Polycystic ovary syndrome

Polycystic ovary syndrome
Other names	Hyperandrogenic anovulation (HA),[1] Stein-Leventhal syndrome[2]
A polycystic ovary
Specialty	Gynecology, endocrinology
Symptoms	Irregular menstrual periods, heavy periods, excess hair, acne, difficulty getting pregnant, patches of thick, darker, velvety skin[3]
Complications	Type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, endometrial cancer[4]
Duration	Long term[5]
Causes	Genetic and environmental factors[6][7]
Risk factors	Obesity, not enough exercise, family history[8]
Diagnostic method	Based on anovulation, high androgen levels, ovarian cysts[4]
Differential diagnosis	Adrenal hyperplasia, hypothyroidism, high blood levels of prolactin[9]
Treatment	Weight loss, exercise[10][11]
Medication	Birth control pills, metformin, GLP-1, anti-androgens[12]
Frequency	5 to 18% of women of childbearing age[13]

Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age.^[14] The name is a misnomer,^[15] as not all women with this condition develop cysts on their ovaries. The name originated from the observation of cysts which form on the ovaries of some women with this condition. However, this is not a universal symptom and is not the underlying cause of the disorder.^[16][17]

The primary characteristics of PCOS include hyperandrogenism, anovulation, insulin resistance, and neuroendocrine disruption.^[18] Women may also experience irregular menstrual periods, heavy periods, excess hair, acne, difficulty getting pregnant, and patches of darker skin.^[3][19]

Beyond its reproductive implications, PCOS is increasingly recognized as a multifactorial metabolic condition with significant long-term health consequences, including an elevated risk of cardiovascular disease and type 2 diabetes.^[20] The exact cause of PCOS remains uncertain.^[21]

Estimates of prevalance vary: PCOS occurs between 5% and 18% of women. Management can involve medication to regulate menstrual cycles, to reduce acne and excess hair growth and to help with fertility. In addition, women can be monitored for cardiometabolic risks and during pregnancy. A healthy lifestyle and weight control are recommended for general management.^[13]

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Signs and symptoms of PCOS include irregular or no menstrual periods, heavy periods, excess body and facial hair, acne, pelvic pain, difficulty getting pregnant, and patches of thick, darker, velvety skin,^[3] ovarian cysts, enlarged ovaries, excess androgens, and weight gain.^[22][23]

Associated conditions include type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.^[4]

Common signs and symptoms of PCOS include the following:

• Menstrual disorders: PCOS mostly produces oligomenorrhea (fewer than nine menstrual periods in a year) or amenorrhea (no menstrual periods for three or more consecutive months), but other types of menstrual disorders may also occur.^[24]
• Infertility: This generally results directly from chronic anovulation (lack of ovulation).^[24]
• High levels of masculinizing hormones: Known as hyperandrogenism, the most common signs are acne and hirsutism (male pattern of hair growth, such as on the chin or chest), but it may produce hypermenorrhea (heavy and prolonged menstrual periods), androgenic alopecia (increased hair thinning or diffuse hair loss), or other symptoms.^[24][25] Approximately three-quarters of women with PCOS (by the diagnostic criteria of NIH/NICHD 1990) have evidence of hyperandrogenemia.^[26]
• Metabolic syndrome: This appears as a tendency towards central obesity and other symptoms associated with insulin resistance, including low energy levels and food cravings.^[24] Serum insulin, insulin resistance, and homocysteine levels are higher in women with PCOS.^[27]
• Acne: A rise in testosterone levels increases the oil production within the sebaceous glands and clogs pores.^[28] For many women, the emotional impact is great and quality of life can be significantly reduced.^[29]
• Androgenic alopecia: Estimates suggest that androgenic alopecia affects 22% of PCOS sufferers.^[28]
• Acanthosis nigricans (AN): A skin condition where dark, thick, and "velvety" patches can form.^[30]
• Polycystic ovaries: There are small cysts on one or both ovaries. Ovaries might enlarge and compress follicles surrounding the eggs. As a result, ovaries might fail to function regularly. This disease is related to the number of follicles per ovary each month, growing from the average range of 6–8 to double, triple, or more.^{[citation needed]}

Women with PCOS tend to have central obesity. Still, studies are conflicting as to whether visceral and subcutaneous abdominal fat is increased, unchanged, or decreased in women with PCOS relative to non-PCOS women with the same body mass index.^[31] In any case, androgens, such as testosterone, androstanolone (dihydrotestosterone), and nandrolone decanoate have been found to increase visceral fat deposition in both female animals and women.^[32]

Although 80% of PCOS presents in women with obesity, 20% of women diagnosed with the disease are non-obese or "lean" women.^[33] However, obese women who have PCOS have a higher risk of adverse outcomes, such as hypertension, insulin resistance, metabolic syndrome, and endometrial hyperplasia.^[34]

