Shiuan Yee Tan, Salleha Khalid, Mohamad Azrai Abu, Abdul Kadir Abdul Karim, Mohd Hashim Omar


Objective: To determine the efficacy of clomiphene citrate (CC) in preventing luteinizing hormone (LH) surge without adding gonadotropin releasing hormone (GnRH) antagonist or GnRH agonist in stimulated first fresh intracytoplasmic sperm injection cycle by evaluating the outcome of oocytes and embryo quality. Design: Retrospective cohort study. Settings: Fertility Clinic registry at Hospital University Kebangsaan Malaysia. Patients: A total of 235 fresh stimulated ICSI cycle for patients aged 18-40 years old using clomiphene citrate plus gonadotropin (n=117) and GnRH antagonist plus gonadotropin (n=118) were studied.  Intervention: Comparing two different ovarian stimulation protocol. Main outcome measure(s): Social economical demographic, ovarian stimulation response and laboratory outcome. Fertilization rate as our primary outcome and our secondary outcome were oocyte retrieval rate, mature oocyte rate and top quality embryo rate. Result(s):There were no difference in the demographic and hormonal characteristic of the study groups. The primary outcome of fertilization rate has significant difference with p value of 0.003; 73.2% for CC group and 64.2% for GnRH antagonist group. The secondary outcome of OR rate (78.4 + 17.6 VS 80.3 + 13.4, p=0.368), mature oocyte rate (85.2 + 19.0 VS 81.7 + 16.7, p=0.130) and top quality embryo rate (79.1 + 24.2 VS 75.8 + 21.9, p=0.178) were comparable between both groups. There were significant difference between the endometrial thickness on the day of trigger and OHSS risk among both groups (8.5 + 0.95 VS 9.4 + 1.1, p<0.001 and 12.8% VS 44.1% respectively).

Discussion: Minimal stimulation protocol with CC and gonadotropin may be the answer to many infertile couples in need of IVF and yet having financial situation deterring them in attempting IVF treatment. GnRH antagonist could be safely replaced by CC by extending to 10 days as this protocol gives better primary outcome and comparable secondary outcomes with less OHSS. CC is recognized to induce thinning of endometrial lining and thus, may impair embryo implantation. However, with advancement of the vitrification system and higher success rate in frozen-thaw embryo transfer worldwide provides an excellent solution for this issue.


Clomiphene citrate, minimal stimulation, GnRH antagonist, premature LH surge, low cost IVF.

Full Text:



Orvieto R, Vanni VS, Gleicher N. The myths surrounding mild stimulation in vitro fertilization (IVF). Reprod Biol Endocrinol. 2017;15(1):48.

Nargund G, Fauser B, Macklon N, Ombelet W, Nygren K, Frydman R et al. The ISMAAR proposal on terminology for ovarian stimulation for IVF. Hum Reprod. 2007;22(11):2801-4.

Verberg M, Macklon NS, Nargund G, Frydman R, Devroey P, Broekmans F, et al. Mild ovarian stimulation for IVF. Hum reprod update. 2009;15(1):13-29.

Hammoud AO, Gibson M. Minimal stimulation IVF. Biennial Review of Infertility: Springer; 2011. p. 11-8.

Fauser BC, Nargund G, Andersen AN, Norman R, Tarlatzis B, Boivin J, et al. Mild ovarian stimulation for IVF: 10 years later. Hum reprod. 2010;25(11):2678-84.

Matsaseng T, Kruger T, Zunza M. A simple method of extended 8 days course of clomiphene citrate versus 5 days course in an attempt to suppress premature luteinizing hormone surge in an assisted reproductive technology program: A randomized controlled trial. IVF Lite. 2016;3(1):11.

Bhandari S, Ganguly I, Chittawar PB, Agarwal P, Singh A, Gupta N. Use of clomiphene to prevent premature luteinizing hormone surge during controlled ovarian hyper stimulation. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2017;5(6):1944-8.

