Citation Information :
Thyagaraju C, Naidu A, Chaturvedula L. Comparison of Low-dose Human Menopausal Gonadotropins with Clomiphene Citrate for Ovarian Stimulation in Intrauterine Insemination: A Randomized Clinical Trial. Int J Infertil Fetal Med 2022; 13 (2):47-51.
Introduction: Intrauterine insemination (IUI) is the treatment of choice for unexplained and mild male factor infertile couples not responding to ovulation induction (OI). Clomiphene citrate (CC) is the most common OI used but the success of pregnancy is very low due to its antiestrogenic effects. Gonadotropins are the second line of treatment in CC-resistant cases but they had the disadvantage of being costly with the risk of multiple pregnancies and ovarian hyperstimulation. However, low-dose human menopausal gonadotropins (hMG) have been found to be effective in these conditions with less risk of side effects.
Objectives: To assess the efficacy of ovarian stimulation of low-dose hMG and CC with IUI on pregnancy rate in unexplained infertility.
Materials and methods: The study was randomized control clinical trial conducted at a tertiary care hospital in South India. A total of 224 patients were randomized to two groups: the low-dose hMG group (75 IU) and CC group (100 mg). Women aged between 25 and 30 years with either unexplained or mild male factor infertility were included. All women were monitored for a follicular response, endometrial thickness, and ovulation. IUI procedure was done after 36–42 hours after HCG trigger. Statistical analysis was done using SPSS version 22 with Chi-square test and student t-test as statistical tests.
Results: The demography characteristics like age, duration of infertility, cause of infertility were almost similar in both groups. Compared to ovarian stimulation with CC, hMG stimulation was associated with more number of dominant follicles (2.2 ± 0.5 vs 1.9 ± 0.4) (p = 0.001), increased endometrial thickness (10 ± 1.3 mm vs 7.8 ± 0.15 mm and better pregnancy rate (31.2% vs 16.9%).
Conclusion: Low-dose human menopausal gonadotropins have a better pregnancy rate (31.2%) in comparison to clomiphene citrate (16.9%) when used for ovulation induction with IUI in patients with unexplained infertility and mild male factor infertility. Low-dose hMG was associated with more dominant follicles and better endometrial thickness which may lead to favorable reproductive outcomes.
Clinical significance: Low-dose gonadotropins can be considered for ovarian stimulation in IUI for better pregnancy rate and without any side effects, especially in low-resource settings.
Agarwal SK, Buyalos RP. Clomiphene citrate with intrauterine insemination: is it effective therapy in women above the age of 35 years? Fertil Steril 1996;65(4):759–763. DOI: 10.1016/s0015-0282(16)58210-7
Gysler M, March CM, Mishell Jr DR, et al. A decade's experience with an individualized clomiphene treatment regimen including its effect on the postcoital test. Fertil Steril 1982;37(2):161–167. DOI: 10.1016/s0015-0282(16)46033-4
Karlström PO, Bergh T, Lundkvist Ö. A prospective randomized trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotropin or clomiphene citrate. Fertil Steril 1993;59(3):554–559.
Ragni G, Levi-Setti PE, Fadini R, et al. Clomiphene citrate versus high doses of gonadotropins for in vitro fertilisation in women with compromised ovarian reserve: a randomised controlled non-inferiority trial. Reprod BiolEndocrinol 2012;10:114. DOI: 10.1186/1477-7827-10-114
Abdelazim IA, Makhlouf HH. Sequential clomiphene citrate/hMG versus hMG for ovulation induction in clomiphene citrate-resistant women. Arch Gynecol Obstet 2013;287(3):591–597. DOI: 10.1007/s00404-012-2597-7
Azargoon A, Toussy JA, Darbanan FF. Pregnancies following the use of sequential treatment of metformin and incremental doses of letrozole in clomiphene-resistant women with polycystic ovary syndrome. Iran J Reprod Med 2012;10(1):33–40.
