Polycystic ovary syndrome

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.[25][27][28][29] 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.[27][29] The phenotype appears to manifest itself at least partially via heightened androgen levels secreted by ovarian follicle theca cells from women with the allele.[28] The exact gene affected has not yet been identified.[7][25][30] In rare instances, single-gene mutations can give rise to the phenotype of the syndrome.[31] Current understanding of the pathogenesis of the syndrome suggests, however, that it is a complex multigenic disorder.[32]

The severity of PCOS symptoms appears to be largely determined by factors such as obesity.[7][17][33]

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.

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 are 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 name PCOD is used when there is ultrasonographic evidence. The term PCOS is used due to the fact that there is a wide spectrum of symptoms possible, and cysts in the ovaries are seen only in 15% of people.[34]

PCOS may be related to or worsened by exposures during the prenatal period, epigenetic factors, environmental impacts (especially industrial endocrine disruptors,[35] such as bisphenol A and certain drugs) and the increasing rates of obesity.[35][36][37][38][39][40][41]

Two definitions are commonly used:

In 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a person has PCOS if they have all of the following:[55]

1. oligoovulation
2. signs of androgen excess (clinical or biochemical)
3. exclusion of other disorders that can result in menstrual irregularity and hyperandrogenism

In 2003 a consensus workshop sponsored by ESHRE/ASRM in Rotterdam indicated PCOS to be present if any 2 out of 3 criteria are met, in the absence of other entities that might cause these findings[17][56][57]

1. oligoovulation and/or anovulation
2. excess androgen activity
3. polycystic ovaries (by gynecologic ultrasound)

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.[58][59]

Androgen Excess PCOS Society

In 2006, the Androgen Excess PCOS Society suggested a tightening of the diagnostic criteria to all of the following:[17]

1. excess androgen activity
2. oligoovulation/anovulation and/or polycystic ovaries
3. exclusion of other entities that would cause excess androgen activity

• 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%).[60]
• 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,[10] 12 or more small follicles should be seen in an ovary on ultrasound examination.[55] 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.[61] The follicles may be oriented in the periphery, giving the appearance of a 'string of pearls'.[62] 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 instead of follicle count.[61]
• 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 (hormones associated with male development), including androstenedione and testosterone may be elevated.[17] Dehydroepiandrosterone sulfate levels above 700–800 µg/dL are highly suggestive of adrenal dysfunction because DHEA-S is made exclusively by the adrenal glands.[63][64] The free testosterone level is thought to be the best measure,[64][65] with ~60% of PCOS patients demonstrating supranormal levels.[20] The Free androgen index (FAI) of the ratio of testosterone to sex hormone-binding globulin (SHBG) is high[17][64] and is meant to be a predictor of free testosterone, but is a poor parameter for this and is no better than testosterone alone as a marker for PCOS,[66] possibly because FAI is correlated with the degree of obesity.[67]

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[68] or 3:1[64] 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.[68] There are often low levels of sex hormone-binding globulin,[64] in particular among obese or overweight women.[69] Anti-Müllerian hormone (AMH) is increased in PCOS, and may become part of its diagnostic criteria.[70][71][72]

• Fasting biochemical screen and lipid profile[64]
• 2-Hour oral glucose tolerance test (GTT) in women with risk factors (obesity, family history, history of gestational diabetes)[17] may indicate impaired glucose tolerance (insulin resistance) in 15–33% of women with PCOS.[64] 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.[17]
• 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 dosages 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).
• Glucose tolerance testing (GTT) instead of fasting glucose can increase diagnosis of impaired glucose tolerance and frank diabetes among people with PCOS according to a prospective controlled trial.[73] While fasting glucose levels may remain within normal limits, oral glucose tests revealed that up to 38% of asymptomatic women with PCOS (versus 8.5% in the general population) actually had impaired glucose tolerance, 7.5% of those with frank diabetes according to ADA guidelines.[73]

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.[17][57][64]

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 5 to 15% weight loss or more, which improves insulin resistance and all hormonal disorders.[76] However, many women find it very difficult to achieve and sustain significant weight loss. A scientific review in 2013 found similar decreases in weight and body composition and improvements in pregnancy rate, menstrual regularity, ovulation, hyperandrogenism, insulin resistance, lipids, and quality of life to occur with weight loss independent of diet composition.[77] Still, a low GI diet, in which a significant part of total carbohydrates are obtained from fruit, vegetables, and whole-grain sources, has resulted in greater menstrual regularity than a macronutrient-matched healthy diet.[77]

Vitamin D deficiency may play some role in the development of the metabolic syndrome, so treatment of any such deficiency is indicated.[78][79] However, a systematic review of 2015 found no evidence that vitamin D supplementation reduced or mitigated metabolic and hormonal dysregulations in PCOS.[80] 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 is insufficient to recommend their use.[81]

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.[78][82] 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.[83][84] 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.[85][86] 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.[87] In addition to this, metformin is associated with several unpleasant side effects: including abdominal pain, metallic taste in the mouth, diarrhoea and vomiting.[88] The use of statins in the management of underlying metabolic syndrome remains unclear.[89]

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. Metformin improves the efficacy of fertility treatment when used in combination with clomiphene.[90] Metformin is thought to be safe to use during pregnancy (pregnancy category B in the US).[91] 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.[92] Liraglutide may reduce weight and waist circumference more than other medications.[93]

Not all women with PCOS have difficulty becoming pregnant. For those that do, anovulation or infrequent ovulation is a common cause. Other factors include changed levels of gonadotropins, hyperandrogenemia and hyperinsulinemia.[94] 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.[95]

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.

For those women that after weight loss still are anovulatory or for anovulatory lean women, then the medications letrozole and clomiphene citrate are the principal treatments used to promote ovulation.[96][97][98] Previously, the anti-diabetes medication metformin was recommended treatment for anovulation, but it appears less effective than letrozole or clomiphene.[99][100]

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).

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), which often results in either resumption of spontaneous ovulations[78] or ovulations after adjuvant treatment with clomiphene or FSH. (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.[78]

When appropriate (e.g., in women of child-bearing age who require contraception), a standard contraceptive pill is frequently effective in reducing hirsutism.[78] Progestogens such as norgestrel and levonorgestrel should be avoided due to their androgenic effects.[78]

Other medications with anti-androgen effects include flutamide,[101] and spironolactone,[78] which can give some improvement in 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 should also benefit from 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.[78] 5-alpha reductase inhibitors (such as finasteride and dutasteride) may also be used;[102] they work by blocking the conversion of testosterone to dihydrotestosterone (the latter of which 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[78]), 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.

If fertility is not the primary aim, then menstruation can usually be regulated with a contraceptive pill.[78] The purpose of regulating menstruation, in essence, is for the woman's convenience, and perhaps her sense of well-being; there is no medical requirement for regular periods, as long as they occur sufficiently often.

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.[103] If menstruation occurs less often or not at all, some form of progestogen replacement is recommended.[102] An alternative is oral progestogen taken at intervals (e.g., every three months) to induce a predictable menstrual bleeding.

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.[104][105] A 2012 and 2017 review have found myo-inositol supplementation appears to be effective in improving several of the hormonal disturbances of PCOS.[106][107] Myo-inositol reduces the amount of gonadotropins and the length of controlled ovarian hyperstimulation in women undergoing in vitro fertilization.[108] A 2011 review found not enough evidence to conclude any beneficial effect from D-chiro-inositol.[109] There is insufficient evidence to support the use of acupuncture.[110][111]

In 2005, 4 million cases of PCOS were reported in the US, costing $4.36 billion in healthcare costs.[128] 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.[129]

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.[54]

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.[54]