Polycystic ovary syndrome (PCOS)

Essentials

• Polycystic ovary syndrome is not purely a gynaecological problem.
• Diagnosis can be made if the patient has two of the following: menstrual disorder, hyperandrogenism, polycystic ovaries.
• Polycystic ovary syndrome is associated with reduced insulin sensitivity which may lead to increased health risks.

Prevalence and consequences

• The prevalence of PCOS is estimated to be 5–15% in women of reproductive age.
• PCOS will mean increased morbidity at various stages throughout the woman's life.

Gynaecological problems

• Patients usually present with menstrual irregularities, hirsutism and infertility problems.
• Pregnancies appear to be associated with a higher risk of miscarriage, hypertension and diabetes. The increased risk is, however, likely to be associated with obesity rather than with PCOS as such.
• Long-term oestrogenic activity with simultaneous lack of luteal hormone activity predispose to endometrial hyperplasia and thus increase the risk of cancer of the uterine corpus. It has been reported that the risk of uterine cancer is increased five-fold in women with PCOS as compared with the general population. However, it is difficult to distinguish between the increased risk caused by obesity and that by PCOS, and large-scale epidemiological studies are needed .
• There is no evidence of a link with breast or ovarian cancer.

Metabolic disturbances

• Women with PCOS often have reduced insulin sensitivity which is associated with truncal obesity and disturbances in lipid metabolism.
• Depending on the population, 20–70% of the women with PCOS are overweight.
• Insulin resistance and the resulting compensatory increased concentration of insulin are more marked in overweight patients with PCOS than in otherwise overweight controls.
• Typical findings include low plasma HDL-cholesterol concentration and hypertriglyceridaemia.
• PCOS appears to increase the risk of developing type 2 diabetes at a considerably early age (the risk is 5–10-fold) and, at a later age, hypertension (the risk is 2–3-fold).
• The risk of venous thrombosis is 1.5–2-fold and the risk of stroke 2-fold in women with PCOS.
• Even though it has been suggested that women with PCOS have a manifold risk of developing ischaemic heart disease, no definite evidence exists to support the claim.
• The risk of complications associated with cerebrovascular disease and diabetes is increased.

Other disturbances

• Women with PCOS have additionally an increased risk of many other diseases, such as thyroid diseases (3-fold), asthma (1.5-fold), depression (3-fold), anxiety disorders (1.4-fold) and migraine (2-fold).

Diagnosis

• Diagnosis is based on the history, clinical findings (menstrual irregularities, male pattern of hair distribution, acne) and, if necessary, on hormone studies.
• A gynaecological ultrasound examination is used to verify the diagnosis; polycystic morphology of the ovaries is evident.
• Two of the following criteria must be present for PCOS diagnosis:
  • anovulation characterized by menstrual irregularities
  • clinical (male pattern of hair distribution) or biochemical (serum testosterone > 2.7 nmol/l or > 2.3 nmol/l depending on the method and laboratory) signs of hyperandrogenism
  • polycystic morphology of the ovaries, verified by ultrasound examination (according to the traditional definition, presence of 12 or more follicles in each ovary measuring 2–9 mm in diameter, and/or increased ovarian volume > 10 ml, but as the quality of ultrasound devices has improved the threshold has been suggested to be raised to up to 25 follicles in each ovary).
• Exclude thyroid disease, hyperprolactinaemia, androgen-secreting tumours and disturbances in adrenal function.
  • If the patient presents with menstrual irregularities, measure serum TSH and prolactin to exclude other causes.
  • If the patient presents with hirsutism and/or acne, measure serum testosterone.
  • Serum FSH and LH concentrations should be determined for differential diagnostics of menstrual disorders. Serum oestradiol assay is not usually of diagnostic benefit.
• Due to the risk of metabolic disturbances the following screening is indicated, particularly in overweight patients:
  • blood glucose, lipids and blood pressure at regular intervals (for example every one to two years)
  • glucose tolerance testing in conjunction with the first visit followed by regular testing in patients who are overweight or obese (for example every two years).

Treatment

• The most important treatment form is weight reduction down to the patient's normal weight. Weight reduction may
  • regularize the menstrual cycle through restoring ovulation
  • significantly reduce the risk of miscarriage during early pregnancy as well as other pregnancy-associated risks
  • enhance the safety and efficacy of ovulation induction treatments and reduce the risk of late complications associated with PCOS, such as type 2 diabetes and coronary heart disease.
• Exercise reduces insulin resistance .
• Smoking cessation is important due to the increased risk of vascular diseases.

Hormone treatment

• Oral contraceptives restore the normal menstrual cycle . In order to improve hirsutism and to minimize the harmful effects on lipids, contraceptive agents containing progestogens which are as little androgenic as possible should be chosen. Choose, for example, drospirenone, cyproterone or desogestrel containing product.
• To prevent endometrial hyperplasia cyclic progestogen (norethisterone, lynestrenol) has to be prescribed (for example, for 10 days on days 15–24 of the cycle or for 14 days every 2 or 3 months).
• If hirsutism is unacceptable despite oral contraceptives an antiandrogen may be added (50 mg of cyproterone acetate on the first 10 days of the cycle) or spironolactone (100–200 mg/day).
  • Monitor plasma electrolytes (sodium and potassium) at regular intervals, for example after the first 3 months after instigating treatment and annually thereafter.

