Polycystic ovary syndrome

Consultant Physician and Endocrinologist Dr Mary Ryan examines the diagnosis and treatment options for polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women, accounting for between 7 per cent and 10 per cent of presentations, and is a major cause of infertility. PCOS can present in any age during the reproductive years. Due to its often-vague presentation, it can take years to reach a diagnosis.
Other names for this syndrome include polycystic ovary disease (PCOD), functional ovarian hyperandrogenism, Stein-Leventhal syndrome (original name, not used in modern literature), ovarian hyperthecosis and sclerocystic ovary syndrome.
The condition was first described as a syndrome in 1935 by Stein and Leventhal. The principal features are obesity, anovulation (resulting in irregular menstruation or oligomenorrhea), acne, enlarged ovaries and excessive amounts or effects of androgenic (masculinising) hormones, which can lead to hirsuitism.
The symptoms and severity of the syndrome vary greatly among women. While the causes are unknown, insulin resistance, diabetes and obesity are all strongly correlated with PCOS. The symptoms vary in severity from subject to subject.
Definition
The following are diagnostic criteria of PCOS:
l Chronic anovulation;
l Clinical (acne hirsutism); or
l Biochemical (elevated androgen level) and evidence of hyperandrogenism.
These features were required to make the diagnosis of polycystic ovary syndrome. However, the most recently revised criteria, by the Rotherham Polycystic Ovarian Syndrome Consensus Group in 2003, have revised these and two of the following are now sufficient for establishing the diagnosis:
l Oligomenorrhea or anovulation;
l Clinical or biochemical evidence of hyperandrogenism;
l Polycystic ovary disease.
Ultrasound criteria that were considered specific and sensitive in defining PCOS include the presence of 12 or more follicles in each ovary, measuring 2mm to 9mm in diameter, and increased ovarian volume and stroma. Only one ovary with these criteria is sufficient. These ultrasound criteria do not apply to women on the contraceptive pill.
Women with PCOS are at risk for the following:
l 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 oestrogen. It is however unclear if this risk is directly due to the syndrome or from the associated obesity, hyperinsulinemia and hyperandrogenism;
l Insulin resistance/type II diabetes;
l High blood pressure;
l Dyslipidemia (disorders of lipid metabolism — cholesterol and triglycerides);
l Cardiovascular disease;
l Strokes;
l Weight gain;
l Miscarriage;
l Acanthosis nigricans (patches of darkened skin under the arms, in the groin area or on the back of the neck);
l Autoimmune thyroiditis.
Although a pelvic ultrasound is a major diagnostic tool, it is not the only one.
Standard diagnostic assessments include: history-taking, specifically for menstrual pattern, obesity, hirsutism and absence of breast discharge; gynaecologic ultrasonography, specifically for small ovarian follicles; laparoscopic examination (which may reveal a thickened, smooth, pearl-white outer surface of the ovary); and serum levels of androgens, including androstenedione, testosterone and dehydroepiandrosterone sulfate, which may be elevated.
Some other blood tests are suggestive but not diagnostic, such as luteinizing hormone (LH), follicle stimulating hormone (FSH) and sex hormone binding globulin.
Exclusions
Obviously it is important to exclude other aetiologies such as androgen secreting tumours, Cushing’s syndrome and non-classical congenital adrenal hyperplasia.
The pathophysiology remains unknown. A prominent characteristic syndrome is that the reproductive (hyperandrogenemia, anovulation) and metabolic (insulin resistance, obesity) disorders co-exist, to the degree that it is unclear which are primary.
No single aetiological factor can account for the whole spectrum of abnormalities seen in PCOS. Increased frequency of hypothalamic release of gonadotropin-releasing hormone (GnRH) is found in women with polycystic ovarian syndrome. It is unclear whether this defect in GnRH post generation is a primary or a secondary abnormality.
Increased frequency of GnRH favours the increasing of LH versus FSH from the anterior pituitary, so that LH causes increased infrequency and amplitude. Therefore, anyone would see an elevated LH to FSH in most women.
The ovary in polycystic ovary syndrome responds to LH stimulation with the preferential increase in the production of androgen versus oestrogen. Estradiol levels are typically normal to low, but oestrone levels are significantly elevated. This is because of a conversion of androstenedione and oestrone tissue, which further stimulates LH and suppresses FSH.
Hyperinsulinemia is a feature of polycystic ovary disease and this observation was first made in 1980. Before this, the observation was made that women with syndromes of extreme insulin resistance also had hyperandrogenemia and anovulation.
