Polycystic ovary syndrome, or polycystic ovarian syndrome (PCOS), is the most common endocrine disorder in women of reproductive age.[14] The syndrome is named after cysts which form on the ovaries of some women with this condition, though this is not a universal symptom, and not the underlying cause of the disorder.[15][16]
A review of international evidence found that the prevalence of PCOS could be as high as 26% among some populations, though ranges between 4% and 18% are reported for general populations.[19][20][21] According to the World Health Organization (WHO), PCOS affects over 8-13% of reproductive-aged women.[22]
The exact cause of PCOS remains uncertain, and treatment involves management of symptoms using medication.[20]
Definition
Two definitions are commonly used:
NIH
In 1990, a consensus workshop sponsored by the NIH/NICHD suggested that a person has PCOS if they have all of the following:[23]
Exclusion of other disorders that can result in menstrual irregularity and hyperandrogenism (e.g.: Congenital Suprarrenal Hyperplasia, androgen producer tumors, hyperprolactinemia).
Rotterdam
In 2003, a consensus workshop sponsored by ESHRE/ASRM in Rotterdam indicated PCOS to be present if any two out of three criteria are met, in the absence of other entities that might cause these findings:[24][25][26]
The Rotterdam definition is wider, including many more women, the most notable ones being women without androgen excess. Critics say that findings obtained from the study of women with androgen excess cannot necessarily be extrapolated to women without androgen excess.[27][28]
Androgen Excess PCOS Society
In 2006, the Androgen Excess PCOS Society suggested a tightening of the diagnostic criteria to all of the following:[24]
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]
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][31] Approximately three-quarters of women with PCOS (by the diagnostic criteria of NIH/NICHD 1990) have evidence of hyperandrogenemia.[32]
Acne: A rise in testosterone levels, increases the oil production within the sebaceous glands and clogs pores.[34] For many women, the emotional impact is great and quality of life can be significantly reduced.[35]
Androgenic alopecia: Estimates suggest that androgenic alopecia affects 22% of PCOS sufferers.[34] This is a result of high testosterone levels that are converted into the dihydrotestosterone (DHT) hormone. Hair follicles become clogged, making hair fall out and preventing further growth.[36]
Acanthosis nigricans (AN): A skin condition where dark, thick and "velvety" patches can form.[37]
Polycystic ovaries: There are small cysts on one or both ovaries. Ovaries might get enlarged and comprise follicles surrounding the eggs. As 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 have higher risk of multiple diseases including infertility, type 2 diabetes mellitus (DM-2), cardiovascular risk, metabolic syndrome, obesity, impaired glucose tolerance, depression, obstructive sleep apnea (OSA), endometrial cancer, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH).[38]
Women with PCOS tend to have central obesity, but 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.[39] 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.[40]
Even though most women with PCOS are overweight or obese, it is important to acknowledge that 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 usually are diagnosed after struggles to conceive.[43] 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 of losing weight and healthy dieting.[44]
Hormone levels
Testosterone levels are usually elevated in women with PCOS.[45][46] In a 2020 systematic review and meta-analysis of sexual dysfunction related to PCOS which included 5,366women with PCOS from 21studies, testosterone levels were analyzed and were found to be 2.34nmol/L (67ng/dL) in women with PCOS and 1.57nmol/L (45ng/dL) in women without PCOS.[46] In a 1995 study of 1,741women with PCOS, mean testosterone levels were 2.6(1.1–4.8) nmol/L (75(32–140)ng/dL).[47] In a 1998 study which reviewed many studies and subjected them to meta-analysis, testosterone levels in women with PCOS were 62 to 71ng/dL (2.2–2.5nmol/L) and testosterone levels in women without PCOS were about 32ng/dL (1.1nmol/L).[48] In a 2010 study of 596 women with PCOS which used liquid chromatography–mass spectrometry (LC–MS) to quantify testosterone, median levels of testosterone were 41 and 47ng/dL (with 25th–75th percentiles of 34–65ng/dL and 27–58ng/dL and ranges of 12–184ng/dL and 1–205ng/dL) via two different labs.[49] If testosterone levels are above 100 to 200ng/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.[47][50][45]
Associated conditions
Warning signs may include a change in appearance. But there are also manifestations of mental health problems, such as anxiety, depression, and eating disorders.[29][medical citation needed]
A diagnosis of PCOS suggests an increased risk of the following:
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).[23][55] PCOS is also associated with higher risk for diabetes.[56]
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.[59]
Cardiovascular disease,[23] with a meta-analysis estimating a 2-fold risk of arterial disease for women with PCOS relative to women without PCOS, independent of BMI.[60]
PCOS is a heterogeneous disorder of uncertain cause.[64][65] 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][64][65] 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.[66]
