PolyCystic Ovary Syndrome (PCOS)

Polycystic ovary shown on ultrasound image (above)

Polycystic ovary syndrome abbreviated PCOS or PCO (also known clinically as Stein-Leventhal syndrome, Sclerocystic ovary syndrome, Hyperthecosis, ovarian, Polycystic ovarian disease PCOD ) is an endocrine disorder that affects approximately 10% of all women .[1] 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.[2][3] The principal features are weight problems, lack of regular ovulation and/or menstruation, 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, diabetes and obesity are all strongly correlated with PCOS.

Nomenclature

Other names for this syndrome include

Polycystic Ovarian Syndrome
Polycystic Ovary Disease (PCOD)
Functional Ovarian Hyperandrogenism
Stein-Leventhal Syndrome (original name, not used in modern literature).

Definition

Two definitions are commonly used:

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.

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 endocrine disorders 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.


Symptoms

Common symptoms of PCOS include :

Oligomenorrhea, amenorrhea — irregular, few, or absent menstrual periods.

Infertility, generally resulting from chronic anovulation (lack of ovulation).

Hirsutism — excessive and increased body hair, typically in a male pattern affecting face, chest and legs.

Hair loss appearing as thinning hair on the top of the head
Acne, oily skin, seborrhea.

Obesity: one of two women with PCOS are obese.

Depression .

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-ovarian axis during the first years following menarche.[5]

PCOS can present in any age during the reproductive years. It is important to find a PCOS knowledgeable doctor to catch this disorder as many miss the diagnoses - sometimes for years.


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. It is however unclear if this risk is directly due to the syndrome or from the associated obesity, hyperinsulinemia, and hyperandrogenism.[6]

Insulin resistance/Type II diabetes

High blood pressure

Dyslipidemia (disorders of lipid metabolism — cholesterol and triglycerides)

Cardiovascular disease

Strokes

Weight gain

Miscarriage

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 discharge. A clinical prediction rule found that these four questions can diagnose PCOS with a sensitivity of 77.1% (95% 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 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 reach the preovulatory size (16 mm or more). According to the Rotterdam criteria, 12 or more small follicles should be seen in a 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).

Elevated serum (blood) levels of androgens (male hormones), including androstenedione and testosterone: free testosterone is more sensitive than total. Free testosterone is reflected as the ratio of testosterone to sex hormone-binding globulin (SHBG).

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.[8] There are often low levels of sex hormone binding globulin, particularly among obese 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.
For exclusion of other disorders that may cause similar symptoms:

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 (glucose-level x insulin-level/22.5).

Glucose tolerance testing instead of fasting glucose can increase diagnosis of increased glucose tolerance and frank diabetes among patients with PCOS according to a prospective controlled trial. [9]. 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. [9]

Differential diagnosis

Other causes of irregular or absent menstruation and hirsutism, such as congenital adrenal hyperplasia, 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.


Pathogenesis

Polycystic Ovaries develop 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.

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 better 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. 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 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.[10][11]


Treatment

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 of the syndrome.


Insulin lowering

Dietary therapy

Where PCOS is associated with overweight or obesity, successful weight loss is probably 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 Glycemic index diet in which a significant part of the total carbohydrates are obtained from fruit, vegetables and whole grain sources[12].


Medications

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. 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. 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.

While insulin sensitizing agents are often used for overweight patients, a cohort study has shown that metformin can also improve insulin resistance in thin PCOS patients without clinically apparent insulin resistance as measured by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). [13]. Treatment of thin PCOS patients with 1500mg Metformin twice daily was shown to reduce HOMA-IR to 1.1 versus 1.7 in control groups. Besides positive effects on insulin resistance, metformin treatment was also shown to improve hirsuitism, acne, and menstrual irregularities in thin PCOS patients. [13]


Treatment of infertility

Not all women with PCOS have difficulty becoming pregnant. For those who do, anovulation is a common cause. The use of basal body temperature or BBT charts were previously advised to predict ovulation, but clinical trials have not supported a useful role. Nowadays, a urine test which detects the preovulatory LH surge is used to predict ovulation, and serum progesterone level in mid-luteal phase (approximately cycle day 21) is used to confirm ovulation. The LH-test can also be used to evaluate the effectiveness of treatments to stimulate ovulation and to time intercourse or insemination appropriately.

For overweight women with PCOS, who are anovulatory, diet adjustments and weight loss are associated with resumption of spontaneous ovulation. For those who after weightloss still are anovulatory or for anovulatory lean women, clomiphene citrate and FSH are the principal treatments used to help infertility. Previously, even metformin was recommended treatment for anovulation. But in the largest trial to date, comparing clomiphene with metformin, clomiphene alone was the most effective.[14] In this trial, 626 women were randomized to three groups: metformin alone, clomiphene alone, or both. The live birth rates following 6 months of treatment were 7.2% (metformin), 22.5% (clomiphene), and 26.8% (both). The major complication of clomiphene was multiple pregnancy, affecting 0%, 6% and 3.1% of women respectively. The overall success rates for live birth remained disappointing, even in women receiving combined therapy, but it is important to consider that the women in this trial had already been attempting to conceive for an average of 3.5 years, and over half had received previous treatment for infertility. Thus, these were women with significant fertility problems, and the live birth rates are probably not representative of the typical PCOS woman. Following this study,the ESHRE/ASRM-sponsored Consensus workshop do not recommend metformin for ovulation stimulation.
The most drastic increase in ovulation rate occurs with a combination of diet modification, weight loss, and treatment with metformin and clomiphene citrate[16]. It is currently unknown if diet change and weight loss alone have an effect on live birth rates comparable to those reported with clomiphene and metformin

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 FSH injections and in vitro fertilisation. Ovarian stimulation with FSH 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 be 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 not commonly performed, the polycystic ovaries can be treated with a laparoscopic procedure called "ovarian drilling" (puncture of 4-10 small follicles with electrocautery), which often results in either resumption of spontanous ovulations or ovulations after adjuvant treatment with clomiphene or FSH.


Treatment of 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/US the available brand is Dianette®/Diane®. Cyproterone acetate is a progestogen with anti-androgen effects that blocks 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, both of 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 is a drug which is applied to the skin in cream form (Vaniqa), and acts directly on the hair follicles to inhibit hair growth. It is usually applied to the face.

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 may vary in their response to different therapies, and 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 treatment are faster and more efficient alternatives than the above mentioned medical therapies.


Treatment of menstrual irregularity, prevention of 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 (see below). Most brands of contraceptive pill result in a withdrawal bleed every 28 days if taken in 3-weeks periods. Dianette (a contraceptive pill containing cyproterone acetate) is also beneficial for hirsutism, and is therefore often prescribed in PCOS.

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 implant such as the Mirena® coil, which provides simultaneous contraception and endometrial protection for years, though often with unpredictable minor bleeding. An alternative is oral progestogen taken at intervals (e.g. every three months) to induce a predictable menstrual bleeding.


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.[17] [18] It has no documented side-effects and is a naturally occurring human metabolite known to be involved in insulin metabolism.[19] 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.