Is there a place for Metformin in the treatment of Polycystic Ovary Syndrome ? International Symposium on Reproductive Medicine June 4-6, The Marmara Hotel, Istanbul Kutay Biberoğlu MD.

Polycystic ovary syndrome most common cause of anovulatory infertility phenotypically diverse, cl. hyperandrogenism / bioch. hyperandrogenemia, mens. irregularities & PCO insulin resistance (IR) & hyperinsulinaemia (HI), is likely to be a key factor in pathogenesis of PCOS IR in lean (30%) & obese ♀ (75%), HI - marked in obese increased risk for dyslipidemia, HT, T2 DM, systemic inflammation, endothelial dysfunction & CVD morbidity

PCOS & Metformin treatment of choice for non-insulin-dependent DM first study reporting beneficial effects in PCOS in 1994 Velazquez EM et al. Metabolism 1994;43:647 increases # receptors but not insulin secretion ; lowers glucose with no hypoglycemia in normoglycemics improves insulin sensitivity & glucose absorption, stimulates gluconeogenesis, inhibits glucogenolysis Reduce weight (±) in obese, induce ovulation, increase SHBG, lower LH, T & FAI Ortega-Gonzalez C et al. J Clin Endocrinol Metab 2005;90:1360 Bridger T et al.. Arch Pediatr Adolesc Med 2006;160:241 Trolle B et al. Hum Reprod 2007;22:2967

Ovulation Induction RCT’s - MTFN alone (7.2%) is inferior to CC (22.5%), [combined 26.8%] at achieving live births Legro RS et al. N Engl J Med 2007;356:551 ; Zain MM et al. Fertil Steril 2009;91:514 No evidence that MTFN improves live birth rates, alone or combined, or when compared with CC. Tang T et al. Cochrane Database Syst Rev 2010;CD ESHRE & ASRM– 1°Rx : OI with CC ≤ 6 ovulatory cycles, + MTFN only for glucose intolerance Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2008 Hum Reprod 23:462 & Fertil Steril 89:505

Tang T et al. Cochrane Database Syst Rev 2010;CD no evidence that MTFN improves live birth (OR 1.00, )

Tang T et al. Cochrane Database Syst Rev 2010;CD MTFN no better than CC in live birth rate (OR 0.67, ) ; in obese, MTFN worse in live birth rate (OR 0.3, ) ; in nonobese, MTFN better as 1° therapy (OR 4.94, )

Tang T et al. Cochrane Database Syst Rev 2010;CD no evidence that MTFN+CC combined versus CC alone (obese or not) improves live birth rate (OR 1.05, )

* Tang T et al. Cochrane Database Syst Rev 2010;CD clinical pregnancy rates are improved for MTFN versus placebo (OR 3.86, ) *The benefit is confined in the non-obese group

Tang T et al. Cochrane Database Syst Rev 2010;CD Overall (OR 0.63, ) & in obese (OR 0.34, ), CC is better in clinical pregnancy rate ; MTFN only better in the non-obese group (OR 3.47, )

Tang T et al. Cochrane Database Syst Rev 2010;CD clinical pregnancy rates are improved for MTFN & CC vs CC alone (OR 1.48, ), in non-obese

Tang T et al. Cochrane Database Syst Rev 2010;CD MTFN marginally improved menstrual pattern

compared with placebo or CC alone, MTFN did not reduce miscarriage rate. Tang T et al. Cochrane Database Syst Rev 2010;CD003053

compared with using CC alone, MTFN did not reduce multiple pgcy rate.

No evidence of an effect of MTFN on BMI & waist circumference, both in obese and non-obese There was evidence of a small effect of MTFN on waist-hip ratio Tang T et al. Cochrane Database Syst Rev 2010;CD003053

The magnitude of the reduction appeared to be greater among non-obese women

Tang T et al. Cochrane Database Syst Rev 2010;CD MTFN significantly reduced fasting insulin in the non-obese group, but not in obese. The effect on fasting glucose levels was small in both groups. MTFN had no effect on serum lipids.

Metformin – PCOS Conclusion improvement in reproductive outcomes, appears limited by itself or combined with CC, is still of benefit in clinical pregnancy & ovulation rates as opposed to placebo or CC alone, but with no evidence of improvement in live birth rates the long term use in reducing the risk of developing metabolic syndrome is questionable

Metformin – clomiphene resistant PCOS Combination of MTFN to CC is more effective in achieving live births than CC alone in infertile clomiphene-resistant PCOS patients Moll E, van der Veen F, vanWely M. The role of metformin in polycystic ovary syndrome: a systematic review. Human Reproduction Updates Sep 1, 2007 Palomba S, Falbo A, Zullo F, Orio F. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev 2009;30:1-50. Palomba S, Pasquali R, Orio Jr F, Nestler JE. Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with PCOS: a systematic review of head-to-head randomized controlled studies and meta-analysis. The optimal duration of MTFN use (< 4 wks vs  4 wks) before starting CC, is unknown