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.[65][68][69][70] 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.[68][70] The phenotype appears to manifest itself at least partially via heightened androgen levels secreted by ovarian follicle theca cells from women with the allele.[69] The exact gene affected has not yet been identified.[7][65][71] In rare instances, single-gene mutations can give rise to the phenotype of the syndrome.[72] Current understanding of the pathogenesis of the syndrome suggests, however, that it is a complex multigenic disorder.[73]
Due to the scarcity of large-scale screening studies, the prevalence of endometrial abnormalities in PCOS remains unknown, though women with the condition may be at increased risk for endometrial hyperplasia and carcinoma as well as menstrual dysfunction and infertility.[citation needed]
The severity of PCOS symptoms appears to be largely determined by factors such as obesity.[7][24][74] 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.[75]
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 lies in hormonal regulation in the hypothalamus, with the involvement of many organs. The term PCOS is used due to the fact that 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.[15]
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.[82] 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.[83]
Pathogenesis
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):[69]
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][33] 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]
Diagnosis
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]
History-taking, specifically for menstrual pattern, obesity, hirsutism and acne. A clinical prediction rule found that these four questions can diagnose PCOS with a sensitivity of 77.1% (95% confidence interval [CI] 62.7%–88.0%) and a specificity of 93.8% (95% CI 82.8%–98.7%).[95]
Gynecologic ultrasonography, specifically looking for small ovarian follicles. These are believed to be the result of disturbed ovarian function with failed ovulation, reflected by the infrequent or absent menstruation that is typical of the condition. In a normal menstrual cycle, one egg is released from a dominant follicle– in essence, a cyst that bursts to release the egg. After ovulation, the follicle remnant is transformed into a progesterone-producing corpus luteum, which shrinks and disappears after approximately 12–14 days. In PCOS, there is a so-called "follicular arrest"; i.e., several follicles develop to a size of 5–7mm, but not further. No single follicle reaches the preovulatory size (16mm or more). According to the Rotterdam criteria, which are widely used for diagnosis of PCOS,[10] 12 or more small follicles should be seen in a suspect ovary on ultrasound examination.[23] More recent research suggests that there should be at least 25 follicles in an ovary to designate it as having polycystic ovarian morphology (PCOM) in women aged 18–35 years.[96] The follicles may be oriented in the periphery, giving the appearance of a 'string of pearls'.[97] If a high-resolution transvaginal ultrasonography machine is not available, an ovarian volume of at least 10 ml is regarded as an acceptable definition of having polycystic ovarian morphology, rather than follicle count.[96]
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.)[98]
Serum (blood) levels of androgens, including androstenedione and testosterone may be elevated.[24]Dehydroepiandrosterone sulfate (DHEA-S) levels above 700–800μg/dL are highly suggestive of adrenal dysfunction because DHEA-S is made exclusively by the adrenal glands.[99][94] The free testosterone level is thought to be the best measure,[94][100] with approximately 60 per cent of PCOS patients demonstrating supranormal levels.[32]
Some other blood tests are suggestive but not diagnostic. The ratio of LH (luteinizing hormone) to FSH (follicle-stimulating hormone), when measured in international units, is elevated in women with PCOS. Common cut-offs to designate abnormally high LH/FSH ratios are 2:1[101] or 3:1[94] as tested on day 3 of the menstrual cycle. The pattern is not very sensitive; a ratio of 2:1 or higher was present in less than 50% of women with PCOS in one study.[101] There are often low levels of sex hormone-binding globulin,[94] in particular among obese or overweight women.[102]Anti-Müllerian hormone (AMH) is increased in PCOS, and may become part of its diagnostic criteria.[103][104][105]
Glucose tolerance testing
Two-hour oral glucose tolerance test (GTT) in women with risk factors (obesity, family history, history of gestational diabetes)[24] may indicate impaired glucose tolerance (insulin resistance) in 15–33% of women with PCOS.[94] Frank diabetes can be seen in 65–68% of women with this condition.[106] 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.[24]
Fasting insulin level or GTT with insulin levels (also called IGTT). Elevated insulin levels have been helpful to predict response to medication and may indicate women needing higher doses of metformin or the use of a second medication to significantly lower insulin levels. Elevated blood sugar and insulin values do not predict who responds to an insulin-lowering medication, low-glycemic diet, and exercise. Many women with normal levels may benefit from combination therapy. A hypoglycemic response in which the two-hour insulin level is higher and the blood sugar lower than fasting is consistent with insulin resistance. A mathematical derivation known as the HOMAI, calculated from the fasting values in glucose and insulin concentrations, allows a direct and moderately accurate measure of insulin sensitivity (glucose-level x insulin-level/22.5).[107]
