Polycystic Ovary Syndrome & Metformin

1. Polycystic Ovary Syndrome & Metformin November 19, 2008

2. Polycystic Ovary Syndrome • Epidemiology • Clinical manifestations • Diagnostic criteria • Metformin and other medical treatments

3. EPIDEMIOLOGY • Very prevalent disease affecting between 6.5 and 8 percent of women overall. • Prevalence much higher in obese women (28% versus 5.5%) • Prevalence between racial groups in Southeastern US not significantly different • Genetic factors – genes involved in insulin secretion and action, gonadotropin secretion and action, and androgen biosynthesis, secretion, transport, and metabolism

4. CLINICAL MANIFESTATIONS

5. Obesity • Up to one half of women with PCOS are obese, with an increased prevalence of abdominal or central obesity • Most women with PCOS are hyperinsulinemic and insulin resistant

6. Oligomenorrhea • Classically have a peripubertal onset • May have apparently regular cycles at first, followed by irregularity and weight gain Normal PCOS

7. Hirsutism and Virilization • Excess body hair in a male distribution • Male pattern balding • Deeper voice, muscle mass, clitoromegaly

8. Infertility • Female infertility occurs when the woman does not conceive after one year of attempting to become pregnant

9. DIAGNOSTIC CRITERIA vs. Rotterdam

10. NIH Criteria • 1990 Consensus • Menstrual irregularity due to oligo/anovulation • Evidence of hyperandrogenism • Exclusion of other causes of the above two

11. Rotterdam Criteria • Oligo- and/or anovulation • Clinical and/or biochemical signs of hyperandrogenism • POLYCYSTIC OVARIES by ultrasound!!!

12. Transvaginal Ultrasound • 12 or more follicles in each ovary • Each follicle measuring 2-9 mm diameter • Increased ovarian volume (>10 mL)

13. MEDICAL TREATMENT • Weight loss • Hyperandrogenism • Endometrial protection • Insulin resistance • Ovulation induction

14. Weight Loss • Weight loss alone is associated with a reduction in testosterone, leading to resumption of ovulation and often pregnancy.

15. Hyperandrogensim • Many women shave, wax, use Nair or get electrolysis • Combination oral contraceptives • Spirinolactone – antiandrogen properties

16. Endometrial Protection • Risk of unopposed estrogen  endometrial hyperplasia • Combination OCPs vs. Intermittent progestin therapy

17. Metformin

18. Metformin • A biguanide – most widely used drug worldwide for the treatment of type 2 diabetes. • Primary action – inhibits hepatic glucose production • Secondarily increases peripheral sensitivity to insulin

19. Clinical Evidence for PCOS • 1996 study by Nestler demonstrated reduced circulating insulin levels and decreased ovarian secretion of androgens Studies demonstrating decreased clinical signs of androgen excess are limited • 2003 Meta-analysis showed PCOS women on Metformin 3.88 times more likely to ovulate

20. Clinical Evidence cont’d • Indian Diabetes Prevention Programme and U.S. Diabetes Prevention Program have shown that metformin decreases the relative risk of progression to type 2 diabetes by 26% and 31% respectively • Limited evidence suggests that OCPs alone can aggravate insulin resistance and glucose intolerance.

21. Recommendations • Androgen Excess Society recommends that all women with PCOS be screened for glucose intolerance at initial presentation and every 2 years thereafter. • AES does not mandate use of metformin until more studies can demonstrate efficacy. • Metformin use should be considered in all patients with PCOS and glucose intolerance.

22. Recommendations cont’d • American Association of Clinical Endocrinologists recommends that metformin be considered the initial intervention in most women with PCOS, particularly those who are overweight or obese.

23. Adverse Effects • Lactic acidosis – rare complication (0.3 episode per 10,000 patient-years). • GI distress – nausea and diarrhea in 10-25% of patients • B12 Malabsorption. • Category B drug – no teratogenic effects in animal models and limited human anecdotal evidence

24. Thank you! Tyler Hansborough and Barack Obama Taquito, 4 years old

25. RESOURCES • Alvarez-Blasco, F., et al. “Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women.” Arch Intern Med. 2006 October. • “Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).” Human Reproduction 2004; 19:41. • Adams, J, Polson, DW, Franks, S. “Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism.” BMJ 1996; 293:355. • Legro, RS, Barnhart, HX, Schlaff, WD, et al. “Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome.” N Engl J Med 2007; 356:551. • Harborne L, Fleming R, Lyall H, Sattar N, Norman J. Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:4116-23 • Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17alpha activity and serum free testosterone after reduction in insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335:617-23. • Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327:951-3. • Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian and Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006;49:289-97. • Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. • Salley KES, Wickham EP, Cheang KI, Essah PA, Karjane NW, Nestler JE. Glucose intolerance in polycystic ovary syndrome: a position statement of the Androgen Excess Society. J Clin Endocrinol Metab 2007;92:4546-56. • Polycystic Ovary Syndrome Writing Committee. American Association of Clinical Endocrinologists positiion statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract 2005;11:126-134.