Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among females. PCOS is a complex, heterogeneous disorder of uncertain etiology, but there is strong evidence that it can, to a large degree, be classified as a genetic disease.
PCOS produces symptoms in approximately 5% to 10% of women of reproductive age (approximately 12 to 45 years old). It is thought to be one of the leading causes of female subfertility and the most frequent endocrine problem in women of reproductive age.
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), then the daughter will have the disease to some extent. 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. The allele appears to manifest itself at least partially via heightened androgen levels secreted by ovarian follicletheca cells from women with the allele. The exact gene affected has not yet been identified.
The clinical severity of PCOS symptoms appears to be largely determined by factors such as obesity.
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.
Polycystic Ovary as seen on Sonography
Transvaginal ultrasound scan of polycystic ovary
Polycystic Ovary as seen on Sonography
Two definitions are commonly used:
In 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a patient has PCOS if she has all of the following:
Other entities are excluded that would cause these.
The Rotterdam definition is wider, including many more patients, most notably patients without androgen excess. Critics say that findings obtained from the study of patients with androgen excess cannot necessarily be extrapolated to patients without androgen excess.
Androgen Excess PCOS Society
In 2006 the Androgen Excess PCOS Society suggested a tightening of the diagnostic criteria to all of:
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.)
2-hour oral glucose tolerance test (GTT) in patients 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 patients, although it is more common in the latter (and in those matching the stricter NIH criteria for diagnosis); 50–80% of PCOS patients 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 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.
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 (almost certainly combined with genetic susceptibility):
through high levels of insulin in the blood (hyperinsulinaemia) in women whose ovaries are sensitive to this stimulus
Alternatively or as well, reduced levels of sex-hormone binding globulin can result 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. 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.
Women with PCOS experience an increased frequency of hypothalamic GnRH pulses, which in turn results in an increase in the LH/FSH ratio.
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. 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 overweight patients.
In many cases PCOS 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.
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).
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 increased level of oxidative stress.
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.
Medical treatment of PCOS is tailored to the patient's goals. Broadly, these 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.
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. 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 increased menstrual regularity than a macronutrient-matched healthy diet.Vitamin D deficiency may play some role in the development of the metabolic syndrome, so treatment of any such deficiency is indicated.
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.
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 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.
When appropriate (e.g. in women of child-bearing age who require contraception), a standard contraceptive pill is frequently 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. On the other hand, progestogens such as norgestrel and levonorgestrel should be avoided due to their androgenic effects.
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.5-alpha reductase inhibitors (such as finasteride and dutasteride) may also be used; 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), 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. For removal of facial hairs, electrolysis or laser treatments are – at least for some – 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. 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.
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. If menstruation occurs less often or not at all, some form of progestogen replacement is recommended. An alternative is oral progestogen taken at intervals (e.g. every three months) to induce a predictable menstrual bleeding.
There is insufficient evidence to conclude an effect from D-chiro-inositol. Myo-inositol however appears to be effective based on a systematic review.
Dyslipidemia – disorders of lipid metabolism — cholesterol and triglycerides. PCOS patients show decreased removal of atherosclerosis-inducing remnants, seemingly independent of 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 of BMI.
Early diagnosis and treatment may reduce the risk of some of these, such as type 2 diabetes and heart disease.
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). 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.
One study in the United Kingdom concluded that the risk of PCOS development was higher in lesbian women than in heterosexuals. However, two subsequent studies of women with PCOS have not replicated this finding. Ultrasonographic findings of polycystic ovaries are found in 8-25% of normal women. 14% women on oral contraceptives are found to have polycystic ovaries.
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.
The earliest published description of a patient with what is now recognized as PCOS was in 1721 in Italy. Cyst-related changes to the ovaries were described in 1844.
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 patients with all the symptoms of amenorrhea with infertility, hirsutism, and enlarged polycystic ovaries.
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 or a string of pearls.
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