Aim: To compare clomiphene citrate (CC) and letrozole for ovarian stimulation (OS) in therapeutic donor sperm insemination (TDI) cycles. Methods: Retrospective cohort study between January 2011 and June 2014 at a University-affiliated private IVF clinic in Montreal, Canada. 257 normo-ovulatory women ≤40 years of age with no history of infertility undergoing 590 TDI cycles in the absence of a male partner (single women and same-sex couples) or azoospermia were included. Patients received 100 mg CC daily (145 women, 321 cycles) or letrozole 5 mg daily (112 women, 269 cycles), from days 3 to 7. Only the first 3 cycles were included per patient. Our main outcome measure was cumulative live birth rates (LBR). Results: Baseline characteristics were comparable between the 2 groups. There were no differences in LBR per cycle (16.5% (53/321) vs. 11.5% (31/269), p = 0.08) and cumulative LBR (36.6% (53/145) vs. 27.7% (31/112), p = 0.13), between CC and letrozole, respectively. Multiple pregnancy rate (11.6% (8/69) vs. 8.7% (4/46), p = 0.6) and miscarriage rate (21.7 vs. 21.7%, p = 1) were also comparable between CC and letrozole, respectively. Conclusion: In normo-ovulatory women undergoing TDI, OS with CC or letrozole resulted in similar live birth and twin pregnancy rates.

Keywords:
Ovarian stimulation, Letrozole, Clomiphene citrate, Therapeutic donor sperm insemination, Live birth
1.
Aboulghar M, Baird DT, Collins J, Evers JL, Fauser BC, Lambalk CB, et al; ESHRE Capri Workshop Group: Intrauterine insemination. Hum Reprod Update 2009;15:265-277.
2.
De Brucker M, Haentjens P, Evenepoel J, Devroey P, Collins J, Tournaye H: Cumulative delivery rates in different age groups after artificial insemination with donor sperm. Hum Reprod 2009;24:1891-1899.
3.
Cantineau AE, Janssen MJ, Cohlen BJ, Allersma T: Synchronised approach for intrauterine insemination in subfertile couples. Cochrane Database Syst Rev 2014;12:CD006942.
4.
Veltman-Verhulst SM, Hughes E, Ayeleke RO, Cohlen BJ: Intra-uterine insemination for unexplained subfertility. Cochrane Database Syst Rev 2016;2:CD001838.
5.
NICE (National Institute for Clinical Excellence): Fertility: Assessment and Treatment for People with Fertility Problems. https://www.nice.org.uk/guidance/cg156.
6.
Goverde AJ, McDonnell J, Vermeiden JP, Schats R, Rutten FF, Schoemaker J: Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis. Lancet 2000;355:13-18.
7.
Zikopoulos K, Kaponis A, Adonakis G, Sotiriadis A, Kalantaridou S, Georgiou I, et al: A prospective randomized study comparing gonadotropin-releasing hormone agonists or gonadotropin-releasing hormone antagonists in couples with unexplained infertility and/or mild oligozoospermia. Fertil Steril 2005;83:1354-1362.
8.
Dickey RP: Strategies to reduce multiple pregnancies due to ovulation stimulation. Fertil Steril 2009;91:1-17.
9.
Fauser BC, Devroey P, Macklon NS: Multiple birth resulting from ovarian stimulation for subfertility treatment. Lancet 2005;365:1807-1816.
10.
Practice Committee of the American Society for Reproductive Medicine: Use of clomiphene citrate in infertile women: a committee opinion. Fertil Steril 2013;100:341-348.
11.
Mitwally MF, Casper RF: Aromatase inhibition: a novel method of ovulation induction in women with polycystic ovarian syndrome. Reprod Technol 2000;10:244-247.
12.
Mitwally MF, Casper RF: Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305-309.
13.
Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group: Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008;23:462-477.
14.
Holzer H, Casper R, Tulandi T: A new era in ovulation induction. Fertil Steril 2006;85:277-284.
15.
Casper RF, Mitwally MF: A historical perspective of aromatase inhibitors for ovulation induction. Fertil Steril 2012;98:1352-1355.
16.
Palomba S: Aromatase inhibitors for ovulation induction. J Clin Endocrinol Metab 2015;100:1742-1747.
17.
Klement AH, Casper RF: The use of aromatase inhibitors for ovulation induction. Curr Opin Obstet Gynecol 2015;27:206-209.
18.