Even though most women with PCOS are overweight or obese, non-overweight women can also be diagnosed with PCOS. Up to 30% of women diagnosed with PCOS maintain a normal weight before and after diagnosis. "Lean" women still face the various symptoms of PCOS with the added challenges of having their symptoms properly addressed and recognized. Lean women often go undiagnosed for years and are usually diagnosed after struggles to conceive.^[35] Lean women are likely to have a missed diagnosis of diabetes and cardiovascular disease. These women also have an increased risk of developing insulin resistance, despite not being overweight. Lean women are often taken less seriously with their diagnosis of PCOS and also face challenges finding appropriate treatment options. This is because most treatment options are limited to approaches for losing weight and healthy dieting.^[36]

Testosterone levels are usually elevated in women with PCOS.^[37][38] In a 2020 systematic review and meta-analysis of sexual dysfunction related to PCOS which included 5,366 women with PCOS from 21 studies, testosterone levels were analyzed and were found to be 2.34 nmol/L (67 ng/dL) in women with PCOS and 1.57 nmol/L (45 ng/dL) in women without PCOS.^[38] If testosterone levels are above 100 to 200 ng/dL, per different sources, other possible causes of hyperandrogenism, such as congenital adrenal hyperplasia or an androgen-secreting tumor, may be present and should be excluded.^[39][40][37]

Warning signs may include a change in appearance. But there are also manifestations of mental health problems, such as anxiety, depression, and eating disorders.^{[22][medical citation needed]}

A diagnosis of PCOS suggests an increased risk of the following:

• Endometrial hyperplasia and endometrial cancer (cancer of the uterine lining) are possible, due to overaccumulation of the uterine lining, and also lack of progesterone, resulting in prolonged stimulation of uterine cells by estrogen.^[41][42] It is not clear whether this risk is directly due to the syndrome or from the associated obesity, hyperinsulinemia, and hyperandrogenism.^[43][44][45]
• Insulin resistance/type 2 diabetes. A review published in 2010 concluded that women with PCOS have an elevated prevalence of insulin resistance and type 2 diabetes, even when controlling for body mass index (BMI).^[41][46] PCOS is also associated with higher risk for diabetes.^[47]
• High blood pressure, in particular if obese or during pregnancy^[48]
• Depression and anxiety^[24][49]
• Dyslipidemia – disorders of lipid metabolism – cholesterol and triglycerides. Women with PCOS show a decreased removal of atherosclerosis-inducing remnants, seemingly independent of insulin resistance/type 2 diabetes.^[50]
• Cardiovascular disease,^[41] with a meta-analysis estimating a 2-fold risk of arterial disease for women with PCOS relative to women without PCOS, independent of BMI.^[51]
• Strokes^[41]
• Weight gain^{[citation needed]}
• Miscarriage^[52][53]
• Sleep apnea, particularly if obesity is present^[54]
• Non-alcoholic fatty liver disease, particularly if obesity is present^[55]
• Acanthosis nigricans (patches of darkened skin under the arms, in the groin area, on the back of the neck)^[41]
• Autoimmune thyroiditis^{[citation needed]}
• Iron deficiency^{[56][better source needed]}

The risk of ovarian cancer and breast cancer is not significantly increased overall, but women with PCOS were about three times more likely to develop endometrial cancer than other women.^[42]

Some medical providers and groups consider PCOS to be an intersex condition because some sex hormones are outside the typical range.^[57] However, medical consensus, including the Endocrine Society and NIH, defines PCOS as an endocrine/metabolic disorder, not intersex, as it lacks congenital sex characteristic variations.^{[58][59][failed verification]} A 2023 study notes two transmasculine individuals self-identified as intersex without medical diagnosis, tying it to identity, not biology.^[60]

PCOS is a heterogeneous disorder of uncertain cause.^[61][62] There is some evidence that it is a genetic disease. Such evidence includes the familial clustering of cases, greater concordance in monozygotic compared with dizygotic twins and heritability of endocrine and metabolic features of PCOS.^[7][61][62] There is some evidence that exposure to higher than typical levels of androgens and the anti-Müllerian hormone (AMH) in utero increases the risk of developing PCOS in later life.^[63]

It may be caused by a combination of genetic and environmental factors.^[6][7][64] Risk factors include obesity, a lack of physical exercise, and a family history of someone with the condition.^[8] Diagnosis is based on two of the following three findings: anovulation, high androgen levels, and ovarian cysts.^[4] Other conditions that produce similar symptoms include adrenal hyperplasia, hypothyroidism, and high blood levels of prolactin.^[9]

