Polycystic ovary syndrome

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Polycystic ovary syndrome
PCOS.jpg
A polycystic ovary shown on an ultrasound image.
Classification and external resources
ICD-10 E28.2
ICD-9 256.4
OMIM 184700
MedlinePlus 000369
eMedicine med/2173 ped/2155 radio/565
Patient UK Polycystic ovary syndrome
MeSH D011085

Polycystic ovary syndrome (PCOS), also called hyperandrogenic anovulation (HA),[1] or Stein–Leventhal syndrome,[2] is a set of symptoms due to a hormone imbalance in women.[3] Symptoms include: irregular or no menstrual periods, heavy periods, excess body and facial hair, acne, pelvic pain, trouble getting pregnant, and patches of thick, darker, velvety skin.[4] Associated conditions include: type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.[3]

PCOS is due to a combination of genetic and environmental factors.[5] Risk factors include obesity, not enough physical exercise, and a family history of someone with the condition.[6] Diagnosis is based on two of the following three findings: no ovulation, high androgen levels, and ovarian cysts.[3] Cysts may be detectable by ultrasound. Other conditions that produce similar symptoms include adrenal hyperplasia, hypothyroidism, and hyperprolactinemia.[7]

PCOS has no cure.[8] Treatment may involve lifestyle changes such as weight loss and exercise. Birth control pills may help with improving the regularity of periods, excess hair, and acne. Metformin and anti-androgens may also help. Other typical acne treatments and hair removal techniques may be used.[9] Efforts to improve fertility include weight loss, clomiphene, or metformin. In vitro fertilization is used by some in whom other measures are not effective.[10]

PCOS is the most common endocrine disorders among women between the ages of 18 and 44.[11] It affects approximately 5% to 10% of this age group.[6] It is one of the leading causes of poor fertility.[3] The earliest known description of what is now recognized as PCOS date from 1721 in Italy.[12]

Signs and symptoms[edit]

Common symptoms of PCOS include the following:

Asians affected by PCOS are less likely to develop hirsutism than those of other ethnic backgrounds.[17]

Cause[edit]

PCOS is a heterogeneous disorder of uncertain cause.[18][19][13] There is strong 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.[18][19][5]

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.[19][20][21][22] 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.[20][22] The allele appears to manifest itself at least partially via heightened androgen levels secreted by ovarian follicle theca cells from women with the allele.[21] The exact gene affected has not yet been identified.[19][5][23]

The severity of PCOS symptoms appears to be largely determined by factors such as obesity.[5][11]

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 the cornerstone of 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 since there is a wide spectrum of symptoms possible, and cysts in the ovaries are seen only in 15% of people.[24]

PCOS may be related to or exacerbated by exposures during the prenatal period, epigenetic factors, environmental impacts (especially industrial endocrine disruptors[25] such as bisphenol A and certain drugs) and the increasing rates of obesity.[25][26][27][28][29][30][31]

Diagnosis[edit]

Not everyone 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.[32] The diagnosis is straightforward using the Rotterdam criteria, even when the syndrome is associated with a wide range of symptoms.

Definition[edit]

Two definitions are commonly used:

NIH[edit]

In 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a person has PCOS if she has all of the following:[33]
  1. oligoovulation
  2. signs of androgen excess (clinical or biochemical)
  3. exclusion of other disorders that can result in menstrual irregularity and hyperandrogenism

Rotterdam[edit]

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[34][11][35]
  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.[36][37]

Androgen Excess PCOS Society
In 2006, the Androgen Excess PCOS Society suggested a tightening of the diagnostic criteria to all of the following:[11]
  1. excess androgen activity
  2. oligoovulation/anovulation and/or polycystic ovaries
  3. exclusion of other entities that would cause excess androgen activity

Standard diagnostic assessments[edit]

