By Shelley Ferrell Advisor: Eileen VanDyke, PA-C PAS Spring 2006

1. ? By Shelley Ferrell Advisor: Eileen VanDyke, PA-C PAS Spring 2006

2. Behind door #1… • 20 yo white female • CC: menstrual irregularity over past year, no period in 5 months • PE: obesity, acne, hirsutism • Labs: (-) HCG, (+) hyperandrogenemia, (+) insulin resistance • Diagnosis: ?

3. Behind door #2 • 21 yo white female • CC: menstrual irregularity over past year, no period in 5 months • PE: thin, mild acne, unremarkable • Labs: (-) HCG, (+) hyperandrogenemia, (-) insulin resistance • Diagnosis: ?

4. Treatment options • Patient #1- Consider Metformin • Patient #2- No obesity, no IR… Metformin???

5. The Use of Metformin in Non-obese Women with Polycystic Ovarian Syndrome By Shelley Ferrell Advisor: Eileen VanDyke, PA-C PAS Spring 2006

6. Why care about PCOS? • Its common • It causes other health problems • It is emotionally painful for women

7. Making the diagnosis • Two out of three • Oligo and/or an-ovulation • Clinical and/or biochemical hyperandrogenemia • Polycystic ovaries on ultrasound • Diagnosis of exculsion

8. www.stilverlangen.com www.pcos-doctors.com www.nufw.com.au http://www.visualsunlimited.com

9. Clinical Presentation • Is there a stereotypical PCOS patient? Sign Prevalence Polycystic Ovaries 80-100% Oligo- or amenorrhea 70% Hyperandrogenism 20-80% Hirsutism 70% Obesity 50% Increased LH 30-90% Insulin Resistance 20-50% Acne 33% • Other symptoms occur more rarely • Obesity makes a difference

10. Pathophysiology

11. Pathophysiology • Three Theories: • Ovarian hypothesis • Central hypothesis • Insulin hypothesis • Role of obesity in pathogenesis • Obesity status/ IR status makes difference

12. Treatment Options • Obese- weight loss! • Non-obese- OCPs, anti-androgens, insulin-sensitizers • Drawbacks to each • Benefits of metformin • Remember the initial question for Patient #2: • Do non-obese pts benefit from metformin? What if they are not insulin resistant?

13. Lean Women with Polycystic Ovary Syndrome Respond to Insulin Reduction with Decreases in Ovarian P450c17{alpha} Activity and Serum Androgens • Nestler et al, 1997 • 31 normal weight women • 1500 mg day metformin vs placebo, 4-6 wks • Drop in serum sex steroids • (total T ↓48%, free T ↓70% and androstenedione ↓ 36%) • Conclusions: Non-obese PCOS patients benefit from metformin treatment

14. Non-obese women with polycystic ovary syndrome respond better than obese women to treatment with metformin • Maciel et al, 2004 • 29 women in 2 groups: obese and non-obese • Metformin 1500 g/day vs placebo, 6 months • Results • Non-obese: ↑menstrual cyclicity, total T↓ 38%, free T ↓58%, androstendione↓30% • Obese: total T ↓48%, otherwise no change • Conclusions: Non-obese women experience more benefit than obese women with metformin txt

15. Effects of metformin and rosiglitazone, alone and in combination, in non-obese women with polycystic ovary syndrome and normal indices of insulin sensitivity • Baillargeon et al, 2004 • 100 non-obese women with normal insulin sens • 1700 mg of metformin, 8 mg of rosiglitazone, a combination of both drugs or placebo daily for 6 months • Results (met vs placebo): ovulation 6x more common, 100% ovulating monthly by study end- vs 10% placebo, sex steroids ↓67% • Conclusions: Metformin benefits non-obese pts without IR

16. Metformin-diet benefits in women with polycystic ovary syndrome in the bottom and top quintiles for insulin resistance • Goldenberg et al, 2005 • 67 women in top and bottom quintiles for IR out of screening of 898 PCOS pts (all weights!) • 2550 mg/day of metformin for 1 year + diet • Results: menstruation doubled in non-IR • Conclusion: metformin benefits non-IR (many non-obese are also non-IR)