Engel J, Ludwig M, Felberbaum R, Albano C, Devroey P, Diedrich K. Use of cetrorelix in combination with clomiphene citrate and gonadotrophins: a suitable approach to ‘friendly IVF’? Hum Reprod. 2002;17(8):2022-6.

Al-Inany H, Azab H, El-Khayat W, Nada A, El-Khattan E, Abou-Setta AM. The effectiveness of clomiphene citrate in LH surge suppression in women undergoing IUI: a randomized controlled trial. Fertil Steril. 2010;94(6):2167-71.

von Wolff M, Nitzschke M, Stute P, Bitterlich N, Rohner S. Low-dosage clomiphene reduces premature ovulation rates and increases transfer rates in natural-cycle IVF. Reprod biomed online. 2014;29(2):209-15.

Herndon CN, Anaya Y, Noel M, Cakmak H, Cedars MI. Outcomes from a university-based low-cost in vitro fertilization program providing access to care for a low-resource socioculturally diverse urban community. Fertil Steril. 2017;108(4):642-9.

Polinder S, Heijnen E, Macklon N, Habbema J, Fauser B, Eijkemans M. Cost-effectiveness of a mild compared with a standard strategy for IVF: a randomized comparison using cumulative term live birth as the primary endpoint. Hum Reprod. 2007;23(2):316-23.

Kuang Y, Chen Q, Fu Y, Wang Y, Hong Q, Lyu Q, et al. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertility and sterility. 2015;104(1):62-70. e3.

Dixon S, Faghih Nasiri F, Ledger W, Lenton E, Duenas A, Sutcliffe P, et al. Cost‐effectiveness analysis of different embryo transfer strategies in England. BJOG: An International Journal of Obstetrics and Gynaecology. 2008;115(6):758-66.

Vayena E, Rowe PJ, Peterson HB. Assisted reproductive technology in developing countries: why should we care? : Elsevier; 2002.

Verberg M, Eijkemans M, Macklon N, Heijnen E, Baart E, Hohmann F, et al. The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis. Hum reprod update. 2009;15(1):5-12.

Mansour RT, Aboulghar MA, Serour GI, Al‐Inany HG, Fahmy I, Amin Y. The use of clomiphene citrate/human menopausal gonadotrophins in conjunction with GnRH antagonist in an IVF/ICSI program is not a cost effective protocol. Acta obstet gynecol Scand. 2003;82(1):48-52.

Dickey RP, Olar TT, Taylor SN, Curole DN, Matulich EM. Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: effect of clomiphene citrate alone and with human menopausal gonadotropin. Fertil steril. 1993;59(4):756-60.

Roque M, Lattes K, Serra S, Solà I, Geber S, Carreras R, et al. Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. Fertil steril. 2013;99(1):156-62.

Luke B, Brown MB, Morbeck DE, Hudson SB, Coddington CC, Stern JE. Factors associated with ovarian hyperstimulation syndrome (OHSS) and its effect on assisted reproductive technology (ART) treatment and outcome. Fertil steril. 2010;94(4):1399-404.

Haas J, Bassil R, Meriano J, Samara N, Barzilay E, Gonen N, et al. Does daily co-administration of letrozole and gonadotropins during ovarian stimulation improve IVF outcome? Reprod Biol Endocrinol. 2017;15(1):70.

Fisher SA, Reid RL, Van Vugt DA, Casper RF. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil steril. 2002;78(2):280-5.

Fernández-Shaw S, Esturo NP, Duque RC, Mallol IP. Mild IVF using GnRH agonist long protocol is possible: Comparing stimulations with 100 IU vs. 150 IU recombinant FSH as starting dose. J assist reprod genet. 2009;26(2-3):75-82.

Penzias A. Improving results with assisted reproductive technologies: individualized patient-tailored strategies for ovulation induction. Reprod biomed online. 2011;22:S83-6.

DOI: http://dx.doi.org/10.24125/sanamed.v13i2.241


  • There are currently no refbacks.

Copyright (c) 2018 Shiuan Yee Tan, Salleha Khalid, Mohamad Azrai Abu, Abdul Kadir Abdul Karim, Mohd Hashim Omar

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.