  • 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%).[38]
  • 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, 12 or more small follicles should be seen in an ovary on ultrasound examination.[33] 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.[39] The follicles may be oriented in the periphery, giving the appearance of a 'string of pearls'.[40] 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.[39]
  • 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.)[citation needed]
  • Serum (blood) levels of androgens (male hormones), including androstenedione and testosterone may be elevated.[11] Dehydroepiandrosterone sulfate levels above 700-800 µg/dL are highly suggestive of adrenal dysfunction because DHEA-S is made exclusively by the adrenal glands.[41][42] The free testosterone level is thought to be the best measure,[42][43] with ~60% of PCOS patients demonstrating supranormal levels.[15] The Free androgen index (FAI) of the ratio of testosterone to sex hormone-binding globulin (SHBG) is high[11][42] 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,[44] possibly because FAI is correlated with the degree of obesity.[45]

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[46] or 3:1[42] 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.[46] There are often low levels of sex hormone-binding globulin,[42] in particular among obese or overweight women.[citation needed]

Anti-Müllerian hormone (AMH) is increased in PCOS, and may become part of its diagnostic criteria.[47][48]

Associated conditions[edit]

  • Fasting biochemical screen and lipid profile[42]
  • 2-Hour oral glucose tolerance test (GTT) in women with risk factors (obesity, family history, history of gestational diabetes)[11] may indicate impaired glucose tolerance (insulin resistance) in 15–33% of women with PCOS.[42] Frank diabetes can be seen in 65–68% of women with this condition.[citation needed] 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.[11]
  • 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).[citation needed]
  • Glucose tolerance testing (GTT) instead of fasting glucose can increase diagnosis of increased glucose tolerance and frank diabetes among people with PCOS according to a prospective controlled trial.[49] 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.[49]

Differential diagnosis[edit]

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.[11][35][42]

Pathogenesis[edit]

Polycystic ovaries develop when the ovaries are stimulated to produce excessive amounts of male hormones (androgens), in particular testosterone, by either one or a combination of the following (almost certainly combined with genetic susceptibility[21]):

  • the release of excessive luteinizing hormone (LH) by the anterior pituitary gland[citation needed]
  • through high levels of insulin in the blood (hyperinsulinaemia) in women whose ovaries are sensitive to this stimulus[13]

The syndrome acquired its most widely used name due to the common sign on ultrasound examination of multiple (poly) ovarian cysts. These "cysts" are actually immature follicles not cysts. The follicles have developed from primordial follicles, but the development has stopped ("arrested") at an early antral 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.[citation needed]

Women with PCOS experience an increased frequency of hypothalamic GnRH pulses, which in turn results in an increase in the LH/FSH ratio.[50]

A majority of people with PCOS have insulin resistance and/or are obese. Their 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, LH over FSH dominance, increased ovarian androgen production,[13] decreased follicular maturation, and decreased SHBG binding; all these steps contribute to the development of PCOS.[citation needed] Insulin resistance is a common finding among women with a normal weight as well as overweight women.[11][16]

Adipose 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 estrogens (which inhibits FSH via negative feedback).[51]

PCOS may be associated with chronic inflammation,[13][52] with several investigators correlating inflammatory mediators with anovulation and other PCOS symptoms.[53][54] Similarly, there seems to be a relation between PCOS and increased level of oxidative stress.[55]

It has previously been suggested that the excessive androgen production in PCOS could be caused by a decreased serum level of IGFBP-1, in turn increasing the level of free IGF-I, which stimulates ovarian androgen production, but recent data concludes this mechanism to be unlikely.[56]

PCOS has also been associated with a specific FMR1 sub-genotype. The research suggests that women with heterozygous-normal/low FMR1 have polycystic-like symptoms of excessive follicle-activity and hyperactive ovarian function.[57]

Transgender men may experience a higher than expected rate of PCOS due to increased testosterone, if they choose to take hormone therapy as part of their gender presentation.[58][59]

Management[edit]

The primary treatments for PCOS include: lifestyle changes, medications and surgery.[60]

Goals of treatment may be considered under four categories:

In each of these areas, there is considerable debate as to the optimal treatment. One of the major reasons for this 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.[61]

Diet[edit]