Metformin

• Metformin may have beneficial effects on metabolic risk factors . The question whether it is beneficial in inducing ovulation and in improving the chances of pregnancy is still disputed, even if metformin was shown to improve both pregnancy and live-birth rates by about 15% in two fresh placebo-controlled studies .
• Refer a patient with PCOS to a gynaecologist with infertility expertise at an earlier stage than normal.
• Consult a gynaecologist before prescribing metformin.
  • Metformin has been presumed to possibly reduce the risk of gestational complications, such as miscarriage in early pregnancy, pre-eclampsia and gestational diabetes, but no significant effect has been verified in adequately large placebo-controlled studies .
  • According to an international consensus guideline, metformin is still indicated for infertility in PCOS only if the patient is diagnosed with impaired glucose tolerance or as an adjuvant treatment to ovulation induction therapy. In such a case, the continuation of metformin therapy during pregnancy should be individually negotiated with a gynaecologist or an obstetrician.
  • The use of metformin therapy can also be individually discussed e.g. if the patient is obese and there is no hurry for infertility treatment (metformin may also help in weight reduction). It can also be used together with ovulation induction drug in case maximal clomiphene dose does not induce ovulation .
  • There is not enough evidence on the benefits of metformin in PCOS women with normal weight.

Treatment of anovulation

• All other ovulation induction treatment is carried out by a gynaecologist who has expertise in fertility treatment.
• Clomiphene citrate is still the drug of choice . It is an oral anti-oestrogen, which increases the gonadotropin release from the pituitary gland which, in turn, will initiate the development of an ovarian follicle in the ovary and induce ovulation. The effect of treatment should be monitored either with an ultrasound on days 11–13 of the cycle or by measuring the progesterone concentration midway through the luteal phase.
• The dose may be increased up to 100 mg/day (maximum dose is 150 mg/day). Ovulation occurs in approximately 80% of patients and the rate of conception is approximately 25–50%, depending on the patient group. Treatment may be continued for the duration of up to 6 ovulatory cycles. If clomiphene does not induce ovulation, it can be combined with metformin .
• Aromatase inhibitors
  Aromatase inhibitors (letrozole and anastrozole) are used in the treatment of breast cancer. They inhibit oestrogen production in the ovaries. The suppressing effect of oestrogens on gonadotropin secretion is thus reduced, and gonadotropin secretion is respectively increased. This stimulates follicle growth in the ovaries. ."?>
  In a large randomized trial ovulation occurred more often with letrozole compared with clomiphene and the number of pregnancies was significantly better (RR 1.44, 95% CI 1.10–1.47).
  Unlike clomiphene, aromatase inhibitors do not have unfavourable anti-oestrogenic effects on cervical mucus or on endometrium. In the future, aromatase inhibitors are projected to possibly become first-line drugs in the treatment of PCOS in addition to clomiphene. The use of aromatase inhibitors must absolutely be left to experts in the treatment of infertility.
  • Aromatase inhibitors are currently in routine use along clomiphene. Use of aromatase inhibitors is strictly limited to experts in the treatment of infertility.
• If other treatments have been unsuccessful, the next step is ovarian diathermy (”drilling”) or the use of gonadotropins . Gonadotropin treatment is more problematic than clomiphene treatment. Gonadotropins are injected daily, and ovulation induction may take a long time. The treatment requires repeated ultrasound examinations, but the risk of multiple pregnancy or hyperstimulation cannot be totally excluded.
  • Laparoscopic ovarian drilling has recently regained popularity along with the development of new techniques . Treatment costs are considerably lower than those of gonadotropin treatment, and the method has been found to be equally effective. It also reduces the risk of multiple pregnancy. Choice between drilling and gonadotropins is made on an individual basis.
• If conception does not occur with ovulation induction, in vitro fertilization is considered.

Related resources

• Cochrane reviews
• Other evidence summaries
• Literature

Ədəbiyyat

1. Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs HS. Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol 1998 Jul;51(7):581-6.
2. Hardiman P, Pillay OC, Atiomo W. Polycystic ovary syndrome and endometrial carcinoma. Lancet 2003 May 24;361(9371):1810-2.
3. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004 Jan;19(1):41-7.
4. Glueck CJ, Goldenberg N, Wang P, Loftspring M, Sherman A. Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Hum Reprod 2004 Mar;19(3):510-21.
5. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008 Mar;23(3):462-77.
6. Morin-Papunen L, Rantala AS, Unkila-Kallio L et al. Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): a multicenter, double-blind, placebo-controlled randomized trial. J Clin Endocrinol Metab 2012;97(5):1492-500.
7. Kjøtrød SB, Carlsen SM, Rasmussen PE et al. Use of metformin before and during assisted reproductive technology in non-obese young infertile women with polycystic ovary syndrome: a prospective, randomized, double-blind, multi-centre study. Hum Reprod 2011;26(8):2045-53.
8. Vanky E, Stridsklev S, Heimstad R et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab 2010;95(12):E448-55.
9. Pavone ME, Bulun SE. Clinical review: The use of aromatase inhibitors for ovulation induction and superovulation. J Clin Endocrinol Metab 2013;98(5):1838-44.
10. Goodman NF, Cobin RH, Futterweit W et al. American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: Guide to the best practices in the evaluation and treatment of polycystic ovary syndrome - Part 1. Endocr Pract 2015;21(11):1291-300.
11. Legro RS, Brzyski RG, Diamond MP et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371(2):119-29.
12. Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2014;20(5):748-58.
13. Glintborg D, Hass Rubin K, Nybo M et al. Morbidity and medicine prescriptions in a nationwide Danish population of patients diagnosed with polycystic ovary syndrome. Eur J Endocrinol 2015;172(5):627-38.
14. Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group.. Consensus on women's health aspects of polycystic ovary syndrome (PCOS). Hum Reprod 2012;27(1):14-24.