Management
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.[108]
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 menstrual cycle. This is especially the case in adolescents.[108]
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.[37] The primary treatments for PCOS include lifestyle changes and use of medications.[110]
Goals of treatment may be considered under these categories:[citation needed]
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.[111] As PCOS appears to cause significant emotional distress, appropriate support may also be useful.[112]
Diet
Where PCOS is associated with being overweight or obesity, 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.[113] 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.[114] 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.[114]
Reducing intake of food groups that cause inflammation, such as dairy, sugars and simple carbohydrates, can be beneficial.[37]
A mediterranean diet is often very effective due to its anti-inflammatory and anti-oxidative properties.[108]
Vitamin D deficiency may play some role in the development of the metabolic syndrome, and treatment of any such deficiency is indicated.[115][116] However, a systematic review of 2015 found no evidence that vitamin D supplementation reduced or mitigated metabolic and hormonal dysregulations in PCOS.[117] 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.[118]
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 return to normal ovulation.[115][120] A newer insulin resistance medication class, the thiazolidinediones (glitazones), have shown equivalent efficacy to metformin, but metformin has a more favorable side effect profile.[121][122] 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.[123][124] 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.[125] In addition to this, metformin is associated with several unpleasant side effects: including abdominal pain, metallic taste in the mouth, diarrhoea and vomiting.[126] Metformin is thought to be safe to use during pregnancy (pregnancy category B in the US).[127] 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.[128] Liraglutide may reduce weight and waist circumference in people with PCOS more than other medications.[129] The use of statins in the management of underlying metabolic syndrome remains unclear.[110]
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 metform 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.[130]
Some individuals with PCOS may have difficulty getting pregnant since their body does not produce the hormones necessary for regular ovulation.[131] PCOS might also increase the risk of miscarriage or premature delivery. However, it is possible to have a normal pregnancy.[citation needed]
For women that do, anovulation or infrequent ovulation is a common cause and PCOS is the main cause of anovulatory infertility.[132] Other factors include changed levels of gonadotropins, hyperandrogenemia, and hyperinsulinemia.[133] 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.[134]
For overweight anovulatory women with PCOS, weight loss and diet adjustments, especially to reduce the intake of simple carbohydrates, are associated with resumption of natural ovulation.[135] Digital health interventions have been shown to be particularly effective in providing combined therapy to manage PCOS through both lifestyle changes and medication.[136]
Femara is an alternative medicine that raises FSH levels and promote the development of the follicle.[37]
For those women that, after weight loss, are still anovulatory, or for anovulatory lean women, ovulation induction using the medications letrozole or clomiphene citrate are the principal treatments used to promote ovulation.[137][138][139] Clomiphene can cause mood swings and abdominal cramping for some.[37]
Previously, the anti-diabetes medication metformin was recommended treatment for anovulation, but it appears less effective than letrozole or clomiphene.[140][141]
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),[143] which often results in either resumption of spontaneous ovulations[115] or ovulations after adjuvant treatment with clomiphene or FSH.[144] (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.[115]
In a small UK randomized trial, bariatric surgery led to more spontaneous ovulations than behavioral interventions combined with medical therapy in adult women with PCOS, raising the prospect that surgery could enhance prospects of spontaneous fertility.[145]
Mental health
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.[35] Researchers suggest that there be mental health screenings performed in tandem with PCOS assessment in order to identify these complications early and treat them accordingly.[146]
PCOS is associated with other mental health related conditions besides depression such as anxiety, bipolar disorder, and obsessive–compulsive disorder.[35] Additionally, it has been found to significantly increase risk of eating disorders.[146] Screening for these mental health conditions will also be helpful in treatment of PCOS.
