repeat diabetes screening every three to five years, or more often if other indications for screening are present. 19 – 21 The Endocrine Society further recommends depression screening, as well as screening for symptoms of obstructive sleep apnea in overweight and obese patients with PCOS. 19 However, routine screening for nonalcoholic fatty liver disease or endometrial cancer (using ultrasonography) is not recommended. 19

Clinical Presentation

The clinical presentation of PCOS is variable. Patients may be asymptomatic or they may have multiple gynecologic, dermatologic, or metabolic manifestations. Patients with PCOS most commonly present with signs of hyperandrogenism and a constellation of oligomenorrhea, amenorrhea, or infertility. 19 , 22 Workup for PCOS is sometimes prompted by an incidental finding of multiple ovarian cysts after ultrasonography.

Diagnostic Workup

The diagnostic workup should begin with a thorough history and physical examination. Clinicians should focus on the patient's menstrual history, any fluctuations in the patient's weight and their impact on PCOS symptoms, and cutaneous findings (e.g., terminal hair, acne, alopecia, acanthosis nigricans, skin tags). 19 Patients should also be asked about factors related to common comorbidities of PCOS.

The Endocrine Society advises clinicians to diagnose PCOS using the 2003 Rotterdam criteria ( Table 1 19 ) , although recommendations differ across guidelines. 23 According to the Rotterdam criteria, diagnosis requires the presence of at least two of the following three findings: hyperandrogenism, ovulatory dysfunction, and polycystic ovaries.

Diagnosis can generally be accomplished with a careful history, physical examination, and basic laboratory testing, without the need for ultrasonography or other imaging. Hyperandrogenism can be diagnosed clinically by the presence of excessive acne, androgenic alopecia, or hirsutism (terminal hair in a male-pattern distribution); or chemically, by elevated serum levels of total, bioavailable, or free testosterone or dehydroepiandrosterone sulfate. 23 Measurement of androgen levels is helpful in the rare occasion that an androgen-secreting tumor is suspected (e.g., when a patient has marked virilization or rapid onset of symptoms associated with PCOS).

Ovulatory dysfunction refers to oligomenorrhea (cycles more than 35 days apart but less than six months apart) or amenorrhea (absence of menstruation for six to 12 months after a cyclic pattern has been established). 24

A polycystic ovary is defined as an ovary containing 12 or more follicles (or 25 or more follicles using new ultrasound technology) measuring 2 to 9 mm in diameter or an ovary that has a volume of greater than 10 mL on ultrasonography. A single ovary meeting either or both of these definitions is sufficient for diagnosis of polycystic ovaries. 23 , 25 However, ultrasonography of the ovaries is unnecessary unless imaging is needed to rule out a tumor or the patient has met only one of the other Rotterdam criteria for PCOS. 19 , 26 Polycystic ovaries meeting the above parameters can be found in as many as 62% of patients with normal ovulation, with prevalence declining as patients increase in age. 27

The goal of further evaluation of suspected PCOS is twofold: to exclude other treatable conditions that can mimic PCOS and to detect and treat long-term metabolic complications. Anovulation is common after menarche, so it is reasonable to delay workup for PCOS in adolescents until they have been oligomenorrheic for at least two years. 28 If an adolescent is evaluated for PCOS, it has been suggested that she meet all three of the Rotterdam criteria before being diagnosed with the condition 28 ( Table 1 19 ) .

The differential diagnosis of PCOS is broad and includes both endocrinologic and malignant etiologies. Figure 1 19 provides an algorithm for the workup of select presentations. For any woman with suspected PCOS, the Endocrine Society recommends excluding pregnancy, thyroid dysfunction, hyperprolactinemia, and nonclassical congenital adrenal hyperplasia. 19 Depending on presentation, conditions such as hypothalamic amenorrhea and primary ovarian insufficiency should also be excluded. In women with rapid symptom onset or significant virilization, such as deepening voice or clitoromegaly, an androgen-secreting tumor should be ruled out. Finally, Cushing syndrome or acromegaly should be excluded in patients with physical findings that suggest either condition. 19 There is no need to order laboratory testing for these conditions if the patient does not have suggestive physical findings.

Other tests that may be helpful but are not necessary for diagnosis include measurement of LH and follicle-stimulating hormone (FSH) levels to determine a serum ratio of LH/FSH. A ratio greater than 2 generally indicates PCOS, but there are no exact cutoff values because many different assays are used. 26 The FSH level is more helpful in ruling out ovarian failure. 26

PCOS is a multifaceted syndrome that affects multiple organ systems with significant metabolic and reproductive manifestations. Treatment should be individualized based on the patient's presentation and desire for pregnancy ( Figure 2 19 , 29 – 35 ) . Devices and medications used to treat manifestations of PCOS, and their associated adverse effects, are described in Table 2 . 19 , 29 – 33 , 36

A team approach involving care by primary care and subspecialist physicians can be helpful to address the multiple manifestations of the syndrome. Goals for treatment (e.g., treating infertility; regulating menses for endometrial protection; controlling hyperandrogenic features, including hirsutism and acne) must account for the patient's preferences because therapy selection may otherwise conflict with outcomes that the patient considers important. Metabolic complications should be addressed in every patient via a blood pressure evaluation, a lipid panel, and a two-hour oral glucose tolerance test. Patients who are overweight should be evaluated for signs and symptoms of obstructive sleep apnea. All patients should be screened for depression ( Figure 1 19 ) .

ANOVULATION AND INFERTILITY

Lifestyle modification and weight reduction reduce insulin resistance and can significantly improve ovulation. Therefore, lifestyle modification is first-line therapy for women who are overweight. 37 A calorie-restricted diet is recommended for all patients with PCOS who are overweight. Weight loss has been shown to have a positive effect on fertility and metabolic profile. 19 , 30 The Endocrine Society recommends clomiphene or letrozole (Femara) for ovulation induction. Recent studies suggest that letrozole is associated with higher live-birth rates and ovulation rates compared with clomiphene in patients with PCOS. 29 The impact of metformin on fertility is controversial; although it was once believed to improve infertility, a 2012 Cochrane review concluded that it does not. 38

MENSTRUAL IRREGULARITY

In a patient not seeking pregnancy, the Endocrine Society recommends hormonal contraception (i.e., oral contraceptive, dermal patch, or vaginal ring) as the initial medication for treatment of irregular menses and hyperandrogenism manifesting as acne or hirsutism. 19 , 30 Small studies have shown that metformin can restore regular menses in up to 50% to 70% of women with PCOS, 39 , 40 but oral contraceptives have been shown to be superior to metformin for regulating menses and lowering androgen levels. 30 There are no studies demonstrating superiority of one oral contraceptive over another in treating PCOS. Prevention of endometrial hyperplasia from chronic anovulation may be accomplished either by progesterone derivatives, progestin-containing oral contraceptives, or the levonorgestrel-releasing intrauterine system (Mirena). 31 , 41 Patient comfort and preference should also be taken into account when treating irregular menses.

Hirsutism is a bothersome hyperandrogenic manifestation of PCOS that may require at least six months of treatment before improvement begins. According to a 2015 Cochrane review, the most effective first-line therapy for mild hirsutism is oral contraceptives. 32 Spironolactone, 100 mg daily, and flutamide, 250 mg twice daily, are safe for patient use, but the evidence for their effectiveness is minimal. 32 Other therapies include eflornithine (Vaniqa), electrolysis, or light-based therapies such as lasers and intense pulsed light. Any of these can be used as monotherapy in mild cases or as adjunctive therapy in more severe cases. 33

Acne is common in the general population and in patients with PCOS. Hormonal contraceptives are first-line medications for treating acne associated with PCOS and can be used in conjunction with standard topical acne therapy (e.g., retinoids, antibiotics, benzoyl peroxide) or as monotherapy. 19 , 34 Antiandrogens, spironolactone being the most common, can be added as second-line medications. 19 , 34

Areas for Future Research

More research is needed to clarify the complex pathophysiology of PCOS. No single test is currently available for its diagnosis. Additionally, once diagnosis is established, the options for treatment are of limited number and effectiveness because they target only the symptoms of PCOS. Finally, patients with PCOS have higher rates of metabolic complications, such as cardiovascular disease, but their impact on mortality is not clear. Therefore, more prospective epidemiologic studies on the topic are necessary.

Data Sources : PubMed, the Cochrane database, UpToDate, and Dynamed were searched using the key terms polycystic ovarian syndrome, metabolic syndrome, infertility, and diagnosis and treatment. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Search dates: April 2015 and March 2016.

This review updates previous articles on this topic by Richardson 35 ; Radosh 36 ; and Hunter and Sterrett . 42

Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89(6):2745-2749.

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Dafopoulos K, Venetis C, Pournaras S, Kallitsaris A, Messinis IE. Ovarian control of pituitary sensitivity of luteinizing hormone secretion to gonadotropin-releasing hormone in women with the polycystic ovary syndrome. Fertil Steril. 2009;92(4):1378-1380.

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Korhonen S, Hippeläinen M, Niskanen L, Vanhala M, Saarikoski S. Relationship of the metabolic syndrome and obesity to polycystic ovary syndrome: a controlled, population-based study. Am J Obstet Gynecol. 2001;184(3):289-296.

DeUgarte CM, Bartolucci AA, Azziz R. Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril. 2005;83(5):1454-1460.

Glueck CJ, Papanna R, Wang P, Goldenberg N, Sieve-Smith L. Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome. Metabolism. 2003;52(7):908-915.

Celik C, Tasdemir N, Abali R, Bastu E, Yilmaz M. Progression to impaired glucose tolerance or type 2 diabetes mellitus in polycystic ovary syndrome: a controlled follow-up study. Fertil Steril. 2014;101(4):1123-1128.e1.

Karoli R, Fatima J, Chandra A, Gupta U, Islam FU, Singh G. Prevalence of hepatic steatosis in women with polycystic ovary syndrome. J Hum Reprod Sci. 2013;6(1):9-14.

Setji TL, Holland ND, Sanders LL, Pereira KC, Diehl AM, Brown AJ. Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(5):1741-1747.

Vgontzas AN, Legro RS, Bixler EO, Grayev A, Kales A, Chrousos GP. Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance. J Clin Endocrinol Metab. 2001;86(2):517-520.

Phelan N, O'Connor A, Kyaw-Tun T, et al. Lipoprotein subclass patterns in women with polycystic ovary syndrome (PCOS) compared with equally insulin-resistant women without PCOS. J Clin Endocrinol Metab. 2010;95(8):3933-3939.

Wang ET, Cirillo PM, Vittinghoff E, Bibbins-Domingo K, Cohn BA, Cedars MI. Menstrual irregularity and cardiovascular mortality. J Clin Endocrinol Metab. 2011;96(1):E114-E118.

Schmidt J, Landin-Wilhelmsen K, Brännström M, Dahlgren E. Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study. J Clin Endocrinol Metab. 2011;96(12):3794-3803.

Bhattacharya SM, Jha A. Prevalence and risk of depressive disorders in women with polycystic ovary syndrome (PCOS). Fertil Steril. 2010;94(1):357-359.

Veltman-Verhulst SM, Boivin J, Eijkemans MJ, Fauser BJ. Emotional distress is a common risk in women with polycystic ovary syndrome: a systematic review and meta-analysis of 28 studies. Hum Reprod Update. 2012;18(6):638-651.

Legro RS, Arslanian SA, Ehrmann DA, et al.; Endocrine Society. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565-4592.

Salley KE, Wickham EP, Cheang KI, Essah PA, Karjane NW, Nestler JE. Glucose intolerance in polycystic ovary syndrome—a position statement of the Androgen Excess Society. J Clin Endocrinol Metab. 2007;92(12):4546-4556.

ACOG Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin No. 108: Polycystic ovary syndrome. Obstet Gynecol. 2009;114(4):936-949.

Mani H, Davies MJ, Bodicoat DH, et al. Clinical characteristics of polycystic ovary syndrome: investigating differences in white and South Asian women. Clin Endocrinol (Oxf). 2015;83(4):542-549.

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19-25.

Woolcock JG, Critchley HO, Munro MG, Broder MS, Fraser IS. Review of the confusion in current and historical terminology and definitions for disturbances of menstrual bleeding. Fertil Steril. 2008;90(6):2269-2280.

Dewailly D, Lujan ME, Carmina E, et al. Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2014;20(3):334-352.

Azziz R, Carmina E, Dewailly D, et al.; Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009;91(2):456-488.

Johnstone EB, Rosen MP, Neril R, et al. The polycystic ovary post-Rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. J Clin Endocrinol Metab. 2010;95(11):4965-4972.

Carmina E, Oberfield SE, Lobo RA. The diagnosis of polycystic ovary syndrome in adolescents. Am J Obstet Gynecol. 2010;203(3):201.e1-201.e5.

Legro RS, Brzyski RG, Diamond MP, et al.; NICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome [published correction appears in N Engl J Med . 2014; 317(15):1465]. N Engl J Med. 2014;371(2):119-129.

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More in AFP

Polycystic Ovary Syndrome (PCOS)

• A hormone disorder that can cause infertility, ovarian cysts, and other health problems
• Symptoms include menstrual irregularities, excessive body hair, acne, and fertility problems
• Treatment includes weight loss, hormonal and other medication types
• Involves Reproductive Endocrinology & Infertility and Obstetrics, Gynecology & Reproductive Sciences
Endometriosis
Primary Ovarian Insufficiency
Ovarian Hyperstimulation Syndrome
Premenstrual Syndrome (PMS)

What is polycystic ovary syndrome (PCOS)?

What are the symptoms of pcos, what causes pcos, how is pcos diagnosed, what are the long-term risks of pcos, how is pcos treated, are surgical options available, what makes yale medicine's approach to pcos stand out.

Often misdiagnosed and poorly understood, polycystic ovary syndrome (PCOS) is a lifelong disorder that can be managed with appropriate medical care. At Yale Medicine, our PCOS Program pulls together a team of specialists to address each aspect of this complex condition, providing guidance and medical intervention to meet every woman's specific needs.

"It's not one condition, it’s a spectrum and it has implications for your overall health," explains Lubna Pal, MD, director of the PCOS Program. "Menstrual irregularities and infertility, bothersome excess of facial and bodily hair, acne and even thinning of scalp hair are common presentations of this complex disorder. But these issues are controllable. PCOS-related infertility is easily fixable."

PCOS is an umbrella term used to describe a collection of symptoms associated with certain classic hormone imbalances. Experts estimate that 5 to 10 percent of women ages 18 to 44 have PCOS. The syndrome is usually detected in women between ages 20 and 30, but the earliest signs can be evident in younger girls including those who have not yet started menstruation.

Menstrual irregularities (infrequent and irregular periods), excessive facial and bodily hair growth, acne and fertility problems are common symptoms of PCOS. Thinning of hair is another symptom experienced by some women with PCOS.

Approximately 50 percent of women in the U.S. with PCOS are obese. PCOS also puts women at a higher risk for type 2 diabetes , heart disease, ovarian cysts, obesity and infertility.

The exact cause of PCOS is unknown, but many women with the syndrome also have a mother or sister with it. And because women with PCOS are often overweight, researchers are studying the relationship between PCOS and the body's production of excess insulin, which can lead to symptoms associated with PCOS. Weight loss alone can improve many of the common symptoms (such as irregular menses, acne) of PCOS.

While there is no single test to diagnose PCOS, it should be suspected in any woman experiencing the common symptoms and signs of PCOS. A combination of clinical presentation, pertinent blood tests and pelvic ultrasound examination are utilized for diagnosis.

"It’s a diagnosis of exclusion," Dr. Pal says. "Patients are frustrated that their doctor is not paying attention. Doctors are equally frustrated with the complexity of this disorder and find it easier to provide a diagnostic label of PCOS, rather than just stepping back and explaining the relationship between obesity and PCOS-related symptoms.”

If health care providers would take the time to better explain the "whats" and "whys" of the relationship between excess weight and a PCOS-like picture, and stress on the importance of weight loss and lifestyle modification to every woman presenting with symptoms of PCOS, "it is highly likely that many of the patients with PCOS will outgrow their PCOS diagnosis," Dr. Lubna says. "Counseling should cover not just the reasons for the symptoms, but should also include discussion on future implications for health and for fertility.”

