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Review
. 2021 Nov 5;11(11):CD005356.
doi: 10.1002/14651858.CD005356.pub3.

Agents for ovarian stimulation for intrauterine insemination (IUI) in ovulatory women with infertility

Astrid Ep Cantineau  1 , Anouk Gh Rutten  2 , Ben J Cohlen  3
Affiliations
Review

Agents for ovarian stimulation for intrauterine insemination (IUI) in ovulatory women with infertility

Astrid Ep Cantineau et al. Cochrane Database Syst Rev. .

Abstract

Background: Intrauterine insemination (IUI), combined with ovarian stimulation (OS), has been demonstrated to be an effective treatment for infertile couples. Several agents for ovarian stimulation, combined with IUI, have been proposed, but it is still not clear which agents for stimulation are the most effective. This is an update of the review, first published in 2007.

Objectives: To assess the effects of agents for ovarian stimulation for intrauterine insemination in infertile ovulatory women.

Search methods: We searched the Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trial registers from their inception to November 2020. We performed reference checking and contacted study authors and experts in the field to identify additional studies.

Selection criteria: We included truly randomised controlled trials (RCTs) that compared different agents for ovarian stimulation combined with IUI for infertile ovulatory women concerning couples with unexplained infertility. mild male factor infertility and minimal to mild endometriosis.

Data collection and analysis: We used standard methodological procedures recommended by Cochrane.

Main results: In this updated review, we have included a total of 82 studies, involving 12,614 women. Due to the multitude of comparisons between different agents for ovarian stimulation, we highlight the seven most often reported here. Gonadotropins versus anti-oestrogens (13 studies) For live birth, the results of five studies were pooled and showed a probable improvement in the cumulative live birth rate for gonadotropins compared to anti-oestrogens (odds ratio (OR) 1.37, 95% confidence interval (CI) 1.05 to 1.79; I2 = 30%; 5 studies, 1924 participants; moderate-certainty evidence). This suggests that if the chance of live birth following anti-oestrogens is assumed to be 22.8%, the chance following gonadotropins would be between 23.7% and 34.6%. The pooled effect of seven studies revealed that we are uncertain whether gonadotropins lead to a higher multiple pregnancy rate compared with anti-oestrogens (OR 1.58, 95% CI 0.60 to 4.17; I2 = 58%; 7 studies, 2139 participants; low-certainty evidence). Aromatase inhibitors versus anti-oestrogens (8 studies) One study reported live birth rates for this comparison. We are uncertain whether aromatase inhibitors improve live birth rate compared with anti-oestrogens (OR 0.75, CI 95% 0.51 to 1.11; 1 study, 599 participants; low-certainty evidence). This suggests that if the chance of live birth following anti-oestrogens is 23.4%, the chance following aromatase inhibitors would be between 13.5% and 25.3%. The results of pooling four studies revealed that we are uncertain whether aromatase inhibitors compared with anti-oestrogens lead to a higher multiple pregnancy rate (OR 1.28, CI 95% 0.61 to 2.68; I2 = 0%; 4 studies, 1000 participants; low-certainty evidence). Gonadotropins with GnRH (gonadotropin-releasing hormone) agonist versus gonadotropins alone (4 studies) No data were available for live birth. The pooled effect of two studies revealed that we are uncertain whether gonadotropins with GnRH agonist lead to a higher multiple pregnancy rate compared to gonadotropins alone (OR 2.53, 95% CI 0.82 to 7.86; I2 = 0; 2 studies, 264 participants; very low-certainty evidence). Gonadotropins with GnRH antagonist versus gonadotropins alone (14 studies) Three studies reported live birth rate per couple, and we are uncertain whether gonadotropins with GnRH antagonist improve live birth rate compared to gonadotropins (OR 1.5, 95% CI 0.52 to 4.39; I2 = 81%; 3 studies, 419 participants; very low-certainty evidence). This suggests that if the chance of a live birth following gonadotropins alone is 25.7%, the chance following gonadotropins combined with GnRH antagonist would be between 15.2% and 60.3%. We are also uncertain whether gonadotropins combined with GnRH antagonist lead to a higher multiple pregnancy rate compared with gonadotropins alone (OR 1.30, 95% CI 0.74 to 2.28; I2 = 0%; 10 studies, 2095 participants; moderate-certainty evidence). Gonadotropins with anti-oestrogens versus gonadotropins alone (2 studies) Neither of the studies reported data for live birth rate. We are uncertain whether gonadotropins combined with anti-oestrogens lead to a higher multiple pregnancy rate compared with gonadotropins alone, based on one study (OR 3.03, 95% CI 0.12 to 75.1; 1 study, 230 participants; low-certainty evidence). Aromatase inhibitors versus gonadotropins (6 studies) Two studies revealed that aromatase inhibitors may decrease live birth rate compared with gonadotropins (OR 0.49, 95% CI 0.34 to 0.71; I2=0%; 2 studies, 651 participants; low-certainty evidence). This suggests that if the chance of a live birth following gonadotropins alone is 31.9%, the chance of live birth following aromatase inhibitors would be between 13.7% and 25%. We are uncertain whether aromatase inhibitors compared with gonadotropins lead to a higher multiple pregnancy rate (OR 0.69, 95% CI 0.06 to 8.17; I2=77%; 3 studies, 731 participants; very low-certainty evidence). Aromatase inhibitors with gonadotropins versus anti-oestrogens with gonadotropins (8 studies) We are uncertain whether aromatase inhibitors combined with gonadotropins improve live birth rate compared with anti-oestrogens plus gonadotropins (OR 0.99, 95% CI 0.3 8 to 2.54; I2 = 69%; 3 studies, 708 participants; very low-certainty evidence). This suggests that if the chance of a live birth following anti-oestrogens plus gonadotropins is 13.8%, the chance following aromatase inhibitors plus gonadotropins would be between 5.7% and 28.9%. We are uncertain of the effect of aromatase inhibitors combined with gonadotropins compared to anti-oestrogens combined with gonadotropins on multiple pregnancy rate (OR 1.31, 95% CI 0.39 to 4.37; I2 = 0%; 5 studies, 901 participants; low-certainty evidence).

