IUI INDICATIONS, OVARIAN STIMULATION PROTOCOLS CC, AROMATASE INHIBITORS, GONADOTROPINS Hakan Özörnek, MD EUROFERTIL İstanbul

Indications Male subfertility Unexplained infertility Endometriosis (mild) Cervical factor Ejaculatory dysfunction Immunologic infertility

Contrindications Tubal infertility Severe male infertility Severe endometriosis Decreased ovarian reserv Age > 40

ART in Europe, 2006: results generated from European registers by ESHRE J. de Mouzon*, V. Goossens, S. Bhattacharya, J.A. Castilla, A.P. Ferraretti, V. Korsak, M. Kupka, K.G. Nygren, A. Nyboe Andersen and The European IVF-monitoring (EIM) Consortium, for the (ESHRE) J. de Mouzon*V. GoossensS. BhattacharyaJ.A. CastillaA.P. FerrarettiV. KorsakM. KupkaK.G. NygrenA. Nyboe Andersen CyclesDeliveries Deliveries (%) Singleton (%) Twin (%)Triplet (%)

ÜYTE yönetmeliği MADDE 18 – (8) İstenmeyen durum olan, anne ve çocuk sağlığını riske eden çoğul gebeliklerin önlenmesi esastır. Bu kapsamda; a) ÜYTE yöntemlerinden biri olan klasik ovulasyon indiksiyonu ile 2 (iki) den fazla folikül gelişmemesi hedeflenmelidir. Çoğul gebeliklerin önlenmesi için üç veya daha fazla folikül gelişmesi halinde artifisyel inseminasyon işlemi yapılması yasaktır.

Male subfertility

Unexplained subfertility

Cervical factor

CC/Letrazol protocol E2 control LH control Ovulation induction

Gonadotropin protocol E2 control LH control Ovulation induction IU/day

Advantages of oral drugs Low incidence of multiple pregnancies Low incidence of OHSS Low cost Less need for cycle monitoring More comfortable

CC Competitive antagonist of ovarian estrogen Requires an intact hypothalamic-pituitary-ovarian axis and serum estradiol > 50 pg/ml. Endometrial thickness is initially decreased, but is later increased compared to natural cycles as rising estrogen concentration overcomes the antiestrogen effect. [Randall JM, F&S, 1991]

Letrazol Third generation aromatase inhibitor Act directly to the ovary to decrease production of estrogen Intraovarian androgens accumulate mid sized follicles become atretic Multiple follicular ovulation are reduced compared to CC Used «off label»

CC IUI Dickey RP, et al., Fertil Steril, 2002

CC IUI Dickey RP, et al., Fertil Steril, 2002

CC IUI Dickey RP, et al., Fertil Steril, 2002

CC IUI Dickey RP, et al., Fertil Steril, 2002

Cumulative pregnancy rate Dickey RP, et al., Fertil Steril, 2002

Cumulative pregnancy rate Dickey RP, et al., Fertil Steril, 2002

Cumulative pregnancy rate Dickey RP, et al., Fertil Steril, 2002

CC for unexplained subfertility in women Objectives Clomiphene citrate in improving pregnancy outcomes in women with unexplained subfertility, dose range of 50 to 250 mg for up to 10 days. The primary outcome was live births. Selection criteria Only randomised controlled trials were included. Data collection and analysis Seven trials were included in this review. Hughes E, et al., Cochrane Database of Systematic Reviews 2010

CC for unexplained subfertility in women Main results 1159 participants from seven trials were collated. There was no evidence that CC was more effective than no treatment or placebo for live birth (odds ratio (OR) 0.79, 95% CI 0.45 to 1.38; P = 0.41) or for clinical pregnancy per woman with intrauterine insemination (IUI) (OR 2.40, 95% CI 0.70 to 8.19; P = 0.16). Authors' conclusions There is no evidence of clinical benefit of clomiphene citrate for unexplained fertility.. Hughes E, et al., Cochrane Database of Systematic Reviews 2010

Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial Ahmed Badawy, et al., Fertil Steril, 2009

Letrazol vs CC A meta-analysis of four published randomized controlled trials for ovulation induction in a total 662 patients with PCOS now provides strong evidence that letrozole is at least as effective as CC, the present gold standard, for ovulation induction with similar pregnancy rates ([RR] 1.02; 95% CI 0.83, 1.26). Letrazole is equally effective in inducing ovulation, but without antiestrogenic adverse effects, as a first-line therapy. Casper RF, Fertil &Steril, 2009

Letrazol vs CC 5 fertility centers in Canada. 911 newborns from women who conceived following CC or letrozole treatment. Congenital malformations and chromosomal abnormalities in the letrozole group 2.4% and in the CC group 4.8%. The major malformation rate in the letrozole group was 1.2% and in the CC group was 3.0%. Tulandi T, et al. Fertil Steril, 2006

Gonadotropins IUI Dickey RP, et al., Fertil Steril, 2002

Gonadotropins IUI Dickey RP, et al., Fertil Steril, 2002

Gonadotropins IUI Dickey RP, et al., Fertil Steril, 2002

Gonadotropins IUI Dickey RP, et al., Fertil Steril, 2002

Gonadotropins IUI Dickey RP, et al., Fertil Steril, 2002

Cumulative pregnancy rate Dickey RP, et al., Fertil Steril, 2002

Cumulative pregnancy rate Dickey RP, et al., Fertil Steril, 2002

Cumulative pregnancy rate Dickey RP, et al., Fertil Steril, 2002

Effect of age Dickey RP, et al., Fertil Steril, 2001

Pregnancy rates following IUI Cantineau et al., Cochrane, 2007

Letrazol vs FSH Baysoy A, et al. RBM Online, 2006

Letrazol vs FSH Baysoy A, et al. RBM Online, 2006

Letrazol vs FSH Odysseas, et al., Fertil Steril, 2008

Pregnancy rate FSH vs FSH+Letrazol Requena, et al. Hum Reprod Update, 2008

CC-FSH vs FSH alone vs Letrazol Ganesh, et al. J Assist Reprod Genet, 2009

CC-FSH vs FSH alone vs Letrazol Ganesh, et al. J Assist Reprod Genet, 2009

Premature LH surge during mild FSH stimulation (203 cycles) Lambalk et al., Hum Reprod,2006

OPR with or without antagonist

A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial Richard H. Reindollar, et al FS x CC/IUI + 3 x FSH/IUI + 6 x IVF (n= 247) 3 x CC/IUI + 6 x IVF (n= 256)

A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial Richard H. Reindollar, et al FS 2010

Conclusion IUI is the first choise particularly in male subfertility and unexplained infertility Letrazol is as effective and safe as CC. Absence of antiöstrogenic effect of Letrazol is an advantage Adding of oral drugs to gonadotropins reduce the cost of the therapy but the pregnancy rate is not differ In a subgroup of patients whose basal E2 < 30 pg/ml is gonadotropins preferable Adding GnRH antagonist to a gonadotropin stimulation bevor IUI increase the pregnancy rates Due to new regulation of ministery of health oral drugs are more cost effective than the gonadotropins

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