Overall Health: Women with PCOS are likely to be overweight or obese, and over the course of their life are at risk for developing high blood pressure , abnormal cholesterol levels and diabetes. Emotional distress and symptoms of depression are also commonly seen in this population.
Fertility: Disturbances in ovulation are a common cause of infertility in women with PCOS.
Endometrial hyperplasia (a thickening of the uterine lining): This risk while uncommon, is a particular concern for women with PCOS who are obese, diabetic or pre-diabetic and insulin resistant and who have a long history of menstrual irregularities.

There is currently no cure for PCOS. Management will differ depending on the most bothersome symptoms and on a woman’s desire to become pregnant. For women who are not seeking pregnancy, treatment will likely focus on correcting or harnessing the underlying hormonal imbalances.

It is important to understand that weight reduction and improvement in lifestyle are essential management strategies; weight loss alone can improve menstrual regularity as well as symptoms of acne and excess hair. Hormonal medications such as birth control pills are commonly used for managing menstrual irregularities, and to a lesser extent for management of acne and hair excess symptoms.

A common diabetes drug is often used in PCOS management, particularly so in women who exhibit signs of insulin resistance or issues in glucose control. Anti-androgens are utilized, often in combination with birth control pills, for women whose symptoms of hair excess and/or acne are not controlled with the use of birth control pill alone.

The Yale Medicine team will also help patients lose weight and manage any cosmetic concerns, such as facial hair. For the overweight to obese women who might want to become pregnant, the first line intervention will be weight loss.

Studies show that as many as 70 percent of women with PCOS have fertility problems. Women consult with a fertility expert to discuss treatment options, which may include common fertility medications, or the newer class of medications (aromatase inhibitors) that has shown better results in achieving ovulation in women with PCOS.

Other options include advanced fertility treatments that utilize injectable hormones or intrauterine insemination. In vitro fertilization is recommended for some who either do not achieve pregnancy after three or more attempts at ovulation induction, or for women with PCOS who have additional contributors to infertility (such as problems with partner’s sperm or blocked tubes).

The vast majority of women with PCOS can be managed with lifestyle modifications including attention to diet, exercise and weight loss and medical treatments. The surgical management option of “ovarian drilling” is uncommonly utilized for fertility seeking women who have tried and failed to achieve ovulation with use of medication, and for whom use of injectable gonadotropin hormones is not an option (either due to financial reasons or medical contraindications).

Ovarian drilling is a procedure where an electrically heated needle punctures the ovarian tissue and destroy tiny areas in each ovary. This procedure is followed by lowering of blood levels of testosterone, and spontaneous resumption of regular menses, although these benefits are unlikely to last beyond a few months.

Yale Medicine's team of experts will tackle each aspect of this complex disorder, offering consultation on metabolic needs, lifestyle changes, and, if needed, medical interventions.

Physicians at Yale Medicine are dedicated to helping girls and women with PCOS. The PCOS Program ensures that all aspects of a woman’s health, both physical and emotional, are assessed, and treatment approach is individualized to meet the needs of and reduce health risks for each patient. Choice of medical treatment takes into account the bothersome symptoms, the overall clinical picture and individualized risk profile of each patient. Also, an adolescent PCOS Program for patients as young as 12 is available to help craft age-specific symptom management plans.

In addition to addressing the hormonal and metabolic aspects of the disorder, we offer psychological counseling and support for women with PCOS, as well as for adolescents and their families who are trying to make sense of the disorder.

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Polycystic ovarian disease.

Lorena I. Rasquin ; Catherine Anastasopoulou ; Jane V. Mayrin .

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Last Update: November 15, 2022 .

Continuing Education Activity

Polycystic ovarian syndrome (PCOS) is the most common hormonal disorder in females of reproductive age. It is characterized by two or more of the following: irregular menstrual periods, hyperandrogenism, and polycystic ovaries. This activity outlines the evaluation and treatment of polycystic ovarian syndrome and reviews the role of the interprofessional team in managing patients with this condition.

Describe the epidemiology of polycystic ovarian syndrome.
Review the role of functional ovarian hyperandrogenism (FOH) in the pathophysiology of polycystic ovarian syndrome.
Summarize the use of the Rotterdam criteria in the evaluation of polycystic ovarian syndrome.
Outline the importance of collaboration and communication among the interprofessional team to emphasize lifestyle changes and close follow-up to improve patient outcomes affected by polycystic ovarian syndrome.
Introduction

Polycystic ovarian syndrome (PCOS) is the most common endocrine pathology in females of reproductive worldwide. Stein and Leventhal initially described it in 1935. The prevalence ranges between 5% and 15% depending on the diagnostic criteria applied. It is widely accepted among specialty society guidelines that the diagnosis of PCOS must be based on the presence of at least two of the following three criteria: chronic anovulation, hyperandrogenism (clinical or biological), and polycystic ovaries. It is a diagnosis of exclusion, and disorders that mimic clinical features of PCOS must be excluded. These include thyroid disease, hyperprolactinemia, and non-classical congenital adrenal hyperplasia. Selected patients may need more extensive workup if clinical features suggest other causes.

Despite its high prevalence, PCOS is underdiagnosed and frequently takes more than one visit or different physicians to get identified, and these usually occur in more than a one-year timeframe. It is a very frustrating process for the patient. Delay in diagnosis can lead to the progression of comorbidities making it more difficult to implement lifestyle intervention, which is critical for the improvement of features of PCOS and quality of life.

Multiple morbidities are associated with PCOS, including infertility, metabolic syndrome, obesity, impaired glucose tolerance, type 2 diabetes mellitus (DM-2), cardiovascular risk, depression, obstructive sleep apnea (OSA), endometrial cancer, and nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis (NAFLD/NASH). There are different screening recommendations for each of these pathologies, but the clinician must have a low threshold for workup if any manifestation is shown in PCOS patients. [1] [2] [3]

PCOS is a multifactorial disease. Several susceptible genes have been identified as contributors to the pathophysiology of the disease. These genes are involved in various levels of steroidogenesis and androgenic pathways. Twin studies have estimated about 70% heritability. Also, the environment is a fundamental component in the expression of these genes and the development and progression of the disease. [4] [5] [6]

Two popular hypotheses postulate that individuals with a genetic predisposition exposed to certain environmental factors lead to the expression of PCOS features. The most common environmental factors include obesity and insulin resistance. Some hypotheses also include fetal androgen exposure. [7]

Epidemiology

As already mentioned, PCOS is the most common endocrine pathology in reproductive-aged females worldwide, affecting between 5% and 15% of females depending on the diagnostic criteria. Rotterdam criteria include a broader prevalence than the National Institute of Health 1990 Criteria. Based on the NIH 2012 workshop report, it is estimated that PCOS affects about 5 million reproductive-aged females in the United States. The cost to the healthcare system for diagnosing and treating PCOS is approximately $4 billion annually, not including the cost of serious comorbidities associated with PCOS.

Multiple conditions have been associated with PCOS, including infertility, metabolic syndrome, obesity, impaired glucose tolerance, DM-2, cardiovascular risk, depression, OSA, endometrial cancer, NAFLD/NASH. Higher prevalence has been associated in first-degree relatives with PCOS, prepubertal obesity, congenital virilizing disorders, above-average or low birth weight for gestational age, premature adrenarche, use of valproic acid as an antiepileptic drug. Studies have also suggested that there is a higher prevalence in Mexican-Americans than non-Hispanic whites and African Americans. [8] [9]

Pathophysiology

PCOS is a hyperandrogenic state with oligo-anovulation that cannot be explained by any other disorder. It is a diagnosis of exclusion. Nevertheless, it accounts for the majority of hyperandrogenic presentations.

Nearly all causes of PCOS are due to functional ovarian hyperandrogenism (FOH). Two-thirds of PCOS presentations have typical functional ovarian hyperandrogenism, characterized by dysregulation of androgen secretion with an over-response of 17-hydroxyprogesterone (17-OHP) to gonadotropin stimulation. The remaining PCOS with atypical FOH lack of overresponse of 17-OHP, but testosterone elevation can detect it after suppressing adrenal androgen production. About 3% of PCOS patients have a related isolated functional adrenal hyperandrogenism. The remainder of PCOS cases is mild. These lack evidence of steroid secretory abnormalities; most of these patients are obese, which practitioners postulate accounts for their atypical PCOS. Specific testing for the FOH subpopulation has low clinical utility in our present day. [10]

Functional ovarian hyperandrogenism PCOS presents with the primary features: hyperandrogenism, oligo anovulation, and polycystic ovaries morphology. Functional ovarian hyperandrogenism is multifactorial, with a combination of hereditable and environmental factors. Causes for this dysregulation include insulin excess, which is known to sensitize the ovary to luteinizing hormone (LH) by interfering with the process of homologous desensitization to LH in the normal ovulation cycle as well as an intrinsic imbalance among intraovarian regulatory systems. Theca cells in PCOS have overexpression of most steroidogenic enzymes and proteins involved in androgen synthesis, which suggested a prominent abnormality at the level and activity of steroidogenic enzymes, including P450c17, which has been highly identified. Granulosa cells prematurely luteinize primarily as a result of androgen and insulin excess.

Androgen excess enhances the initial recruitment of primordial follicles into the growth pool. Simultaneously, it initiates premature luteinization, which impairs the selection of the dominant follicle. This results in classical PCOS histopathologic and gross anatomic changes that constitute PCOM. PCOS is perpetuated by increased LH, but it is not caused by it. LH excess is common and is necessary for the expression of gonadal steroidogenic enzymes and sex hormone secretion but is less likely to be the primary cause of ovarian androgen excess because of LH-induced desensitization of theca cells.

About one-half of patients with functional ovarian hyperandrogenism have an abnormal degree of insulin-resistant hyperinsulinism, which acts on theca cell, increasing steroidogenesis and prematurely luteinizes granulosa cells, and stimulates fat accumulation. Hyperandrogenemia provokes LH excess, which then acts on both theca and luteinized granulosa sustaining cycle.

Ovarian hormonal dysregulation alters the pulsatile gonadotropin-releasing hormone (GnRH) release, potentially leading to a relative increase in LH versus follicle-stimulating hormone (FSH) biosynthesis and secretion. LH stimulates ovarian androgen production, while the relative decrease of FSH prevents adequate stimulation of aromatase activity within the granulosa cells, decreasing androgen conversion to the potent estrogen estradiol. This becomes a self-perpetuating noncyclic hormonal pattern.

Elevated serum androgens are converted in the periphery to estrogens, mostly estrone. As conversion occurs primarily in the stromal cells of adipose tissue, estrogen production will be augmented in obese PCOS patients. This conversion results in chronic feedback at the hypothalamus and pituitary gland, in contrast to the normal fluctuations in feedback observed in the presence of a growing follicle and rapidly changing estradiol levels. Unopposed estrogen stimulation of the endometrium may lead to endometrial hyperplasia. [11] [12] [13]

History and Physical

A complete history and physical exam are critical for the diagnosis of PCOS. Two out of three diagnostic criteria rely on history and physical exam, including menstrual history and features of hyperandrogenism. Additionally, PCOS represents a diagnosis of exclusion, and identifying clinical presentation of other conditions should be done.

Most society guidelines have accepted that diagnosis of PCOS; most meet two out of three criteria: chronic anovulation, clinical or biological hyperandrogenism, and polycystic ovaries morphology in the absence of any other pathology. These clinical features are part of the Rotterdam Criteria. The National Institute of Health criteria also requires clinical or biochemical hyperandrogenism and oligo or anovulation. The American Excess PCOS Society requires hyperandrogenism with one of two of the remaining criteria.

Disorders that mimic the clinical features of PCOS should be excluded. These include thyroid disease, hyperprolactinemia, and non-classic congenital adrenal hyperplasia with 21-hydroxylase deficiency, for which measurement of serum 17-hydroxyprogesterone (17-OHP) should be done, which may require further testing with adrenocorticotropin stimulation test. [14] [15] [16]

PCOS in Adolescents

Diagnosing PCOS in adolescents is especially challenging given the developmental issues in this group. Many features of PCOS are common in normal puberty, for example, acne, menstrual irregularities, and hyperinsulinemia. Menstrual irregularities with anovulatory cycles occur due to the immaturity of the hypothalamic-pituitary-ovarian axis during the first 2 to 3 years after menarche. Persistent oligomenorrhea beyond this period predicts ongoing menstrual irregularities and a higher chance of underlying ovarian or adrenal dysfunction. Ultrasound is also not very helpful in adolescents because they commonly have large, multicystic ovaries.

Chronic Anovulation

The cycle length of more 35 days suggest chronic anovulation, but cycle length between 32 to 35-36 day needs to be assessed for ovulatory dysfunction. The threshold for oligomenorrhea is 35 days cycles in adults and 40 days in adolescents. A patient with cycles shorter than 35 days can be assessed by measuring progesterone levels in the mid-luteal phase (days 20 to 21). Implications of ovulatory dysfunction include infertility, endometrial hyperplasia, and endometrial cancer.

Hyperandrogenism

Clinical hyperandrogenism is diagnosed in adult women with hirsutism, alopecia, and acne, and these are a good substitute for biochemical hyperandrogenism. However, adolescent-only hirsutism should be considered as a substitute for biochemical hyperandrogenism. Hair loss patterns are variable, typically in a vertex, crown, or diffuse pattern. Women with more severe hyperandrogenemia may suffer from bitemporal hair loss and loss of the frontal hairline. Adolescents with severe or resistant acne to oral and topical antibiotics may have a 40% likelihood of developing PCOS. There is high suspicion for hyperandrogenism in females in their mid-20s to 30s with persistent or exacerbated acne.

Hirsutism is defined as coarse, dark, terminal hairs distributed in a male pattern. Signs of virilization such as increased muscle mass, decreased breast size, deepening of the voice, and clitoromegaly are not typical of PCOS. Virilization reflects higher androgen levels, and further investigation should be done; the clinician should have higher suspicion for an androgen-producing tumor of the ovary or the adrenal gland.

Free testosterone levels are more sensitive than the measurement of total testosterone for establishing the existence of androgen excess. Methodologic problems in commercial testosterone assays have emerged. The physician should be aware of the method used by the laboratory. Equilibrium dialysis techniques such as mass spectrometry coupled with liquid chromography have the highest sensitivity and specificity and give accurate results. Direct analog radioimmunoassay does not give reliable results through RIA with purification techniques has shown to be more accurate. It is preferable to rely on calculated free testosterone when the equilibrium dialysis method is not available.

The value of measuring levels of androgens other than free testosterone is relatively low. Although dehydroepiandrosterone sulfate (DHEAS) levels are increased in 30% to 35% of PCOS patients, it has been estimated that 5% of patients have an exclusive increase in DHEAS.

Polycystic Ovaries Morphology

Ovarian morphology assessment is more accurate when done by transvaginal ultrasound. New ultrasound machines allow the diagnosis of PCOM (polycystic ovarian morphology) in patients having at least 25 small follicles (2 mm to 9 mm) in the whole ovary. Ovarian size at 10 ml remains the normal size cutoff. 2004 Rotterdam criteria indicate PCOM by the presence of at least 12 follicles measuring 2 mm to 9 mm in the whole ovary or increased ovarian size more than 10 ml. Ultrasound technology has advanced and can improve the diagnosis of PCOS. Androgen Excess and PCOS Society has reviewed current data and published updated guidelines for PCOM diagnosis, increasing follicle count to 25. Ovary size has not been modified. Recent studies have shown evidence that measuring anti-Mullerian hormone can be useful for determining the diagnosis of PCOS when no accurate ovarian ultrasound is available.

Additional Assessment

PCOS represents a higher risk for cardiovascular, metabolic, and other comorbidities. Appropriate evaluation and interventions need to be done.

Infertility

Endocrine Society Guidelines recommend screening for ovulatory status in all patients. Even a patient with eumenorrheic menstrual cycles may have anovulation which can be measured by mid-luteal serum progesterone. Excluding other causes of infertility is also recommended.

Endometrial Cancer

Multiple studies have shown an increased risk of endometrial cancer in patients with PCOS. Multiple risk factors are shared between both pathologies. Endocrine Society suggests against routine ultrasound (US) endometrial thickness screening in asymptomatic patients. But women should be counseled to report unexpected or abnormal uterine bleeding.

