Polycystic Ovarian Syndrome

Polycystic Ovary by Sonography

Polycystic ovary syndrome (PCOS, also known clinically as Stein-Leventhal syndrome), is an endocrine disorder that affects 5–10% of 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 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 disorder include:

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

Definition

There are two definitions that 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 ultrasonography), and other causes of PCOS are excluded.

The Rotterdam definition is wider, including many more patients, notably patients without androgen excess, while in the NIH/NICHD definiton androgen excess is a prerequisite. Critics maintain that findings obtained from the study of patients with androgen excess cannot be necessarily 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 comprise heavy bleeding (check with a gynaecologist, since heavy bleeding is also an early warning sign of endometrial cancer, for which women with PCOS are at 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
• Androgenic alopecia (male-pattern baldness)
• Acne / oily skin / seborrhea
• Acanthosis nigricans (dark patches of skin, tan to dark brown/black)
• Acrochordons (skin tags) - tiny flaps of skin
• Prolonged periods of PMS-like symptoms (bloating, mood swings, pelvic pain, backaches)
• Sleep apnea

Signs are:

• Multiple cysts on the ovaries. Sonographycally they may present as a "string of pearls".
• Enlarged ovaries, generally 1.5 to 3 times larger than normal, resulting from multiple cysts
• Thickened, smooth, pearl-white outer surface of ovary
• Chronic pelvic pain, possibly due to pelvic crowding from enlarged ovaries; however, the actual cause is not yet known
• The ratio of LH (Luteinizing hormone) to FSH (Follicle stimulating hormone) is 2:1 or more, particularly in the early phase of the menstrual cycle.
• Increased levels of testosterone.
• Decreased 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 hyperinsulinaemia
• High blood pressure
• Dyslipidaemia (disorders of lipid metabolism - cholesterol and triglycerides)
• Cardiovascular disease

Some data suggest that women with PCOS have an increased risk of miscarriages. As well, many women with PCOS have a difficult time conceiving, due to the irregular cycles and lack of ovulation. However, it is possible for these women to have normal pregnancies with the aid of medication and diet.

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 of how they present themselves in individuals (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 in 15-30% of obese women with PCOS. Frank diabetes can be seen in 6-8% of women with this condition.
• For exclusion purpose:
  • Prolactin
  • TSH
  • 17-hydroxyprogesterone

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 require either higher doses 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 medicaiton, low glycemic diet and exercise. Many women with normal levels may benefit from combination therapy. A hypoglycemic response where the two hour insulin level is higher and the blood sugar lower than fasting, is consistent with insulin resistance.
• LH:FSH ratio
• DHEAS
• SHBG
• Androstenedione

Differential diagnosis

As well, other causes of irregular/absent menstruation and hirsutism such as congenital adrenal hyperplasia, Cushing's syndrome, hyperprolactinemia and other pituitary and/or adrenal disorders, should be investigated.

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 pituitary gland, or due to 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 symptom is multiple (poly) ovarian cysts. These form where egg follicles matured, but were never released from the ovary due to 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.

Although the cause of PCOS is not known, research to date suggests that obesity is a prime indicator. It may have a genetic predisposition and further research into this possibility is currently taking place. No specific gene has been identified, and it is thought that there are many genes that could contribute to the development of PCOS.

A majority of patients with PCOS - some investigators may say all - have insulin resistance. Their increased 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 leading to the development of PCOS. Insulin resistance is a common finding in obese people.

Treatment

Medical treatment of PCOS used to be directed mainly at the symptoms (ovarian and adrenal suppression, and anti-androgen therapy) and restoring ovulation. Some medications used for these purposes are:

• Oral contraceptives (ovarian suppression) - since these cause regular menstruation, they reduce the risk of endometrial carcinoma
• Spironolactone or finasteride (anti-androgen therapy) - reduce the excessive hair growth by blocking the effects of male hormones
• Clomiphene citrate and/or human chorionic gonadotropin or dexamethasone (inducing ovulation)

Recent research suggests that the insulin resistance and over-release of insulin may be at the root of PCOS. Many women find insulin-lowering medications such as metformin hydrochloride (Glucophage®), pioglitazone hydrochloride (Actos®), and rosiglitazone maleate (Avandia®) helpful to them, and indeed ovulation may resume when using these agents. Many women report that metformin use is associated with upset stomach, diarrhea and weight-loss. 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 dose and gradually increasing the dosage over 2-3 weeks and taking the medication towards the end of a meal may reduce side effects. The use of basal body temperature charts or BBT charts is an effective way to follow progress. It may take up to six months to see results, but when combined with exercise and a low-glycemic diet up to 85% will improve menstrual cycle regularity and ovulation.

Low-carbohydrate diets and sustained regular exercise are also beneficial. As well, initial research 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 needs to be done in this area.

For patients who do not respond to these and related medications/procedures, 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 obstruct fertility)
• ovarian drilling

Reference

• Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223-36. PMID 15788499.

External links

• OMIM 184700
• PCOS Treatment Overview from IVF.com
• The University of Chicago Center for Polycystic Ovary Syndrome
• The Polycystic Ovarian Syndrome Association (PCOSA)
• Soulcysters.com (support site for women with PCOS)
• Polycystic Ovarian Syndrome Association of Australia
• International Council on Infertility Information Dissemination - PCOS Frequenty Asked Questions
• InfertilityBlues.com - Mind Body Resources to Support Coping with PCOS
• Ovarian-cysts-pcos.com: Natural therapies and self-help strategies for PCOS
• PCOS Coach