Authors' conclusions: Based on the available results, gonadotropins probably improve cumulative live birth rate compared with anti-oestrogens (moderate-certainty evidence). Gonadotropins may also improve cumulative live birth rate when compared with aromatase inhibitors (low-certainty evidence). From the available data, there is no convincing evidence that aromatase inhibitors lead to higher live birth rates compared to anti-oestrogens. None of the agents compared lead to significantly higher multiple pregnancy rates. Based on low-certainty evidence, there does not seem to be a role for different combined therapies, nor for adding GnRH agonists or GnRH antagonists in IUI programs.

PubMed Disclaimer

Conflict of interest statement

AEP Cantineau and BJ Cohlen are authors of an included study comparing FSH with a GnRH antagonist with FSH alone. This is an investigators‐initiated trial. Medication used in this trial was supplied by Serono B.V. only. Serono B.V. was unable to interfere with the results of this RCT, and have had no influence on this Cochrane Review. In conclusion, all three review authors have involvement in primary research in the subject area of our review, but no personal financial support has been gained.

Figures

1
1
tudy flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
4
4
Funnel plot of comparison: 1 Gonadotropins versus anti‐oestrogens, outcome: 1.3 clinical pregnancy rate per couple.
5
5
Funnel plot of comparison: 4 Gonadotropins with GnRH antagonist versus gonadotropins alone, outcome: 4.3 clinical pregnancy rate per couple.
1.1
1.1. Analysis
Comparison 1: Gonadotropins versus anti‐oestrogens, Outcome 1: live birth rate per couple
1.2
1.2. Analysis
Comparison 1: Gonadotropins versus anti‐oestrogens, Outcome 2: multiple pregnancy rate per couple
1.3
1.3. Analysis
Comparison 1: Gonadotropins versus anti‐oestrogens, Outcome 3: clinical pregnancy rate per couple
1.4
1.4. Analysis
Comparison 1: Gonadotropins versus anti‐oestrogens, Outcome 4: miscarriage rate per couple
1.5
1.5. Analysis
Comparison 1: Gonadotropins versus anti‐oestrogens, Outcome 5: OHSS rate per couple
1.6
1.6. Analysis
Comparison 1: Gonadotropins versus anti‐oestrogens, Outcome 6: ectopic pregnancy rate per couple
2.1
2.1. Analysis
Comparison 2: Aromatase inhibitors versus anti‐oestrogens, Outcome 1: live birth rate per couple
2.2
2.2. Analysis
Comparison 2: Aromatase inhibitors versus anti‐oestrogens, Outcome 2: multiple pregnancy rate per couple
2.3
2.3. Analysis
Comparison 2: Aromatase inhibitors versus anti‐oestrogens, Outcome 3: clinical pregnancy rate per couple
2.4
2.4. Analysis
Comparison 2: Aromatase inhibitors versus anti‐oestrogens, Outcome 4: miscarriage rate per couple
2.5
2.5. Analysis
Comparison 2: Aromatase inhibitors versus anti‐oestrogens, Outcome 5: OHSS rate per couple
2.6
2.6. Analysis
Comparison 2: Aromatase inhibitors versus anti‐oestrogens, Outcome 6: ectopic pregnancy rate per couple
3.1
3.1. Analysis
Comparison 3: Gonadotropins with GnRH agonist versus gonadotropins alone, Outcome 1: multiple pregnancy rate per couple