Insulin and insulin-like growth factor can impact several of the pathways that contribute to the pathogenesis of polycystic ovarian syndrome. Insulin decreases the synthesis of sex hormone binding globulin, the effect of which would be to increase androgen bioactivity.
A direct role of insulin in the production of adrenal androgens in the hypothalamic pituitary gonadal axis disorder has been proposed. There is evidence to suggest that PCOS is heritable, but the pathogenesis of the syndrome points to a complex multigenic disorder. Candidate genes that may be responsible for alterations of ovarian, hypothalamic and insulin receptor function have been the focus of linkage and case control studies.
Infertility and obesity
Women with polycystic ovary syndrome may ovulate intermittently and it therefore takes longer for them to conceive. If pregnancy does occur, there is an increased risk for pregnancy-induced hypertension, pre-eclampsia, gestational diabetes, pregnancy loss and preterm labour.
A subset of women with polycystic ovary syndrome has persistent anovulation and infertility.
Central obesity affects 40 per cent to 50 per cent of women with polycystic ovary syndrome. Interestingly, the main body mass index for women with PCOS in the United States is between 35 per cent and 40 per cent.
In Europe and other countries, this is between 25 per cent and 28 per cent, or less.
Obesity is not considered a triggering event in the development of polycystic ovary syndrome, but it is an independent risk factor for reproductive and metabolic complications. The increased waist-to-hip ratio that is associated with higher risk for insulin resistance and development of type II diabetes has been noted in both obese and lean women with polycystic ovary syndrome.
Insulin resistance and hyperinsulinemia can be present even in the absence of obesity, but these conditions are exasperated by the presence of it. Severe insulin resistance is usually appreciated clinically by the presence of acanthosis nigricans.
Many women may have a mild form with slightly elevated fasting serum insulin levels.
Reducing insulin resistance by weight loss or pharmacological means, such as with metformin or thiazolidinediones, can be associated with increased ovulation and lower androgen levels — thereby suggesting an important role for insulin resistance in the pathogenesis for this disorder.
Treatment
The treatment of women with polycystic ovary syndrome should be individualised to the patient and can involve both non-pharmacological and pharmacological approaches. There are several treatment options for each of the manifestations of PCOS.
Most manifestations can be reversed by improving insulin resistance either by weight loss or pharmacological therapy. Typical response to therapy is slow, with clinical changes lagging behind chemical improvement by several months.Pregnancy should be excluded before initiating pharmacological therapy with oral contraceptives or anti-androgens. Weight loss should be the first line of therapeutic option in all women who are overweight and obese.
Weight loss of greater than 5 per cent of body weight has been shown to decrease testosterone levels, improve hirsutism, increase sex hormone-binding globulin, improve menstruation and ovulation and increase pregnancy rates.
Hirsutism can be treated by removing the hair by bleaching, waxing or laser treatment, but obviously anti-androgens can also help in this regard. Enflornithine hydrochloride cream (Vaniqa), which slows hair growth, can be used to treat facial hirsutism. Insulin sensitisers can reduce insulin and androgen levels and increase ovulation.
Clomiphene citrate has been shown to be superior to metformin in achieving contraception, but has a risk of multiple pregnancies. Finasteride, which blocks conversion of testosterone to dihydrotesterone, can be used to treat hirsutism. Because of the teratogenic potential of anti-androgens, they must be used in women who have been treated with effective contraception.
Long-term risks for CVD
Long-term metabolic and cardiovascular disease (CVD) associated with PCOS heightens the importance of a proper diagnosis. The prevalence of impaired glucose tolerance and type II diabetes increase in women with polycystic ovary syndrome (where there is a three-to-seven times higher risk of developing diabetes).
This association is seen in both obese and lean women with polycystic ovary syndrome. Patients with a family history of type II diabetes are at an even greater risk of developing diabetes.
Studies have shown that a longer irregular menstrual cycle can mean a twofold increase in the risk of hypertension in women with polycystic ovary syndrome. The development of hypertension increases dramatically by the time of perimenopause. Women with PCOS are also at increased risk of developing dyslipidemia and they have also been shown to have abnormal vascular function and an increased risk of inflammation.
Whether women with polycystic ovary syndrome and metabolic syndrome are at increased cardiovascular risk remains a question for future investigation, although predictions of a sevenfold risk for myocardial infarction have been made.
l Dr Mary Ryan,
Consultant Physician & Endocrinologist,
Barrington’s Hospital,
Georges Quay, Limerick.
Aut Even Hospital,
Freshford Road,
Kilkenny