Obesity, metabolic disorder, impaired glucose tolerance (IGT), type-2 diabetes mellitus, and cardiovascular disease

Screening for obesity must be done for PCOS women and adolescents by body mass index (BMI) calculation and waist circumference. Obesity increases the risk of hyperandrogenemia and metabolic disorders, which has a negative impact on PCOS. Blood pressure measurement and lipid screening should be done.

Insulin resistance has been associated highly with PCOS. Around one to two-thirds of PCOS have an abnormal degree of insulin resistance. Obesity prevalence is similar, with considerable variability among populations. Obesity increases insulin resistance, and the result is increased hyperinsulinism further aggravates hyperandrogenism. In some obese women with PCOS, metabolic abnormalities related to insulin resistance and obesity are in many instances more important in the mechanism of anovulation in PCOS than androgen excess.

Endocrine Society guidelines recommend using an oral glucose tolerance test, with fasting and 2-hour glucose after a 75 g oral glucose tolerance test (OGTT) to screen for IGT and type-2 diabetes mellitus. OGTT is preferred over HbA1c due to decrease sensitivity with PCOS patients. Rescreening should be done every 3 to 4 years due to more frequent risk factors than the general population.

Additionally, obese and overweight patients should be screened for symptoms of OSA and referred for sleep studies when this test is positive.

NAFLD and NASH

Women with PCOS have 3 times the increased risk of NAFLD; it has been associated with androgen excess and low sex hormone-binding globulin (SHBG).

Routine measurement of LFT is not recommended unless the patient is overweight or obese, given low sensitivity and specificity for NAFLD diagnosis. In these patients, a change in management with newer antidiabetic medications like GLP-1 agonist can decrease the risk of development of NAFLD.

Evidence for the increased rate of depression symptoms was found for PCOS women compared to non-BMI-matched controls. Major depression, recurrent depression, and suicide attempts were also higher in PCOS women. Screening and identifying depression and anxiety disorders should be done. Appropriate treatment should be given.

Treatment / Management

Lifestyle Modification

In overweight and obese PCOS women and adolescents, exercise and calorie-restrictive diets are the best first-line interventions for weight loss and IGT. Different studies have shown that hirsutism can improve as well as regulation of the menstrual cycle and ovulation. Low-carbohydrate diets have been used, hoping that these will have a better effect on hyperinsulinism, but studies have shown no difference in outcomes with low-carbohydrate diets. [3] [17] [18]

Hormonal Contraceptive

First-line treatment for menstrual abnormalities, hirsutism, and acne is a hormonal contraceptive, either oral contraceptive, patch, or vaginal rings. The Endocrine Society does not favor any choice over another. The progestin component decreases LH levels, indirectly decreasing ovarian androgen production and increasing sex hormone-binding globulin. Additionally, some progestins have been shown to have direct antiandrogenic properties as a direct inhibitor 5 alpha-reductase activity to prevent the conversion of free testosterone to its more potent form, 5 alpha-dihydrotestosterone. For this reason, they are highly effective for symptoms of hyperandrogenism and controlling the menstrual cycle.

Screening for contraindication for hormonal contraceptives should be done in all patients. Women 35 or older who smoke more than 15 cigarettes daily, uncontrolled hypertension greater than 160/100, uncontrolled diabetes with severe peripheral vascular disease are considered absolute contraindications. The United States Medical Eligibility Criteria For Contraceptive Use are a valuable tool when multiple comorbidities are present. Patients with diabetes and without vascular complications do not have any contraindication to use hormonal contraceptives.

Regarding the metabolic effect of hormonal contraceptives, higher estrogen activity increases HDL cholesterol and decreases LDL cholesterol. No impact on body weight and fat distribution between PCOS and healthy women.

Oral contraceptive initial dosing of 20 mcg of ethinyl estradiol combined with a progestin with antiandrogenic properties such as desogestrel and drospirenone or with neutral effects like norethindrone acetate. Progestin with antiandrogenic properties has been shown to have a higher risk of venous thromboembolism (VTE). If hyperandrogenic symptoms are not controlled completely with this initial dose, ethinyl estradiol can be increased to 30 to 35 mcg.

Endocrine Society recommends starting metformin in PCOS patients with DM2 or IGT who fail lifestyle modifications. It decreases progression from IGT to DM2. Metformin also improves menstrual cycles, abnormal waist to hip ratio, and vascular markers in non-obese women with PCOS. [19]

Metformin is also second-line therapy for menstrual irregularities in patients with a contraindication for hormonal contraceptives. It is commonly used in the adolescent as monotherapy, and it helps restore normal menses, weight loss, and reduce insulin resistance. Even though it should not be used primarily to treat clinical hyperandrogenism, it can mildly improve androgen excess symptoms.

Infertility Treatment

First-line therapy for infertility in PCOS patients is clomiphene citrate. This is a selective estrogen receptor modulator (SERM), competitive inhibitor of estrogen receptors (ERs), and has mixed agonist and antagonist activity.

Clomiphene enhances fertility and ovulation, especially by its effect on the hypothalamus, where it binds for a prolonged period to estrogen receptors and depletes them, blocking the negative feedback inhibition effect of circulating endogenous estrogen. This results in the pulsatile release of a hypothalamic gonadotropin-releasing hormone (GnRH), promoting the secretion of FSH and LH and indirectly stimulating ovulation.

New evidence for estrogen modulators such as letrozole has shown that it can be used in ovulatory infertility. This is an aromatase inhibitor that blocks estrogen synthesis, reducing negative estrogenic feedback at the pituitary. A National Institute of Health founded a double-blind, multicenter trial that reported that letrozole, compared to clomiphene, was associated with higher live-birth and ovulation rates among infertile women with polycystic ovary syndrome. Additional studies regarding relative teratogenicity need to be done, but future guidelines can change after this new evidence.

Metformin is suggested as an adjuvant treatment for infertility, helping prevent ovarian hyperstimulation syndrome in a patient undergoing in vitro fertilization. It has shown higher benefits in obese patients. After pregnancy is confirmed, it is now allowed for patients with diabetes or glucose intolerance to continue the medication as a treatment for sugar control, but attention should be given to avoid maternal gastrointestinal disturbances.

Treatment for Hyperandrogenism

Clinical hyperandrogenism requires long-term treatment and takes several months before effects are evident.

Cosmetic interventions should be initiated while medications start working. These can be bleaching and temporary hair removal methods, using galvanic or blended electrolysis for localized areas with the experienced operator, using laser photo-epilation for generalized hirsutism.

Pharmacological interventions include topical eflornithine for face hirsutism which can be an expensive treatment with potentially serious side effects if the body absorbs it.

First-line treatment of hirsutism is low-dose neutral or antiandrogenic oral contraceptives which effectively lowers androgens level and effect. Additionally, contraceptive properties are beneficial when combined with antiandrogenic drugs because the latter requires reliable contraception as they are highly teratogenic. Mild hirsutism can be treated OCP alone.

Adjuvant antiandrogen administration can be done for moderate, severe hirsutism and mild hirsutism without adequate hair growth control after 6 months to 1 year of OCP. As those drugs have similar efficacy, androgen excess and the PCOS Society suggest prescribing finasteride, cyproterone acetate, which is not available in the United States, or spironolactone, instead of flutamide when an antiandrogen is needed, due to potential side effects like hepatotoxicity. They act by blocking androgens effects over the hair follicle; finasteride also has inhibition of 5 alpha-reductase.

Spironolactone is the most common adjuvant anti-androgen medication prescribed after OCP; it is a nonselective mineralocorticoid receptor antagonist and suppresses testosterone levels. Spironolactone also has additional benefits regarding the risk of CVD compared to OCP. Combinations of spironolactone with metformin were superior to monotherapy with either drug regarding improved menstrual cycles, glucose during OGTT, assessed by the area under the curve, and testosterone levels. [20] [21] [20]

Metformin alone or other insulin sensitizers are not considered target treatment for hirsutism due to no consistent evidence showing superior effect than placebo. [22] [23]

Additional Insulin Sensitizing Treatment in PCOS

GLP-1 agonists

GLP-1 agonists bind to the GLP-1 receptor and stimulate glucose-dependent insulin release from the pancreatic islets. They have a longer half-life than our bodies GLP-1 because of resistance to degradation by the enzyme dipeptidyl peptidase 4 (DPP-4). Data shows that GLP-1 secretion was significantly lower in obese compared with lean women with PCOS. [24]

Treatment with GLP-1 agonist was associated with decreased BMI and testosterone and improved ovulation rate in obese women with PCOS. [25]

There is increasing evidence that weight loss and insulin sensitivity are higher with GLP-1 agonists than metformin. [26] The wide implementation of GLP-1 agonists in PCOS management can be affected by the high cost of the medications and lack of coverage by insurance companies.

DPP4 inhibitors

DPP4 inhibitors decrease the degradation of incretins, therefore, increasing glucose-dependent insulin release. In patients with type 2 diabetes, they are considered weight neutral. New data suggest that in obese women with PCOS, DPP4 inhibitors have beneficial effects in weight loss and lower blood glucose levels. It prevented weight gain in women who were transitioning from GLP-1 agonists.

Evidence suggests that the effect of DPP4 inhibitors on the weight of women with PCOS is based on increasing growth hormone, which is reduced in patients with PCOS. These, in turn, decrease visceral fat mass. Data is still limited, and it is considered experimental. [27]

SGLT2 inhibitors

SGLT2 inhibitors increase urinary glucose secretion, improves weight loss and cardiovascular risk in patients with type 2 diabetes. Limited data in obese patients shows promising data for weight loss and fat mass reduction with treatment with SGLT2 inhibitors compared to metformin, but its effect on hormonal and metabolic parameters was similar. More data is needed to implement this medication in clinical practice. [28]

Peroxisome proliferator-activated receptor gamma (PPARg) agonist

In PCOS, PPARg agonist treatment improved hormonal and metabolic outcomes but had an adverse effect on weight. It can be superior in patients with NAFLD compared to metformin. [29]

Myoinositol

Myoinositol is an over-the-counter food supplement that increases insulin sensitivity. Compared with placebo improved insulin sensitivity in women with PCOS without significant effect on BMI. Data is limited, and its use has been mostly applied as fertility treatment of PCOS or when metformin is not tolerated, given it has fewer gastrointestinal side effects. [30]

Differential Diagnosis
Use of androgenic steroids
Hypothyroidism
Late-onset congenital adrenal hyperplasia
Idiopathic/familial hirsutism
Ovarian malignancies
Enhancing Healthcare Team Outcomes

PCOS affects many organ systems and is best managed by an interprofessional team of healthcare professionals. This team includes clinicians (MDs, DOs, NPs, PAs), specialists, nursing staff, and pharmacists. There is no cure for the disorder, and hence the aim of treatment is to reduce the risk of complications and improve lifestyle. A dietary and physical therapy consults are highly recommended as these are considered first-line treatments. The women often require a number of medications to manage the hirsutism, anovulation, and menstrual irregularities; hence the pharmacist should ensure that the patient is not developing any adverse reactions to these drugs. All women with PCOS should be encouraged to exercise as this can reduce insulin resistance, body weight, blood lipids, and glucose; more importantly, exercise also enhances self-esteem. Because these women can develop a wide range of complications, close follow-up is highly recommended. Women with POS are at high risk for developing gestational diabetes, preeclampsia, and preterm deliveries. Finally, all women with PCOS should be encouraged to join a support group to help reduce the stress and boost their confidence. [17] [31] [Level 5]

More evidence is accumulated on women with PCOS potentially being at high risk for CNS and cardiovascular disease. Many of these women have extremely high levels of serum lipoprotein, blood glucose, and cholesterol, which also increase the risk of insulin resistance. Women with PCOS may also be at high risk for endometrial cancer. [32] [33] [Level 5]

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Disclosure: Lorena Rasquin declares no relevant financial relationships with ineligible companies.

Disclosure: Catherine Anastasopoulou declares no relevant financial relationships with ineligible companies.

Disclosure: Jane Mayrin declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Cite this Page Rasquin LI, Anastasopoulou C, Mayrin JV. Polycystic Ovarian Disease. [Updated 2022 Nov 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Polycystic Ovary Syndrome (PCOS)

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Some women have a condition in which their ovaries generate abnormal quantities of androgens. These are a type of hormones that control lots of processes in their bodies, and this dysregulation can cause missed periods, hirsutism, infertility and acne, among many others. There is little to no information about this available to women, specially young ones who must be specially aware of the symptoms of irregular periods. Speak about PCOS, the illness that causes all these symptoms, and raise awareness on this issue!

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Polycystic ovary syndrome (PCOS) care at Mayo Clinic

Cholesterol test
Glucose tolerance test

PCOS treatment focuses on managing the things that are concerning you. This could include infertility, hirsutism, acne or obesity. Specific treatment might involve lifestyle changes or medication.

Lifestyle changes

Your health care provider may recommend weight loss through a low-calorie diet combined with moderate exercise activities. Even a modest reduction in your weight — for example, losing 5% of your body weight — might improve your condition. Losing weight may increase the effectiveness of medications your provider recommends for PCOS , and it can help with infertility. Your health care provider and a registered dietitian can work with you to determine the best weight-loss plan.

Medications

To regulate your periods, your health care provider might recommend:

Combination birth control pills. Pills that contain both estrogen and progestin decrease androgen production and regulate estrogen. Regulating your hormones can lower your risk of endometrial cancer and correct irregular bleeding, excess hair growth and acne.
Progestin therapy. Taking progestin for 10 to 14 days every 1 to 2 months can regulate your periods and protect against endometrial cancer. This progestin therapy doesn't improve androgen levels and won't prevent pregnancy. The progestin-only minipill or progestin-containing intrauterine device is a better choice if you also wish to avoid pregnancy.

To help you ovulate so that you can become pregnant, your health care provider might recommend:

Clomiphene. This oral anti-estrogen medication is taken during the first part of your menstrual cycle.
Letrozole (Femara). This breast cancer treatment can work to stimulate the ovaries.
Metformin. This medicine for type 2 diabetes that you take by mouth improves insulin resistance and lowers insulin levels. If you don't become pregnant using clomiphene, your provider might recommend adding metformin to help you ovulate. If you have prediabetes, metformin can slow the progression to type 2 diabetes and help with weight loss.
Gonadotropins. These hormone medications are given by injection.

If needed, talk with your health care provider about procedures that may help you become pregnant. For example, in vitro fertilization may be an option.

To reduce excessive hair growth or improve acne, your health care provider might recommend:

Birth control pills. These pills decrease androgen production that can cause excessive hair growth and acne.
Spironolactone (Aldactone). This medication blocks the effects of androgen on the skin, including excessive hair growth and acne. Spironolactone can cause birth defects, so effective birth control is needed while taking this medication. This medication isn't recommended if you're pregnant or planning to become pregnant.
Eflornithine (Vaniqa). This cream can slow facial hair growth.
Hair removal. Electrolysis and laser hair removal are two options for removing hair. Electrolysis uses a tiny needle inserted into each hair follicle. The needle sends out a pulse of electric current. The current damages and then destroys the follicle. Laser hair removal is a medical procedure that uses a concentrated beam of light to remove unwanted hair. You might need multiple treatments of electrolysis or laser hair removal. Shaving, plucking or using creams that dissolve unwanted hair may be other options. But these are temporary, and hair may thicken when it grows back.
Acne treatments. Medications, including pills and topical creams or gels, may help improve acne. Talk to your health care provider about options.

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Lifestyle and home remedies

To help ease the effects of PCOS , try to:

Stay at a healthy weight. Weight loss can lower insulin and androgen levels. It also may restore ovulation. Ask your health care provider about a weight-control program, if you need one. Meet with a registered dietitian for help in reaching weight-loss goals.
Limit carbohydrates. High-carbohydrate diets might make insulin levels go higher. Ask your provider if a low-carbohydrate diet could help if you have PCOS . Choose complex carbohydrates, which raise your blood sugar levels more slowly. Complex carbohydrates are found in fruits, vegetables, whole grains and cooked dry beans and peas.
Be active. Exercise helps lower blood sugar levels. If you have PCOS , increasing your daily activity and getting regular exercise may treat or even prevent insulin resistance. Being active may also help you keep your weight under control and avoid developing diabetes.