3.2
3.2. Analysis
Comparison 3: Gonadotropins with GnRH agonist versus gonadotropins alone, Outcome 2: clinical pregnancy rate per couple
3.3
3.3. Analysis
Comparison 3: Gonadotropins with GnRH agonist versus gonadotropins alone, Outcome 3: miscarriage rate per couple
3.4
3.4. Analysis
Comparison 3: Gonadotropins with GnRH agonist versus gonadotropins alone, Outcome 4: OHSS rate per couple
4.1
4.1. Analysis
Comparison 4: Gonadotropins with GnRH antagonist versus gonadotropins alone, Outcome 1: live birth rate per couple
4.2
4.2. Analysis
Comparison 4: Gonadotropins with GnRH antagonist versus gonadotropins alone, Outcome 2: multiple pregnancy rate per couple
4.3
4.3. Analysis
Comparison 4: Gonadotropins with GnRH antagonist versus gonadotropins alone, Outcome 3: clinical pregnancy rate per couple
4.4
4.4. Analysis
Comparison 4: Gonadotropins with GnRH antagonist versus gonadotropins alone, Outcome 4: miscarriage rate per couple
4.5
4.5. Analysis
Comparison 4: Gonadotropins with GnRH antagonist versus gonadotropins alone, Outcome 5: OHSS rate per couple
4.6
4.6. Analysis
Comparison 4: Gonadotropins with GnRH antagonist versus gonadotropins alone, Outcome 6: ectopic pregnancy rate per couple
5.1
5.1. Analysis
Comparison 5: Gonadotropins with anti‐oestrogens versus gonadotropins alone, Outcome 1: multiple pregnancy rate per couple
5.2
5.2. Analysis
Comparison 5: Gonadotropins with anti‐oestrogens versus gonadotropins alone, Outcome 2: clinical pregnancy rate per couple
5.3
5.3. Analysis
Comparison 5: Gonadotropins with anti‐oestrogens versus gonadotropins alone, Outcome 3: OHSS rate per couple
6.1
6.1. Analysis
Comparison 6: Aromatase inhibitors versus gonadotropins, Outcome 1: live birth rate per couple
6.2
6.2. Analysis
Comparison 6: Aromatase inhibitors versus gonadotropins, Outcome 2: multiple pregnancy rate per couple
6.3
6.3. Analysis
Comparison 6: Aromatase inhibitors versus gonadotropins, Outcome 3: clinical pregnancy rate per couple
6.4
6.4. Analysis
Comparison 6: Aromatase inhibitors versus gonadotropins, Outcome 4: miscarriage rate per couple
6.5
6.5. Analysis
Comparison 6: Aromatase inhibitors versus gonadotropins, Outcome 5: OHSS rate per couple
6.6
6.6. Analysis
Comparison 6: Aromatase inhibitors versus gonadotropins, Outcome 6: ectopic pregnancy per couple
7.1
7.1. Analysis
Comparison 7: Aromatase inhibitors with gonadotropins versus anti‐oestrogens with gonadotropins, Outcome 1: live birth rate per couple
7.2
7.2. Analysis
Comparison 7: Aromatase inhibitors with gonadotropins versus anti‐oestrogens with gonadotropins, Outcome 2: multiple pregnancy rate per couple
7.3
7.3. Analysis
Comparison 7: Aromatase inhibitors with gonadotropins versus anti‐oestrogens with gonadotropins, Outcome 3: clinical pregnancy rate per couple
7.4
7.4. Analysis
Comparison 7: Aromatase inhibitors with gonadotropins versus anti‐oestrogens with gonadotropins, Outcome 4: miscarriage rate per couple
7.5
7.5. Analysis
