Polycystic ovary syndrome

Polycystic ovary syndrome
Specialty	Endocrinology, gynaecology

Polycystic ovary syndrome (PCOS, also known clinically as Stein-Leventhal syndrome), is an endocrine disorder that affects approximately one in ten women. It occurs amongst all races and nationalities, is the most common hormonal disorder among women of reproductive age, and is a leading cause of infertility. The principal features are lack of regular ovulation and excessive amounts or effects of androgenic (masculinizing) hormones. The symptoms and severity of the syndrome vary greatly between women. While the causes are unknown, insulin resistance (often secondary to obesity) is heavily correlated with PCOS.

Nomenclature

Other names for this syndrome include

• Polycystic ovary disease (although this is not correct because PCOS is characterized as a syndrome rather than a disease)
• Functional ovarian hyperandrogenism
• Hyperandrogenic chronic anovulation
• Ovarian dysmetabolic syndrome
• Polycystic ovarian syndrome

Definition

Two definitions are commonly used:

1. In 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a patient has PCOS if she has (1) signs of androgen excess (clinical or biochemical), (2) oligoovulation, and (3) other entities are excluded that would cause polycystic ovaries.
2. In 2003 a consensus workshop sponsored by ESHRE/ASRM in Rotterdam indicated PCOS to be present if 2 out of 3 criteria are met: (1) oligoovulation and/or anovulation, (2) excess androgen activity, (3) polycystic ovaries (by gynecologic ultrasound), and other causes of PCOS are excluded.

The Rotterdam definition is wider, including many more patients, notably patients without androgen excess, whereas in the NIH/NICHD definition androgen excess is a prerequisite. Critics maintain that findings obtained from the study of patients with androgen excess cannot necessarily be extrapolated to patients without androgen excess.

Signs and symptoms

Common symptoms of PCOS include

• Oligomenorrhea, amenorrhea — irregular, few, or absent menstrual periods; cycles that do occur may be heavy (heavy bleeding is also an early warning sign of endometrial cancer(in post menopausal women), for which women with PCOS are at slightly higher risk)
• Infertility, generally resulting from chronic anovulation (lack of ovulation)
• Elevated serum (blood) levels of androgens (male hormones), specifically testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS), causing hirsutism and occasionally masculinization
• Central obesity — "apple-shaped" obesity centered around the lower half of the torso
• Dyspareunia Pain during sexual intercourse
• Androgenic alopecia (male-pattern baldness)
• Acne, oily skin, seborrhea
• Acanthosis nigricans (dark patches of skin, tan to dark brown or black, a sign of insulin resistance, which is associated with PCOS)
• Acrochordons (skin tags) — tiny flaps of skin
• Prolonged periods of PMS-like symptoms (bloating, mood swings, pelvic pain, backaches)
• Sleep apnea

Mild symptoms of hyperandrogenism, such as acne or hyperseborrhea, are frequent in adolescent girls and are often associated with irregular menstrual cycles. In most instances, these symptoms are transient and only reflect the immaturity of the hypothalamic-pituitary-ovary axis during the first years following menarche.

Signs are:

• Multiple small follicles on the ovaries (10 or more) (one form of ovarian cyst). Sonographically they may look like a string of pearls.
• Enlarged ovaries, generally 1.5 to 3 times larger than normal(volume >20mls), resulting from multiple peripherally located small follicles and echogenic ovarian stroma.
• Thickened, smooth, pearl-white outer surface of ovary on laproscopic examination.
• 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.
• High levels of testosterone.
• Low levels of sex hormone binding globulin.
• Hyperinsulinemia.

Risks

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
• Insulin resistance/Type II diabetes, generally thought to be caused by hyperinsulinemia
• High blood pressure
• Dyslipidemia (disorders of lipid metabolism — cholesterol and triglycerides)
• Cardiovascular disease
• Weight gain

PCOS is a risk factor for miscarriage. According to a study released in 2002, approximately 40% of first pregnancies in women with PCOS end in miscarriage, compared with 15-25% of women without the syndrome. In women with a history of miscarriage, the risk rises to approximately 60%. With the use of metformin, this study demonstrated that women with PCOS can reduce this risk significantly. The risk of first pregnancy loss was reduced to approximately 9% with metformin use. In women with a history of miscarriage, the risk of loss was lowered to 11% with the use of metformin..