The genetic component appears to be inherited in an autosomal dominant fashion with high genetic penetrance but variable expressivity in females; this means that each child has a 50% chance of inheriting the predisposing genetic variant(s) from a parent, and, if a daughter receives the variant(s), the daughter will have the disease to some extent.^{[62][65][66][67]} The genetic variant(s) can be inherited from either the father or the mother, and can be passed along to both sons (who may be asymptomatic carriers or may have symptoms such as early baldness and/or excessive hair) and daughters, who will show signs of PCOS.^[65][67] The phenotype appears to manifest itself at least partially via heightened androgen levels secreted by ovarian follicle theca cells from women with the allele.^[66] The exact gene affected has not yet been identified.^[7][62][68] In rare instances, single-gene mutations can give rise to the syndrome phenotype.^[69] Current understanding of the pathogenesis of the syndrome suggests, however, that it is a complex multigenic disorder.^[70]

The severity of PCOS symptoms appears to be largely determined by factors such as obesity.^[7][24][71] PCOS has some aspects of a metabolic disorder, since its symptoms are partly reversible. Even though considered as a gynecological problem, PCOS consists of 28 clinical symptoms.^[72]

Even though the name suggests that the ovaries are central to disease pathology, cysts are a symptom instead of the cause of the disease. Some symptoms of PCOS will persist even if both ovaries are removed; the disease can appear even if cysts are absent. Since its first description by Stein and Leventhal in 1935, the criteria of diagnosis, symptoms, and causative factors have been subject to debate. Gynecologists often see it as a gynecological problem, with the ovaries being the primary organ affected. However, recent insights show a multisystem disorder, with the primary problem lying in hormonal regulation in the hypothalamus, with the involvement of many organs. The term PCOS is used because there is a wide spectrum of symptoms possible. It is common to have polycystic ovaries without having PCOS; approximately 20% of European women have polycystic ovaries, but most of those women do not have PCOS.^[16]

PCOS may be related to or worsened by exposures^{[clarification needed]} during the prenatal period,^[73][74][75] epigenetic factors, environmental impacts (especially industrial endocrine disruptors, such as bisphenol A and certain drugs)^[76][77][78] and the increasing rates of obesity.^[77]

Endocrine disruptors are defined as chemicals that can interfere with the endocrine system by mimicking hormones such as estrogen. According to the NIH (National Institute of Health), examples of endocrine disruptors can include dioxins and triclosan. Endocrine disruptors can cause adverse health impacts in animals.^[79] Additional research is needed to assess the role that endocrine disruptors may play in disrupting reproductive health in women and possibly triggering or exacerbating PCOS and its related symptoms.^[80]

The study of epigenetic changes in PCOS in utero or after birth has become an emerging area of research. While extensive research is not currently available, some studies are looking into the connection between abnormal DNA methylation changes in various tissues and the development of PCOS.^[81]  Environmental exposure to endocrine disruptors such as phthalates could alter DNA methylation patterns, particularly in the ovaries, granulosa cells, and adipose tissue.^[81]

One study observed early embryonic development of mice subjected to di--(2-ethylhexyl) phthalate (DEHP) and the results showed abnormal methylation patterns in the Stra8 gene involved in meiosis initiation.^[82] The gene for transcription factor Lhx8, involved in early follicular changes, was also impacted by DEHP when the neonatal mouse ovaries were analyzed. Together, these results showed DEHP induced epigenetic changes via DNA methylation to interfere with folliculogenesis, symptomatic of PCOS.^[82] Although DNA methylation in human embryonic development is not fully characterized, the animal model studies on epigenetic changes provide information to suggest that PCOS may have fetal origins.

Androgen excess is a central feature in the PCOS phenotype, and exposure in utero has shown PCOS-like features in adulthood. A study from 2014 induced DNA hypomethylation in the ovarian tissue of zebrafish exposed to androgens early in development.^[83] Glucose homeostasis alterations were also observed. Furthermore, these effects were carried into the next generation, suggesting that epigenetic changes caused by excess androgens in the fetus could be transgenerational.^[83]

Polycystic ovaries develop when the ovaries are stimulated to produce excessive amounts of androgenic hormones, in particular testosterone, by either one or a combination of the following (almost certainly combined with genetic susceptibility):^[66]

• The release of excessive luteinizing hormone (LH) by the anterior pituitary gland
• through high levels of insulin in the blood (hyperinsulinaemia) in women whose ovaries are sensitive to this stimulus

A majority of women with PCOS have insulin resistance and/or are obese, which is a strong risk factor for insulin resistance, although insulin resistance is a common finding among women with PCOS in normal-weight women as well.^[10][24][27] Elevated insulin levels contribute to or cause the abnormalities seen in the hypothalamic–pituitary–ovarian axis that lead to PCOS. Hyperinsulinemia increases GnRH pulse frequency,^[84] which in turn results in an increase in the LH/FSH ratio^[84][85] increased ovarian androgen production; decreased follicular maturation; and decreased SHBG binding.^[84] Furthermore, excessive insulin increases the activity of 17α-hydroxylase, which catalyzes the conversion of progesterone to androstenedione, which is in turn converted to testosterone. The combined effects of hyperinsulinemia contribute to an increased risk of PCOS.^[84]

