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 Menstrual irregularity due to oligo/anovulation Evidence of hyperandrogenism Evidence of hyperandrogenism Exclusion of other causes of the above two 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! Taquito, 4 years old Tyler Hansborough and Barack Obama

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.