17. Predictive value of glucose-insulin ratio in PCOS and profile of women who will benefit from metformin therapy: Obese, lean, hyper or normoinsulinemic? • Onalan et al, 2005 • 169 women into 6 groups based on glucose-insulin ratio (normoinsulinemic and hyperinsulinemic) and BMI (lean, overweight and obese) • 1700- 2550 mg/day of metformin (based on BMI) or placebo for 6 months • Results: • IR/Lean group: ↑ ovulation, ↓ hirsutism • Both Lean groups, IR/obese group: ↓ Total T • No other significant results • Conclusion: Pts who are both lean and IR benefit most from metformin therapy

18. Inconsistancy? • Onalan did not show benefit to overweight women (still considered non-obese) Author Group Name Inclusion Criteria Average BMI Nestler Lean <23.7 21.6 Maciel Non-obese <30 25.2 Baillargeon Non-obese <27 24.5 Onalan Lean <25 21.3  Overweight <30 28.2 • No inconsistancy- there may be an inverse relationship between BMI and response to metformin, even within non-obese or normal weight populations

19. Conclusion • OCPs very effective • Metformin should be considered also • Talk to your patient- see what her goals are

20. If the intended result…

21. …isn’t quite achieved, Yikes!

22. just try something else! • Find a treatment that the patient is satisfied with • Be sensitive to the effects that PCOS can have on self esteem • Let the patient know that there are websites and online groups for “cysters”

23. Bibliography • Allen H.F., C. Mazzoni, R.A. Heptulla R.A., et al. (2005) “Randomized controlled trial evaluating response to metformin versus standard therapy in the treatment of adolescents with polycystic ovary syndrome.” J Pediatr Endocrinol Metab 18(8):761-8. • American College of Obstetricians and Gynecologists (2002). "Clinical Management Guidelines for Obstetrician--Gynecologists. Number 41, December 2002: Polycystic Ovary Syndrome." Obstet Gynecol 100(6): 1389-1402. • Archer, J.S., R.J. Chang. (2004) “Hirsutism and acne in polycystic ovary syndrome.”Best Pract Res Clin Obstet Gynaecol 18(5):737-54. • Baillargeon, J.P., D. J. Jakubowicz, et al. (2004). "Effects of metformin and rosiglitazone, alone and in combination, in non-obese women with polycystic ovary syndrome and normal indices of insulin sensitivity." Fertility and Sterility 82(4): 893. • Baillargeon, J.P. and J. E. Nestler (2006). "Polycystic Ovary Syndrome: A Syndrome of Ovarian Hypersensitivity to Insulin?" J Clin Endocrinol Metab 91(1): 22-24. • Balen, A. (2004). "The pathophysiology of polycystic ovary syndrome: trying to understand PCOS and its endocrinology." Best Practice & Research Clinical Obstetrics & Gynaecology 18(5): 685. • Bhatia, V. (2005). "Insulin Resistance in Polycystic Ovarian Disease." Southern Medical Journal 98(9): 903-913. • Ciampelli, M., A.M. Fulghesu, F. Cucinelli, et al. (1999). "Impact of Insulin and Body Mass Index on Metabolic and Endocrine Variables in Polycystic Ovary Syndrome." Metabolism 48(2): 167-172. • Cibula, D., M. Fanta, J. Vrbikova, et al. (2005)“The effect of combination therapy with metformin and combined oral contraceptives (COC) versus COC alone on insulin sensitivity, hyperandrogenaemia, SHBG and lipids in PCOS patients.” Hum Reprod 20(1):180-4. • Deglin, J., A.H. Vallerand (2004). Davis' Drug Guide for Nurses. Philadelphia, F. A. Davis Company. • Dereli, D., T. Dereli, F. Bayraktar, et al. (2005). "Endocrine and Metabolic Effects of Rosiglitazone in Non-obese Women with Polycystic Ovary Disease." Endocrine Journal 52(3): 299-308. • Diamanti-Kandarakis, E., K. Alexandraki, et al. (2005). "Metformin administration improves endothelial function in women with polycystic ovary syndrome." Eur J Endocrinol 152(5): 749-756.

