Treatment of Polycystic Ovary Syndrome

MANAGEMENT OF THE POLYCYSTIC OVARY SYNDROME

The management of the PCOS is symptom orientated. Whilst obesity aggravates the symptoms, the metabolic scenario conspires against weight loss. Diet and exercise are key to symptom control. Initial reports of the use of insulin-sensitizing agents (e.g. metformin)  have been encouraging and suggest an improvement in biochemistry, symptoms and an increase in fertility. Ovulation induction has traditionally involved the use of clomiphene citrate and then gonadotropin therapy or laparoscopic ovarian surgery in those who are clomiphene resistant. Patients with PCOS are not estrogen deficient and those with amenorrhea are at risk not of osteoporosis but rather of endometrial hyperplasia or adenocarcinoma. Cycle control and regular withdrawal bleeding is achieved with the combined oral contraceptive pill, which has the additional beneficial effect of suppressing serum testosterone concentrations and hence improving hirsutism and acne. Dianette and Yasmin, containing the anti-androgens cyproterone acetate and drospirenone, respectively, are usually recommended. 

 

Glucose tolerance

Women who are obese, and also many slim women with PCOS, will have insulin resistance and elevated serum concentrations of insulin (usually <30mU/1 fasting). We suggest that a 75 g oral glucose tolerance test (GTT) be performed in women with PCOS and a BMI > 30 kg/m2, with an assessment of the fasting and 2-h glucose concentration. It has been suggested that South Asian women should have an assessment of glucose tolerance if their BMI is > 25 kg/m2 because of the greater risk of insulin resistance at a lower BMI than seen in the Caucasian population.

Obesity

The clinical management of a woman with PCOS should be focused on her individual problems. Obesity worsens both symptomatology and the endocrine profile and so obese women (BMI > 30 kg/m2) should therefore be encouraged to lose weight. Weight loss improves the endocrine profile, the likelihood of ovulation and a healthy pregnancy. Much has been written about diet and PCOS. The right diet for an individual is one that is practical, sustainable and compatible with her lifestyle. It is sensible to keep carbohydrate content down and to avoid fatty foods. It is often helpful to refer to a dietician. Anti-obesity drugs may help with weight loss. These can be prescribed by general practitioners and their use must be closely monitored. Metformin may improve with insulin resistance and may aid some women with weight loss, combined with a healthy diet and exercise program.

Menstrual irregularity

The easiest way to control the menstrual cycle is the use of a low-dose combined oral contraceptive preparation. This will result in an artificial cycle and regular shedding of the endometrium. An alternative is a progestogen (such as medroxyprogesterone acetate (Provera) or dydrogesterone (Duphaston) for 12 days every 1–3 months to induce a withdrawal bleed. It is also important once again to encourage weight loss. In women with anovulatory cycles the action of estradiol on the endometrium is unopposed because of the lack of cyclical progesterone secretion. This may result in episodes of irregular uterine bleeding, and in the long-term endometrial hyperplasia and even endometrial cancer (see above). An ultrasound assessment of endometrial thickness provides a bioassay for estradiol production by the ovaries and conversion of androgens in the peripheral fat. If the endometrium is thicker than 15 mm a withdrawal bleed should be induced and, if the endometrium fails to shed, then endometrial sampling is required to exclude endometrial hyperplasia or malignancy. The only young women to get endometrial carcinoma (< 35 years), which otherwise has a mean age of occurrence of 61 years in the UK, are those with anovulation secondary to PCOS or estrogen-secreting tumors.

Infertility

Ovulation can be induced with the antiestrogens, clomiphene citrate (50–100mg) or tamoxifen (20–40 mg), days 2–6 of a natural or artificially induced bleed. Whilst clomiphene is successful in inducing ovulation in over 80% of women, pregnancy only occurs in about 40%. Clomiphene citrate should only be prescribed in a setting where ultrasound monitoring is available (and performed) in order to minimize the 10% risk of multiple pregnancy and to ensure that ovulation is taking place. A daily dose of more than 100 mg rarely confers any benefit and can cause thickening of the cervical mucus, which can impede passage of sperm through the cervix. Once an ovulatory dose has been reached, the cumulative conception rate continues to increase for up to 10–12 cycles. However, clomiphene is only licensed for 6 months use in the UK, and so we would advise careful counseling of patients if clomiphene citrate therapy is continued beyond 6 months. The therapeutic options for patients with anovulatory infertility who are resistant to antiestrogens are either parenteral gonadotropin therapy or laparoscopic ovarian diathermy. Because the polycystic ovary is very sensitive to stimulation by exogenous hormones, it is very important to start with very low doses of gonadotropins and follicular development must be carefully monitored by ultrasound scans.The advent of transvaginal ultrasonography has enabled the multiple pregnancy rate to be reduced to approximately 7% because of its higher resolution and clearer view of the developing follicles. Cumulative conception and livebirth rates after 6 months may be 62% and 54%, respectively, and after 12 months 73% and 62%, respectively. Close monitoring should enable treatment to be suspended if three or more mature follicles develop, as the risk of multiple pregnancy obviously increases.

Women with PCOS are also at increased risk of developing the ovarian hyperstimulation syndrome (OHSS).This occurs if too many follicles (> 10 mm) are stimulated and results in abdominal distension, discomfort, nausea, vomiting and sometimes difficulty in breathing. The mechanism for OHSS is thought to be secondary to activation of the ovarian renin-angiotensin pathway and excessive secretion of vascular epidermal growth factor (VEGF).The ascites, pleural and pericardial effusions exacerbate this serious condition and the resultant hemoconcentration can lead to thromboembolism. The situation worsens if a pregnancy has resulted from the treatment as human chorionic gonadotropin from the placenta further stimulates the ovaries.

Hospitalization is sometimes necessary in order for intravenous fluids and heparin to be given to prevent dehydration and thromboembolism. Although the OHSS is rare it is potentially fatal and should be avoidable with appropriate monitoring of gonadotropin therapy.

Ovarian diathermy is free of the risks of multiple pregnancy and ovarian hyperstimulation and does not require intensive ultrasound monitoring. Laparoscopic ovarian diathermy has taken the place of wedge resection of the ovaries (which resulted in extensive peri-ovarian and tubal adhesions), and it appears to be as effective as routine gonadotropin therapy in the treatment of clomiphene-insensitive PCOS.

Hyperandrogenism and hirsutism

The bioavailability of testosterone is affected by the serum concentration of SHBG. High levels of insulin lower the production of SHBG and so increase the free fraction of androgen. Elevated serum androgen concentrations stimulate peripheral androgen receptors, resulting in an increase in 5α-reductase activity directly increasing the conversion of testosterone to the more potent metabolite, dihydrotestosterone. Symptoms of hyperandrogenism include hirsutism, which is a distressing condition. Hirsutism is characterized by terminal hair growth in a male pattern of distribution, including chin, upper lip, chest, upper and lower back, upper and lower abdomen, upper arm, thigh and buttocks. A standardized scoring system, such as the modified Ferriman and Gallwey score should be used to evaluate the degree of hirsutism before and during treatments. Treatment options include cosmetic and medical therapies. As drug therapies may take 6–9 months or longer before any Improvement of hirsutism is perceived, physical treatments including electrolysis, waxing and bleaching may be helpful whilst waiting for medical treatments to work. For many years, the most ‘permanent’ physical treatment for unwanted hair has been electrolysis. It is time-consuming, painful and expensive and should be performed by an expert practitioner. Regrowth is not uncommon and there is no really permanent cosmetic treatment, but the last few years have seen much development in the use of laser and photothermolysis techniques.