Polycystic ovarian syndrome: an Asian phenomenon? Premila Jeevan Kollipara MD FRCOG Clinical Director & Consultant in Obstetrics and Gynaecology Queen’s Hospital, London, England

Defining polycystic ovarian syndrome (PCOS) Identified by Slein & Leventhal (1935) Oligo/amenorrhoea Bilateral polycystic ovaries on surgery NIH definition (1990) Hyperandrogenism Ovarian dysfunction Presence of PCO morphology not required Rotterdam Consensus Workshop (2003) Presence of PCO morphology Any 2 of these 3 could lead to a diagnosis

Incidence Reported incidence ranges from 10% to 80% across epidemiological studies Seen in women of all races and nationalities Very common in the South Asian population, including many from the Indian subcontinent

Symptoms Oligomenorrhea (>35 day cycle) / Amenorrhoea (>6 months) Either may be associated with heavy bleeding Difficulty in losing weight Infertility Hirsutism Dyspareunia Androgenic alopecia Acne Seborrhea Acanthosis nigricans Acrochordons Prolonged periods of PMS like symptoms (bleeding, mood swings, pelvic pain, backache) Obstructive sleep apnoea

Presentation Women may present with these symptoms: at any age to a gynaecologist, dermatologist or endocrinologist

Signs On biochemical tests: LH to FSH ratio greater than 1 on day 3 of the menstrual cycle High level of testosterone High level of sex hormone binding globulin Hyperinsulinaemia On scan: 10 or more peripherally located small follicles in ovary (echogenic ‘string of pearls’ appearance) Ovary enlarged 1.5 to 3 times normal On laparascopy: Multiple smooth, thickened, pearl-white areas on the outer surface of the ovary

Risks Endometrial hyperplasia and cancer Insulin resistance and type II diabetes Gestational diabetes Weight gain Infertility Miscarriage Hypertension Dyslipidaemia Cardiovascular disease Stroke

Diagnosing PCOS Difficult and therefore characterised as a syndrome and not as a disease Standard diagnostic assessments: History – 4 key questions: Menstrual patterns Obesity Hirsutism Absence of breast discharge Sensitivity 77.1% and specificity 93.8% Transvaginal ultrasound scan Serum testosterone level Free more sensitive than total Free androgen index = free testosterone/SHBG x 100

Diagnosing PCOS (continued) Common assessments for associated conditions or risks: Fasting biochemical screen Lipid profile 2 hour oral GTT Impaired GTT in 15-30% Frank diabetes in 65-68% Insulin resistance in both normal and overweight Exclusions: Prolactin level TSH / Free thyroxine 17 hydroxyprogesterone DHEAS Androstenedione

Diagnosing PCOS (continued) Controversial tests Fasting insulin level GTT with insulin level – IGTTT HOMAI – mathematical derivation calculated from the fasting values of glucose and insulin allows a direct and moderately accurate measure of insulin sensitivity LH/FSH ratio not very specific – present in less than 50% in 1 study

Differential diagnosis CAH Cushing’s Hyperprolactinaemia Other pulmonary and adrenal disorders PCOS has been reported in patients with acromegaly, an insulin resistant condition

Pathogenesis PCOS develops when: Ovaries are stimulated to produce more androgens through the release of LH by the anterior pituitary Ovaries are stimulated to produce more androgens through high levels of insulin

↓ follicular maturation Aetiology Cause still unknown as it involves a diverse and complex set of symptoms However, a number of theories have been put forward Insulin resistance hypothesis: Hyperinsulinaemia ↓ ↑ GHRH pulse frequency LH over FSH dominance ↑ovarian androgens ↓ follicular maturation ↓ SHBG binding PCOS

Aetiology (continued) Genetic hypothesis: Interpopulation variation in the frequency of phenotypic expression of PCOS Disease familial More common in monozygotic twins Some link to the D193884 dinucleotide repeat marker linked to insulin receptor gene on chromosome 19p13.2

Aetiology (continued) Environmental hypothesis: Low birth weight females have a higher chance of precocious pubarche, hyperinsulinaemia and hyperandrogenism Hypothesized that poor foetal and infant growth can promote development of PCOS in individuals with genetic susceptibility when exposed to a nutritional environment of excess later in life Exposure to androgens during pregnancy Animal studies in rhesus monkeys and sheep

Aetiology (continued) Evolutionary hypothesis: At some point in evolution PCOS may have been selectively advantageous Women with PCOS have a high chance of being obese and anovulatory during times of normal or excess food availability During periods of food shortage and weight loss they begin to ovulate Selective advantage in being able to reproduce when other women become anovulatory With a modern Westernised lifestyle with abundant food and limited physical activity these thrifty genes have become disadvantageous High waist to hip ratio and carbohydrate intolerance in many hunter-gatherer populations throughout the world The suggestion is that a thrifty gene would code for famine resistant glucose metabolism Genotype leads to anabolic metabolism and fat deposition Traditionally not obese when living in their own lifestyle where food supplies are at or just above subsistence level or seasonally available

Aetiology (continued) Food deprivation hypothesis: Weight loss results in spontaneous medically unassisted pregnancies in 33% of cases Thus the onset of severe food deprivation, whether incidental or seasonal, might present reproductive advantage to women with the PCOS genotype

Aetiology (continued) Re-feeding hypothesis: Chronic food deprivation leads to famine related amenorrhoea Amenorrhoeic women, when fed, will reach the critical BMI This will open the leptin gate This will favour earlier ovulation

Aetiology (continued) Trans-generational privation hypothesis Nutrition of mothers and grandmothers has a profound influence on the health of the offspring in adulthood

Treatment of PCOS The mainstay of treatment is: To start the patient on a weight loss diet A low glycaemic index (GI) diet is the ideal A significant part of carbohydrate should be from fruit, vegetable and wholegrain sources To ensure good aerobic exercise for 30 minutes every day

Aims of medical treatment Medical treatment of PCOS should be tailored to the patients’ goals: Restoration of menstruation Prevention of endometrial hyperplasia Prevention of endometrial cancer Restoration of fertility Treatment of hirsutism or acne

Correction of insulin levels Drugs that reduce insulin resistance are helpful: Metformin hydrochloride Proglitazone hydrochloride Rosiglitazone maleate Combined with exercise and low GI diet, 85% of patients will improve in terms of menstrual cycle regularity and ovulation

Restoration of menstruation and prevention of endometrial hyperplasia Combined contraceptive pill Mirena IUD Oral progesterone taken every 3 months to induce a predictable menstrual bleed D-chiro-inositol Naturally occurring human metabolite known to be involved in insulin metabolism Available as a nutritional supplement in the US

Treatment of infertility Clomiphene citrate +/- metformin Drastic increase in ovulation occurs with a combination of diet, moderate weight loss and the above drugs Controlled ovarian hyperstimulation In vitro fertilisation In vitro maturation Ovarian drilling Laparoscopic electrocauterisation Ovarian wedge resection

Treatment of androgenic symptoms Cyproterone acetate (contained in Dianette) Spiranolactone Eflornithine Electrolysis / laser therapy

Summary PCOS is an enormous problem, with significant effects on both body morphology and fertility Its incidence could be as high as 80% in the Indian female population Although its aetiology is not fully understood, a low GI diet and regular exercise may help to ameliorate symptoms

Thank you!