Lifestyle changes for people with PCOS have been proven to be difficult due to 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 with the goal of supporting women with PCOS in managing their symptoms.[147]
When appropriate (e.g., in women of child-bearing age who require contraception), a standard contraceptive pill is frequently effective in reducing hirsutism.[115] Progestogens such as norgestrel and levonorgestrel should be avoided due to their androgenic effects.[115] Metformin combined with an oral contraceptive may be more effective than either metformin or the oral contraceptive on its own.[148]
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) [37]
Other medications with anti-androgen effects include flutamide,[149] and spironolactone,[115] 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.[115]5-alpha reductase inhibitors (such as finasteride and dutasteride) may also be used;[150] 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[115]), 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.[151]
Menstrual irregularity
If fertility is not the primary aim, then menstruation can usually be regulated with a contraceptive pill.[115] 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.[152]
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.[153] If menstruation occurs less often or not at all, some form of progestogen replacement is recommended.[150]
Alternative medicine
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.[154][155] A 2012 and 2017 review have found myo-inositol supplementation appears to be effective in improving several of the hormonal disturbances of PCOS.[156][157] Myo-inositol reduces the amount of gonadotropins and the length of controlled ovarian hyperstimulation in women undergoing in vitro fertilization.[158] A 2011 review found not enough evidence to conclude any beneficial effect from D-chiro-inositol.[159] There is insufficient evidence to support the use of acupuncture, current studies are inconclusive and there's a need for additional randomized controlled trials.[160][161]
Epidemiology
PCOS is the most common endocrine disorder among women between the ages of 18 and 44.[24] It affects approximately 2% to 20% of this age group depending on how it is defined.[8][13] When someone is infertile due to lack of ovulation, PCOS is the most common cause and could guide to patients' diagnosis.[4] The earliest known description of what is now recognized as PCOS dates from 1721 in Italy.[162]
The prevalence of PCOS depends on the choice of diagnostic criteria. The World Health Organization estimates that it affects 116million women worldwide as of 2010 (3.4% of women).[163] Another estimate indicates that 7% of women of reproductive age are affected.[164] Another study using the Rotterdam criteria found that about 18% of women had PCOS, and that 70% of them were previously undiagnosed.[24] Prevalence also varies across countries due to lack of large-scale scientific studies; India, for example, has a purported rate of 1 in 5 women having PCOS.[165]
There are few studies that have investigated the racial differences in cardiometabolic factors in women with PCOS. There is also limited data on the racial differences in the risk of metabolic syndrome and cardiovascular disease in adolescents and young adults with PCOS.[166] The first study to comprehensively examine racial differences discovered notable racial differences in risk factors for cardiovascular disease. African American women were found to be significantly more obese, with a significantly higher prevalence of metabolic syndrome compared to white adult women with PCOS.[167] It is important for the further research of racial differences among women with PCOS, to ensure that every woman that is affected by PCOS has the available resources for management.[168][169]
Ultrasonographic findings of polycystic ovaries are found in 8–25% of women non-affected by the syndrome.[170][171][172][173] 14% women on oral contraceptives are found to have polycystic ovaries.[171] Ovarian cysts are also a common side effect of levonorgestrel-releasing intrauterine devices (IUDs).[174]
There are few studies that have investigated the racial differences in cardiometabolic factors in women with PCOS.[175]
History
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][23] 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.[51]
The earliest published description of a person with what is now recognized as PCOS was in 1721 in Italy.[162] Cyst-related changes to the ovaries were described in 1844.[162]
Etymology
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]
Society and culture
In 2005, 4 million cases of PCOS were reported in the US, costing $4.36 billion in healthcare costs.[176] In 2016 out of the National Institute Health's research budget of $32.3 billion for that year, 0.1% was spent on PCOS research.[177] Among women aged between 14 and 44, PCOS is conservatively estimated to cost $4.37 billion per year.[25]
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.[178] 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.[178][179]
Public figures
A number of celebrities and public figures have spoken about their experiences with PCOS, including:
Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin hirsutus meaning "hairy". It usually refers to a male pattern of hair growth in a female that may be a sign of a more serious medical condition, especially if it develops well after puberty. Cultural stigma against hirsutism can cause much psychological distress and social difficulty. Discrimination based on facial hirsutism often leads to the avoidance of social situations and to symptoms of anxiety and depression.