Preparing for your appointment

For PCOS , you may see a specialist in female reproductive medicine (gynecologist), a specialist in hormone disorders (endocrinologist) or an infertility specialist (reproductive endocrinologist).

Here's some information to help you get ready for your appointment.

What you can do

Before your appointment, make a list of:

Symptoms you've been having, and for how long
Information about your periods, including how often they occur, how long they last and how heavy they are
All medications, vitamins, herbs and other supplements you take, including the dosages
Key personal and medical information, including other health conditions, recent life changes and stressors
Questions to ask your health care provider

Some basic questions to ask include:

What tests do you recommend?
How does PCOS affect my chance of getting pregnant?
Are there any medicines that might help improve my symptoms or chance of getting pregnant?
What lifestyle changes can improve symptoms?
How will PCOS affect my health in the long term?
I have other medical conditions. How can I best manage them together?

Don't hesitate to ask other questions as they occur to you.

What to expect from your doctor

Your health care provider is likely to ask you a number of questions, including:

What are your symptoms? How often do they happen?
How bad are your symptoms?
When did each symptom begin?
When was your last period?
Have you gained weight since you first started having periods? How much weight did you gain, and when did you gain it?
Does anything seem to improve your symptoms? Make them worse?
Are you trying to get pregnant, or do you wish to become pregnant?
Has any close blood relative, such as your mother or a sister, ever been diagnosed with PCOS ?
Tremblay-Davis AC, et al. Diagnosis and treatment of polycystic ovary syndrome in primary care. Journal for Nurse Practitioners. 2021; doi:10.1016/j.nurpra.2021.08.008.
Rocha AL, et al. Recent advances in the understanding and management of polycystic ovary syndrome. F1000Research. 2022; doi:10.12688/f1000research.15318.1.
Polycystic ovary syndrome. Office on Women's Health. https://www.womenshealth.gov/a-z-topics/polycystic-ovary-syndrome. Accessed May 2, 2022.
Ferri FF. Polycystic ovary syndrome. In: Ferri's Clinical Advisor 2022. Elsevier; 2022. https://www.clinicalkey.com. Accessed May 4, 2022.
FAQs. Polycystic ovary syndrome (PCOS). American College of Obstetricians and Gynecologists. https://www.acog.org/womens-health/faqs/polycystic-ovary-syndrome-pcos. Accessed May 2, 2022.
Polycystic ovary syndrome (PCOS). Eunice Kennedy Shriver National Institute of Child Health and Human Development. https://www.nichd.nih.gov/health/topics/factsheets/pcos. Accessed May 2, 2022.
AskMayoExpert. Polycystic ovary syndrome. Mayo Clinic; 2022.
Collee J, et al. Polycystic ovarian syndrome and infertility: Overview and insights of the putative treatments. Gynecological Endocrinology. 2021; doi:10.1080/09513590.2021.1958310.
Lentscher JA, et al. Clinical presentation and diagnosis of polycystic ovarian syndrome. Clinical Obstetrics and Gynecology. 2021; doi:10.1097/GRF.0000000000000563.
Nimmagadda R. Allscripts EPSi. Mayo Clinic. April 27, 2022.
Burnett TL (expert opinion). Mayo Clinic. May 27, 2022.
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Pathophysiology & Clinical Presentation

Normal physiology.

Ovaries are organs found on both sides of the uterus in females. Ovaries sit on the ovarian fossa and are connected by ligaments. These important organs have two main jobs: to release female sex hormones, estrogen and progesterone, and to produce ova or eggs.

In a healthy individual, there is a normal hormonal feedback system which enables the body to stimulate the menstrual cycle. A female is born with all the eggs she will produce in her life. Over time these eggs, which are encapsulated in what is termed a follicle, will mature. This happens in the first half of the menstrual cycle. The ovaries will also produce estrogen during the maturation process. In each cycle, one of the mature eggs is eventually released into the fallopian tube, which is called ovulation. The corpus luteum is the leftover follicle, which then releases lower estrogen and increases the release of progesterone into the body. This will prepare the uterus for when the egg and sperm are ready for attachment in the uterus lining. If the egg is not fertilized, menses will begin to shed the uterine lining and another cycle will follow.

Alterations That Occur with PCOS

Polycystic Ovarian Syndrome is a multifactorial endocrine abnormality that leads to ovarian dysfunction of follicle development (Thornton et al., 2015). The follicles will mature to a certain point and then fail to release the egg into the fallopian tube. This is a reason some females with PCOS have trouble conceiving. The enlarged follicles are then considered ovarian cysts. The accumulation of cysts will eventually cause ovarian enlargement.

The specific pathophysiology of Polycystic Ovarian Syndrome is poorly understood, however, practitioners do know that it is a combination of metabolic and reproductive abnormalities (Thornton et al., 2015). Inappropriate gonadotropin secretion, chronic hyperandrogenism, and an increase in estrogen concentration are present in the typical PCOS patient. Although not present in all patients, glucose intolerance and hyperinsulinemia are strongly associated with this syndrome and may aggravate hyperandrogenic states (McCance & Huether, 2019). This occurs as insulin stimulates androgen secretion and reduces a serum globin that binds to sex hormones (SHBG), increasing testosterone levels. Insulin and excess androgens decrease apoptosis and allow the follicles to remain intact in the ovary. Further, it appears weight gain can worsen signs and symptoms of PCOS. Currently, researchers are focusing on the possibility that increased intraovarian receptors for estrogen receptor-α or insulin growth factor 1, elevated leptin levels, or direct infrared radiation within selective ovarian cells may also contribute to the development of PCOS (McCance & Huether, 2019).

Ultimately, dysfunction in the normal hormonal feedback is affected by this prolonged elevation of androgens and estrogen. There is an increase in luteinizing hormone and estradiol and may be a decrease in FSH as well. The diagram below explains how all these alterations interact with one another.

The typical patient presents with several of the following: dyslipidemia, obesity, acne, hair loss, acanthosis nigricans or discoloration in body folds, hirsutism, irregular menses, infertility, dry skin, or changes in the voice (Thornton et al., 2015).

Studies have also shown that practitioners tend to see familial traits associated with PCOS. However, the genetic cause or process remains unknown. It is reasonable to suspect that it is multifactorial and that intrauterine and childhood environments could have an impact (McCance & Huether, 2019). During a thorough reproductive history, it is important to question the patient if PCOS is present in other family members.

Key Criteria for Diagnosis

Practitioners should be aware there are several different diagnostic guidelines. The preferred guideline is Rotterdam Criteria. This can be found in the Diagnosis and Treatment of Polycystic Ovarian Syndrome: An Endocrine Society Clinical Practice Guideline (Thornton et al., 2015) .

Rotterdam Criteria requires two of three of the following manifestations:

Hyperandrogenism : can be determined based on clinical observation (hirsutism + virilization) or laboratory testing (testosterone, androstenedione, or Dehydroepiandrosterone)
Ovulatory Irregularities: important to obtain a thorough reproductive history asking about irregular menses and amenorrhea
Polycystic Ovaries: 12(+) follicles in at least one ovary present on transvaginal ultrasound; appear as pearly white capsules when examined

This is an example of an ovary ultrasound in a PCOS patient.

Most diagnoses require ruling out many other disorders before an official diagnosis is made, especially since it cannot be confirmed with the presence of a polycystic ovary alone. It is important to note that PCOS symptoms can mimic normal changes that occur during puberty so an adolescent diagnosis requires all three of these manifestations. A practitioner should also exclude endocrinopathies that mimic PCOS in women of all ages. This can be done by testing TSH, free T4, prolactin, fasting glucose, glucose tolerance test, 17-OHP, and testosterone levels (Thornton et al., 2015).

If there is a rapid onset of these signs and symptoms it would also be important to consider an ovarian or adrenal tumor that is producing androgens. Practitioners should make patients aware that a diagnosis of PCOS can increase a female’s chance of having uterine cancer later on in life (Thornton et al., 2015).

There are many treatments practitioners may use to promote quality of life in PCOS patients. Common therapies include oral contraceptives, lifestyle modifications to decrease weight, a prescription for metformin, and possibly progesterone therapy. The main goal is to reverse the symptoms of hyperandrogenism, restoring fertility, and addressing metabolic concerns (McCance & Huether, 2019).

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Article Contents

1. pathophysiology, 2. diagnosis of pcos, 3. treatment of adolescent pcos, acknowledgments, additional information, references and notes.

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Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls

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Selma Feldman Witchel, Sharon E Oberfield, Alexia S Peña, Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls, Journal of the Endocrine Society , Volume 3, Issue 8, August 2019, Pages 1545–1573, https://doi.org/10.1210/js.2019-00078

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Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. Depending on diagnostic criteria, 6% to 20% of reproductive aged women are affected. Symptoms of PCOS arise during the early pubertal years. Both normal female pubertal development and PCOS are characterized by irregular menstrual cycles, anovulation, and acne. Owing to the complicated interwoven pathophysiology, discerning the inciting causes is challenging. Most available clinical data communicate findings and outcomes in adult women. Whereas the Rotterdam criteria are accepted for adult women, different diagnostic criteria for PCOS in adolescent girls have been delineated. Diagnostic features for adolescent girls are menstrual irregularity, clinical hyperandrogenism, and/or hyperandrogenemia. Pelvic ultrasound findings are not needed for the diagnosis of PCOS in adolescent girls. Even before definitive diagnosis of PCOS, adolescents with clinical signs of androgen excess and oligomenorrhea/amenorrhea, features of PCOS, can be regarded as being “at risk for PCOS.” Management of both those at risk for PCOS and those with a confirmed PCOS diagnosis includes education, healthy lifestyle interventions, and therapeutic interventions targeting their symptoms. Interventions can include metformin, combined oral contraceptive pills, spironolactone, and local treatments for hirsutism and acne. In addition to ascertaining for associated comorbidities, management should also include regular follow-up visits and planned transition to adult care providers. Comprehensive knowledge regarding the pathogenesis of PCOS will enable earlier identification of girls with high propensity to develop PCOS. Timely implementation of individualized therapeutic interventions will improve overall management of PCOS during adolescence, prevent associated comorbidities, and improve quality of life.

The female hypothalamic–pituitary–ovarian (HPO) axis is a meticulously synchronized and tightly regulated network ultimately responsible for reproductive competence and survival of the species. The HPO axis responds to internal signals ( i.e. , hormonal and neuronal) and external factors ( i.e. , environment influences). Beginning during gestation, these factors impact future generations through epigenetic factors affecting the brain and the developing germ cells [ 1 ].

Polycystic ovary syndrome (PCOS), a disorder primarily characterized by signs and symptoms of androgen excess and ovulatory dysfunction, disrupts HPO axis function. Depending on diagnostic criteria, this disorder affects ∼6% to 20% of reproductive aged women [ 2 , 3 ]. Typical clinical features include hirsutism, irregular menses, chronic anovulation, and infertility. The persistent hyperandrogenism is associated with impaired hypothalamic–pituitary feedback, LH hypersecretion, premature granulosa cell luteinization, aberrant oocyte maturation, and premature arrest of activated primary follicles [ 4 ].

By the time the diagnosis is established, PCOS presents as a phenotype reflecting a self-perpetuating vicious cycle involving neuroendocrine, metabolic, and ovarian dysfunction. Over the years, numerous hypotheses have been proposed regarding the proximate physiologic origins for PCOS. PCOS reflects the interactions among multiple proteins and genes influenced by epigenetic and environmental factors ( Fig. 1 ) [ 5 ]. Specific sections of this article deconstruct the factors contributing to the development of PCOS in humans and preclinical models. Clinical and biochemical hyperandrogenism are major features of PCOS.

Factors contributing to PCOS phenotype. PCOS encompasses a woman’s life cycle. Factors potentially impacting the pathophysiology of PCOS are shown in circles. Not all factors affect each individual. PCOS epitomizes a biologic network of interacting neuroendocrine, hormonal, metabolic, genetic, and environmental influences.

PCOS develops during the early pubertal years [ 6 ]. However, most relevant information has been accrued through clinical studies involving adult women in which referral bias focuses on investigation of the more severe phenotypes [ 7 ]. Preclinical models involving animal and in vitro studies supplement clinical investigation and benefit from other approaches to study this complex disorder. Recent clinical, experimental, and genetic data emphasize neuroendocrine involvement in the pathophysiology of PCOS.

A. Ovary, Adrenal, and Androgen Excess

PCOS is characterized by excessive ovarian and/or adrenal androgen secretion. Intrinsic ovarian factors such as altered steroidogenesis and factors external to the ovary such as hyperinsulinemia contribute to the excessive ovarian androgen production. Characteristic features include more growing follicles in women with PCOS compared with normal controls with premature growth arrest of antral follicles at 5 to 8 mm. The classic ovarian phenotype of enlarged ovaries with string-of-pearl morphology and theca interstitial hyperplasia reflects androgen exposure; this morphology has also been observed in women with congenital adrenal hyperplasia (CAH) and female-to-male transgender individuals [ 8 ]. Distorted interactions among the endocrine, paracrine, and autocrine factors responsible for follicular maturation may contribute to ovarian dysregulation in PCOS.

The stages of follicular maturation are briefly reviewed ( Fig. 2 ). Developing during gestation, primordial follicles are comprised of meiotically arrested oocytes surrounded by pregranulosa cells. Hence, a woman’s ovaries have been exposed to the ambient maternal environment during gestation. Ovaries are relatively quiescent until the onset of puberty. Detailed knowledge regarding follicular morphology in prepubertal and early pubertal ovaries is lacking. Ovarian tissue obtained from prepubertal and early pubertal girls shows differences in follicle morphology and growth potential. Specifically, prepubertal ovaries contain a high proportion of abnormal nongrowing follicles, which are not found in pubertal ovaries [ 9 ]. The physiologic relevance of this finding is unclear.

Ovarian follicle development. This illustration shows ovarian follicular development during developmental periods.

The precise signaling mechanisms initiating follicular activation are poorly understood. Presumably a balance of factors influences the options—continuation in a resting state or activation. One such factor appears to be follicle density [ 10 ]. Following activation from the resting pool, initial follicular growth is gonadotropin-independent until the antral stage.

Anti-Müllerian hormone (AMH), a glycoprotein secreted by granulosa cells, inhibits initial follicular recruitment and indicates follicular reserve. In contrast to mice where AMH inhibits preantral follicle growth and antral follicle maturation, AMH appears to promote growth of preantral follicles to the antral stage in nonhuman primate (NHP) ovaries [ 11 , 12 ]. Peak AMH concentrations are found in antral follicles. Once FSH-stimulated granulosa cell estradiol concentrations achieve the necessary threshold, estradiol suppresses AMH expression [ 13 ].

Despite prior assumptions that androgens negatively impact follicles, androgens synthesized in preantral follicle theca cells promote growth of preantral and antral follicles and induce granulosa cell FSH receptor (FSHR) expression in early antral follicles [ 14 ]. Androgens promote aromatase expression and, ultimately, LH/chorionic gonadotropin receptor (LHCGR) expression in granulosa cells. As a follicle matures, androgens appear to inhibit proliferation and promote apoptosis. This biphasic androgen action was initially demonstrated in an NHP, the marmoset; androgens augmented FSH action in small antral follicles but had an inhibitory effect in larger follicles [ 15 ].

Androgen actions are mediated by androgen receptors (ARs), which are expressed in theca cells, granulosa cells, oocytes, and stromal cells [ 16 ]. Both canonical androgen signaling where AR functions as ligand-dependent transcription factor and nongenomic signaling occur. Peak AR gene expression occurs in small antral follicles (∼6 mm in diameter) and decreases in antral and preovulatory follicles [ 17 ].

Typically, one follicle is “selected” as the dominant follicle [ 18 ]. With increasing estrogen secretion, pituitary FSH secretion declines due to negative feedback. The dominant follicle compensates for this loss of FSH stimulation through increased LHCGR expression and increased responsiveness to LH stimulation. Subordinate follicles undergo atresia, presumably due to relative FSH deficiency and androgen excess. Upon achieving a sufficient estradiol concentration, neuroendocrine mechanisms trigger the LH surge to induce ovulation.

