Polycystic ovary syndrome

PCOS has a wide variety of signs and symptoms. They include issues with ovulation (such as irregular periods), excess levels of androgens (hormones that trigger male characteristics, such as facial hair growth), and metabolism (such as weight gain). • A "male" pattern of hair growth, including hair on the chin, upper lip, chest, upper thighs, and on the belly. Associated conditions Women with PCOS have an increased risk of a range of metabolic, cardiovascular, reproductive and mental health conditions. The likelihood of developing metabolic disorders is about three to seven times higher than in women without PCOS. Insulin resistance is common, even in lean women with PCOS. Overweight or obese women with PCOS are at higher risk of type 2 diabetes than women without PCOS at the same BMI. Lean women with PCOS do not appear to be at higher risk of developing diabetes. PCOS increases the risk of pregnancy complications, such as gestational diabetes, high blood pressure, low blood sugar levels, and pre-eclampsia. Miscarriages are more likely, and when a baby is delivered, they are more likely to require admission to the neonatal intensive care unit. PCOS is associated with mental health-related conditions including depression, anxiety, bipolar disorder, and obsessive–compulsive disorder. Those with PCOS often report reduced quality of life due to excess body weight, and to a lesser extent due to hirsutism, infertility and menstrual cycles. In regions where infertility or hirsutism are stigmatised, the impact on mental health is more severe. and PCOS increases the risk of eating disorders, such as binge eating. Women with PCOS are about three times more likely to develop endometrial cancer. This is linked to lack of periods and lower levels of sex hormone-binding globulin (SHBG) and progesterone. Women with PCOS more often have sleep apnea, particularly if obesity is present. == Cause ==

PCOS's root cause is unknown. Risk factors include a family history of PCOS, early development of pubic hair and sweat gland development (adrenarche), and obesity. Low birth weight, exposure to androgens in the womb, and exposure to hormone disruptors may also predispose people to PCOS. Genetics PCOS has a clear genetic component and high heritability. Environment PCOS may also be impacted by epigenetics, which regulates how active genes are. High levels of androgens and AMH during pregnancy and early weight gain can hinder the fetal environment. Obesity is implicated in PCOS development. As fat tissue can produce androgens, obesity leads to increased androgen levels. It also leads to suppression of the SHBG hormone, increased insulin resistance, and abnormally increased insulin levels. Some of the effects go both ways: PCOS might impact appetite, so that weight gain becomes more likely. Weight loss using diet is equally effective in people with and without PCOS. == Mechanism ==

(GnRH) pulse frequency raises levels of luteinizing hormone (LH), which stimulates ovarian follicles to produce more androgens. Excess androgens slow follicle development, leading to the accumulation of small follicles that produce anti-Müllerian hormone (AMH), increasing testosterone levels. Insulin resistance raises blood sugar and insulin levels, lowering sex hormone-binding globulin (SHBG), which further raises testosterone levels. Insulin also enhances the effect of LH on androgen production.|alt=see caption PCOS involves both hormonal and metabolic changes. Women with PCOS often have higher levels of androgens, mainly produced by the ovaries, as part of a disrupted hypothalamus–pituitary–ovarian axis. In the brain, the hypothalamus sends out gonadotropin-releasing hormone (GnRH) pulses with higher frequency. This raises luteinising hormone (LH), while follicle-stimulating hormone (FSH) stays the same or is slightly lower. The higher LH stimulates theca cells in the ovary to produce more androgens. but obesity makes it worse. PCOS is associated with cardiovascular and liver dysfunction. For instance, women with PCOS can have coronary and aortic calcification. Obesity, impaired glucose metabolism, and excess androgens are all risk factors for liver dysfunction (MASLD). == Diagnosis ==