Amenorrhea or amenorrhoea is the absence of a menstrual period in a female who has reached reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses during childhood and after menopause.
Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).
Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.
Pubarche refers to the first appearance of pubic hair at puberty. It is one of the physical changes of puberty and can occur independently of complete puberty. The early stage of sexual maturation, also known as adrenarche, is marked by characteristics including the development of pubic hair, axillary hair, adult apocrine body odor, acne, and increased oiliness of hair and skin. The Encyclopedia of Child and Adolescent Health corresponds SMR2 with pubarche, defining it as the development of pubic hair that occurs at a mean age of 11.6 years in females and 12.6 years in males. It further describes that pubarche's physical manifestation is vellus hair over the labia or the base of the penis. See Table 1 for the entirety of the sexual maturity rating description.
Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infrequent or absent menstruation. Complications may include high blood cholesterol and diabetes. It occurs in approximately 5% of women of reproductive age.
Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.
Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differentiation and folliculogenesis. In humans, it is encoded by the AMH gene, on chromosome 19p13.3, while its receptor is encoded by the AMHR2 gene on chromosome 12.
Follicular atresia refers to the process in which a follicle fails to develop, thus preventing it from ovulating and releasing an egg. It is a normal, naturally occurring progression that occurs as mammalian ovaries age. Approximately 1% of mammalian follicles in ovaries undergo ovulation and the remaining 99% of follicles go through follicular atresia as they cycle through the growth phases. In summary, follicular atresia is a process that leads to the follicular loss and loss of oocytes, and any disturbance or loss of functionality of this process can lead to many other conditions.
Pattern hair loss is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front hairline, loss of hair on the crown and vertex of the scalp, or a combination of both. Female-pattern hair loss (FPHL) typically presents as a diffuse thinning of the hair across the entire scalp.
1D-chiro-Inositol or D-chiro-inositol is a chemical substance with formula C6H12O6, one of the nine isomers of cyclohexane-1,2,3,4,5,6-hexol. The molecule has a ring of six carbon atoms, each bound to one hydrogen atom and one hydroxyl (OH) group. The hydroxyls on atoms 1, 2, and 4, in counterclockwise order, lie above the plane of the ring. The molecule being distinct from its mirror image, the compound is chiral, hence its name. Its enantiomer is 1L-chiro-inositol.
Free Androgen Index (FAI) is a ratio used to determine abnormal androgen status in humans. The ratio is the total testosterone level divided by the sex hormone binding globulin (SHBG) level, and then multiplying by a constant, usually 100. The concentrations of testosterone and SHBG are normally measured in nanomols per liter. FAI has no unit.
Hyperthecosis, or ovarian hyperthecosis, is hyperplasia of the theca interna of the ovary. Hyperthecosis occurs when an area of luteinization occurs along with stromal hyperplasia. The luteinized cells produce androgens, which may lead to hirsutism and virilization in affected women.
Ovarian drilling, also known as multiperforation or laparoscopic ovarian diathermy, is a surgical technique of puncturing the membranes surrounding the ovary with a laser beam or a surgical needle using minimally invasive laparoscopic procedures. It differs from ovarian wedge resection, which involves the cutting of tissue. Minimally invasive ovarian drilling procedures have replaced wedge resections. Ovarian drilling is favored over wedge resection because cutting into the ovary might result in adhesions, potentially complicating postoperative outcomes. Ovarian drilling and ovarian wedge resection are treatment options to reduce the amount of androgen producing tissue in women with polycystic ovarian syndrome (PCOS). PCOS is the primary cause of anovulation, which results in female infertility. The induction of mono-ovulatory cycles can restore fertility.
Infertility in polycystic ovary disease (PCOS) is a hormonal imbalance in women that is thought to be one of the leading causes of female infertility. Polycystic ovary syndrome causes more than 75% of cases of anovulatory infertility.