Under normal circumstances, the ovarian stroma provides a structural framework undergoing dynamic changes to support follicular growth. However, the ovarian stroma from women with PCOS tends to be more rigid. The developing oocyte and its surrounding scaffolding rely on endocrine, paracrine, and autocrine signaling mechanisms to maintain cell-to-cell communication and assure synchronized developmental progression. Aberrant development during these earliest stages of follicular growth likely contributes to the ovarian aspects of PCOS [ 19 ]. Another feature of PCOS ovaries is accelerated transition from primordial to growing follicles with increased numbers of 2- to 3-mm and 3- to 4-mm follicles [ 20 , 21 ]. AMH concentrations correlate with the number of these small antral follicles [ 22 ]. The growing follicle is exposed to an atypical environment with increased LH, insulin, androgen, and AMH concentrations accompanied by insufficient FSH concentrations [ 19 ]. Additional differences in PCOS ovaries include factors impacting vascular function and immune responsiveness [ 23 ].

Additionally, intrinsic alterations in ovarian steroidogenesis likely contribute to excessive ovarian androgen production. Available data document constitutively increased androgen production and CYP17A1 expression in cultured theca cells isolated from PCOS ovaries [ 24–26 ]. Steroidogenesis in the ovary involves both theca and granulosa cells. The theca cells produce ovarian androgens, which are converted to estrogens in the granulosa cell due to the actions of FSH-stimulated aromatase.

One interesting locus identified through genetic studies is DENND1A (see “H. Genetics” below). Overexpression of the alternative spliced variant, DENND1A.V2 , of this gene recapitulated a PCOS phenotype in cultured theca cells obtained from normal women, indicating a role for this variant in the excessive theca cell androgen production [ 27 ]. Overexpression of DENND1A.V2 in an adrenal cell line led to increased expression of the mRNAs for CYP17A1 and CYP11A1 . However, the mechanisms responsible for increased expression of this alternatively spliced variant of DENND1A remain to be elucidated [ 28 ].

The adrenal zona reticularis is responsible for biosynthesis of the C-19 adrenal androgens, including dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione, and testosterone. At least three distinct adrenal pathways contribute to androgen synthesis: (i) canonical/classical, (ii) “alternative backdoor,” and (iii) 11-oxo-androgens ( Fig. 3 ). In the canonical/classical pathway, progesterone is successively transformed by the enzyme 17 α -hydroxylase/17,20-lyase (P450c17) to DHEA, which is subsequently converted by 3 β -hydroxysteroid dehydrogenase type 2 to androstenedione. The alternative backdoor pathway bypasses the usual steroid hormone intermediates, DHEA, androstenedione, and testosterone, to produce dihydrotestosterone [ 29 ]. This pathway likely contributes to virilization of the external genitalia among girls with classical CAH and normal male external genital development [ 30 , 31 ]. The extent of the contribution of the alternative backdoor pathway to adrenal and ovarian steroid biosynthesis in PCOS is unclear [ 32 ].

Androgen biosynthesis. This illustration shows the classical/canonical, alternative backdoor, and 11-oxo-steroid pathways for androgen biosynthesis.

The adrenal steroidogenic enzyme, 11 β -hydroxylase (P450c11B1), encoded by CYP11B1 , is expressed in both zona fasciculata and zona reticularis; this enzyme converts androstenedione and testosterone to their respective 11 β -hydroxyl derivatives, 11 β -hydroxy-androstenedione and 11 β -hydroxy-testosterone. Both 11 β -hydroxy-androstenedione and 11 β -hydroxy-testosterone can be converted to their 11-keto counterparts, 11-ketoandrostenedione and 11-ketotestosterone. Testosterone, DHT, 11-ketotestosterone, and 11-ketodihydrotestosterone bind to the human AR and promote AR-regulated gene expression [ 33 ]. The concentrations of these 11-oxygenated steroids were reported to be higher in women with PCOS than among healthy premenopausal women [ 34 ]. Urinary steroid profiling using 24-hour urine collections in a relatively small number of women with PCOS and controls found androstanediol concentrations to discriminate between PCOS and controls; the overall pattern of steroid hormone excretion indicated enhanced androgen biosynthesis via canonical/classical, alternative backdoor, and 11-oxygenated steroid pathways rather than a specific steroid enzyme disorder [ 35 ].

A-1. Preclinical models

One unresolved conundrum regarding folliculogenesis is the regulation and interrelationships between androgens and AMH. Androgens and AMH are essential for normal cyclic ovulation. Using short hairpin RNAs to decrease AMH expression in macaques, preantral follicle growth and survival were reduced. Cotreatment with supplemental AMH overcame these effects. These results emphasize the important role of AMH as a critical factor to promote preantral follicle survival and growth in primates [ 36 ]. AMH treatment of cultured antral stage rhesus macaque follicles decreased estradiol production compared with untreated follicles despite similar follicle size [ 12 ]. Hence, AMH appears to have a dual role: whereas AMH promotes preantral follicle survival, it negatively impacts later stages of antral follicle maturation [ 12 ].

In a series of in vivo and in vitro experiments, a subset of hypothalamic GnRH neurons, both mouse and human, were shown to express AMR receptors; AMH treatment increased GnRH-dependent LH pulsatility and secretion [ 37 ]. Using a mouse model, AMH treatment of pregnant mice was associated with diminished placental metabolism of testosterone to estradiol, decreased aromatase expression, masculinization of exposed female offspring, estrus cycle disturbances, increased LH pulse frequency, brain masculinization, and infertility compared with unexposed mice; postnatal GnRH antagonist treatment reversed this PCOS-like phenotype [ 38 ]. These data suggest that excessive prenatal AMH exposure could promote the aberrant neuroendocrine function typical of PCOS and that AMH can modulate GnRH neuron function [ 37 , 38 ].

Knockout mice have been used to explore consequences of gene deletions. Using a postnatal androgen PCOS model, global AR knockout mice were protected from DHT-induced PCOS-like features. Curiously, neuron-specific AR knockout mice were protected from DHT-induced ovarian dysfunction and several metabolic traits, reinforcing a role for extraovarian tissues in the pathophysiology of PCOS [ 39 ]. Hence, intricate interrelationships exist between androgens, AMH, follicle growth, metabolism, and neuroendocrine factors in PCOS.

Recently, a group of naturally hyperandrogenic female rhesus monkeys have been described. The high testosterone animals had increased LH, AMH, and androstenedione concentrations. Additionally, five of the six high-testosterone monkeys had no live offspring [ 40 ]. Future study of these animals will provide insight into the pathogenesis of PCOS.

B. Neuroendocrine Factors

Increased LH pulse frequency, LH pulse amplitude, and increased LH/FSH ratios are described in women with PCOS. The initial features of PCOS emerge during the early pubertal years, concomitant with reactivation of the hypothalamic GnRH pulse generator, increased gonadotropin secretion, and subsequent increased ovarian estrogen production. Loci identified in the genome-wide association studies (GWASs) studies include LHCGR , FSHR , and FSH- β polypeptide ( FSHB ) genes, emphasizing neuroendocrine contributions to PCOS pathophysiology (see H. Genetics below).

Hypothalamic neurons in the arcuate nucleus secrete kisspeptin, neurokinin B, and dynorphin. These neurons, labeled as the KNDy neurons, are the leading contenders for the hypothalamic GnRH pulse generator because of the colocalization of these three peptides and their roles in episodic GnRH secretion [ 41 ]. Rather than initiating puberty, the GnRH pulse generator and GnRH neurons represent downstream nodes modulated by other hormones and neurosecretory factors [ 42 ]. In other words, activation of excitatory inputs and inactivation of inhibitory inputs moderated by multiple influences regulate the output of the GnRH pulse generator to govern the timing of puberty [ 43–45 ]. This process culminates in increased GnRH and gonadotropin secretion.

The hypothalamic GnRH neurons secrete GnRH in discrete pulses that travel through the median eminence to the pituitary gonadotrophs, resulting in pulsatile LH and FSH secretion [ 46 ]. LH and FSH pulse frequencies are modulated by GnRH pulse frequency. Increased GnRH pulse frequency increases LH pulse frequency and decreases FSH pulse frequency [ 47 ]. The GnRH neurons integrate diverse influences, decode metabolic signals, and serve as the output “managers” of the HPO axis [ 48 , 49 ].

Increased LH pulse amplitude and pulse frequency observed in PCOS are likely driven by increased pulsatile GnRH secretion. Manipulation of the hypothalamic kisspeptin–neurokinin B–GnRH pathway with an NK3 receptor antagonist, AZD4901, reduced serum LH pulse frequency and, subsequently, serum LH and testosterone concentrations. These data suggest the possibility of targeting neuroendocrine pathophysiology to treat HPO axis dysfunction in PCOS [ 50 ].

GnRH neurons express estrogen receptor- β , but they do not express AR, progesterone receptor, or estrogen receptor- α . Hence, steroid-mediated negative feedback is indirect and is mediated through the hypothalamic neuronal network upstream of the GnRH neuron. This negative feedback mechanism is impaired in some women with PCOS who appear to require higher progesterone and estradiol concentrations. This effect can be abrogated with androgen antagonist treatment [ 51 ].

One conundrum is that LH hypersecretion is less obvious in women with obesity with PCOS. Although GnRH and LH pulses generally exhibit a 1:1 ratio, preclinical data exist suggesting that a faster GnRH pulse frequency may be associated with decreased LH secretion [ 52 ]. Potential explanations for this mismatch between GnRH and LH pulses include the longer half-life of LH obscuring pulse detection, exhaustion of the pituitary pool of readily releasable LH, or lower amplitude GnRH pulses [ 53 ]. Measurement of circulating kisspeptin and LH concentrations showed temporal kisspeptin–LH pulse coupling in eumenorrheic women with PCOS; however, a greater frequency of kisspeptin pulses was associated with a loss of temporal coupling in women with oligomenorrhea with PCOS [ 54 ]. This study identified dissociated coupling of kisspeptin and LH pulses in women with oligomenorrhea with PCOS.

Tanycytes are specialized nonciliated cells lining the floor of the third ventricle. These polarized cells contribute to regulation of reproduction and metabolism in the median eminence. Specifically, tanycytes affect GnRH secretion, generate active forms of thyroid hormone, and influence exchange of signaling factors such as leptin between the blood and hypothalamic extracellular fluid [ 55 ]. Dynamic structural remodeling of tanycytes modulates GnRH neuron access to the pituitary portal system. Leptin and ghrelin enter the hypothalamus through the tanycytes [ 56 ]. Astrocytes, located at the interface between blood vessels and neurons, can function as metabolic sensors. This physical location enables them to modulate glucose fluxes between the periphery and the central nervous system [ 57 ]. Hence, dynamic tanycyte–neuron interactions and astrocytes orchestrate the ongoing communication between the neuroendocrine axis and the periphery [ 58 ]. Whereas the precise role of tanycytes in PCOS is indeterminate, these cells likely allow leptin, ghrelin, and AMH access to GnRH neurons.

B-1. Preclinical models

Numerous studies have described the development of neuroendocrine features reminiscent of PCOS following prenatal androgen exposure in rodents, sheep, and rhesus macaques [ 59–61 ]. Prenatal androgen exposure during early gestation (late first to second trimester) increased LH and androgen secretion in female rhesus monkeys [ 59 ]. Prenatally androgenized (PNA) female mice showed increased γ -aminobutyric acid (GABA)ergic transmission to GnRH neurons by 3 weeks of age, suggesting that prenatal androgen treatment affected neuronal development [ 62 ]. Questions regarding prenatal imprinting of the neuroendocrine components of the HPO axis persist.

C. Valproate and HPO Axis Function

Valproic acid (VPA), a branched short-chain fatty acid derived from valeric acid, is used to treat epilepsy, bipolar disorders, and prevent migraine headaches. VPA increases GABA levels by interfering with GABA degradation pathways [ 63 ]. GnRH neurons express both GABA A and GABA B receptors, implicating GABA signaling in the regulation of GnRH secretion. Signaling through the GABA A receptor can elicit an excitatory effect on GnRH neurons [ 64 ].

Women treated with VPA can develop PCOS-like symptoms. Lean women with PCOS had significantly higher CSF GABA concentrations compared with eumenorrheic lean control women; the women with PCOS also demonstrated increased LH pulse amplitude and LH pulse frequency on frequent blood sampling [ 65 ]. These clinical observations suggest that GABA signaling could influence the neuroendocrine changes associated with PCOS such as LH pulse frequency.

C-1. Preclinical models

PNA mice models have enabled investigation regarding the consequences of prenatal androgen exposure. In an elegant series of experiments, Silva et al. [ 66 ] demonstrated increased GABA synaptic input in prepubertal PNA mice. Their observations suggest that prenatal androgenization is associated with prenatal enhanced GABAergic structural wiring input onto GnRH neurons, that these changes are reversible with long term antiandrogen treatment, and that these structural changes precede postpubertal development of PCOS features [ 66 ].

D. Insulin Resistance, Hyperinsulinemia, and the β -Cell

The phenotype of female patients with insulin receptor gene mutations includes insulin resistance (IR), compensatory hyperinsulinemia, and hyperandrogenism [ 67 ]. Although IR and hyperinsulinemia are commonly detected in women with PCOS, insulin receptor gene mutations are extremely rare among women with PCOS.

Women with PCOS have intrinsic IR independent of the extent of obesity and magnitude of androgen concentrations [ 68 ]. Even lean women with PCOS manifest IR; increasing body mass index (BMI) exacerbates IR [ 69 ]. Normal-weight adolescent girls with PCOS have peripheral IR, increased liver fat, and muscle mitochondrial dysfunction compared with normal-weight girls [ 70 ].

Insulin is the hormone primarily responsible for glucose homeostasis and lipogenesis. In addition to its effects on carbohydrate, fat, and protein metabolism, insulin functions as a mitogenic hormone. Insulin actions are mediated by insulin receptors, which are found in numerous tissues of the HPO axis. In steroidogenic tissues such as the ovary and the adrenal cortex, insulin potentiates the cognate trophic hormones to promote steroidogenesis. The compensatory hyperinsulinemia associated with IR provokes excessive ovarian/adrenal androgen secretion and decreases hepatic SHBG synthesis with the net result of increasing circulating testosterone concentrations. This leads to the paradox of insulin signaling in PCOS; liver, skeletal muscle, and adipose tissue exhibit IR, whereas steroid-producing tissues and the pituitary retain insulin sensitivity [ 71 , 72 ]. This paradox is illustrated by differences in insulin actions in granulosa–lutein cells obtained from women with anovulation with PCOS; insulin-stimulated glucose uptake is impaired whereas insulin-stimulated progesterone production is preserved [ 73 ].

The central role of compensatory hyperinsulinemia has been established by improved clinical features with insulin-sensitizing medications and weight loss. The transient IR and hyperinsulinemia typical of early puberty may kindle the factors associated with development of PCOS [ 74 , 75 ].

The prevalence of the metabolic syndrome defined as obesity, hypertension, dyslipidemia, and hyperglycemia is approximately threefold higher in women with PCOS [ 76 ]. Although a consensus definition of metabolic syndrome in adolescents is lacking, published pediatric criteria are based on adult criteria and include a combination of elevated triglyceride concentration, elevated low high-density lipoprotein cholesterol concentration, fasting blood glucose ≥110 mg/dL, increased waist circumference, and hypertension for age [ 77 ]. A meta-analysis suggested that although IR is likely a common factor linking the metabolic and reproductive features of PCOS, the metabolic and reproductive features develop through independent mechanisms [ 78 ]. One relatively consistent finding is that obesity exacerbates the symptoms of PCOS, especially regarding the risk for development of T2D and the metabolic syndrome [ 76 ].

Primary hyperinsulinemia can precede the development of peripheral tissue IR. It is beyond the scope of this review to discuss arguments supporting the opposing viewpoints, that is, primary IR vs primary hyperinsulinemia [ 79 ]. Importantly, numerous genetic and epigenetic factors, nonheritable prenatal and extrauterine environmental influences, and varying adaptations to nutrient excess likely contribute to the development of IR and hyperinsulinemia.

D-1. Preclinical models

Preclinical data show β -cell dysfunction associated with hyperinsulinemia in monkeys and sheep prenatally exposed to androgens [ 80 , 81 ].

