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. 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, which in turn results in an increase in the lh/fsh ratio increased ovarian androgen production; decreased follicular maturation; and decreased shbg binding. 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. 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). 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. pcos may be associated with chronic inflammation, with several investigators correlating inflammatory mediators with anovulation and other pcos symptoms. similarly, there seems to be a relation between pcos and an increased level of oxidative stress. 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. the diagnosis is fairly straightforward using the rotterdam criteria, even when the syndrome is associated with a wide range of symptoms. transvaginal ultrasound scan of polycystic ovary polycystic ovary as seen on sonography differential diagnosis other causes of irregular or absent menstruation and hirsutism, such as hypothyroidism, congenital adrenal hyperplasia (21-hydroxylase deficiency), cushing's syndrome, hyperprolactinemia, androgen-secreting neoplasms, and other pituitary or adrenal disorders, should be investigated. standard assessment 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 62.7%–88.0%) and a specificity of 93.8% (95% ci 82.8%–98.7%). 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 5–7 mm, but not further. no single follicle reaches the preovulatory size (16 mm or more). according to the rotterdam criteria, which are widely used for diagnosis of pcos, 12 or more small follicles should be seen in a suspect ovary on ultrasound examination. 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. the follicles may be oriented in the periphery, giving the appearance of a 'string of pearls'. 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. 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.) serum (blood) levels of androgens, including androstenedione and testosterone may be elevated. dehydroepiandrosterone sulfate (dhea-s) levels above 700–800 µg/dl are highly suggestive of adrenal dysfunction because dhea-s is made exclusively by the adrenal glands. the free testosterone level is thought to be the best measure, with approximately 60 per cent of pcos patients demonstrating supranormal levels. 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 or 3:1 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. there are often low levels of sex hormone-binding globulin, in particular among obese or overweight women. anti-müllerian hormone (amh) is increased in pcos, and may become part of its diagnostic criteria. glucose tolerance testing two-hour oral glucose tolerance test (gtt) in women with risk factors (obesity, family history, history of gestational diabetes) may indicate impaired glucose tolerance (insulin resistance) in 15–33% of women with pcos. frank diabetes can be seen in 65–68% of women with this condition. 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. 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). management the primary treatments for pcos include lifestyle changes and use of medications. goals of treatment may be considered under four categories: lowering of insulin resistance 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. as pcos appears to cause significant emotional distress, appropriate support may be useful. diet where pcos is associated with 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 hormonal disorders. 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. 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. vitamin d deficiency may play some role in the development of the metabolic syndrome, and treatment of any such deficiency is indicated. however, a systematic review of 2015 found no evidence that vitamin d supplementation reduced or mitigated metabolic and hormonal dysregulations in pcos. 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. medications medications for pcos include oral contraceptives and metformin. the oral contraceptives increase sex hormone binding globulin production, which increases binding of free testosterone. this reduces the symptoms of hirsutism caused by high testosterone and regulates return to normal menstrual periods. 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. spironolactone can be used for its antiandrogenic effects, and the topical cream eflornithine can be used to reduce facial hair. a newer insulin resistance medication class, the thiazolidinediones (glitazones), have shown equivalent efficacy to metformin, but metformin has a more favorable side effect profile. 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. 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. in addition to this, metformin is associated with several unpleasant side effects: including abdominal pain, metallic taste in the mouth, diarrhoea and vomiting. the use of statins in the management of underlying metabolic syndrome remains unclear. 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. metformin is thought to be safe to use during pregnancy (pregnancy category b in the us). 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. liraglutide may reduce weight and waist circumference in people with pcos more than other medications. infertility main article: infertility in polycystic ovary syndrome not all women with pcos have difficulty becoming pregnant. but some women with pcos may have difficulty getting pregnant since their body does not produce the hormones necessary for regular ovulation. pcos might also increase the risk of miscarriage or premature delivery. however, it is possible to have a normal pregnancy. including medical care and a healthy lifestyle to follow. for those that do, anovulation or infrequent ovulation is a common cause and pcos is the main cause of anovulatory infertility. other factors include changed levels of gonadotropins, hyperandrogenemia, and hyperinsulinemia. 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. 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. digital health interventions have been shown to be particularly effective in providing combined therapy to manage pcos through both lifestyle changes and medication. for those women that after weight loss still are anovulatory or for anovulatory lean women, then ovulation induction using the medications letrozole or clomiphene citrate are the principal treatments used to promote ovulation. previously, the anti-diabetes medication metformin was recommended treatment for anovulation, but it appears less effective than letrozole or clomiphene. for women not responsive to letrozole or clomiphene and diet and lifestyle modification, there are