Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders. It is a genetic disorder that can be inherited from either parent.

PCOS produces symptoms in approximately 5% to 10% of women of reproductive age (12–45 years old) and is thought to be one of the leading causes of female subfertility.

The principal features are anovulation, resulting in irregular menstruation, amenorrhea, ovulation-related infertility, and polycystic ovaries; excessive amounts or effects of androgenic (masculinizing) hormones, resulting in acne and hirsutism; and insulin resistance, often associated with obesity, Type 2 diabetes, and high cholesterol levels. The symptoms and severity of the syndrome vary greatly among affected women.

Names
Other names for this syndrome include polycystic ovary disease, functional ovarian hyperandrogenism, Stein-Leventhal syndrome (original name, not used in modern literature), ovarian hyperthecosis and sclerocystic ovary syndrome.

The common names 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 or a string of pearls.

Definition
Two definitions are commonly used:


 * NIH
 * In 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a patient has PCOS if she has ALL of the following:


 * 1) oligoovulation
 * 2) signs of androgen excess (clinical or biochemical)
 * 3) other entities are excluded that would cause polycystic ovaries


 * Rotterdam
 * 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


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

The Rotterdam definition is wider, including many more patients, notably patients without androgen excess and with other conditions that might cause polycystic ovaries. Critics say that findings obtained from the study of patients with androgen excess cannot necessarily be extrapolated to patients without androgen excess.

The prevalence of PCOS depends on the choice of diagnostic criteria. 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.

Signs and symptoms
Common symptoms of PCOS include
 * Menstrual disorders: mostly oligomenorrhea (few menstrual periods) or amenorrhea (no menstrual periods), but other types of menstrual disorders may also occur.
 * Infertility: generally resulting from chronic anovulation (lack of ovulation).
 * High levels of masculinizing hormones: mostly acne and hirsutism (excess hair), but may produce hypermenorrhea (very frequent menstrual periods) or other symptoms. Approximately three-quarters of patients with PCOS (by the diagnostic criteria of NIH/NICHD 1990) have evidence of hyperandrogenemia.
 * Metabolic syndrome: This appears as a tendency towards central obesity and other symptoms associated with insulin resistance.  Serum insulin, insulin resistance and homocysteine levels are significantly higher in subjects having PCOS.

Diagnosis
Not all women with PCOS have polycystic ovaries (PCO), nor do all women with ovarian cysts have PCOS; although a pelvic ultrasound is a major diagnostic tool, it is not the only one. The diagnosis is straightforward using the Rotterdam criteria, even when the syndrome is associated with a wide range of symptoms.
 * Standard diagnostic assessments:
 * History-taking, specifically for menstrual pattern, obesity, hirsutism, and the absence of breast development. 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%).
 * 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 - essentially 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. The follicles may be oriented in the periphery, giving the appearance of a 'string of pearls'. The numerous follicles contribute to the increased size of the ovaries, that is, 1.5 to 3 times larger than normal.
 * 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 (male hormones), including androstenedione and testosterone may be elevated. Dehydroepiandrosterone sulfate levels above 700mcg/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 ~60% of PCOS patients demonstrating supranormal levels. The Free androgen index of the ratio of testosterone to sex hormone-binding globulin (SHBG) is high, 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, possibly because FAI is correlated with the degree of obesity.
 * Some other blood tests are suggestive but not diagnostic. The ratio of LH (Luteinizing hormone) to FSH (Follicle stimulating hormone) is greater than 1:1, as tested on Day 3 of the menstrual cycle. The pattern is not very specific and was present in less than 50% in one study. There are often low levels of sex hormone binding globulin, particularly among obese or overweight women.
 * Common assessments for associated conditions or risks
 * Fasting biochemical screen and lipid profile
 * 2-hour oral glucose tolerance test (GTT) in patients with risk factors (obesity, family history, history of gestational diabetes) and may indicate impaired glucose tolerance (insulin resistance) in 15-30% 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 patients.


 * 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 who will need 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 increased glucose tolerance and frank diabetes among patients with PCOS according to a prospective controlled trial. 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.

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. PCOS has been reported in other insulin-resistant situations such as acromegaly.

Cause
PCOS is a common inherited genetic condition. It is inherited in an autosomal dominant system with high genetic penetrance but variable expressivity in females, meaning that each child has a 50% chance of inheriting the gene from a parent who carries the gene, and if a daughter receives the gene, then the daughter will have the disease to some extent. The gene can be inherited from either the father or the mother, and can be passed along to both sons, who are asymptomatic carriers, and daughters, who will show signs of PCOS. The exact gene that is affected has not yet been identified.

Pathogenesis
Polycystic ovaries develop when the ovaries are stimulated to produce excessive amounts of male hormones (androgens), particularly testosterone, by either one or a combination of the following:
 * the 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
 * reduced levels of sex-hormone binding globulin resulting in increased free androgens.

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 ("polyfollicular ovary syndrome" would have been a more accurate name). 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.

A majority of patients 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.

PCOS is characterized by a complex set of symptoms, and the cause cannot be determined for all patients. In many cases it is characterised by a complex positive feedback loop of insulin resistance and hyperandrogenism. In most cases it can not be determined which (if any) of those two should be regarded causative. Experimental treatment with either antiandrogens or insulin sensitizing agents improves both hyperandrogenism and insulin resistance. PCOS is also likely to have a genetic predisposition, and further research into this possibility is taking place. A few specific genetic defects are known accounting only for a small fraction of cases, the rest may be due to the combination of several factors.

