Does the addition of gonadotropin-releasing hormone analogs improve the pregnancy rates in intrauterine insemination?

in this pilot study for IUI suggest this regimen could be further evaluated for scheduling IUI and IVF cycles. Attempting to compare the rates of premature luteini- zation (PL), clinical pregnancy, and cycle cancellation in ovulation induction (OI)-IUI cycles with and without the GnRH antagonist, cetrorelix, a randomized-controlled trial was undertaken by Steward et al. 12 in which patients were randomly assigned to one of two OI-IUI protocols. Those in the cetrorelix arm showed a significantly reduced rate of PL and no change in clinical pregnancy or cycle cancellation rate, leading to the conclusion that GnRH antagonists can decrease the rate of PL, but appear to have no effect on pregnancy or cycle cancellation in gonadotropin OI-IUI cycles. Stadtmauer et al. 13 conducted a study to evaluate the effect of ganirelix, the GnRH antagonist, on gonadotropin OI in patients with polycystic ovary syndrome (PCOS). Patients were treated with rFSH alone (group 1) or in conjunction with ganirelix when the leading follicle was ≥13 mm (group 2) versus from the beginning of stimulation (group 3), followed by IUI. Data are suggestive of improved CPR in group 2 versus group 1 (33 vs. 19%) and LBR (35 vs. 20%), but not significantly different. Premature luteinization was highest in group 1 (21 vs. 1.8% in group 2 and 2.1% in group 3). Group 3 had the highest cancellation rate and cost without improving CPR and LBR. No differences were noted in peak serum E2, total gonadotropin dose, or days of stimulation. Adding ganirelix in a flexible protocol to gonadotropin OI cycles in women with PCOS may be beneficial by decreasing premature luteinization 13. Ertunc et al.14 conducted a trial to observe the effects of ganirelix on controlled ovarian stimulation (COS) and IUI cycles in women with PCOS. In women with PCOS and anovulatory infertility undergoing COS/IUI, rFSH therapy was started on day 3. In women assigned to the control group (n=47), treatment was continued up to the day of hCG administration. In patients assigned to receive GnRH antagonist (n= 42), ganirelix was added when the leading follicle was ≥14 mm. GnRH antagonist resulted in more monofollicular development, less premature luteinization, and less cycle cancellation in IUI cycles of patients with PCOS; however, the cost of stimulation increased without an improvement in pregnancy rates 14. Lee et al.14 conducted a prospective, randomized clinical trial to evaluate the effectiveness of a GnRH antagonist in preventing premature LH surge under a letrozole and gonadotropin protocol. A total of 61 patients were randomly assigned to either letrozole or gonadotropin treatment groups. These were distinguished by the absence (group I) or presence (group II) of supplementation with 0.25 mg of cetrorelix. Compared Editorial The Journal of Obstetrics and Gynecology of India May / June 2011 262 JOGI_Pg 261-274:JOGI 6/27/2011 11:37 AM Page 262 with group I, the rate of premature LH surge was statistically significantly lower for group II, but the amount of gonadotropins used was statistically significantly higher. In a meta-analysis by Kosmos et al 6, 521 patients were administered a GnRH antagonist and 548 conservatively treated patients served as control subjects. Prospective trials were retrieved from Medline and Cochrane Library (last update October 2006). Six comparisons were retrieved including 1,069 patients. Higher pregnancy rates were found in the randomized controlled trials when a GnRH antagonist was added to a gonadotropin superovulated IUI protocol. A parallel trend for multiple pregnancy rates in the GnRH antagonist group was observed, although this did not reach statistical significance. The flexible regimen was widely used. Certain issues need to be addressed by future clinical research. The role of LH rise in pregnancy outcome is controversial. Although the presence of an LH surge is associated with higher pregnancy rates in clomiphene citrate (CC) IUI cycles, the opposite is true for FSH cycles 16. Interestingly, when FSH is added to a CC cycle, the favorable effect of LH surge remains 16. In such a cycle, two benefits may arise. First, the combined effect of endogenous and exogenous FSH may decrease the total FSH required, and second, premature luteinization may have a positive effect on pregnancy rates. Further research is needed to identify which group of patients will benefit from adding GnRH analogs to an IUI stimulation protocol. Older patients with short follicular phase and reduced ovarian reserve might benefit. This clinical recommendation is based on the facts that young age and number of follicles of diameter 15 mm on the day of hCG administration are significant factors for multiple pregnancy 18. Also for women with reduced ovarian reserve, premature luteinization occurs more frequently. This is due to defective production of gonadotropin surge attenuating factor (GnSAF) 19. On the contrary, a prolongation of follicular phase might allow for an increased number of mature follicles, which may enhance the possibility of pregnancy. In addition, patients with a previous canceled cycle because of premature luteinization are candidates for this treatment.