E. Obesity, the Adipocyte, and Nutrient Excess

Overweight and obesity are common among adolescent girls and adult women with PCOS. In response to nutrient excess, adipocytes can enlarge (hypertrophy) or form new adipocytes (hyperplasia). According to the adipose tissue expandability hypothesis, adipocyte hypertrophy establishes a microenvironment characterized by hypoxia, proinflammatory cytokine secretion, free fatty acid “spillover,” macrophage invasion, and IR [ 82 ]. IR decreases suppression of adipocyte lipolysis, resulting in increased serum free fatty acids and triglycerides, ultimately leading to increased hepatic de novo lipogenesis and hyperlipidemia [ 83 ]. Another consequence is increased fat storage in skeletal muscle, liver, and pancreas because the adipose tissue capacity to store lipid is exceeded. In the liver, ectopic fat storage is labeled hepatic steatosis, which can develop into nonalcoholic fatty liver disease [ 84 ].

White adipose tissue has several distinct locations, that is, visceral and subcutaneous. Partitioning of fat among different storage sites influences metabolic consequences: increased abdominal fat is associated with greater risk for dysglycemia and cardiovascular disease. Investigation of normal-weight women with PCOS showed increased total abdominal fat mass due to preferential deposition of intra-abdominal fat with an increased population of small subcutaneous abdominal adipocytes [ 85 ]. In a pilot study involving normal-weight women with PCOS, subcutaneous adipose IR correlated with serum androgen concentrations and the percentage of small subcutaneous abdominal adipocytes. These data support the hypothesis that expansibility of the subcutaneous abdominal adipose depot is limited and unable to expand sufficiently to meet the metabolic needs for most normal-weight women with PCOS [ 86 ]. Emerging pilot data in adolescent girls with PCOS showed that reduction of visceral fat improved menstrual irregularity [ 87 ].

In a small cross-sectional study, girls related to women with PCOS showed higher 17-hydroxyprogesterone concentrations, decreased insulin sensitivity, and decreased insulin-induced suppression of nonesterified fatty acid concentrations compared with healthy control girls. These findings suggest onset of adipocyte dysfunction, IR, and possible lipotoxicity among girls aged ∼9 to 15 years [ 88 ]. In another small study using frequently sampled IV glucose tolerance tests, the authors reported early β -cell dysfunction in first-degree female relatives with overweight/obesity of women with PCOS compared with control girls with overweight/obesity [ 89 ]. Small sample sizes limit the conclusions that can be drawn from these studies. Nevertheless, the studies hint that β -cell function and insulin sensitivity may differ beginning in childhood and early adolescent years among girls “destined” to develop PCOS.

Mismatches between prenatal and postnatal weights have led to the advance of the developmental origins of disease hypothesis [ 90 ]. The longitudinal prospective population-based study (Northern Finland Birth Cohort Study) found that women with PCOS had lower birth weights, experienced adiposity rebounds at younger ages, and had higher subsequent BMI values [ 91 ]. These findings are consistent with the concept that a mismatch between prenatal weight and postnatal weight gain is associated with increased risk for PCOS, ectopic fat storage, and hepatic steatosis [ 92–94 ].

Adipose tissue expresses enzymes that activate and inactivate androgen precursors. The enzyme aldo-ketoreductase type 1C, encoded by the AKR1C3 gene, is expressed in adipose tissue and converts the preandrogen androstenedione to testosterone. Additionally, the enzyme 5 α -reductase type 1, encoded by the SRD5A1 gene, converts testosterone to DHT and is expressed in adipose tissue. A deep in vivo metabolic phenotyping study showed increased AKR1C3 and decreased SRD5A1 mRNA expression in subcutaneous fat of women with PCOS [ 95 ]. Activation appears to regulate adipocyte proliferation and differentiation, insulin sensitivity, adipokine signaling, and lipid metabolism [ 96 ]. Using a human preadipocyte cell line, both testosterone and DHT increased de novo lipogenesis in the absence of insulin [ 95 ], whereas pharmacologic inhibition of AKR1C3 activity prevented androgen-mediated adverse effects on adipocyte lipogenesis. Using this model system, insulin increased AKR1C3 expression. Based on these data, O’Reilly et al. [ 95 ] proposed the existence of a vicious cycle linking adipocyte androgen biosynthesis and adipocyte lipid accumulation to IR and hyperinsulinemia.

Another situation demonstrating androgen effects on lipid metabolism was described in girls with obesity with and without PCOS. Girls with obesity with PCOS compared with those without PCOS demonstrated decreased lipid mobilization, diminished fat oxidation, and impaired ability to switch from lipid to carbohydrate oxidation during insulin stimulation (metabolic inflexibility) [ 97 ].

E-1. Preclinical models

In a treatment paradigm comparing a high-fat diet with/or without testosterone treatment in rhesus monkeys, the combination of a high-fat diet and testosterone treatment accelerated development of white adipose tissue dysfunction [ 98 ].

F. Developmental Hypothesis/Fetal Origins

The developmental theory of PCOS proposes that exposure of the female fetus to elevated androgen concentrations contributes to the development of PCOS. Potential mechanisms include effects on steroidogenesis, insulin signaling, pancreatic β -cell function, hypothalamic–pituitary organization, neuroendocrine secretory patterns, and epigenetic modifications [ 99 ].

Fetal, neonatal, prepubertal, and/or pubertal ovaries may be genetically predisposed to increased androgen secretion [ 100 , 101 ]. Women with classical CAH often develop a secondary PCOS phenotype; it is unclear whether this reflects prenatal imprinting of the hypothalamus and GnRH pulse generator or androgen effects on the ovary [ 102 ]. Available data support the hypothesis that prenatal androgen exposure programs the neuroendocrine, metabolic, and reproductive manifestations of PCOS [ 103 ]. Women with PCOS typically have higher androgen concentrations than do women without PCOS. One report involving 23 mothers self-reporting PCOS and 277 women reporting no PCOS indicated increased anogenital differences, a marker of prenatal androgen exposure, in daughters of women with PCOS [ 104 ]. How the fetus is exposed to androgen excess when placental aromatase and maternal SHBG limit fetal exposure to maternal androgens remains an enigma.

F-1. Preclinical models

Preclinical models involving androgen exposure in rodents, sheep, and NHPs recapitulate features of PCOS. Impaired adipocyte differentiation has been demonstrated in NHP models [ 105 ]. Among prenatally androgenized NHPs, when the capacity of subcutaneous adipocytes to store fat is exceeded, excess free fatty acids may be deposited in ectopic locations such a liver and muscle; consequences of ectopic fat deposition may include impaired tissue hypoxia, inflammation, and IR [ 106 ]. Curiously, transient pancreatic dysfunction manifested by hypoglycemia, an increased number of β -cells, small islets, and relative hyperinsulinemia have been observed in this NHP model of early gestational androgen exposure [ 80 ]. Early pubertal NHP treated with testosterone and a “Western style diet” with increased fat content showed increased larger visceral adipocytes, greater IR, and ectopic fat storage [ 106 ].

G. Microbiome

Bacteria, archaea, fungi, and viruses comprise the microbial community or microbiome of the gastrointestinal tract. These organisms play roles in fermentation of dietary fiber, bile acid metabolism, host defense, and modulation of metabolism. It has been suggested that the gut microbiome influences development of nonalcoholic fatty liver disease and is associated with insulin sensitivity [ 107 , 108 ]. Sex and sex steroids modulate the composition of the gut microbiome. Women are reported to show greater α -diversity. α -Diversity represents the number of species, and β -diversity indicates similarity between samples. Decreased α -diversity has been described in women with PCOS [ 109 , 110 ]. Numerous questions remain to be answered regarding the functional relationships, if any, between sex steroids, metabolic dysregulation, and the gut microbiome [ 111 ]. To the best of our knowledge, no data for adolescents are available.

H. Genetics

Twin studies suggest that the hereditability is ∼70% [ 112 ]. The few identified genetic loci explain only a modest proportion of estimated hereditability. GWASs involving women of Han Chinese and European origins have identified at least 16 susceptibility loci for PCOS [ 113–116 ]. Several genetic variants are similar in both Han Chinese and European populations, implying that PCOS is an ancient disease [ 117 ]. Several novel loci have recently been identified [ 118 ]. A meta-analysis showed that identified loci are linked to genes plausibly associated with the metabolic and reproductive characteristics of PCOS [ 118 ]. Linkage disequilibrium score regression analysis demonstrated genetic correlations with metabolic traits, that is, fasting insulin, lipid levels, and PCOS. With the exception of the GATA4/NEIL2 locus, the genetic architecture did not differ whether National Institutes of Health or Rotterdam criteria were used to diagnose PCOS [ 118 ]. Genes involved in HPO axis function, that is, LHCGR , FSHR , and FSHB , were identified in these GWASs implicating gonadotropins in the pathophysiology of PCOS [ 115 ]. Using family-based quantitative trait meta-analysis, rare DENND1A variants were associated with metabolic and reproductive traits in PCOS families; these data are consistent with the hypothesis that complex disorders such as PCOS are associated with genetic variations in noncoding regions [ 119 ]. Epigenetic modifications such as changes in methylation and miRNAs offer another level of regulation affecting the PCOS phenotype. Epigenetic variants have been reported for adipose tissue and muscle [ 120 , 121 ].

The classic features of PCOS include clinical or biochemical hyperandrogenism, oligomenorrhea or amenorrhea associated with chronic anovulation, and polycystic ovary syndrome morphology [ 122 ]. The current consensus is that use of the Rotterdam criteria is appropriate for adult women. For diagnosis of PCOS, women must fulfill two of the three characteristics: oligo-ovulation or anovulation, clinical and/or biochemical hyperandrogenism, or polycystic ovary morphology on ultrasound with exclusion of other disorders. The 2012 National Institutes of Health–sponsored Evidence-Based Methodology PCOS Workshop categorized PCOS into four phenotypes as follows: phenotype A, hyperandrogenism, ovulatory dysfunction, and polycystic ovary morphology; phenotype B, hyperandrogenism and ovulatory dysfunction; phenotype C, hyperandrogenism and polycystic ovary morphology; and phenotype D, ovulatory dysfunction and polycystic ovary morphology [ 123 , 124 ].

However, delineating appropriate diagnostic criteria for PCOS among adolescent girls has been problematic because irregular menses, cystic acne, mild hyperandrogenism, and multifollicular ovarian morphology occur during normal pubertal maturation. These similarities between normal pubertal development and the clinical features associated with PCOS confound the diagnosis in adolescent girls ( Table 1 ) [ 125–127 ]. Similar to the evaluation of adult women, other disorders associated with irregular menses and/or hyperandrogenism need to be excluded. These disorders include CAH, typically nonclassic 21-hydroxylase deficiency, androgen-secreting tumors, thyroid dysfunction, hyperprolactinemia, Cushing syndrome, exogenous use of steroid hormones/androgens, or severe IR syndrome [ 128 , 129 ].

Definition of Irregular Menses in Adolescent Girls

[Adapted from: Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018;110(3):364–379.].

With reactivation of the GnRH pulse generator, increased gonadotropin secretion stimulates ovarian estrogen secretion and follicular development. Estrogen promotes uterine growth and endometrial proliferation; endometrial estrogen exposure eventually culminates in vaginal withdrawal bleeding and menarche. A longitudinal study found that the median age at menarche for American girls was 12.25 years, with lower menarcheal ages in black and Hispanic girls compared with white and Asian girls [ 130 ]. By age 15 years, 98% of girls will have experienced menarche [ 131 ].

Contemporary understanding is that it takes 3 to 4 years postmenarche for adult menstrual cyclicity to mature. By the third year after menarche, 10 or more menses occur annually in 90% of adolescent girls [ 132 ]. Approximately 41% of girls have achieved ovulatory cycles by the fourth gynecologic year [ 133 ]. Importantly, ovulation may occur despite irregular menses [ 134 ].

Currently, evidence-based data regarding the first gynecologic year are limited and are largely derived from studies published prior to 2000. A 2018 systemic review of menstrual patterns during the first gynecologic year concluded that menstrual and ovulatory patterns are diverse during this time period. In 22 studies involving >2000 adolescents, frequent menstrual bleeding (<21 days) occurred in 23% and prolonged menstrual bleeding (>30 to 45 days) occurred in at least 33% [ 135 ]. A pilot study entailing serial hormone concentrations and ultrasound studies in ovulatory postmenarcheal girls revealed lower steroid (estrogen and progesterone) concentrations, slower dominant follicle growth rate, and longer follicular phases compared with adult women; these data suggest that coordinated development of all components of the HPO axis may take up to 5 years postmenarche [ 136 , 137 ].

Oligomenorrheic adolescents tend to have persistent oligomenorrhea [ 138 , 139 ]. Secondary amenorrhea for >90 days is uncommon and warrants additional consideration. Girls presenting with primary amenorrhea at ages 15 to 16 years merit further evaluation.

B. Hyperandrogenism

Hirsutism, defined as excessive terminal hair growth in male pattern distribution in women, is the primary clinical sign of hyperandrogenism. The modified semisubjective Ferriman–Gallwey scoring system is one widely used approach [ 140 , 141 ]. The extent of the clinical features of hyperandrogenism represents the interactions between circulating androgen concentrations, local androgen concentrations, and sensitivity of the pilosebaceous unit/hair follicle to androgens. The severity of hirsutism does not correlate with circulating androgen concentrations. Ethnic and genetic variations influence the development of hirsutism [ 141 ]. Depending on ethnicity, a modified Ferriman–Gallwey score ≥4 to 6 indicates hirsutism [ 125 ]. Other cutaneous signs of androgen excess include severe cystic acne and male pattern baldness.

Biochemical hyperandrogenism is confirmed by documentation of elevated serum androgen concentrations. One caveat is the importance of measuring androgens using high-quality assays such as liquid chromatography–tandem mass spectrometry or extraction/chromatography immunoassays [ 142 ]. Calculated free testosterone, free androgen index, calculated bioavailable testosterone, androstenedione, and DHEAS may provide helpful information. Testosterone determinations are confounded by several problems, including inadequate assay sensitivity to accurately measure low concentrations, limited evidence-based normal ranges, assay interference due to other steroid molecules or SHBG, and technical aspects of the assay methodology. In view of these constraints, the Canadian Laboratory Initiative in Pediatric Reference Intervals (CALIPER) project has developed sensitive and accurate liquid chromatography–tandem mass spectrometry methodology to simultaneously measure eight steroids [ 143 ]. Measuring 11-oxo-androgens shows promise as a method to assess for hyperandrogenism [ 144 , 145 ].

C. Polycystic Ovary Morphology

Polycystic ovary morphology (PCOM) is defined as enlarged ovaries with increased stroma and more small peripheral cysts. The Androgen Excess–PCOS Society Task Force recommended that PCOM is defined as ≥20 follicles per ovary using a transvaginal probe and high-resolution technology (transducer frequency ≥8 MHz) [ 146 ]. However, assessment of ovarian morphology is difficult in the adolescent girl because the increased gonadotropin stimulation leads to increased ovarian volume and follicular growth, giving rise to the appearance of multifollicular ovaries in adolescent girls. Additionally, use of transvaginal probes are problematic in adolescent girls. PCOM is an inconsistent finding in adolescent girls and is not associated with anovulation or metabolic abnormalities [ 147 ]. Hence, ovarian ultrasounds are unnecessary in adolescent girls.

D. Evaluation and Diagnosis

The approach to the evaluation of a girl with signs and symptoms suggestive of PCOS begins with a thorough history, including detailed family history and complete physical examination. The individualized laboratory evaluation typically includes thyroid function studies as well as the determination of prolactin, total testosterone, androstenedione, SHBG, DHEAS, and 17-hydroxyprogesterone concentrations. Direct free testosterone assays should be avoided due to inadequate sensitivity, accuracy, and reproducibility of available assays. Fasting glucose, HbA1c, and lipid concentrations should be determined. Ideally, the blood sample should be obtained prior to 8:30 am . If CAH is a diagnostic possibility, an ACTH stimulation test can be obtained. The cut point of a basal 17-hydroxyprogesterone >200 ng/dL has been suggested as the threshold for performing ACTH stimulation tests [ 148 ]. Nevertheless, when the clinical picture is highly suggestive of a steroidogenic enzyme deficiency, an ACTH stimulation test might be warranted. Adrenal and pelvic imaging may be considered depending on the clinical information, physical examination, and initial laboratory data.