Comparison 7: Aromatase inhibitors with gonadotropins versus anti‐oestrogens with gonadotropins, Outcome 5: OHSS rate per couple
8.1
8.1. Analysis
Comparison 8: Gonadotropins with GnRH antagonist versus anti‐oestrogens, Outcome 1: multiple pregnancy rate per couple
8.2
8.2. Analysis
Comparison 8: Gonadotropins with GnRH antagonist versus anti‐oestrogens, Outcome 2: clinical pregnancy rate per couple
9.1
9.1. Analysis
Comparison 9: Different types of gonadotropins, Outcome 1: multiple pregnancy rate per couple
9.2
9.2. Analysis
Comparison 9: Different types of gonadotropins, Outcome 2: clinical pregnancy rate per couple
9.3
9.3. Analysis
Comparison 9: Different types of gonadotropins, Outcome 3: miscarriage rate per couple
9.4
9.4. Analysis
Comparison 9: Different types of gonadotropins, Outcome 4: OHSS rate per couple
10.1
10.1. Analysis
Comparison 10: Different dosage regimens for anti‐oestrogens or aromatase inhibitors, Outcome 1: clinical pregnancy rate per couple
11.1
11.1. Analysis
Comparison 11: Different dosage regimens for gonadotropins, Outcome 1: live birth rate per couple
11.2
11.2. Analysis
Comparison 11: Different dosage regimens for gonadotropins, Outcome 2: multiple pregnancy rate per couple
11.3
11.3. Analysis
Comparison 11: Different dosage regimens for gonadotropins, Outcome 3: clinical pregnancy rate per couple
11.4
11.4. Analysis
Comparison 11: Different dosage regimens for gonadotropins, Outcome 4: miscarriage rate per couple
11.5
11.5. Analysis
Comparison 11: Different dosage regimens for gonadotropins, Outcome 5: OHSS rate per couple
12.1
12.1. Analysis
Comparison 12: Other comparisons, Outcome 1: aromatase inhibitors+gonadotropins versus aromatase inhibitors
12.2
12.2. Analysis
Comparison 12: Other comparisons, Outcome 2: FSH+GnRH antagonist versus hMG+GnRH antagonist
12.3
12.3. Analysis
Comparison 12: Other comparisons, Outcome 3: different regimens of GnRH agonist
12.4
12.4. Analysis
Comparison 12: Other comparisons, Outcome 4: aromatase inhibitors (AI)+tamoxifen+hMG versus AI+hMG
12.5
12.5. Analysis
Comparison 12: Other comparisons, Outcome 5: anti‐oestrogens with gonadotropins with GnRH antagonist versus anti‐estrogens with gonadotrophins
12.6
12.6. Analysis
Comparison 12: Other comparisons, Outcome 6: anti‐oestrogens with gonadotropins and hCG versus anti‐estrogens with gonadotrophins
12.7
12.7. Analysis
Comparison 12: Other comparisons, Outcome 7: anti‐oestrogens with gonadotropins versus anti‐estrogens with hCG
12.8
12.8. Analysis
Comparison 12: Other comparisons, Outcome 8: anti‐oestrogens with hMG versus anti‐oestrogens with rFSH
12.9
12.9. Analysis
Comparison 12: Other comparisons, Outcome 9: GnRHa+FSH versus GnRHa+hMG
12.10
12.10. Analysis
Comparison 12: Other comparisons, Outcome 10: aromatase inhibitors+FSH+GnRH antagonist versus AI+FSH
12.11
12.11. Analysis
Comparison 12: Other comparisons, Outcome 11: CC+FSH+GnRH antagonist flexible vs CC+FSH+GnRH antagonist fixed
12.12
12.12. Analysis
Comparison 12: Other comparisons, Outcome 12: rFSH+rLH versus hMG
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References