1. Cantineau AE, Cohlen BJ, Heineman MJ. Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility. Cochrane Database Syst Rev. 2007; (2): CD005356. 2. Eskandar MA. Does the addition of a gonadotropin- releasing hormone agonist improve the pregnancy rate in intrauterine insemination? A prospective controlled trial. Gynecol Endocrinol. 2007; 23 (10): 551-5. 3. Schmidt-Sarosi CL, Y erovi LA Jr. The efficacy of nafarelin acetate versus leuprolide acetate in conjunction with human menopausal gonadotropins for superovulation/intrauterine insemination. Int J Fertil Menopausal Stud. 1994; 39 (1): 20-5. 4. Kim CH, Cho YK, Mok JE. Simplified ultralong protocol of gonadotrophin-releasing hormone agonist for ovulation induction with intrauterine insemination in patients with endometriosis. Hum Reprod. 1996; 11 (2): 398-402. 5. Bellver J, Labarta E, Bosch E, et al. GnRH agonist administration at the time of implantation does not improve pregnancy outcome in intrauterine insemination cycles: a randomized controlled trial. Fertil Steril. 2010; 94 (3): 1065-71. 6. Kosmas IP , Tatsioni A, Kolibianakis EM, et al. Effects and clinical significance of GnRH antagonist administration for IUI timing in FSH superovulated cycles: a meta- analysis. Fertil Steril. 2008; 90 (2): 367-72. 7. Checa MA, Prat M, Robles A, Carreras R. Use of gonadotropin-releasing hormone antagonists to overcome the drawbacks of intrauterine insemination on weekends. Fertil Steril. 2006; 3: 573-7. 8. Gomez-Palomares JL, Julia B, Cevedo-Martin B, Martinez-Burgos M, Hernandez ER, Ricciarelli E. Timing ovulation for intrauterine insemination with a GnRH antagonist. Hum Reprod. 2005; 2: 368-72. 9. Allegra A, Marino A, Coffaro F , et al. GnRH antagonist- induced inhibition of the premature LH surge increases pregnancy rates in IUI-stimulated cycles. A prospective randomized trial. Hum Reprod. 2007; 22: 101-8. 10. Williams RS, Hillard JB, De VG, et al. A randomized, multicenter study comparing the efficacy of recombinant FSH vs recombinant FSH with Ganirelix during superovulation/IUI therapy. Am J Obstet Gynecol. 2004; 2: 648-51. 11. Meldrum DR, Cassidenti DL, Rosen GF , Y ee B, Wisot AL. Oral contraceptive pretreatment and half dose of ganirelix does not excessively suppress LH and may be an excellent choice for scheduling IUI cycles. J Assist Reprod Genet. 2008; 25 (8): 417-20. 12. Steward RG, Gill I, Williams DB, Witz CA, Griffith J, Haddad GF . Cetrorelix lowers premature luteinization rate in gonadotropin ovulation induction-intrauterine The Journal of Obstetrics and Gynecology of India May / June 2011 Editorial 263 JOGI_Pg 261-274:JOGI 6/27/2011 11:37 AM Page 263 264 Editorial The Journal of Obstetrics and Gynecology of India May / June 2011 insemination cycles: a randomized-controlled clinical trial. Fertil Steril. 2011; 95 (1): 434-6. 13. Stadtmauer LA, Sarhan A, Duran EH, Beydoun H, Bocca S, Pultz B, Oehninger S. The impact of a gonadotropin- releasing hormone antagonist on gonadotropin ovulation induction cycles in women with polycystic ovary syndrome: a prospective randomized study. Fertil Steril. 2011; 95 (1): 216-20. 14. Ertunc D, Tok EC, Savas A, Ozturk I, Dilek S. Gonadotropin-releasing hormone antagonist use in controlled ovarian stimulation and intrauterine insemination cycles in women with polycystic ovary syndrome. Fertil Steril. 2010; 93 (4): 1179-84. 15. Lee TH, Lin YH, Seow KM, Hwang JL, Tzeng CR, Y ang YS. Effectiveness of cetrorelix for the prevention of premature luteinizing hormone surge during controlled ovarian stimulation using letrozole and gonadotropins: a randomized trial. Fertil Steril. 2008; 90 (1): 113-20. 16. Mitwally MF , Abdel-Razeq S, Casper RF . Human chorionic gonadotropin administration is associated with high pregnancy rates during ovarian stimulation and timed intercourse or intrauterine insemination. Reprod Biol Endocrinol. 2004; 2: 55-59. 17. Dickey RP , Taylor SN, Lu PY , Sartor BM, Rye PH, Pyrzak R. Risk factors for high-order multiple pregnancy and multiple birth after controlled ovarian hyperstimulation:

of 4,062 intrauterine insemination cycles. Fertil Steril. 2005; 3: 671-83. 18. Kaplan PF , Patel M, Austin DJ, Freund R. Assessing the risk of multiple gestation in gonadotropin intrauterine inse- mination cycles. Am J Obstet Gynecol. 2002; 6: 1244-7. 19. Martinez F , Barri PN, Coroleu B, et al. Women with poor response to IVF have lowered circulating gonadotrophin surge-attenuating factor (GnSAF) bioactivity during spontaneous and stimulated cycles. Hum Reprod. 2002; 3: 634-40. Allahbadia Gautam Medical Director, Rotunda-The Center For Human Reproduction, Bandra, Mumbai For all correspondence: [email protected] JOGI_Pg 261-274:JOGI 6/27/2011 11:37 AM Page 264