AMH concentrations are often elevated in women with PCOS. AMH concentrations reflect ovarian reserve and are correlated with the number of growing follicles [ 149 ]. Although it is premature to use AMH concentrations to diagnose PCOS, AMH concentrations have been found to be elevated in nonobese girls with PCOS [ 150 , 151 ]. AMH concentrations were found to be higher in girls with obesity with PCOS compared to girls with obesity without PCOS of comparable age and pubertal status [ 152 ].

Insulin resistance, hyperinsulinemia, and obesity are commonly identified in women with PCOS. However, with the exception of a single publication, none of the current definitions, recommendations, or guidelines includes IR and/or hyperinsulinemia as a diagnostic feature [ 153 ].

Hence, the diagnosis of PCOS can be considered for the adolescent girl with persistence of oligoamenorrhea for 3 to 4 years postmenarche with clinical and/or biochemical hyperandrogenism after exclusion of other disorders associated with irregular menses or hyperandrogenism. When oligomenorrhea has not persisted for >2 years, these girls can be considered to be “at risk” for PCOS and require longitudinal evaluation to assess for ongoing features of PCOS. Deferred diagnosis attempts to avoid overdiagnosis with its potential for premature labeling, anxiety, and unnecessary interventions. Nevertheless, diagnostic labeling needs to be balanced with the patient’s desire for a diagnosis and specific therapeutic interventions [ 125–127 , 154 , 155 ].

Adolescents presenting with PCOS features, before the diagnosis is confirmed, often require management of their symptoms [ 125–127 ]. The management of adolescents with a clear diagnosis of PCOS should include education about the condition and lifestyle interventions. The interventions can be individualized to target the foremost complaints and symptoms. Interventions include metformin, combined oral contraceptive pills (COCPs), spironolactone, and local treatments for hirsutism and acne. Management should also include management of comorbidities, regular follow-up, and a plan for transition to adult care providers.

A. Education and Counseling

Education and counseling about the condition is very important. The explanation and discussion of PCOS should be culturally sensitive as well as appropriate, comprehensive, and tailored to the individual [ 125 ]. This discussion should use an empathetic approach, promote self-care, and highlight peer support groups, which are available in multiple countries ( www.pcoschallenge.org/ , www.verity-pcos.org.uk/ , and www.facebook.com/PCOSAustralia/ ). Counseling about fertility concerns is important, as adolescents with PCOS are more concerned than theirs peers about future fertility after diagnosis [ 156 ].

B. Lifestyle Interventions

Healthy lifestyle interventions must be incorporated in the management plan of all adolescents with PCOS [ 125–127 ] because a large proportion of these adolescents are overweight/obese or are at risk for gaining excessive weight [ 157 ]. Lifestyle interventions comprise multiple components, including healthy diets, physical activity, decreased sedentary behaviors, and behavioral strategies [ 158 ]. The interventions should also include the family, as parents’ involvement and their readiness to change affect adolescent outcomes [ 159 , 160 ]. Engagement and adherence to lifestyle interventions can be improved by management of psychological factors such as anxiety, body image concerns, and disordered eating, which are common in adolescents [ 125 , 161 ]. Two systematic reviews of lifestyle interventions in women with PCOS show improvements in weight, hyperandrogenism, and IR [ 162 , 163 ]. Lifestyle interventions in adolescents with PCOS have shown additional improvements in quality of life [ 160 , 164 , 165 ].

Limited data are available regarding the specific type of diet to achieve weight loss in PCOS [ 125 ]. Five randomized controlled trials (RCTs) have evaluated diets in the management of adolescents with overweight/obesity with PCOS, with only three that evaluated diet as a single intervention [ 160 , 164 , 166–168 ]. A low-carbohydrate diet (20 to 40 g/d) and a hypocaloric diet (<40 g of fat per day) during 12 weeks improved weight and menstrual irregularities with no difference between the diets. Similarly, both low–glycemic load and low-fat diets during 6 months improved weight with no difference between diets [ 168 ]. A low-energy diet compared with a healthy diet for 6 months was associated with weight loss, more regular menses, and decreased hirsutism [ 167 ]. Nutrition education in addition to exercise training and behavioral therapy for 12 months resulted in weight loss, as well as improvement of menstrual irregularities and androgen levels in adolescents with obesity and PCOS [ 160 ].

Physical activity of longer duration, frequency, and intensity results in better maintenance of health. Importantly, moderate to vigorous physical activity for at least 60 minutes per day is associated with better physical and psychosocial health in children and adolescents [ 169 ]. Sixty minutes of moderate to vigorous physical activity at least 3 times a week should be encouraged for the prevention of weight gain and maintenance of health in PCOS [ 125 , 170 ]. Exercise interventions can also improve cardiometabolic risk factors in women with PCOS [ 171 ]. Alternative exercise activities such as yoga for 12 weeks can also improve PCOS symptoms during adolescence [ 172 ]. Limiting sedentary behaviors such as watching television and the use of tablets, computers, and/or mobile phones to 2 h/d is advised for adolescents and relates to better health [ 173 ].

Data regarding behavioral interventions in adolescents with PCOS are limited [ 125 ]. However, family therapy in addition to other lifestyle interventions show beneficial effects on adolescent PCOS symptoms, and a small open trial shows that cognitive behavior therapy improved depressive symptoms [ 160 , 174 ].

Prevention of weight gain and effective weight management is important in adolescent PCOS, as obesity exacerbates metabolic and psychological comorbidities of PCOS [ 175 , 176 ]. Additionally, weight loss strategies up to 7% of body weight have resulted in improving menstrual irregularity and testosterone levels [ 164 , 167 ]. There are limited data for the use of weight loss medications in adolescents.

C. Metformin

Metformin is the single most studied insulin sensitizer in PCOS. It is commonly used in adolescents 15 to 19 years of age despite being “off label” for this indication [ 177 ]. Additionally, according to the recent international evidence-based guidelines for assessment and management of PCOS, “The use of metformin in addition to lifestyle could be considered in adolescents with a clear diagnosis of PCOS or with symptoms of PCOS before the diagnosis is made” [ 125 ].

A meta-analysis of metformin use with and without lifestyle changes in PCOS (including two RCTs in adolescents [ 164 , 178 ]) showed beneficial effects on BMI and menstrual cycles [ 164 , 178 , 179 ]. There have been multiple observational studies and six RCTs evaluating the effect of metformin on a total of 275 adolescents with PCOS. These studies have demonstrated short-term beneficial effects mostly in adolescents with overweight/obesity [ 164 , 180–183 ]. Metformin doses used ranged from 1000 to 2000 mg daily with the major side effect being mild gastrointestinal distress. Limitations are that the frequency of side effects and adherence to medications have not been fully reported. Side effects can be reduced by starting metformin at a lower dose with slow increments and the use of extended release preparations. RCTs were mostly of 6-month duration; only one study lasted 24 months, and no longer-term studies have been reported.

Metformin at a dose of 1700 to 2000 mg/d is associated with greater improvement of BMI, and COCPs are associated with improvement in menstrual irregularity and acne according to a meta-analysis of metformin vs oral contraceptives in adolescents with PCOS and including four RCTs (170 adolescents) [ 164 , 180–184 ]. Both metformin and oral contraceptives had similar beneficial effects on hirsutism, triglycerides, and high-density lipoprotein cholesterol, but the estimates of effect were derived from low-quality evidence involving small studies [ 184 ]. Meta-analyses including larger number of RCTs in women with PCOS showed limited or no benefit of insulin sensitizers on hirsutism [ 185 , 186 ].

Metformin also can be used in addition to COCPs, especially in adolescents with PCOS and BMI ≥25 kg/m 2 , as well as high–metabolic risk groups such as certain ethnicities and individuals at increased risk of type 2 diabetes [ 125 ].

COCPs (estrogen and progestin preparations) should be considered for management of menstrual irregularity and/or clinical hyperandrogenism in adolescents with a clear diagnosis of PCOS and in adolescents at risk of PCOS before the diagnosis is confirmed according to the recent international evidence-based guidelines [ 125 ]. There are limited evidence-based data regarding specific types or doses of progestins, estrogens, or combinations of COCPs for management of PCOS in adolescents and women, but the lowest effective estrogen dose (20 to 30 µg of ethinylestradiol) should be considered [ 125 ]. Contraindications such as thromboembolism risk should be assessed when prescribing COCPs by obtaining thorough medical histories of the patient and her family. In most instances, 35 µg of ethinylestradiol plus cyproterone acetate preparations should not be considered first line in PCOS [ 125 , 187 ]. Duration of treatment has not been evaluated beyond 24 months in adolescents with PCOS. However, COCPs have been used for contraception in longer periods of time.

COCPs improve menstrual irregularity in adolescents with PCOS [ 164 , 180–184 ]. COCPs should be also offered when contraception is required and/or medical treatment of hirsutism or acne is needed [ 184 ]. When no contraception is required, menstrual irregularity alone can also be managed with cyclical medroxyprogesterone acetate (10 mg per day for 10 days) [ 188 , 189 ]. This can be offered when there is a desire to have fewer menstrual cycles and/or a preference for not taking daily medications or being on COCPs due to cultural reasons.

E. Management of Hirsutism

Acknowledgment of the significance of the hirsutism, irrespective of the severity, for a particular adolescent is important when offering treatment options as well as understanding expectations of the treatment [ 125 ]. Long-term commitment is required for any topical and/or medical interventions. More severe hirsutism may require a combination of strategies. Current available therapies have been mostly evaluated in women and include physical hair removal methods, topical medications, light-based therapies, COCPs, and antiandrogens [ 190–192 ].

Physical hair removal methods include waxing, shaving, chemical epilation, plucking, bleaching, and electrolysis. All but electrolysis are temporary hair removal methods, easily available and commonly used by adolescents even before they are evaluated for PCOS. There have been no RCTs evaluating these methods. Electrolysis is a permanent hair removal method, as it causes destruction of hair bulb, but it requires an experienced technician and can cause scaring and pigmentation changes [ 193 ].

Topical medications such as 13.9% eflornithine cream, an irreversible inhibitor of ornithine decarboxylase, affects hair follicle growth and differentiation and can improve mild facial hirsutism in women with mild skin irritation [ 194 , 195 ].

Professional light-based therapies include lasers (alexandrite, diode, and neodymium-doped yttrium aluminum) and intense pulsed light. These light therapies provide wavelengths of 600 to 1100 nm that are absorbed by the melanin in the hair and destroy the hair. This approach provides a prolonged solution for hirsutism after multiple treatments. The light can also be absorbed by epidermal melanin, which is greater in darker skinned individuals, increasing the risk of blisters, dyspigmentation, and scarring [ 196 ]. The neodymium-doped yttrium laser has longer wavelengths, which is less absorbed by epidermal melanin of darker skinned individuals, decreasing side effects. Light-based therapies should be the first line of treatment of localized hirsutism [ 125 , 126 ]. Laser treatment was associated with a 50% reduction of hair at 6 months after treatment with mild side effects such as pain, skin redness, and perifollicular edema [ 197 ]. Uncommon side effects include burns, blisters, hyperpigmentation/hypopigmentation, and scarring that can be reduced by topical anesthetic creams prior to treatment and by cooling mechanisms after treatment. Sun exposure should be avoided before and after treatment. Improvement of hirsutism with laser has been associated with improvement in quality of life, anxiety, and depression in young women with PCOS [ 198 , 199 ].

Light-based home-use devices are also available and approved by the US Food and Drug Administration. These devices provide less optical energy and should be carefully used to avoid injuries to skin and eyes [ 200 , 201 ]. Fewer RCTs have evaluated the efficacy of these devices [ 202 ].

Hormonal therapies should be considered in moderate or severe forms of hirsutism and include COCPs and antiandrogens [ 192 ]. COCPs alone improve hirsutism in adolescents with PCOS [ 184 ]. Estrogens in the COCPs decrease free androgens by increasing hepatic production of SHBG and decrease ovarian and adrenal androgen production by suppressing LH levels [ 203 ]. Progestins in the COCPs also have some antiandrogenic properties by blocking the AR and inhibiting 5 α -reductase activity. A small RCT involving adolescents with PCOS showed no difference in hirsutism improvement when two COCPs were compared during 12 months (30 µg of ethinyl estradiol and 0.15 mg of desogestrel vs 35 µg of ethinyl estradiol and 2 mg of cyproterone acetate) [ 204 ]. However, cyproterone acetate is not available in the United States.

Spironolactone, cyproterone acetate (which can be part of COCPs), and flutamide are antiandrogens that have been evaluated and used to treat hirsutism in women [ 191 ]. Spironolactone is an aldosterone antagonist that blocks the AR. It should be used after 6 months of COCPs; monitoring for side effects such as volume depletion and electrolyte disturbances should be explained and performed [ 125 , 205 ]. The starting dose for spironolactone is ∼25 mg/d. Subsequently, doses can range from 100 to 200 mg/d divided in two doses. Flutamide at a dose of 250 to 500 mg/d divided in two doses during 12 months has shown beneficial effects on hirsutism in women, but there are no RCTs evaluating the effect of flutamide alone or in combination with COCPs in adolescents. Low doses of flutamide (125 mg/d) in combination with metformin have been used in adolescents with ovarian hyperandrogenism [ 206 ]. Flutamide has been associated with severe side effects such as liver toxicity [ 191 , 207 ]. Finasteride is a topical medication that inhibits 5 α -reductase that should be avoided in adolescents, as data are very limited even among adult women [ 190 ].

Antiandrogens alone could be considered to treat hirsutism or alopecia when COCPs are contraindicated or poorly tolerated. However, antiandrogens must be used with effective contraception in sexually active adolescents to avoid fetal undervirilization [ 125 , 126 ]. The combination of COCPs and antiandrogens is superior for management of hirsutism [ 186 ].

F. Management of Acne

Treatment will be guided by severity of acne with the following goals of treatment: reduction of sebum production, prevention of formation of microcomedones, suppression of Propionibacterium acnes , and reduction of inflammation to prevent scaring [ 208 ]. Mild acne can be managed initially with over-the-counter topical treatments such as benzoyl peroxide 0.1%/2.5% (Epiduo gel) or topical retinoids or the combination of the two agents as well as appropriate skin care. Moderate and severe forms of acne require the addition of systemic antibiotics (macrolides) for 3 or 4 months but discontinuation after new inflammatory lesions have stopped appearing [ 208 , 209 ]. COCPs can also be added for management of moderate to severe acne in adolescents [ 184 ]. Timely referral to a dermatologist should be considered when the response is poor or in severe cases, as acne has a major negative impact on adolescent psychosocial well-being.

G. Screening of Other Comorbidities

Additional comorbidities can occur in adolescents with PCOS that might be independent of overweight status. These comorbidities include impaired glucose tolerance and type 2 diabetes [ 125 , 126 , 210 , 211 ]. Additional comorbidities include decreased quality of life, depression, anxiety, eating disorders and disordered eating, and altered body image [ 192 , 212–214 ]. Identification of IR, hyperinsulinemia, and obesity galvanizes efforts to investigate and initiate treatment of associated comorbidities such as impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, and sleep apnea. Adequate screening for comorbidities should be guided by symptoms, clinical examination, and specific personal and family risks factors. This should be followed by appropriate management to avoid further complications [ 125 , 215 , 216 ].

As per management of any adolescent, the HEEADDSS screening tool should be used (that is, H, home environment; E, education and employment; E, exercise and healthy eating; A, activity and peers; D, drugs, smoking, and alcohol; D, depression and suicide ideation; S, sexuality and sexual health; S, sleep) [ 217 ]. Prompt referral to social work, psychology, and counseling in the presence of psychosocial comorbidities is necessary, as these comorbidities will affect adherence to any interventions. Self-management strategies such as mindfulness and yoga in PCOS are emerging and require more research [ 172 , 218 ]. Contraception should be discussed in sexually active adolescents with PCOS who are not taking COCPs for PCOS.

H. Transition to Adult Care Providers

Preparation for transition to adult care will require reinforcement of education about PCOS, its comorbidities, lifestyle interventions, medical treatment, and the need of long-term follow-up [ 125 , 126 , 219 ]. Women with PCOS are best managed by multidisciplinary health care teams comprised of endocrinologists, general physicians, gynecologists, family doctors, or general practitioners. Therapeutic options should be discussed with the adolescent or emerging adult. The selection of an appropriate specialist for adult care should be based on adolescent preferences and major complaints, local availability of health care professionals or specialized clinics, health care insurance, and the possible need of fertility management in the near future.