Metformin also restores ovulation in a large number of women with PCOS, making it possible for them to conceive . Diet adjustments and treatment with clomiphene citrate also increase rates of pregnancy. The most drastic increase in ovulation rate occurs with a combination of diet modification, weight loss, and treatment with metformin and clomiphene citrate. It is currently unknown if diet change and weight loss have an effect on miscarriage rates similar to treatment with metformin. It does not seem that clomiphene citrate reduces the risk of miscarriage as metformin does.

Diagnosis

It is vital to note that not all women with PCOS have polycystic ovaries, nor do all women with ovarian cysts have PCOS; although a pelvic ultrasound is a major diagnostic tool, it is not the only one. Diagnosis can be difficult, particularly because of the wide range of symptoms and the variability in presentation (which is why this disorder is characterized as a syndrome rather than a disease). There is a lot of controversy about the appropriate testing:

• gynecologic ultrasonography
• testosterone: free more sensitive than total
• 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.
• For exclusion purpose:
  • Prolactin to rule out hyperprolactinemia
  • TSH to rule out hypothyroidism
  • 17-hydroxyprogesterone to rule out 21-hydroxylase deficiency (CAH). Many such women may appear similar to PCOS and be made worse by insulin resistance or obesity, but they can be greatly helped by adrenal suppression with low-dose glucocorticoid therapy.

The role of other tests is more controversial, including:

• 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.
• LH:FSH ratio elevation; FSH normal or low, LH high. Seen in only a subset of patients; present in less than 50% in one study.
• DHEAS
• SHBG
• Androstenedione

Differential diagnosis

Other causes of irregular or absent menstruation and hirsutism, such as congenital adrenal hyperplasia, Cushing's syndrome, hyperprolactinemia, and other pituitary or adrenal disorders, should be investigated. PCOS has been reported in other insulin resistant situations such as acromegaly.

Pathogenesis

PCOS develops when the ovaries are stimulated to produce excessive amounts of male hormones (androgens), particularly testosterone, either through the release of excessive luteinizing hormone (LH) by the anterior pituitary gland or through high levels of insulin in the blood (hyperinsulinaemia) in women whose ovaries are sensitive to this stimulus.

This syndrome acquired its most widely used name because a common sign is multiple (poly) ovarian cysts. These form where egg follicles matured but were never released from the ovary because of abnormal hormone levels. These generally take on a 'string of pearls' appearance. The condition was first described in 1935 by Dr. Stein and Dr. Leventhal, hence its original name of Stein-Leventhal syndrome.

PCOS is characterized by a complex set of symptoms, and the cause cannot be determined for all patients. However, research to date suggests that insulin resistance could be a leading cause. PCOS may also have a genetic predisposition, and further research into this possibility is taking place. No specific gene has been identified, and it is thought that many genes could contribute to the development of PCOS.

A majority of patients with PCOS have insulin resistance. Their elevated insulin levels contribute to or cause the abnormalities seen in the hypothalamic-pituitary-ovarian axis that lead to PCOS.

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

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

Treatment

Medical treatment of PCOS is tailored to the patient's goals:

• If restoration of ovulation and fertility are desired, then metformin and or clomiphene citrate are indicated. In cases of clomiphene resistance, injections of follicle stimulating hormone may be used.
• If hirsutism is a primary concern, then oral contraceptives and either cyproterone acetate or spironolactone (a blocker of androgen receptors) are indicated.
• If the goal is to prevent the unopposed estrogen effect of anovulation, which can lead to endometrial hyperplasia and endometrial cancer, then oral contraceptives or cyclic progestins are indicated.

Low-carbohydrate diets and sustained regular exercise are also beneficial. More recently doctors and nutritional experts are recommending a low-GI diet in which a significant part of the total carbohydrates are obtained from fruit, vegetables and wholegrain sources. These diets help women with PCOS to maintain steady blood sugar and insulin levels and may assist in weight loss. A diet composed of mainly low-GI foods combined with regular exercise also helps to combat the effects of insulin resistance.