Kar S. Clomiphene citrate or letrozole as first-line ovulation induction drug in infertile PCOS women: a prospective randomized trial. J Hum Reprod Sci 2012;5(3):262–265. DOI: 10.4103/0974-1208.106338
Hembram M, Biswas R, Jain A. A study of controlled ovarian stimulation with clomiphene citrate or letrozole in combination with gonadotropins and IUI in unexplained infertility. J Hum Reprod Sci 2017;10(3):173–177. DOI: 10.4103/jhrs.JHRS_120_16
Dickey RP, Holtkamp DE. Development, pharmacology, and clinical experience with clomiphene citrate. Human Reprod Update 1996;2(6):483–506. DOI: 10.1093/humupd/2.6.483
Ecochard R, Mathieu C, Royere D, et al. A randomized prospective study comparing pregnancy rates after clomiphene citrate and human menopausal gonadotropin before intrauterine insemination. Fertility Sterility 2000:73(1):90–93. DOI: 10.1016/s0015-0282(99)00474-4. PMID: 10632419.
Peeraer K, Debrock S, Loecker PD, et al. Low-dose human menopausal gonadotrophin versus clomiphene citrate in subfertile couples treated with intrauterine insemination: a randomized controlled trial. Human Reprod 2015;30(5):1079–1088. DOI: 10.1093/humrep/dev062
Nuojua-Huttunen S, Tomas C, Bloigu R, et al. Intrauterine insemination treatment in subfertility: an analysis of factors affecting the outcome. Hum Reprod 1999;14(3):698–703. DOI: 10.1093/humrep/14.3.698
Ashrafi M, Rashidi M, Ghasemi A, et al. The role of infertility etiology in the success rate of intrauterine insemination cycles: an evaluation of predictive factors for pregnancy rate. Cell J (Yakhteh) 2013;7(2):100–107.
Al-Fozan H, Al-Khadouri M, Tan SL, et al. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertility and Sterility 2004:82(6):1561–1563. DOI: 10.1016/j.fertnstert.2004.04.070
Jee BC, Ku SY, Suh CS, et al. Use of letrozole versus clomiphene citrate combined with gonadotropins in intrauterine insemination cycles: a pilot study. Fertility and sterility 2006;85(6);1774–1777. 10.1016/j.fertnstert.2006.02.070
Robab D, Ashgharnia M, Tayebi J. Comparison of the success rate of letrozole and clomiphene citrate in women undergoing intrauterine insemination. JRMS 2006;11(6):382–387.
Gerli S, Gholami H, Manna A, et al. Use of Ethinyl estradiol to reverse the antiestrogenic effects of clomiphene citrate in patients undergoing intrauterine insemination: a comparative, randomized study. Fertil Steril 2000;73(1):85–89. DOI: 10.1016/s0015-0282(99)00447-1
Gelety TJ, Buyalos RP. The effect of clomiphene citrate and menopausal gonadotropins on cervical mucus in ovulatory cycles. Fertil Steril 1993;60(3):471–476. DOI: 10.1016/s0015-0282(16)56163-9
Manganiello PD, Stern JE, Stukel TA, et al. A comparison of clomiphene citrate and human menopausal gonadotropin for use in conjunction with intrauterine insemination. Fertil Steril 1997;68(3):405–412. DOI: 10.1016/s0015-0282(97)00260-4
Gleicher N, Oleske DM, Tur-Kaspa I, et al. Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins. N Engl J Med 2000;343(1):2–7. DOI: 10.1056/NEJM200007063430101
Wramsby H, Fredga K, Liedholm P. Chromosome analysis of human oocytes recovered from preovulatory follicles in stimulated cycles. N Engl J Med 1987;316(3):121–124. DOI: 10.1056/NEJM198701153160301
Randall JM, Templeton A. The effects of clomiphene citrate upon ovulation and endocrinology when administered to patients with unexplained infertility. Hum Reprod 1991;6(5):659–664. DOI: 10.1093/oxfordjournals.humrep.a137401
Bateman BG, Kolp LA, Nunley WC, et al. Subclinical pregnancy loss in clomiphene citrate-treated women. Fertil Steril 1992;57(1):25–27.
Hamilton-Fairley D, Kiddy D, Watson H, et al. Low-dose gonadotrophin therapy for induction of ovulation in 100 women with polycystic ovary syndrome. Hum Reprod 1991;6(8):1095–1099. DOI: 10.1093/oxfordjournals.humrep.a137491
Olivennes F, Righini C, Fanchin R, et al. A protocol using a low-dose of gonadotrophin-releasing hormone agonist might be the best protocol for patients with high follicle-stimulating hormone concentrations on day 3. Hum Reprod 1996;11(6):1169–1172. DOI: 10.1093/oxfordjournals.humrep.a019348
Raslan A. Low dose hMG as the first choice for ovarian stimulation in IUI cycles. Evidence-Based Women's Health Journal 2011;1(1).