Adipose (fat) tissue possesses aromatase, an enzyme that converts androstenedione to estrone and testosterone to estradiol. The excess of adipose tissue in obese women creates the paradox of having both excess androgens (which are responsible for hirsutism and virilization) and excess estrogens (which inhibit FSH via negative feedback).^[86]

The syndrome acquired its most widely used name due to the common sign on ultrasound examination of multiple (poly) ovarian cysts. These "cysts" are in fact immature ovarian follicles. The follicles have developed from primordial follicles, but this development has stopped ("arrested") at an early stage, due to the disturbed ovarian function. The follicles may be oriented along the ovarian periphery, appearing as a 'string of pearls' on ultrasound examination.^[87]

PCOS may be associated with chronic inflammation,^[88] with several investigators correlating inflammatory mediators with anovulation and other PCOS symptoms.^[89][90] Similarly, there seems to be a relation between PCOS and an increased level of oxidative stress.^[91]

Not every person with PCOS has polycystic ovaries (PCO), nor does everyone with ovarian cysts have PCOS; although a pelvic ultrasound is a major diagnostic tool, it is not the only one.^[92] The diagnosis is fairly straightforward using the Rotterdam criteria, even when the syndrome is associated with a wide range of symptoms.^[93]

There are different criteria for PCOS; the 2023 International Evidence-based Guidelines for Assessment and Management of PCOS recommend the revised Rotterdam criteria for diagnosing PCOS. That is, PCOS is present in adults when two out of these three criteria are met:^[94][95]

1. Signs of androgen excess (clinical or biochemical). Androgens are "male" hormones, which can for instance cause facial hair.^[96]
2. Ovulatory dysfunction with irregular or absent menstrual cycles
3. Polycystic ovaries on ultrasound or elevated anti-mullerian hormone (AMH) levels

Other causes of these issues need to be excluded. In adolescents, both androgen excess and ovulatory dysfunction are required, as AMH and ultrasounds are not specific in this population.^[97] Adolescents that only meet one criterion are considered 'at risk', to be reassessed when they are adults.^[95] Older criteria are the 1990 NIH criteria and the 2006 Androgen Excess Society criteria.^[13] The Androgen Excess criteria were never adopted widely. The old NIH criteria are stricter than the Rotterdam criteria, as both oligoovulation and signs of androgen excess need to be present:^[98]

1. Oligoovulation
2. Signs of androgen excess (clinical or biochemical)
3. Exclusion of other disorders that can result in the above

There is a three-step algorithm for diagnosis PCOS. In the first step, clinical androgen excess and irregular menstrual cycles are assessed. If someone has both and other causes are excluded, PCOS is diagnosed. In step 2, those with only irregular cycles undergo a laboratory test for excess androgens in the blood. If that shows excess male hormones, again excluding other causes of systems, PCOS is diagnosed. In the third step, for those with either irregular cycles or excess androgens, an ultrasound is performed or a AMH test, but not both to prevent overdiagnosis. If this test shows polycystic ovaries or elevated AMH levels, PCOS is diagnosed.^[99]

Clinical androgen excess in adults can result in acne, hirsutism (male pattern of hair growth, such as on the chin or chest) and in female pattern hair loss. Hirsutism can be assessed using the standardised Ferriman–Gallwey visual scoring system, with a score above 4 to 6 indicating clinical significance.^[100] The recommended cut-off score depends on ethnicity, with a lower cut-off for Asian women, and a higher cut-off for Hispanic and Middle Eastern women.^[101] Assessment may be complicated by self-treatment.^[102] Hair loss can be assessed with the Ludwig visual score. In adolescents, androgen excess shows as severe acne and hirsutism.^[100]

For individuals who had their first menstrual cycle more than three years ago, menstrual cycles are considered irregular if they occur less than 21 days apart or more than 35 days apart. For those whose first menstrual cycle was between one and three years ago, the cycle is considered irregular if it is less than 21 days apart or more than 45 days apart. Finally, for anyone whose first cycle was over a year ago, a single cycle lasting over 90 days is considered irregular.^[99]

Biochemical androgen excess in PCOS is assessed using total and free testosterone. Accurate measurement requires tandem mass spectometry assays, as direct free testosterone tests are not reliable. Interpretation is based on laboratory reference ranges. Hormonal contraception can interfere with hormone levels, so a withdrawal period of at least three months with alternative contraception may be needed. Markedly elevated androgen levels may indicate other conditions.^[99]