24. Bibliography Diamanti-Kandarakis, E., J.-P. Baillargeon, et al. (2003). "A Modern Medical Quandary: Polycystic Ovary Syndrome, Insulin Resistance, and Oral Contraceptive Pills." J Clin Endocrinol Metab 88(5): 1927-1932. Doi, S. A., P. A. Towers, et al. (2005). "PCOS: an ovarian disorder that leads to dysregulation in the hypothalamic-pituitary-adrenal axis?" European Journal of Obstetrics & Gynecology and Reproductive Biology 118(1): 4. Elter, K., G. Imir and F. Durmusoglu. (2002) “Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study.” Hum Reprod 17(7):1729-37. Gennarelli, G., V. Rovei, et al. (2005). "Preserved Insulin Sensitivity and {beta}-Cell Activity, but Decreased Glucose Effectiveness in Normal-Weight Women with the Polycystic Ovary Syndrome." J Clin Endocrinol Metab 90(6): 3381-3386. Goldenberg, Glueck, et al. (2005). "Metformin-diet benefits in women with polycystic ovary syndrome in the bottom and top quintiles for insulin resistance." Metabolism 54(1): 113. Rotterdam consensus workshop group (2004). "Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome." Fertility and Sterility 81(1): 19. Hann L.E., D.A. Hall, C.R. McArdle, et al. (1984). “Polycystic ovarian disease: sonographic spectrum.” Radiology 150(2): 531-4. Hart, R., M. Hickey, et al. (2004). "Definitions, prevalence and symptoms of polycystic ovaries and polycystic ovary syndrome." Best Practice & Research Clinical Obstetrics & Gynaecology 18(5): 671. Lam, P. M., L.P. Cheung, C. Haines (2004). "Revisit of metformin treatment in polycystic ovarian syndrome." Gynecologic Endocrinology 19: 33-39. Luque-Ramirez, M., J. L. San Millan, et al. "Genomic variants in polycystic ovary syndrome." Clinica Chimica Acta In Press, Corrected Proof. Maciel, G. A., J. M. Soares Junior, et al. (2004). "Non-obese women with polycystic ovary syndrome respond better than obese women to treatment with metformin." Fertility and Sterility 81(2): 355. Morin-Papunen, L., I. Vauhkonen, R. Koivunen, et al. (2003). “Metformin Versus Ethinyl Estradiol-Cyproterone Acetate in the Treatment of Nonobese Women with

25. Bibliography • Polycystic Ovary Syndrome: A Randomized Study.” J Clin Endocrinol Metab 88(1):148-56. • Nestler, J. E. and D. J. Jakubowicz (1997). " J Clin Endocrinol Metab 82(12): 4075-4079. • Onalan, G., U. Goktolga, et al. (2005). "Predictive value of glucose-insulin ratio in PCOS and profile of women who will benefit from metformin therapy: Obese, lean, hyper or normoinsulinemic?" European Journal of Obstetrics & Gynecology and Reproductive Biology 123(2): 204. • Orio, F., Jr., S. Palomba, et al. (2005). "Improvement in Endothelial Structure and Function after Metformin Treatment in Young Normal-Weight Women with Polycystic Ovary Syndrome: Results of a 6-Month Study." J Clin Endocrinol Metab 90(11): 6072-6076. • Palomba, S., F. Orio, Jr., et al. (2005). "Prospective Parallel Randomized, Double-Blind, Double-Dummy Controlled Clinical Trial Comparing Clomiphene Citrate and Metformin as the First-Line Treatment for Ovulation Induction in Non-obese Anovulatory Women with Polycystic Ovary Syndrome." J Clin Endocrinol Metab 90(7): 4068-4074. • Premoli, A. C., L. F. Santana, et al. (2005). "Growth hormone secretion and insulin-like growth factor-1 are related to hyperandrogenism in non-obese patients with polycystic ovary syndrome." Fertility and Sterility 83(6): 1852. • Salehi, M., R. Bravo-Vera, et al. (2004). "Pathogenesis of polycystic ovary syndrome: what is the role of obesity?" Metabolism 53(3): 358. • Velásquez, E.M., S. Mendoza, T. Hamer, et al. (1994) “Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.” Metabolism 43(5):647-54. • VrbIkova, J., D. Cibula, et al. (2004). "Insulin Sensitivity in Women with Polycystic Ovary Syndrome." J Clin Endocrinol Metab 89(6): 2942-2945.