Many women find insulin-lowering medications such as metformin hydrochloride (Glucophage®), pioglitazone hydrochloride (Actos®), and rosiglitazone maleate (Avandia®) helpful, and ovulation may resume when they use these agents. Many women report that metformin use is associated with upset stomach, diarrhea, and weight-loss. Such side effects usually resolve within 2–3 weeks. Both symptoms and weight loss appear to be less with the extended release versions. Most published studies use either generic metformin or the regular, non-extended release version. Starting with a lower dosage and gradually increasing the dosage over 2–3 weeks and taking the medication toward the end of a meal may reduce side effects. Though the use of basal body temperature or BBT charts is sometimes advised to predict ovulation, clinical trials have not supported a useful role. It may take up to six months to see results, but when combined with exercise and a low glycemic index diet up to 85% will improve menstrual cycle regularity and ovulation.

Initial research also suggests that the risk of miscarriage is significantly reduced when metformin is taken throughout pregnancy (9% as opposed to as much as 45%); however, further research is needed in this area.

For patients who do not respond to insulin-sensitizing medications and who wish to achieve pregnancy, there are many options available including, clomiphene citrate to induce ovulation or ART procedures such as controlled ovarian hyperstimulation and IVF. Ovarian stimulation has an associated risk of ovarian hyperstimulation in women with PCOS — a dangerous condition with morbidity and rare mortality. Thus recent developments have allowed the oocytes present in the multiple follicles to extracted in natural, unstimulated cycles and then matured in vitro, prior to IVF. This technique is known as IVM (in-vitro-maturation)

Though surgery is usually the treatment option of last resort, the polycystic ovaries can be treated with surgical procedures such as

• laparoscopy electrocauterization or laser cauterization
• ovarian wedge resection (rarely done now because it is more invasive and has a 30% risk of adhesions, sometimes very severe, which can impair fertility) was an older therapy
• ovarian drilling

Alternative approaches

D-chiro-inositol (DCI) offers a well-tolerated and effective alternative treatment for PCOS. It has been evaluated in two peer-reviewed, double-blind studies and found to help both lean and obese women with PCOS; diminishing many of the primary clinical presentations of PCOS. It has no known side-effects and is a naturally occurring human metabolite known to be involved in insulin metabolism. Contrary to common — but false — claims, DCI is not a drug but rather a nutrient (as defined by the DSHEA) and is commercially available as a nutritional supplement in the USA.

Ian Stoakes, a UK-based scientist has recently claimed some success in treating PCOS through tailored diets, believing that there is a strong link between PCOS, diabetes (and associated diseases) and inflammation caused by the failure of the blood to absorb specific foods. Blood samples are tested to see how they react to different food types to provide the patient with a list of foods she can eat and foods to avoid. Weight loss, alleviation of symptoms and successful pregnancies are claimed for this approach. It remains a totally unproven approach with no research papers listed in PubMed by Stoakes concerning PCOS.

References

• Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223-36. PMID 15788499.
• (UK) Royal College of Obstetricians and Gynaecologists. Guideline No. 33 - Long-term Consequences of Polycystic Ovary Syndrome (PDF). Retrieved 2006-06-06. {{cite book}}: Unknown parameter |origmonth= ignored (help)

External links

Overviews

• 4women.gov Polycystic Ovarian Syndrome (PCOS)
• The University of Chicago Center for Polycystic Ovary Syndrome
• PCOS Section of The Hormone Foundation
• The Polycystic Ovary Syndrome: a starting point, not a diagnosis. and Introduction Chapter by Dr John Eden (PDF) from Polycystic Ovarian Syndrome Association of Australia POSAA
• PCOS and infertility news
• PCOS Today Magazine (based in United States) Unique perspectives about PCOS
• "Polycystic Ovary Syndrome (PCOS) FAQ". International Council on Infertility Information Dissemination. 10/9/2006. Retrieved 2006-11-21. {{cite web}}: Check date values in: |date= (help)
• Project PCOS (also based in United States) Free flow of information about PCOS
• Discusses what it is like to live with PCOS

Support groups

• Soulcysters.net (support site and forum for women from all walks of life with PCOS)
• Verity PCOS, UK support group
• The Polycystic Ovarian Syndrome Association (PCOSA)

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