Diagnostic criteria Different criteria are used for diagnosing PCOS, but the (revised) Rotterdam criteria are recommended by clinical guidelines. • Signs of androgen excess, either clinical (visible signs such as facial hair or acne) or biochemical (detected through a blood test). Androgens are "male" hormones like testosterone. • Irregular or absent menstrual cycles • Polycystic ovaries on ultrasound or high levels of anti-Müllerian hormone (AMH) Other causes of these issues need to be excluded for diagnosis. In adolescents, both androgen excess and irregular or absent periods are required, as it is normal for adolescents to have many follicles ("cysts") visible in their ovaries, so it does not help with diagnosis. Adolescents who only meet one criterion are considered 'at risk', and are to be reassessed when they are adults. • Infrequent or irregular cycles • Signs of androgen excess (clinical or biochemical) • Exclusion of other disorders that can result in the above Assessment and testing There is a three-step algorithm to diagnose PCOS. Step one assesses signs of androgen excess and irregular menstrual cycles. If someone has both, and other causes are excluded, PCOS is diagnosed. In step two, those with only irregular cycles undergo a blood test for testosterone. If elevated, again excluding other causes of the symptoms, PCOS is diagnosed. For adolescents, step two is the final step. Step three applies to adults with either irregular cycles or androgen excess. An ultrasound or AMH test (but not both, to avoid overdiagnosis) is performed. If polycystic ovaries or elevated AMH levels are detected, PCOS is diagnosed. Clinical androgen excess in adults can result in acne, hirsutism (male pattern of hair growth, such as on the chin or chest), and female pattern hair loss. Hirsutism can be assessed using the standardised Ferriman–Gallwey visual scoring system, with a score above four to six indicating clinical significance. 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. Assessment may be complicated by self-treatment. Hair loss can be assessed with the Ludwig visual score. In adolescents, androgen excess shows as severe acne and hirsutism. 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. Biochemical androgen excess in PCOS is assessed using total and free testosterone. Accurate measurement requires tandem mass spectrometry 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. Severely elevated androgen levels may indicate other conditions. image showing polycystic ovary morphology|alt=Three ultrasound images at different locations in the ovary (different planes), and a reconstructed 3D image of ovarian follicles. In adults, an ultrasound can be used to look for small ovarian follicles. In adolescents, this is not assessed because larger numbers of follicles are normal at that age. In PCOS, these follicles are often on the ovary's periphery, forming a "string of pearls". To count as polycystic ovaries, at least 20 follicles must be present, smaller than 9 mm. (Older diagnostic criteria required only 12. Alternatively, AMH levels can be tested in the blood. Differential diagnosis 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. == Management ==

PCOS has no cure, and management focuses on relief of symptoms. Metabolic issues can further be treated with metformin or GLP-1 receptor agonists. For women with a BMI over 35, bariatric surgery may be an option. Other typical acne treatments and hair removal techniques may be used. Lifestyle interventions for women with PCOS may include strategies such as setting goals, tracking progress, learning assertiveness, and relapse prevention. These approaches aim to support weight control, a healthy lifestyle, and emotional well-being. Support may also involve using SMART goals (specific, measurable, achievable, realistic, and timely). Broader behavioural or cognitive behavioural programmes may help increase motivation, continued participation, and long-term healthy habits. Medications Medications for PCOS include metformin and oral contraceptives. Metformin is a medication commonly used in type 2 diabetes mellitus, and is used frequently off-label in the management of PCOS. It can also be used to help women get pregnant, but it is not the most effective drug for it. Combined oral contraceptives (COCs) can be used to reduce the symptoms of hirsutism and regulate menstrual periods. They increase sex hormone binding globulin production, and reduce levels of androgens. A regular cycle reduces the risk of endometrial cancer. Contraceptive pills with only progestogens can be used to improve menstrual regularity, but not for symptoms of androgen excess. It may take six to twelve months for COCs to be effective for hirsutism. Pregnancy in PCOS is more risky than normal, and treatment is focused on getting a single pregnancy, rather than, for instance, twins (multiple pregnancy). Other medications that can be used to treat infertility, listed from most to least effective, are metformin + clomiphene citrate, clomiphene citrate alone, and metformin alone. Gonadotrophin therapy may be effective too, but requires monitoring and increases the risks of multiple pregnancies. When medication and lifestyle interventions are ineffective, infertility can be treated with a laparoscopic procedure called "ovarian drilling", which involves puncture of 4–10 small follicles with electrocautery, laser, or biopsy needles. This procedure can induce ovulation, typically leads to a single pregnancy, but other risks may be higher compared to medication. As a final treatment option, in vitro fertilisation (IVF) can be considered. IVF does increase the risk of ovarian hyperstimulation syndrome. Using a 'freeze all' strategy makes it easier to transfer a single embryo and provides time for the ovaries to recover from hyperstimulation. Although oral contraceptives have shown significant efficacy in clinical trials (60–100% of individuals for treatment of hirsutism), severe acne or hirsutism might require additional treatment. Antiandrogens are sometimes used, such as finasteride, but they are contraindicated in pregnancy. Finasteride inhibits the conversion of testosterone to its stronger form dihydrotestosterone. Mental health Women with PCOS are far more likely to have depression than women without PCOS. Symptoms of depression might be heightened by certain symptoms of the condition, such as hirsutism or obesity, that can lead to low self-esteem or poor body image. Screening for depression and anxiety disorders is recommended using validated questionnaires, for instance, at diagnosis as well as afterwards, based on clinical judgement. For eating disorders and body image distress, screening is only recommended when clinically indicated. For sexually active women who give permission to discuss it, psychosexual dysfunction can be assessed too. Treatment of PCOS shows no to moderate effect on depression or anxiety, and standard therapies (such a psychotherapy and anti-depressants) are recommended instead. Cognitive behaviour therapy can be used for girls and women with low self-esteem, poor body image, disordered eating or psychosexual dysfunction. Screening for cardiometabolic issues Given the higher risk of cardiometabolic conditions, monitoring is recommended. This includes testing of glucose tolerance, using a two-hour oral glucose tolerance test (GTT) in all women with PCOS. After initial testing at diagnosis, follow-up assessments are advised every one to three years, depending on the presence of diabetes risk factors. Screening for cardiovascular risk factors includes lipid profile tests and yearly blood pressure measurements. == Epidemiology ==

