1. Polycystic Ovarian Disorder Max Brinsmead MB BS PhD August 2014

2. Criteria for the diagnosis of PCO Has been controversial… Has been controversial… In the US the NIH states that it is: In the US the NIH states that it is: Menstrual abnormalities and anovulation Menstrual abnormalities and anovulation Cinical or biochemical evidence of androgen excess Cinical or biochemical evidence of androgen excess And the exclusion of: And the exclusion of: Prolactin excess, thyroid disorder, congenital adrenal hyperplasia & Cushings syndrome Prolactin excess, thyroid disorder, congenital adrenal hyperplasia & Cushings syndrome

3. Criteria for the diagnosis of PCO In 2003 a European Consensus statement simplified this to… In 2003 a European Consensus statement simplified this to… Any two of the following: Any two of the following: Menstrual abnormalities and anovulation Menstrual abnormalities and anovulation Cinical or biochemical evidence of androgen excess Cinical or biochemical evidence of androgen excess Polycystic ovaries on ultrasound Polycystic ovaries on ultrasound (Transient states e.g. adolescence and simple obesity need to be excluded) (Transient states e.g. adolescence and simple obesity need to be excluded)

4. But what is PCO for the practising doctor ? A genetic variant that affects 5 – 10% of the female population A genetic variant that affects 5 – 10% of the female population Manifests itself as different problems at different stages of adult life Manifests itself as different problems at different stages of adult life Can vary in severity from mild to severe Can vary in severity from mild to severe Best regarded as an evolutionary variant that has permitted survival of the species during times of famine Best regarded as an evolutionary variant that has permitted survival of the species during times of famine The problem is that there are few famines in the developed world in the 21 st century! The problem is that there are few famines in the developed world in the 21 st century!

5. Common clinical manifestations of PCO Obesity Obesity Hirsutism or Acne Hirsutism or Acne Menstrual irregularity Menstrual irregularity Infertility Infertility Type 2 diabetes Type 2 diabetes Dyslipidaemia Dyslipidaemia

6. Other manifestations of PCO Axillary/Groin Follicular Adenitis (Hydranitis suppurativa) Axillary/Groin Follicular Adenitis (Hydranitis suppurativa) Premature pubarche Premature pubarche Bulimia Bulimia Acanthosis nigrans Acanthosis nigrans Recurrent miscarriage Recurrent miscarriage Frontal balding or clitoromegaly Frontal balding or clitoromegaly Homosexuality (Controversial) Homosexuality (Controversial) Cardiovascular disease Cardiovascular disease Endometrial hyperplasia and cancer Endometrial hyperplasia and cancer

7. Essential Tests for possible PCO Ultrasound of pelvis Ultrasound of pelvis More than 12 follicles 5 – 10 mm diam in one or both ovaries More than 12 follicles 5 – 10 mm diam in one or both ovaries NB 20% of cycling women have “polycystic ovaries” NB 20% of cycling women have “polycystic ovaries” Serum androgens Serum androgens Must measure free testosterone or equivalent Must measure free testosterone or equivalent Fasting glucose, cholesterol & triglycerides Fasting glucose, cholesterol & triglycerides Preferably measure insulin as well Preferably measure insulin as well Exclude other causes of the presenting problem Exclude other causes of the presenting problem Prolactin, Thyroid function, HydroxyPROG or dexamethasone suppression as clinically indicated Prolactin, Thyroid function, HydroxyPROG or dexamethasone suppression as clinically indicated

8. Laboratory Manifestations of PCO Elevated free testosterone or free androgen index Elevated free testosterone or free androgen index Hyperinsulinaemia Hyperinsulinaemia Elevated LH or raised LH:FSH ratio Elevated LH or raised LH:FSH ratio Mild chronic hyperoestrinism Mild chronic hyperoestrinism Elevated CHOL, LDL or triglycerides Elevated CHOL, LDL or triglycerides Elevated tissue plasminogen activators Elevated tissue plasminogen activators Evidence of low grade chronic inflammation Evidence of low grade chronic inflammation (Measures of serum leptin correlate with obesity and not PCO) (Measures of serum leptin correlate with obesity and not PCO)

9. Management of the PCO Disorder Will depend on the principal problem… Will depend on the principal problem… Hirsutism Hirsutism Menstrual dysfunction Menstrual dysfunction Infertility Infertility Obesity Obesity Diabetes and or Dyslipidaemia Diabetes and or Dyslipidaemia

