1. Polycystic ovary syndrome Dr. Raghad Abdul-Halim Al-Issa Polycystic ovary syndrome Dr. Raghad Abdul-Halim Al-Issa

2. The polycystic ovary syndrome (PCOS) is a heterogeneous collection of signs and symptoms that gathered together form a spectrum of adisorder with a mild presentation in some, while in others a severe disturbance of reproductive, endocrine and metabolic function.

3. Definition of the PCOS definition of the PCOS was agreed: namely the presence of two out of the following three criteria: Oligo- and/or anovulation;(oligomenorrhoea or amenorrhoea) Hyperandrogenism (clinical and/or biochemical); Polycystic ovaries by ultrasound Other aetiologies of hyperandrogenism and menstrual cycle disturbance should be excluded by appropriate investigations. The morphology of the polycystic ovary, has been defined as an ovary with 12 or more follicles measuring 2–9 mm in diameter and increased ovarian volume (>10 cm3)

4. Genetics of PCOS: Polycystic ovarian syndrome appears to cluster in families, and it seems likely that there is a gene or collection of genes that are important in its development

5. The pathophysiology of PCOS Hypersecretion of androgens by the stromal theca cells of the polycystic ovary leads not only to the cardinal clinical manifestation of the syndrome, hyperandrogenism, but is also one of the mechanisms whereby follicular growth is inhibited with the resultant excess of immature follicles. Hypersecretion of luteinizing hormone (LH) by the pituitary – a result both of disordered ovarian-pituitary feedback and exaggerated pulses of GnRH from the hypothalamus – stimulates testosterone secretion by the ovary. Furthermore, insulin is a potent stimulus for androgen secretion by the ovary which, by way of a different receptor for insulin, does not exhibit insulin resistance. Insulin therefore amplifies the effect of LH, and additionally magnifies the degree of hyperandrogenism by suppressing liver production of the main carrier protein sex hormone binding globulin (SHBG), thus elevating the ‘free androgen index’. It is a combination of genetic abnormalities. combined with environmental factors, such as nutrition and body weight, which then affect expression of the syndrome.

6. Clinical features: Oligomenorrhoea/amenorrhoea: this occurs in up to 65-75 per cent of patients with PCOS and is predominantly related to chronic anovulation. Hirsutism: this occurs in 30-70 per cent of women. Subfertility: up to 75 per cent of women with PCOS who try to conceive have difficulty doing so. Obesity: at least 40 per cent of patients with PCOS are clinically obese. Recurrent miscarriage: PCOS is seen in around 50-60 per cent of women with more than three early pregnancy losses. Acanthosis nigricans: areas of increased skin pigmentation that are velvety in texture and occur in the axillae and other flexures occur in around 2 per cent of women with PCOS.

7. Laboratory tests: Elevated testosterone levels. Decreased sex hormone binding globulin (SHBG) levels. Elevated LH levels. Elevated LH:FSH ratio. Increased fasting insulin levels. It is important to note that total testosterone levels may be only marginally elevated (or even normal) in women with PCOS. Free testosterone is higher than normal, since SHBG levels are low. Testosterone levels of > 5 nmol/L should prompt a search for an androgensecreting tumour.

8. Management of the polycystic ovary syndrome: Management of the polycystic ovary syndrome:

9. Treatment There is no treatment for PCOS as such. Treatment should be directed at the symptoms that the patient complains of:

10. 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. Metformin has not been shown to be valuable to aiding weight reduction.

11. Oligomenorrhoea/amenorrhoe a Women with PCOS tend to be anovulatory, but to have normal or high oestrogen levels.Without treatment, there is a theoretical risk that unopposed oestrogenic stimulation of the endometrium may increase the risk of endometrial cancer. Additionally, oligomenorrhoeic women with PCOS tend to have infrequent but heavy bleeds, as the endometrium that develops under the influence of oestrogen eventually becomes unsustainable and sheds. For these reasons, cyclical progesterone is often useful in the treatment of women with PCOS, in order to induce regular menstruation and to protect the endometrium. Oral progesterone should be given for at least 10 days in each month (e.g. medroxyprogesterone acetate 10 mg daily for 10 days). An alternative treatment for women who do not wish to conceive is the oral contraceptive pill. Since PCOS is driven in part by insulin resistance, it is not surprising that metformin, a drug that increases insulin sensitivity, is partially effective in its treatment.