Nordqvist S, Sydsjö G, Lampic C, Åkerud H, Elenis E, Skoog Svanberg A: Sexual orientation of women does not affect outcome of fertility treatment with donated sperm. Hum Reprod 2014;29:704-711.
19.
Van Weert JM, Repping S, Van Voorhis BJ, van der Veen F, Bossuyt PM, Mol BW: Performance of the postwash total motile sperm count as a predictor of pregnancy at the time of intrauterine insemination: a meta-analysis. Fertil Steril 2004;82:612-620.
20.
Merviel P, Heraud MH, Grenier N, Lourdel E, Sanguinet P, Copin H: Predictive factors for pregnancy after intrauterine insemination (IUI): an analysis of 1038 cycles and a review of the literature. Fertil Steril 2010;93:79-88.
21.
Arici A, Byrd W, Bradshaw K, Kutteh WH, Marshburn P, Carr BR: Evaluation of clomiphene citrate and human chorionic gonadotropin treatment: a prospective, randomized, crossover study during intrauterine insemination cycles. Fertil Steril 1994;61:314-318.
22.
Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, et al: Letrozole, gonadotropin, or clomiphene for unexplained infertility. N Engl J Med 2015;373:1230-1240.
23.
Franik S, Kremer JA, Nelen WL, Farquhar C: Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev 2014;2:CD010287.
24.
Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al: Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371:119-129.
25.
Badawy A, Elnashar A, Totongy M: Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Fertil Steril 2009;92:1355-1359.
26.
Sammour A, Biljan MM, Tan SL, Tulandi T: Prospective randomized trial comparing the effects of letrazole (LE) and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation prior to intrauterine insemination (IUI). Fertil Steril 2001;76(suppl 1):S110.
27.
Al-Fozan H, Al-Khadouri M, Tan SL, Tulandi T: A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril 2004;82:1561-1563.
28.
Badawy A, Shokeir T, Allam AF, Abdelhady H: Pregnancy outcome after ovulation induction with aromatase inhibitors or clomiphene citrate in unexplained infertility. Acta Obstet Gynecol Scand 2009;88:187-191.
29.
Ibrahim MI, Moustafa RA, Abdel-Azeem AA: Letrozole versus clomiphene citrate for superovulation in Egyptian women with unexplained infertility: a randomized controlled trial. Arch Gynecol Obstet 2012;286:1581-1587.
30.
Fouda UM, Sayed AM: Extended letrozole regimen versus clomiphene citrate for superovulation in patients with unexplained infertility undergoing intrauterine insemination: a randomized controlled trial. Reprod Biol Endocrinol 2011;9:84.
31.
Badawy A, Mosbah A, Tharwat A, Eid M: Extended letrozole therapy for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a novel protocol. Fertil Steril 2009;92:236-239.
32.
Al-Fadhli R, Sylvestre C, Buckett W, Tan SL, Tulandi T: A randomized trial of superovulation with two different doses of letrozole. Fertil Steril 2006;85:161-164.
33.
Badawy A, Metwally M, Fawzy M: Randomized controlled trial of three doses of letrozole for ovulation induction in patients with unexplained infertility. Reprod Biomed Online 2007;14:559-562.
34.
Young SL, Opsahl MS, Fritz MA: Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women. Fertil Steril 1999;71:639-644.
35.
Cortínez A, De Carvalho I, Vantman D, Gabler F, Iñiguez G, Vega M: Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients. Fertil Steril 2005;83:110-115.
36.
Bao SH, Sheng SL, Peng YF, Lin QD: Effects of letrozole and clomiphene citrate on the expression of HOXA10 and integrin alpha v beta 3 in uterine epithelium of rats. Fertil Steril 2009;91:244-248.
37.
Reefhuis J, Honein MA, Schieve LA, Rasmussen SA; National Birth Defects Prevention Study: Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997-2005. Hum Reprod 2011;26:451-457.
38.
Biljan MM, Hemmings R, Brassard N: The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins. Fertil Steril 2005;84(suppl 1):S95.
39.
Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, et al: Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761-1765.
40.
Forman R, Gill S, Moretti M, Tulandi T, Koren G, Casper R: Fetal safety of letrozole and clomiphene citrate for ovulation induction. J Obstet Gynaecol Can 2007;29:668-671.
41.
Sharma S, Ghosh S, Singh S, Chakravarty A, Ganesh A, Rajani S, et al: Congenital malformations among babies born following letrozole or clomiphene for infertility treatment. PLoS One 2014;9:e108219.
42.
Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H, et al: Reproductive technologies and the risk of birth defects. N Engl J Med 2012;366:1803-1813.
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