COH / IVF - PCOS Patients with PCOS require ; higher total FSH dose longer duration of treatment produce ; a large number of follicles & oocytes high serum estradiol resulting in ; an increased risk of OHSS an elevated cancellation rate a lower conception rate Aboulghar MA, Mansour RT. Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures. Human Reproduction Update 2003;9:275–89

Metformin before/during IVF in PCOS suppression of insulin levels might ; act directly on theca cells to decrease androgen production and prevent ; adverse effects of ovarian stimulation improve ovulation & pregnancy rates no evidence that MTFN before / during ART cycles improvedno evidence that MTFN before / during ART cycles improved live birth rate (3 RCT’s) OR 0.77 ( ) live birth rate (3 RCT’s) OR 0.77 ( ) clinical pregnancy rate (5 RCT’s) OR 0.71 ( ) clinical pregnancy rate (5 RCT’s) OR 0.71 ( ) reduced OHSS risk OR 0.27 ( )reduced OHSS risk OR 0.27 ( ) Tso LO et al. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD

Laparoscopic ovarian diathermy vs CC + MTFN in PCOS clinically confirmed efficacy of LOD in CC- resistant PCOS comparable with GTH’s in ongoing pregnancies & live births Farquhar C et al. Cochrane Database Systematic Review 2007;20:CD Palomba S et al. Hum Reprod 2004;19:2682 van Wely M et al. Hum Reprod 2004;19:1741 CC + MTFN - preferred option before starting with LOD or FSH Moll E, van der Veen F, van Wely M. Hum Reprod Update 2007;13:527 Palomba S et al. Am J Obstet Gynecol 2010;202 A. LOD B. CC+MTFN

Letrozole vs MTFN & CC in CC-resistant women with PCOS LTZ vs MTFN & CC – ovulation 64.9 vs 69.6% ; pgcy 14.7 vs 14.4% ; fol.# 4.4 vs 6.8 ; endometrium 9.5 vs 9.1 mm Letrozole & combined MTFN–CC are equally effective in patients with CC-resistant PCOS Letrozole is well tolerated and an acceptable alternative if long- term MTFN cannot be tolerated Hashim HA et al. Fertil Steril 2009

COC & PCOS long history of common use, obtain regular menses, improve signs of clinical hyperandrogenism 19 nor-T reduce insulin sensitivity ; 2° progestins decrease peripheral insulin receptors ; 3° progestins are neutral ; may activate coagulation system, deteriorate carbohydrate metabolism & lipid profile, use in PCOS is still under scrutiny DRP + 20 μg EE - lack of negative impact on carbohydrates, improvement in insulin sensitivity, no deleterious changes in lipids + MTFN to DRP does not modify insulin effects, only increase HDL mg CPA to DRP/EE20 decreases insulin sensitivity & glucose tolerance, increase triglyceride & cholesterol Fruzetti F et al. Fertil Steril 2009

MTFN vs COC in PCOS MTFN less effective in improving mens pattern (OR 0.08, ) MTFN less effective in reducing TT (0.54, ) free androgen index (3.69, ) MTFN more effective in reducing fasting insulin ( 3.46, ) not increasing triglyceride (-0.48, ) insufficient evidence regarding comparative effects on reducing glucose or cholesterol levels, effect on hirsutism, acne & for preventing DM, CVD, endometrial cancer limited data in either MTFN or COC (alone or in combination) use for the long-term medical management of PCOS Costello MF, Shrestha B, Eden J, Sjoblom P, Johnson N, Moran LJ. The Cochrane Library 2009, Issue 1

Conclusion in CC-resistant women MTFN & CC leads to higher live birth rate as compared to one achieved with CC monotherapy ESHRE & ASRM recommend that MTFN should be restricted to women with glucose intolerance for those women with a short term but not immediate desire for pregnancy, consideration should be given to pretreatment with MTFN before prescribing CC for ovulation induction. pretreatment of obese patients with MTFN combined with lifestyle modification may result in weight loss, which reduces the likelihood of CC resistance & risk for gestational complications metformin co-administration may reduce the risk of OHSS

Conclusion Although has no toxicity, there have been concerns regarding the potential impact of MTFN in pregnancies complicated with impaired placental perfusion and fetal growth restriction. In such conditions, the fetus may rely on the development of peripheral IR to enhance survival, and an insulin modulator, such as MTFN, may interfere with this adaptive mechanism metformin treatment has been used in pregnant women with PCOS with favorable results However, current data on safety and efficacy await confirmation by randomized controlled studies before it is recommended for widespread use in pregnant women with PCOS