12. Hirsutism Hirsutism arises from the growth-promoting effects of androgen at the hair follicle. Some of these growth-promoting effects are irreversible, even when androgen levels fall. Thus treatments aimed at reducing testosterone levels will not restore the hair to its pre-PCOS pattern. However, lowering free androgen levels will slow the rate of hair growth, which most patients see as a benefit.

13. The possible treatment options include the following. Cyproterone acetate: an anti-androgen that competitively inhibits the androgen receptor. It may be given either as a low dose (in the form of the contraceptive pill Dianette, which consistsof cyproterone acetate 2 mg and 35 mcg of ethinylestradiol), or at a higher dose of 50-100 mg daily. If the higher dose is chosen, it is usual to give it for the first 10 days of each month, initially in combination with oestrogen, and then followed by oestrogen alone for a further 11 days - the 'reverse sequential regimen'. A low-dose oral contraceptive may be given as an alternative to oestrogen in this regimen. Metformin: a recent study showed metformin and Dianette to have similar efficacies on both subjective and objective measures of hirsutism in women with PCOS. GnRH analogues with low-dose HRT: this regime should be reserved for women intolerant to other therapies, or for short-term treatment, since bone loss is an inevitable side effect. Surgical treatments aimed at destroying the hair follicle, such as laser or electrolysis: surgical treatments are effective permanent methods of hair removal. Some, such as electrolysis, are Associated with side effects such as scarring. AnewCOCP,(Yasmin (3 mg drospirenone and 30 mcg ethenylestradiol)may also be of benefit spironolactone, Flutamide and finasteride are not routinely prescribed because of potential adverse effects.

14. INFERTILITY combination of exercise and diet to achieve weight reduction is important to improve the prospects of both spontaneous and drug induced ovulation. In addition, overweight women with PCOS are at increased risk of obstetrical complications including gestational diabetes mellitus and pre-eclampsia.Ovulation can be induced with the anti-oestrogen clomifene citrate (50–100 mg) taken from days 2–6 of a natural or artificially induced bleed. Clomifene citrate should only be prescribed in a setting where ultrasound monitoring is available (and performed) to minimize the10% risk of multiple pregnancy and to ensure that ovulation is taking place

15. The therapeutic options for patients with anovulatory infertility who are resistant to anti-oestrogens 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 less than 5% because of its higher resolution and clearer view of the developing follicles. Close monitoring should enable treatment to be suspended if more than two mature follicles develop, as the risk of multiple pregnancy increases. Women with the polycystic ovary syndrome are also at increased risk of developing the ovarian hyperstimulation syndrome (OHSS). 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 carries a reduced risk of multiple pregnancy compared with gonadotropin therapy in the treatment of clomiphine- insensitive PCOS.

16. In summary Management is symptom orientated. If obese, weight loss improves symptoms and endocrinology and should be encouraged. A GTT should be performed if the BMI is >30 kg/m2. Dietary advice and exercise are essential components of a weight-reducing programme. Anti-obesity drugs or surgery may be indicated. Menstrual cycle control may be achieved by cyclical oral contraceptives or progestogens. Ovulation induction may be difficult and require progression through various treatments which should be monitored carefully to prevent multiple pregnancy. Hyperandrogenism is usually managed with Dianette, containing ethinyloestradiol in combination with cyproterone acetate. AnewCOCP,(Yasmin) may also be of benefit. Alternatives include spironolactone. Flutamide and finasteride are not routinely prescribed because of potential adverse effects. Reliable contraception is required. Insulin-sensitizing agents (e.g. metformin) are showing promise for ovulation induction but require further long-term evaluation and should only be prescribed by endocrinologists/reproductive endocrinologists. Weight loss is not guaranteed

17. Long-term sequleae Emerging evidence suggests that women with PCOS are at increased risk of developing diabetes and cardiovascular disease ( e.g ischemic heart diseases, dyslipidemia, hypertension) later in life. However, at present there is no evidence that they would benefit from any pharmacological intervention prior to the development of established disease. Clearly, however, lifestyle advice (such as dietary modification and increasing exercise) is appropriate. PCOS is regareded as a risk for endometrial hyperplasia and endometrial adenocarcinoma.

18. GOOD LUCK