Gynecologic ultrasonography first looks for small ovarian follicles.^[100] To count as polycystic ovaries, at least 20 follicles need to be present smaller than 9 mm. This used to be 12 in older diagnostic criteria.^[95] A less clear marker of PCOS is enlarged ovaries.^[100] Ovary need to be at least 10 cm³ to count.^[95] For sexually active individuals or those that agree, a transvaginal ultrasound approach is preferred. Alternatively, AMH levels can be tested in the blood.^[100] Laparoscopic examination may reveal a thickened, smooth, pearl-white outer surface of the ovary. This would usually be an incidental finding if laparoscopy were performed for some other reason, as it would not be routine to examine the ovaries in this way to confirm a diagnosis of PCOS.^[103]

• 
  Transvaginal ultrasound scan of polycystic ovary
• 
  Polycystic ovary as seen on sonography

To diagnose PCOS, other conditions must first be ruled out. These include thyroid disease (assessed via thyroid stimulating hormone), hyperprolactinemia (assessed via prolactin), and non-classic congenital adrenal hyperplasia (tested via 17-hydroxy progesterone). For those without any periods whatsoever or more severe signs or symptoms, further tests are recommended to exclude hypogonadotropic hypogonadism, any androgen producing tumors or Cushing's disease. Overt virilisation (development of male sex characteristics) is not characteristic of PCOS and indicates that another underlying condition may be responsible.^[97]

PCOS has no cure.^[5] Treatment may involve lifestyle changes such as weight loss and exercise.^[10][11] Recent research suggests that daily exercise including both aerobic and strength activities can improve hormone imbalances.^[104]

Birth control pills may help with improving the regularity of periods, excess hair growth, and acne.^[12] Combined oral contraceptives are especially effective and used as the first line of treatment to reduce acne and hirsutism and regulate the menstrual cycle. This is especially the case in adolescents.^[104]

Metformin, GLP-1, and anti-androgens may also help.^[12] Other typical acne treatments and hair removal techniques may be used.^[12] Efforts to improve fertility include weight loss, metformin, and ovulation induction using clomiphene or letrozole.^[105] In vitro fertilization is used by some in whom other measures are not effective.^[105]

Certain cosmetic procedures may also help alleviate symptoms in some cases. For example, the use of laser hair removal, electrolysis, or general waxing, plucking, and shaving are all effective methods for reducing hirsutism.^[30] The primary treatments for PCOS include lifestyle changes and the use of medications.^[106]

Goals of treatment may be considered under these categories:^{[citation needed]}

• Lowering of insulin resistance
• Reducing androgen and testosterone levels
• Restoration of fertility
• Treatment of hirsutism or acne
• Restoration of regular menstruation, and prevention of endometrial hyperplasia and endometrial cancer

In each of these areas, there is considerable debate as to the optimal treatment. One of the major factors underlying the debate is the lack of large-scale clinical trials comparing different treatments. Smaller trials tend to be less reliable and hence may produce conflicting results. General interventions that help to reduce weight or insulin resistance can be beneficial for all these aims because they address what is believed to be the underlying cause.^[107] As PCOS appears to cause significant emotional distress, appropriate support may also be useful.^[108]

Where PCOS is associated with being overweight or obese, successful weight loss is the most effective method of restoring normal ovulation/menstruation. The American Association of Clinical Endocrinologists guidelines recommend a goal of achieving 10–15% weight loss or more, which improves insulin resistance and all^{[clarification needed]} hormonal disorders.^[109] Still, many women find it very difficult to achieve and sustain significant weight loss. Insulin resistance itself can cause increased food cravings and lower energy levels, which can make it difficult to lose weight on a regular weight-loss diet. A scientific review in 2013 found similar improvements in weight, body composition and pregnancy rate, menstrual regularity, ovulation, hyperandrogenism, insulin resistance, lipids, and quality of life to occur with weight loss, independent of diet composition.^[110] Still, a low GI diet, in which a significant portion of total carbohydrates is obtained from fruit, vegetables, and whole-grain sources, has resulted in greater menstrual regularity than a macronutrient-matched healthy diet.^[110]

Reducing the intake of food groups that cause inflammation, such as dairy, sugars, and simple carbohydrates, can be beneficial.^[30]

A mediterranean diet is often very effective due to its anti-inflammatory and anti-oxidative properties.^[104]

It has been suggested that vitamin D deficiency may play some undetermined role in the development of the metabolic syndrome, and that treatment might be beneficial.^[111][112] However, a systematic review of 2015 found no evidence that vitamin D supplementation reduced or mitigated metabolic and hormonal dysregulations in PCOS.^[113] As of 2012, interventions using dietary supplements to correct metabolic deficiencies in people with PCOS had been tested in small, uncontrolled and nonrandomized clinical trials; the resulting data are insufficient to recommend their use.^[114]