Where PCOS is associated with overweight or obesity, successful weight loss is the most effective method of restoring normal ovulation/menstruation, but 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.[62] 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.[62] Vitamin D deficiency may play some role in the development of the metabolic syndrome, so treatment of any such deficiency is indicated.[63]

Medications[edit]

Reducing insulin resistance by improving insulin sensitivity through medications such as metformin, and the newer thiazolidinedione (glitazones), have been an obvious approach and initial studies seemed to show effectiveness.[13][63][64] Although metformin is not licensed for use in PCOS, 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.[65] However subsequent reviews in 2008 and 2009 have noted that randomised control trials have in general not shown the promise suggested by the early observational studies.[66][67] A review in 2014 concluded that there is no evidence that metformin could cause any increased risk of major birth defects in women affected by PCOS and treated during the first trimester.[68]

Infertility[edit]

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.[69] 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.

For those women that after weight loss still are anovulatory or for anovulatory lean women, then the ovulation-inducing medications clomiphene citrate[63] and FSH are the principal treatments used to promote ovulation.[13] Previously, the anti-diabetes medication metformin was recommended treatment for anovulation,[13] but it appears less effective than clomiphene.[70]

For women not responsive to 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[63] or ovulations after adjuvant treatment with clomiphene or FSH.[citation needed] (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.[63]

Hirsutism and acne[edit]

For more details on this topic, see Hirsutism.

When appropriate (e.g., in women of child-bearing age who require contraception), a standard contraceptive pill is frequently effective in reducing hirsutism.[13][63] Progestogens such as norgestrel and levonorgestrel should be avoided due to their androgenic effects.[63]

Other drugs with anti-androgen effects include flutamide,[71] and spironolactone,[13][63] which can give some improvement in hirsutism. Spironolactone is probably the most-commonly used drug in the US. 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 drug 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.[63] 5-alpha reductase inhibitors (such as finasteride and dutasteride) may also be used;[72] 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[63]), 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 drug treatments if one does not work, but drug treatments do not work well for all individuals.

Menstrual irregularity and endometrial hyperplasia[edit]

If fertility is not the primary aim, then menstruation can usually be regulated with a contraceptive pill.[13][63] 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.[73] If menstruation occurs less often or not at all, some form of progestogen replacement is recommended.[72] An alternative is oral progestogen taken at intervals (e.g., every three months) to induce a predictable menstrual bleeding.[13]

Alternative medicine[edit]

There is insufficient evidence to conclude an effect from D-chiro-inositol.[74] Myo-inositol however appears to be effective based on a systematic review.[75] There is preliminary evidence but no high quality evidence looking at acupuncture in PCOS.[76][60]

Prognosis[edit]

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

Early diagnosis and treatment may reduce the risk of some of these, such as type 2 diabetes and heart disease.[13]

The risk of ovarian cancer and breast cancer is not significantly increased overall.[77]

Epidemiology[edit]

The prevalence of PCOS depends on the choice of diagnostic criteria. The World Health Organization estimates that it affects 116 million women worldwide as of 2010 (3.4% of women).[88] One community-based prevalence study using the Rotterdam criteria found that about 18% of women had PCOS, and that 70% of them were previously undiagnosed.[11]

One study in the United Kingdom concluded that the risk of PCOS development was higher in lesbian women than in heterosexuals.[89] However, two subsequent studies of women with PCOS have not replicated this finding.[90][91] Ultrasonographic findings of polycystic ovaries are found in 8-25% of normal women.[92][93][94][95] 14% women on oral contraceptives are found to have polycystic ovaries.[93]

History[edit]

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.[32][33]

The earliest published description of a person with what is now recognized as PCOS was in 1721 in Italy.[12] Cyst-related changes to the ovaries were described in 1844.[12]

Names[edit]

Other names for this syndrome include 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.[32]

Most common names for this disease derive from a typical finding on medical images, called a polycystic ovary.[13] A polycystic ovary has an abnormally large number of developing eggs visible near its surface,[32] looking like many small cysts[96] or a string of pearls.

See also[edit]

References[edit]

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