10. Management of Hirsutism Is primarily cosmetic Is primarily cosmetic Shaving Shaving Waxing Waxing Dye or Depilation Dye or Depilation Spironolactone Spironolactone Cyproterone acetate (Androcur) Cyproterone acetate (Androcur) Combined oral contraceptive Combined oral contraceptive Preferably with cyproterone acetate e.g. Diane Preferably with cyproterone acetate e.g. Diane Other measures Other measures Ketoconazole Ketoconazole Flutamide (not available in Australia) Flutamide (not available in Australia) Topical Eflornithine ( “ “ “ “ ) Topical Eflornithine ( “ “ “ “ )

11. Management of menstrual dysfunction due to PCO Disorder Diet, exercise and lifestyle changes if obese Diet, exercise and lifestyle changes if obese Combined oral contraceptive Combined oral contraceptive Use 3 rd or 4 th generation or cyproterone acetate e.g. Diane Use 3 rd or 4 th generation or cyproterone acetate e.g. Diane Contraindicated if >35 years AND smoking or morbidly obese Contraindicated if >35 years AND smoking or morbidly obese Mirena IUS is a good alternative Mirena IUS is a good alternative Cyclical or continuous progestin Cyclical or continuous progestin Depot provera Depot provera An alternative for those who do not want “the pill” An alternative for those who do not want “the pill” There may be a role for Metformin There may be a role for Metformin Endometrial resection Endometrial resection Hysterectomy Hysterectomy

12. Management of Infertility due to PCO Disorder Diet, exercise and lifestyle changes if obese Diet, exercise and lifestyle changes if obese Is as effective as drugs! Is as effective as drugs! Clomiphene citrate (Clomid) Clomiphene citrate (Clomid) In a dbRCT Letrozole was more effective than Clomid (OR 1.44, CI 1.10 – 1.17, p=0.007) In a dbRCT Letrozole was more effective than Clomid (OR 1.44, CI 1.10 – 1.17, p=0.007) Metformin Metformin Ovarian drilling Ovarian drilling FSH and HCG FSH and HCG IVF and ET IVF and ET

13. Management of Obesity and Dyslipidaemia with PCO Disorder Diet, exercise and lifestyle changes Diet, exercise and lifestyle changes Metformin Metformin A possible role for Glitazones A possible role for Glitazones Sustained release Metformin may improve compliance Sustained release Metformin may improve compliance

14. So is Metformin the panacea for PCO Disorder? Results from combined trials: Results from combined trials: Decrease androgens by a mean of 20% Decrease androgens by a mean of 20% Increase ovulation from a mean of 1:5 months to 2:5 months Increase ovulation from a mean of 1:5 months to 2:5 months Decrease BMI by a mean of 4% Decrease BMI by a mean of 4% So the outcomes are modest So the outcomes are modest

15. Problems in the use of Metformin for PCO Disorder There are relatively few large scale and long term studies There are relatively few large scale and long term studies Is not as effective as lifestyle changes in RCTs Is not as effective as lifestyle changes in RCTs Nausea and diarrhoea are common Nausea and diarrhoea are common A small risk of hepatoxicity, lactic acidosis and B 12 deficiency A small risk of hepatoxicity, lactic acidosis and B 12 deficiency May be teratogenic if used in pregnancy May be teratogenic if used in pregnancy

16. So what is the role of Metformin in PCO Disorder? To encourage weight loss To encourage weight loss Non significant effect in meta analysis of RCT’s Non significant effect in meta analysis of RCT’s To enhance the effectiveness of Clomid To enhance the effectiveness of Clomid Non significant effect in meta analysis of RCT’s Non significant effect in meta analysis of RCT’s Improves egg and embryo quality during IVF Improves egg and embryo quality during IVF Pregnancy rates doubled and risk of miscarriage reduced Pregnancy rates doubled and risk of miscarriage reduced Reduces the risk of OHSS during IVF Reduces the risk of OHSS during IVF 4Xfold reduced risk 4Xfold reduced risk May prevent the onset of Type 2 Diabetes May prevent the onset of Type 2 Diabetes Does reduce the risk of cardiovascular disease when used for Type 2 Diabetes Does reduce the risk of cardiovascular disease when used for Type 2 Diabetes So the long term use remains controversial So the long term use remains controversial

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