Adipose tissue possesses aromatase, an enzyme that converts androstenedione to estrone and testosterone to estradiol. The excess of adipose tissue in obese patients creates the paradox of having both excess androgens (which are responsible for hirsutism and virilization) and estrogens (which inhibits FSH via negative feedback).

Hyperinsulinemia increases GnRH pulse frequency, LH over FSH dominance, increased ovarian androgen production, decreased follicular maturation, and decreased SHBG binding; all these steps contribute to the development of PCOS. Insulin resistance is a common finding among patients of normal weight as well as those overweight patients.

PCOS may be associated with chronic inflammation, with several investigators correlating inflammatory mediators with anovulation and other PCOS symptoms.

One study in the United Kingdom concluded that the risk of PCOS development was shown to be higher in lesbian women than in heterosexuals. It should be noted however that all the participants in this study were referred after infertility was discovered or highly suspected and conclusion made is purely conjecture. Until further studies have been conducted and the research collaborated there is no assumption that female homosexuality will increase the occurrence of PCOS.

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.

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

Management
Medical treatment of PCOS is tailored to the patient's goals. Broadly, these may be considered under four categories:
 * Lowering of insulin levels
 * 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 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.

Diet
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. Low-carbohydrate diets and sustained regular exercise may help. Some experts recommend a low GI diet in which a significant part of total carbohydrates are obtained from fruit, vegetables and whole grain sources.

Medications
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. 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. 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.

Infertility
Not all women with PCOS have difficulty becoming pregnant. For those who do, anovulation or infrequent ovulation is a common cause. Other factors include changed levels of gonadotropins, hyperandrogenemia and hyperinsulinemia. Like women without PCOS, women with PCOS who 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 who after weight loss still are anovulatory or for anovulatory lean women, then the ovulation-inducing medications clomiphene citrate and FSH 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 clomiphene. For patients who do not respond to clomiphene, 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) or wedge resection, which often results in either resumption of spontaneous ovulations or ovulations after adjuvant treatment with clomiphene or FSH.

Hirsutism and acne
When appropriate (e.g. in women of child-bearing age who require contraception), a standard contraceptive pill may be effective in reducing hirsutism. A common choice of contraceptive pill is one that contains cyproterone acetate; in the UK the available brands are Dianette/Diane. Cyproterone acetate is a progestogen with anti-androgen effects that block the action of male hormones that are believed to contribute to acne and the growth of unwanted facial and body hair.

Other drugs with anti-androgen effects include flutamide and spironolactone, 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 which 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. Medications that reduce acne by indirect hormonal effects also include ergot dopamine agonists such as bromocriptine.

Although all of these agents have shown some efficacy in clinical trials, the average reduction in hair growth is generally in the region of 25%, which may not be enough to eliminate the social embarrassment of hirsutism, or the inconvenience of plucking/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. For removal of facial hairs, electrolysis or laser treatments are faster and more efficient alternatives than the above mentioned medical therapies.

Menstrual irregularity and endometrial hyperplasia
If fertility is not the primary aim, then menstruation can usually be regulated with a contraceptive pill, though the effects are caused by substituted hormones that can easily cause more problems if the pill is taken for a long period of time. The purpose of regulating menstruation is essentially for the woman's convenience, and perhaps her sense of well-being; there is no medical requirement for regular periods, so long as they occur sufficiently often (see below).

If a regular menstrual cycle is not desired, then therapy for an irregular cycle is not necessarily required - most experts consider 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. If menstruation occurs less often or not at all, some form of progestogen replacement is recommended. Some women prefer a uterine progestogen device such as the intrauterine system (Mirena) or the progestin implant (Implanon), which provides simultaneous contraception and endometrial protection for years. An alternative is oral progestogen taken at intervals (e.g. every three months) to induce a predictable menstrual bleeding.

Alternative approaches
At least two inositol isomers - D-chiro-inositol and myo-inositol did show considerable promise in improving PCOS. They are generally very well tolerated and have been evaluated by several small scale trials. Inositol has no documented side-effects and is a naturally occurring human metabolite known to be involved in insulin metabolism. DCI is regulated as a dietary supplement in the United States. Myo-inositol is naturally present in many foods although not readily digestible from most of them.

Prognosis
Women with PCOS are at risk for the following:
 * Endometrial hyperplasia and endometrial cancer (cancer of the uterine lining) are possible, due to overaccumulation of uterine lining, and also lack of progesterone resulting in prolonged stimulation of uterine cells by estrogen. It is not clear if this risk is directly due to the syndrome or from the associated obesity, hyperinsulinemia, and hyperandrogenism
 * Insulin resistance/Type II diabetes. A review published in 2010 concluded that women with PCOS had an elevated prevalence of insulin resistance and type II diabetes, also when controlling for body mass index (BMI).
 * High blood pressure
 * Depression/Depression with Anxiety
 * Dyslipidemia - disorders of lipid metabolism &mdash; cholesterol and triglycerides. PCOS patients show decreased removal of atherosclerosis-inducing remnants, seemingly independent on insulin resistance/Type II diabetes.
 * Cardiovascular disease, with a meta-analysis estimating a 2-fold risk of arterial disease for women with PCOS relative to women without PCOS, independent on BMI.
 * Strokes
 * Weight gain
 * Miscarriage
 * Acanthosis nigricans (patches of darkened skin under the arms, in the groin area, on the back of the neck)
 * Autoimmune thyroiditis

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.