Obesity is defined as an abnormal accumulation of body fat, usually 20% or more over an individual's ideal body weight. This is often described as a body mass index (BMI) over 30. However, BMI does not account for whether the excess weight is fat or muscle, and is not a measure of body composition. For most people, however, BMI is an indication used worldwide to estimate nutritional status. Obesity is usually the result of consuming more calories than the body needs and not expending that energy by doing exercise. There are genetic causes and hormonal disorders that cause people to gain significant amounts of weight but this is rare. People in the obese category are much more likely to suffer from fertility problems than people of normal healthy weight.
The HAIR-AN syndrome is a rare subtype of polycystic ovary syndrome (PCOS) characterized by hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN). The symptoms of the HAIR-AN syndrome are largely due to severe insulin resistance, which can be secondary to blocking antibodies against the insulin receptor or genetically absent/reduced insulin receptor number/function. Insulin resistance leads to hyperinsulinemia which, in turn, leads to an excess production of androgen hormones by the ovaries. High levels of androgen hormones (hyperandrogenism) in females causes excessive hair growth, acne and irregular menstruation. Patients with both underlying mechanisms of insulin resistance may have more severe hyperandrogenism. Insulin resistance is also associated with diabetes, heart disease and excessive darkening of the skin
Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anterior pituitary and the ovarian cycle. During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion.
Ovarian follicle dominance is the process where one or more follicles are selected per cycle to ovulate.
Female fertility agents are medications that improve female’s ability to conceive pregnancy. These agents are prescribed for infertile female who fails to conceive pregnancy after 1-year of regular and unprotected sexual intercourse. The following will cover the advancements of female fertility agents, major causes of female infertility. Next, it emphasizes on common female fertility agents in terms of their mechanism of action, side effects, fetal consideration and clinical application and ended up by the introduction of supplements and herbal medicines for female infertility.
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1 2 Mazze R, Strock ES, Simonson GD, Bergenstal RM (11 January 2007). "Type 2 Diabetes and Metabolic Syndrome in Children and Adolescents". Staged Diabetes Management: A Systematic Approach (2nded.). John Wiley & Sons. pp.213–. ISBN978-0-470-06171-8. OCLC1039172275. Archived from the original on 29 May 2024. Retrieved 18 September 2022. Diagnosis and treatment. The first diagnostic test [of PCOS] is measurement of total testosterone and free testosterone by radioimmunoassay. If total testosterone is between 50 ng/dL and 200 ng/dL above normal (<2.5 ng/dL) PCOS is present. If >200 ng/dL then serum DHEA-S should be measured. If total testosterone or DHEA-S >700 μg/dL then rule out an ovarian or adrenal tumor. These tests should be followed by tests for hypothyroidism, hyperprolactinemia, and adrenal hyperplasia.
1 2 Loh HH, Yee A, Loh HS, Kanagasundram S, Francis B, Lim LL (September 2020). "Sexual dysfunction in polycystic ovary syndrome: a systematic review and meta-analysis". Hormones (Athens). 19 (3): 413–423. doi:10.1007/s42000-020-00210-0. PMID32462512. S2CID218898082. A total of 5366 women with PCOS from 21 studies were included. [...] Women with PCOS [...] [had higher] serum total testosterone level (2.34 ± 0.58 nmol/L vs 1.57 ± 0.60 nmol/L, p < 0.001) compared with women without PCOS. [...] PCOS is characterized by high levels of androgens (dehydroepiandrosterone, androstenedione, and testosterone) and luteinizing hormone (LH), and increased LH/follicle stimulating hormone (FSH) ratio [52].
1 2 Balen AH, Conway GS, Kaltsas G, Techatrasak K, Manning PJ, West C, etal. (August 1995). "Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients". Hum Reprod. 10 (8): 2107–11. doi:10.1093/oxfordjournals.humrep.a136243. PMID8567849. The criteria for the diagnosis of the polycystic ovary syndrome (PCOS) have still not been agreed universally. A population of 1741 women with PCOS were studied, all of whom had polycystic ovaries seen by ultrasound scan. The frequency distributions of the serum concentrations of [...] testosterone [...] were determined and compared with the symptoms and signs of PCOS. [...] A rising serum concentration of testosterone [mean and 95th percentiles 2.6 (1.1-4.8) nmol/1] was associated with an increased risk of hirsutism, infertility and cycle disturbance. [...] If the serum testosterone concentration is >4.8 nmol/1, other causes of hyperandrogenism should be excluded.
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