Medications for PCOS include oral contraceptives and metformin. The oral contraceptives increase sex hormone binding globulin production, which increases the binding of free testosterone. This reduces the symptoms of hirsutism caused by high testosterone and regulates return to normal menstrual periods.^[111] Anti-androgens such as finasteride, flutamide, spironolactone, and bicalutamide do not show advantages over oral contraceptives, but could be an option for people who do not tolerate them.^[115] Finasteride is the only oral medication for the treatment of androgenic alopecia, that is FDA approved.^[30]

Metformin is a medication commonly used in type 2 diabetes mellitus to reduce insulin resistance and is used off label (in the UK, US, AU, and EU) to treat insulin resistance seen in PCOS. In many cases, metformin also supports ovarian function and a return to normal ovulation.^[111][116] A newer insulin resistance medication class, the thiazolidinediones (glitazones), have shown equivalent efficacy to metformin, but metformin has a more favorable side effect profile.^[117][118] The United Kingdom's National Institute for Health and Clinical Excellence recommended in 2004 that women with PCOS and a body mass index above 25 be given metformin when other therapy has failed to produce results.^[119][120] Metformin may not be effective in every type of PCOS, and therefore there is some disagreement about whether it should be used as a general first-line therapy.^[121] In addition to this, metformin is associated with several unpleasant side effects: including abdominal pain, metallic taste in the mouth, diarrhoea and vomiting.^[122] Metformin is thought to be safe to use during pregnancy (pregnancy category B in the US).^[123] A review in 2014 concluded that the use of metformin does not increase the risk of major birth defects in women treated with metformin during the first trimester.^[124] Liraglutide may reduce weight and waist circumference in people with PCOS more than other medications.^[125] The use of statins in the management of underlying metabolic syndrome remains unclear.^[106]

It can be difficult to become pregnant with PCOS because it causes irregular ovulation. Medications to induce fertility when trying to conceive include the ovulation inducer clomiphene or pulsatile leuprorelin. Evidence from randomised controlled trials suggests that in terms of live birth, metformin may be better than placebo, and metformin plus clomiphene may be better than clomiphene alone, but that in both cases women may be more likely to experience gastrointestinal side effects with metformin.^[126]

For women who do, anovulation or infrequent ovulation is a common cause and PCOS is the main cause of anovulatory infertility.^[127] Other factors include changed levels of gonadotropins, hyperandrogenemia, and hyperinsulinemia.^[128] Like women without PCOS, women with PCOS that are ovulating may be infertile due to other causes, such as tubal blockages due to a history of sexually transmitted diseases.^[129]

For overweight anovulatory women with PCOS, weight loss and diet adjustments, especially to reduce the intake of simple carbohydrates, are associated with the resumption of natural ovulation.^[130] Digital health interventions are particularly effective in providing combined therapy to manage PCOS through both lifestyle changes and medication.^[131]

For those women that, after weight loss, are still anovulatory, or for anovulatory lean women, ovulation induction using the medications letrozole (Femara) or clomiphene citrate are the principal treatments used to promote ovulation.^{[132][133][134]} Clomiphene can cause mood swings and abdominal cramping for some.^[30]

Previously, the anti-diabetes medication metformin was a recommended treatment for anovulation, but it appears less effective than letrozole or clomiphene.^[135][136]

For women not responsive to letrozole or clomiphene and diet and lifestyle modification, there are options available including assisted reproductive technology procedures such as controlled ovarian hyperstimulation with follicle-stimulating hormone (FSH) injections followed by in vitro fertilisation (IVF).^[137]

Though surgery is not commonly performed, the polycystic ovaries can be treated with a laparoscopic procedure called "ovarian drilling" (puncture of 4–10 small follicles with electrocautery, laser, or biopsy needles),^[138] which often results in either resumption of spontaneous ovulations^[111] or ovulations after adjuvant treatment with clomiphene or FSH.^[139] (Ovarian wedge resection is no longer used as much due to complications such as adhesions and the presence of frequently effective medications.) There are, however, concerns about the long-term effects of ovarian drilling on ovarian function.^[111]

Women with PCOS are far more likely to have depression than women without. Symptoms of depression might be heightened by certain physiological manifestations of this disease such as hirsutism or obesity that can lead to low self-esteem or poor body image.^[29]  Researchers suggest that there be mental health screenings performed in tandem with PCOS assessment to identify these complications early and treat them accordingly.^[140]

PCOS is associated with other mental health-related conditions besides depression such as anxiety, bipolar disorder, and obsessive–compulsive disorder.^[29] Additionally, it has been found to significantly increase the risk of eating disorders.^[140]  Screening for these mental health conditions will also be helpful in the treatment of PCOS.