PCOS is a complex disorder involving multiple organ systems with onset during the early pubertal years ( Fig. 1 ). The list of factors involved in the pathophysiology continues to expand, with accruing evidence indicating that hyperandrogenism is a pivotal factor affecting multiple tissues [ 220 , 221 ]. GWASs have identified genes common to both Han Chinese and white populations that are involved in neuroendocrine, metabolic, and reproductive pathways [ 118 ]. Data obtained from animal models have consistently implicated testosterone as an important factor in the pathogenesis of PCOS. The important contributions of ectopic fat storage and adipocyte androgen biosynthesis are emerging. Promising clinical and preclinical data point toward neuroendocrine involvement with supporting roles for GABA signaling and neuronal ARs.

At this time, an individualized treatment plan can be developed for the adolescent girl with features of PCOS. Attention to the history, physical examination, and laboratory data is important to identify adolescent girls at risk to develop PCOS. Whereas deferring diagnostic labeling may be appropriate, treatment of clinical features and comorbidities is vital to the health and self-esteem of these patients. One future goal includes prevention through timely identification of at-risk prepubertal and early pubertal girls through lifestyle interventions.

Financial Support: This work was supported in part by the Australian National Health and Medical Research Council Centre for Research Excellence scheme in the origins, outcomes, and optimal management of PCOS (Grant APP1078444 to A.S.P.).

Disclosure Summary: The authors have nothing to disclose.

Data Availability: Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

Abbreviations:

anti-Müllerian hormone

androgen receptor

body mass index

congenital adrenal hyperplasia

combined oral contraceptive pill

dehydroepiandrosterone

dehydroepiandrosterone sulfate

FSH receptor

γ -aminobutyric acid

genome-wide association study

hypothalamic–pituitary–ovarian

insulin resistance

LH/chorionic gonadotropin receptor

nonhuman primate

polycystic ovary morphology

polycystic ovary syndrome

prenatally androgenized

randomized controlled trial

valproic acid

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Clinical Presentation and Diagnosis of Polycystic Ovarian Syndrome

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1 Program of Reproductive Endocrinology and Infertility, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
PMID: 32701517
PMCID: PMC10683967
DOI: 10.1097/GRF.0000000000000563

Polycystic ovarian syndrome (PCOS) is a common endocrinopathy with many clinical manifestations. The effects on women's lives start at puberty and can last throughout her lifetime. Women frequently experience anovulatory menstrual cycles, infertility, hirsutism, obesity and increased risk of diabetes mellitus, hypertension, lipid abnormalities, and metabolic syndrome. PCOS is a heterogenous disorder, and a diagnosis of exclusion. In general, women afflicted will have menstrual irregularities, ultrasound findings of abnormal ovarian size and morphology, and clinical or laboratory evidence of hyperandrogenism. This chapter reviews the current understanding of PCOS, associated metabolic abnormalities, and diagnosis in reproductive-aged women, as well as adolescents.

Hirsutism / diagnosis
Hirsutism / etiology
Hyperandrogenism* / diagnosis
Hyperandrogenism* / etiology
Menstruation Disturbances / diagnosis
Menstruation Disturbances / etiology
Metabolic Syndrome* / complications
Metabolic Syndrome* / diagnosis
Polycystic Ovary Syndrome* / complications
Polycystic Ovary Syndrome* / diagnosis

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Danielle O'Laughlin, PA-C, MS: Navigating Long-Term Risks, Family Planning in PCOS

The matters of long-term PCOS management may heavily depend on what stage of life the patient is in—and how the disease itself has presented.

Polycystic ovary syndrome (PCOS) carries a high prevalence among women—estimated at approximately 1 in 10 and increasing over time. 1 But an exacerbation of that high prevalence rate for clinicians who manage patients with PCOS is the multitude of ways by which it can impact them long-term—and how it may alter lifestyle decisions and behaviors.

In an interview with HCPLive during the American Academy of Physician Associates (AAPA) 2024 Conference & Expo in Houston, TX, this week, Danielle O’Laughlin, PA-C, MS, a physician associate in Mayo Clinic’s division of community internal medicine, geriatrics and palliative care, discussed her session presentation on PCOS management in the primary care setting.

O’Laughlin discussed the matter of navigating treatment in a patient with PCOS who may be interested in bearing children. As she explained, the issue may be as heterogenous as the condition itself—but the sentiment of treatment is fairly consistent.

“A lot of times, our treatment and our education is focused on, 'Okay, let's reduce your risk factors’,” O’Laughlin said. “You need to have regular menstrual periods so that you can ovulate on a regular basis, so you can get pregnant. So to do that, we want to make sure that you don't have impaired fasting glucose or diabetes, we want to make sure we're preventing all the things that we can.”

Weight loss in patients who are overweight may help restore menstrual regulation, O’Laughlin said; diet and exercise are common recommendations for PCOS, as may be metformin. 2

Another recourse may be recommending birth control to affected patients prior to their attempts to get pregnant, O’Laughlin said.

“And then sometimes we have to jump to ovulation induction—whether we're using medications or we're referring for that, but there's lots of options,” O’Laughlin said. “It just depends on how long have they been trying to get pregnant, when do they want to get pregnant and where they're at on that spectrum.”

O’Laughlin additionally discussed the matter of long-term outcome risks in patients with PCOS, which can range from metabolic disease like diabetes, hormonal effects like early menopause onset or endometrial cancer, 3 and even psychological burdens.

“I will say that if in today's life phase, you don't want to be on birth control, that's fine. We can do the things to get you pregnant and that sort of thing,” she said. “But long term, we need to have some plan to protect the endometrium. That might be birth control…that's going to reduce the risk of endometrial hyperplasia and then reduce their risk of endometrial cancer.”

From the risk of metabolic diseases, behavior modification in exercise, sleep and diet are primary topics. But regarding psychological effects, the matter may be diverse: O’Laughlin said anxiety, depression, eating disorders and psychosexual dysfunction are more common in women with PCOS.

“This is a disease process that has different risks at different parts of your life,” O’Laughlin said. “And we can do a lot to prevent that and monitor those (risks). They need to know education for the pre-family planning, the family planning stage, or the post-family planning stage, depending on where they're at.”

Deswal R, Narwal V, Dang A, Pundir CS. The Prevalence of Polycystic Ovary Syndrome: A Brief Systematic Review. J Hum Reprod Sci . 2020;13(4):261-271. doi:10.4103/jhrs.JHRS_95_18
Johnson NP. Metformin use in women with polycystic ovary syndrome. Ann Transl Med . 2014;2(6):56. doi:10.3978/j.issn.2305-5839.2014.04.15
Kunzmann K. PCOS status linked to menopause age onset. Contemporary OB/GYN. Published March 28, 2024. https://www.contemporaryobgyn.net/view/pcos-status-linked-to-menopause-age-onset

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COMMENTS

Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. Depending on diagnostic criteria, 6% to 20% of reproductive aged women are affected. Symptoms of PCOS arise during the early pubertal years.
Diagnosis and Treatment of Polycystic Ovary Syndrome
Learn about the diagnosis and management of PCOS, the most common endocrinopathy affecting women of childbearing age. This article covers the clinical criteria, metabolic complications, lifestyle interventions, and hormonal therapies for PCOS.
Polycystic Ovary Syndrome (PCOS)
This presentation briefly discuss the polycystic ovary syndrome in terms of pathogenesis, features and management. Then, It moves on to discuss the various guidelines laid down by Endocrine Society in 2013 for the management of patients with polycystic ovary syndrome.
Polycystic ovarian syndrome
Feb 28, 2019 •. 104 likes • 101,488 views. Nosrullah Ayodele. Definition, Epidemiology, Pathophysiology, Clinical Features, Investigation and Treatment of PCOS. Health & Medicine. 1 of 36. Download now. Download to read offline. Polycystic ovarian syndrome - Download as a PDF or view online for free.
Polycystic Ovary Syndrome (PCOS) > Fact Sheets > Yale Medicine
Polycystic Ovary Syndrome (PCOS) is a hormone disorder that can cause infertility, ovarian cysts, and other health problems. Learn about symptoms and treatment. ... it should be suspected in any woman experiencing the common symptoms and signs of PCOS. A combination of clinical presentation, pertinent blood tests and pelvic ultrasound ...
Polycystic ovary syndrome (PCOS)
Polycystic ovary syndrome (PCOS) is a problem with hormones that happens during the reproductive years. If you have PCOS, you may not have periods very often. Or you may have periods that last many days. You may also have too much of a hormone called androgen in your body. With PCOS, many small sacs of fluid develop along the outer edge of the ...
PDF Polycystic Ovary/Ovarian Syndrome (PCOS)
Polycystic ovary/ovarian syndrome (PCOS) is a set of symptoms related to an imbalance of hormones that can affect women and girls of reproductive age.1-7 It is defined and diagnosed by a combination of signs and symptoms of androgen excess, ovarian dysfunction, and polycystic ovarian morphology on ultrasound.2.
PDF POLYCYSTIC OVARY SYNDROME
• PCOS affects 7-10% of women of childbearing age and is one of the most common causes of infertility. • In the United States, an estimated 5-6 million women have PCOS. • Sleep apnea may occur in up to 50% of women with PCOS. • Pregnant women with PCOS appear to have higher rates of: • Miscarriage • Diabetes during pregnancy
Clinical Presentation and Diagnosis of Polycystic Ovarian Syndrome
Abstract. Polycystic ovarian syndrome (PCOS) is a common endocrinopathy with many clinical manifestations. The effects on women's lives start at puberty and can last throughout her lifetime. Women frequently experience anovulatory menstrual cycles, infertility, hirsutism, obesity and increased risk of diabetes mellitus, hypertension, lipid ...
Polycystic Ovarian Disease
Polycystic ovarian syndrome (PCOS) is the most common endocrine pathology in females of reproductive worldwide. Stein and Leventhal initially described it in 1935. The prevalence ranges between 5% and 15% depending on the diagnostic criteria applied. It is widely accepted among specialty society guidelines that the diagnosis of PCOS must be based on the presence of at least two of the ...
Diagnosis of polycystic ovary syndrome in adults
The polycystic ovary syndrome (PCOS) is an important cause of both menstrual irregularity and androgen excess in women. PCOS can be readily diagnosed when women present with the classic features of hirsutism, irregular menstrual cycles, and polycystic ovarian morphology on transvaginal ultrasound (TVUS). However, there has been considerable ...
Polycystic Ovary Syndrome (PCOS) Presentation
Polycystic Ovary Syndrome (PCOS) Presentation . Medical . Free Google Slides theme, PowerPoint template, and Canva presentation template . Some women have a condition in which their ovaries generate abnormal quantities of androgens. These are a type of hormones that control lots of processes in their bodies, and this dysregulation can cause ...
Clinical manifestations of polycystic ovary syndrome in adults
It is important to appreciate that PCOS is a syndrome, reflecting multiple potential etiologies and variable clinical presentations. Its key features are oligo- or anovulation and hyperandrogenism. Other features are polycystic ovaries on pelvic ultrasonography, infertility due to oligo-ovulation, obesity, and insulin resistance.
Patient education: Polycystic ovary syndrome (PCOS) (Beyond ...
PCOS OVERVIEW. Polycystic ovary syndrome (PCOS) is a condition that causes irregular menstrual periods, symptoms of excess androgens (acne, hirsutism, and scalp hair loss), and ovaries that appear "polycystic" on pelvic ultrasound. The condition occurs in approximately 5 to 10 percent of females. Many females with PCOS are overweight or obese ...
Polycystic Ovarian Syndrome Clinical Presentation
Many patients with PCOS have characteristics of metabolic syndrome; one study showed a 43% prevalence of metabolic syndrome in women with PCOS. [] In women, metabolic syndrome is characterized by abdominal obesity (waist circumference >35 in), dyslipidemia (triglyceride level >150 mg/dL, high-density lipoprotein cholesterol [HDL-C] level < 50 mg/dL), elevated blood pressure, a proinflammatory ...
PCOS (Polycystic Ovary Syndrome): Symptoms & Treatment
Typically, healthcare providers diagnose PCOS if you have at least two of the three symptoms: Irregular or missed periods. Some people with PCOS have very heavy bleeding when they do have a period. Signs of excess androgens such as acne or excessive hair growth. Or a blood test confirming high androgen levels.
Polycystic ovary syndrome (PCOS)
There's no single test to specifically diagnose polycystic ovary syndrome (PCOS). Your health care provider is likely to start with a discussion of your symptoms, medications and any other medical conditions. ... Lentscher JA, et al. Clinical presentation and diagnosis of polycystic ovarian syndrome. Clinical Obstetrics and Gynecology. 2021 ...
Pathophysiology & Clinical Presentation
The specific pathophysiology of Polycystic Ovarian Syndrome is poorly understood, however, practitioners do know that it is a combination of metabolic and reproductive abnormalities (Thornton et al., 2015). Inappropriate gonadotropin secretion, chronic hyperandrogenism, and an increase in estrogen concentration are present in the typical PCOS ...
Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. Depending on diagnostic criteria, 6% to 20% of reproductive aged women are affected. ... Presentation, and Treatment With Emphasis on Adolescent Girls J Endocr Soc. 2019 Jun 14;3(8):1545-1573. doi: 10.1210/js.2019-00078 ...
Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. Depending on diagnostic c. ... Alexia S Peña, Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls, Journal of the Endocrine Society, Volume 3, Issue 8, August 2019 ...
Clinical Presentation and Diagnosis of Polycystic Ovarian Syndrome
Abstract. Polycystic ovarian syndrome (PCOS) is a common endocrinopathy with many clinical manifestations. The effects on women's lives start at puberty and can last throughout her lifetime. Women frequently experience anovulatory menstrual cycles, infertility, hirsutism, obesity and increased risk of diabetes mellitus, hypertension, lipid ...
Polycystic Ovarian Syndrome (PCOS) by Dr. Aryan
Dr. Aryan (Anish Dhakal) Polycystic Ovarian Syndrome is heterogeneous, multisystem endocrinopathy in women of reproductive age characterized by chronic anovulation resulting in infertility, irregular bleeding, obesity and hirsutism. Most common, although the least understood, cause of androgen excess.
Danielle O'Laughlin, PA-C, MS: Navigating Long-Term Risks, Family
Polycystic ovary syndrome (PCOS) carries a high prevalence among women—estimated at approximately 1 in 10 and increasing over time. 1 But an exacerbation of that high prevalence rate for clinicians who manage patients with PCOS is the multitude of ways by which it can impact them long-term—and how it may alter lifestyle decisions and behaviors. In an interview with HCPLive during the ...
Presentation on Diagnosis of Polycystic Ovary Syndrome (PCOS)
Criteria for diagnosis of PCOS NIH (1990) - include all of the following 1. Hyperandrogenism &/or hyperandrogenaemia 2. Oligo-ovulation 3. Exclusion of related disorders ESHRE/ASRM (Rotterdam 2003)- two of the following 1. Oligo or anovulation 2. Clinical &/or biochemical signs of Hyperandrogenism 3. Polycystic ovaries Androgen Excess Society ...

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Pathophysiology & Clinical Presentation

Alterations That Occur with PCOS

Key Criteria for Diagnosis

This is an example of an ovary ultrasound in a PCOS patient.

Article Contents

Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls

A. Ovary, Adrenal, and Androgen Excess

A-1. Preclinical models

B. Neuroendocrine Factors

B-1. Preclinical models

C. Valproate and HPO Axis Function

C-1. Preclinical models

D. Insulin Resistance, Hyperinsulinemia, and the β -Cell

D-1. Preclinical models

E. Obesity, the Adipocyte, and Nutrient Excess

E-1. Preclinical models

F. Developmental Hypothesis/Fetal Origins

F-1. Preclinical models

G. Microbiome

H. Genetics

B. Hyperandrogenism

C. Polycystic Ovary Morphology

D. Evaluation and Diagnosis

A. Education and Counseling

B. Lifestyle Interventions

C. Metformin

E. Management of Hirsutism

F. Management of Acne

G. Screening of Other Comorbidities

H. Transition to Adult Care Providers

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