PCOS is the most common hormonal disorder (endocrine disorder) among women of reproductive age. When someone is infertile due to a lack of ovulation, PCOS is the most common cause. A 2022 review noted a prevalence between 5% and 18%. Prevalence seems fairly even among people with different ethnicities, but may be higher in people from Southeast Asia and the Eastern Mediterranean. But PCOS can express differently. For instance, in African and Hispanic American people with PCOS, there is more insulin resistance compared to other ethnic groups. == History ==

Historical descriptions of possible PCOS symptoms date to ancient Greece, where Hippocrates described women with "thick, oily skin and absence of menstruation." The earliest known description of what is now recognized as PCOS dates from 1721 in Italy, which described "Young married peasant women, moderately obese and infertile, with two larger than normal ovaries, bumpy, shiny and whitish, just like pigeon eggs". Polycystic ovaries were likely first formally described in 1844 by the French doctor Achille Chereau. In 1935, American gynecologists Irving F. Stein and Michael L. Leventhal published a report linking polycystic ovaries to hirsutism, infertility, and lack of periods. The report also hypothesised that PCOS results from endocrine dysfunction, initiating research into its hormonal causes and giving rise to the term Stein–Leventhal syndrome. By the 1980s, the metabolic side of PCOS started to be studied, before the start of genetics research in the 1990s. == Terminology ==

The name polycystic ovary syndrome derives from a typical finding on medical images called polycystic ovary morphology. A polycystic ovary has an abnormally large number of developing follicles, looking like many small cysts. There are various objections to the name polycystic ovary syndrome: the "cysts" are not truly cysts, but arrested follicles. Having many follicles in the ovaries is also not unique to PCOS, and is often seen in women without PCOS, particularly adolescents. Furthermore, the name implies that PCOS is a gynecological condition only, rather than a metabolic and endocrine condition. Previous names for PCOS are Stein–Leventhal syndrome and polycystic ovary disease. Suggested names include hyperandrogenic (chronic) anovulation, estrogenic ovulatory dysfunction or functional female hyperandrogenism. For specific subgroups, suggested names include multi-follicular ovarian disorder for those with polycystic ovary morphology, and metabolic hyperandrogenic syndrome for those meeting the NIH PCOS criteria. A majority of clinicians and people with PCOS are in favour of renaming the condition, and, , a survey is underway to find a new name. == Research directions ==

Key research questions in PCOS focus on the best way to manage the condition, including with new anti-obesity drugs. In terms of criteria for diagnosis, age-specific levels of AMH need to be specified. Biomarkers are needed for early diagnosis and to guide drug development. Another open question is how to define the male phenotype to assess male relatives of women with PCOS. Both can be derived from individuals with PCOS 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 way to stimulate the development of reproductive disorders such as PCOS in vitro. ==Society and culture==

The direct economic costs of PCOS in the United States are estimated to be over $15 billion per year (in 2021 USD). This includes the costs of managing PCOS, treating its complications such as strokes, and its mental health costs. Compared to arthritis and lupus—diseases with a similar or lower prevalence and similar severity—PCOS received lower NIH research funding between 2005 and 2015. , no research on PCOS has been funded by the EU since 2020. This possible underfunding reflects a gender bias in health care, where conditions mostly affecting women receive less research funding. There is substantial misinformation on PCOS in social media. For example, some health influencers promote restrictive diets, such as eliminating gluten or dairy, for which there is no evidence of effectiveness. Others recommend against intensive exercise, despite its usefulness. Some social media influencers without medical qualifications, including those with large followings, have presented themselves as authorities on PCOS to promote their unproven treatments, taking advantage of the limited medical options available for treating the condition. Research has identified notable gaps in physician knowledge and education related to PCOS, which may contribute to challenges in timely diagnosis and treatment. For instance, health care professionals in primary care, but also in gynecology and reproductive specialists, are often unfamiliar with the precise diagnostic criteria. In terms of management, many professionals have limited knowledge of associated metabolic conditions, recommended screening, and psychological impacts. Diagnosis is often delayed, and those with PCOS are usually dissatisfied with care. == See also ==