Lifestyle changes for people with PCOS have been proven to be difficult due to a lack of intrinsic motivation, altered risk perception, or other PCOS-related barriers. However, self-management techniques and behavior change can be taught in a multidisciplinary approach to support women with PCOS in managing their symptoms.^[141]

A standard contraceptive pill is frequently effective in reducing hirsutism.^[111] Progestogens such as norgestrel and levonorgestrel should be avoided due to their androgenic effects.^[111] Metformin combined with an oral contraceptive may be more effective than either metformin or the oral contraceptive on its own.^[142]

In the case of taking medication for acne, Kelly Morrow-Baez PHD, in her exposition titled Thriving with PCOS, informs that it "takes time for medications to adjust hormone levels, and once those hormone levels are adjusted, it takes more time still for pores to be unclogged of overproduced oil and for any bacterial infections under the skin to clear up before you will see discernible results." (p. 138) ^[30]

Other medications with anti-androgen effects include flutamide,^[143] and spironolactone,^[111] which can improve hirsutism. Metformin can reduce hirsutism, perhaps by reducing insulin resistance, and is often used if there are other features such as insulin resistance, diabetes, or obesity that are likely to respond to metformin. Eflornithine (Vaniqa) is a medication that is applied to the skin in cream form, and acts directly on the hair follicles to inhibit hair growth. It is usually applied to the face.^[111] 5-alpha reductase inhibitors (such as finasteride and dutasteride) may also be used;^[144] they work by blocking the conversion of testosterone to dihydrotestosterone (the latter of which is responsible for most hair growth alterations and androgenic acne).

Although these agents have shown significant efficacy in clinical trials (for oral contraceptives, in 60–100% of individuals^[111]), the reduction in hair growth may not be enough to eliminate the social embarrassment of hirsutism or the inconvenience of plucking or shaving. Individuals vary in their response to different therapies. It is usually worth trying other medications if one does not work, but medications do not work well for all individuals.^[145]

If fertility is not the primary aim, then menstruation can usually be regulated with a contraceptive pill.^[111] The purpose of regulating menstruation, in essence, is for the patient's convenience, and perhaps their sense of well-being; there is no medical requirement for regular periods, as long as they occur sufficiently often.^[146]

If a regular menstrual cycle is not desired, then therapy for an irregular cycle is not necessarily required. Most experts say that, if a menstrual bleed occurs at least every three months, then the endometrium (womb lining) is being shed sufficiently often to prevent an increased risk of endometrial abnormalities or cancer.^[147] If menstruation occurs less often or not at all, some form of progestogen replacement is recommended.^[144]

Given the higher risk of cardiometabolic conditions, monitoring is recommended.^[13] Two-hour oral glucose tolerance test (GTT) in women with risk factors (obesity, family history, history of gestational diabetes)^[148] may indicate impaired glucose tolerance (insulin resistance) in 15–33% of women with PCOS.^[149] Frank diabetes can be seen in 65–68% of women with this condition.^[150] Insulin resistance can be observed in both normal weight and overweight people, although it is more common in the latter (and in those matching the stricter NIH criteria for diagnosis); 50–80% of people with PCOS may have insulin resistance at some level.^[148]

A 2017 review concluded that while both myo-inositol and D-chiro-inositols may regulate menstrual cycles and improve ovulation, there is a lack of evidence regarding effects on the probability of pregnancy.^[151][152] A 2012 and 2017 review have found myo-inositol supplementation appears to be effective in improving several of the hormonal disturbances of PCOS.^[153][154] Myo-inositol reduces the amount of gonadotropins and the length of controlled ovarian hyperstimulation in women undergoing in vitro fertilization.^[155] A 2011 review found not enough evidence to conclude any beneficial effect from D-chiro-inositol.^[156] There is insufficient evidence to support the use of acupuncture, current studies are inconclusive and there's a need for additional randomized controlled trials.^[157][158]

PCOS is the most common endocrine disorder among women between the ages of 18 and 44.^[24] According to the World Health Organization (WHO), PCOS affects over 6 to 13% of reproductive-aged women.^[159] A 2022 review noted a prevalence between 5% to 18%.^[13] When someone is infertile due to lack of ovulation, PCOS is the most common cause and could guide to patients' diagnosis.^[4]

The prevalence of PCOS depends on the choice of diagnostic criteria.^[160] Using the Rotterdam criteria, around 10–13% of women have PCOS.^[161] Based on the NIH criteria, the global prevalence was 5.5%, increasing to approximately 7.1% when using the Androgen Excess Society criteria. Irrespective of criteria, the prevalance of PCOS is increasing, likely due to an aging population, more awareness and increasing obesity rates.^[162]

Prevalance seems fairly even among people with different ethnicities, but is perhaps higher in people from South East Asia and the Eastern Mediterranean.^[161] PCOS may express differently however. For instance, in African and Hispanic American people with PCOS, there is more insulance resistance compared to other ethnic groups.^[95] The same is true for South Asian people with PCOS, who also have more metabolic symptoms and higher BMIs. East Asian women typically have less hirsutism and lower BMI compared to other groups.^[13]

Ultrasonographic findings of polycystic ovaries are found in 8–25% of women non-affected by the syndrome.^{[163][164][165][166]} 14% women on oral contraceptives are found to have polycystic ovaries.^[164] Ovarian cysts are also a common side effect of levonorgestrel-releasing intrauterine devices (IUDs).^[167]

Historical descriptions of possible PCOS symptoms date back to ancient Greece, where Hippocrates described women with "thick, oily skin and absence of menstruation."^[168] The earliest known description of what is now recognized as PCOS dates from 1721 in Italy.^[169] Cyst-related changes to the ovaries were described in 1844.^[169]

In modern times, the condition was first described in 1935 by American gynecologists Irving F. Stein Sr. and Michael L. Leventhal, from whom its original name of Stein–Leventhal syndrome is taken.^[92][41] Stein and Leventhal first described PCOS as an endocrine disorder in the United States, and since then, it has become recognized as one of the most common causes of oligo-ovulatory infertility among women.^[42]

Other names for this syndrome include polycystic ovarian syndrome, polycystic ovary disease, functional ovarian hyperandrogenism, ovarian hyperthecosis, sclerocystic ovary syndrome, and Stein–Leventhal syndrome. The eponymous last option is the original name; it is now used, if at all, only for the subset of women with all the symptoms of amenorrhea with infertility, hirsutism, and enlarged polycystic ovaries.^[92]

Most common names for this disease derive from a typical finding on medical images, called a polycystic ovary. A polycystic ovary has an abnormally large number of developing eggs visible near its surface, looking like many small cysts.^[92]

Human embryonic stem cells (hESCs) derived from the inner cell mass of blastocyst-stage embryos of women with PCOS have shown abnormal lipid metabolism, consistent with the pathophysiology of the disease.^[170] When the hESCs are differentiated into adipocytes, gene expression data from these fat cells reveal a downregulation or a decrease in genes linked to glucose, lipid, and steroid metabolism.^[171]

Recent studies have successfully developed in vitro PCOS disease models through Induced pluripotent stem cell technology (iPSC).^[170] Similar to hESCs, iPSC cells can be derived from patients and can differentiate into various cell types. Using adult somatic cells, iPSCs can reprogram the cells into a pluripotent state, which can then be specified to replicate PCOS-like traits. Furthermore, 3D “organoid” models of female reproductive tissue, such as the uterus and ovaries, produced from iPSCs, present a powerful way to stimulate the development of reproductive disorders such as PCOS in vitro.^[170]

Although not widely used, some researchers have explored the use of this biotechnology to model PCOS. One study that characterized the link between obesity and PCOS reprogrammed PCOS-derived urine epithelial cells into adipocytes and found that iPSC lines had greater glucose consumption along with lower insulin response compared to controls.^[172] These are results consistent with symptoms of the disease. Studies on iPSCs have also contributed significantly to understanding the behavior of ovarian granulosa cells, which maintain follicular development and secrete steroid hormones.^[173] The transcriptome data from the PCOS-derived iPSCs indicate dysfunctions in folliculogenesis and disruptions in the oocyte microenvironment.

Current growing data shows a strong association between mitochondrial malfunction and PCOS. iPSCs from PCOS patients have provided some evidence of impairments in glycolytic and mitochondrial functions.^[170] These cells exhibited a higher number of copies of mitochondrial DNA compared to the control. This may support the idea that mitochondrial biosynthesis is elevated in these patients as a compensatory response to the aberrations seen in the metabolic processes.^[170]

In 2005, 4 million cases of PCOS were reported in the US, costing $4.36 billion in healthcare costs.^[174] In 2016 out of the National Institute of Health's research budget of $32.3 billion for that year, 0.1% was spent on PCOS research.^[175] Among women aged between 14 and 44, PCOS is conservatively estimated to cost $4.37 billion per year.^[176]

As opposed to women in the general population, women with PCOS experience higher rates of depression and anxiety. International guidelines and Indian guidelines suggest psychosocial factors should be considered in women with PCOS, as well as screenings for depression and anxiety.^[177] Globally, this aspect has been increasingly focused on because it reflects the true impact of PCOS on the lives of patients. Research shows that PCOS adversely impacts a patient's quality of life.^[177][178]

Several celebrities and public figures have spoken about their experiences with PCOS, including:

• Androgen-dependent syndromes

• Teede HJ, Tay CT, Laven JJ, Dokras A, Moran LJ, Piltonen TT, et al. (2023). International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome 2023. Melbourne, Australia: Monash University. ISBN 978-0-6458209-0-4.

• Media related to Polycystic ovary syndrome at Wikimedia Commons