References to studies included in this review

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    1. Kabouk GB, Donadio NF. A prospective randomized study comparing clomiphene citrate supplemented with recombinant FSH or low-dose HCG in ovarian stimulation for intrauterine insemination. Fertility and Sterility 2010;4 Suppl 1:S160.
Kamath 2013 {published data only}
    1. Kamath MS, Bhave P, Muthukumar RR, Aleyamma MK, George K. Effectiveness of GnRH antagonist in intrauterine insemination cycles. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2013;166(2):168-72. - PubMed
Kamel 1995 {published data only}
    1. Kamel MA. Effect of induction protocols on pregnancy rate in artificial insemination by husband. Human Reproduction 1995;10 Suppl 1:116.
Karlström 1993 {published data only}
    1. Karlstrom PO, Bergh T, Lundkvist O. A prospective randomized trial of artificial insemination versus intercourse in cycles with human menopausal gonadotropin or clomiphene citrate. Fertility and Sterility 1993;59(3):554-9. - PubMed
Karlström 1998 {published data only}
    1. Karlström PO, Berkurezion M, Bergh T, Lundkvist O. An extended prospective randomized trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotrophins (hMG) or clomiphene citrate (CC). Fertility and Sterility 1998;70 Suppl 2(3):S420. - PubMed
Karthik 2018 {published data only}
    1. Karthik S, Kriplani A, Kachhawa G, Khadgawat R, Aggarwal N, Bhatla N. Comparison of two regimens of gonadotropin-releasing hormone antagonists in clomiphene-gonadotropin induced controlled ovulation and intrauterine insemination cycles: randomized controlled study. Journal of Human Reproductive Sciences 2018;11(2):148-54. - PMC - PubMed
Kaur 2019 {published data only}
    1. Kaur J, Suri V, Gainder S, Arora A. Prospective randomized trial comparing efficacy of letrozole step-up protocol with letrozole plus gonadotropins for controlled ovarian stimulation and intrauterine insemination in patients with unexplained infertility. Archives of Gynecology and Obstetrics 2019;300(6):1767-71. - PubMed
Kim 1996 {published data only}
    1. Kim CH, Cho YK, Mok JE. Simplified ultralong protocol of gonadotrophin-releasing hormone agonist for ovulation induction with intrauterine insemination in patients with endometriosis. Human Reproduction 1996;11(2):398-402. - PubMed
Kim 2010 {published data only}
    1. Kim Ch, Kang HJ, Kim SR, Jeon GH, Lee HA, Kim SH, et al. Effectiveness of soft stimulation protocol, compared with conventional GnRH antagonist multiple dose protocol in patients undergoing controlled ovarian stimulation with intrauterine insemination. Korean Journal of Reproductive Medicine 2010;37(2):135-42.
Labarta 2016 {published data only}
    1. Labarta E, Bosch E, Simon C, Remohi J, Pellicer A. A prospective, randomized controlled trial comparing highly purified hMG with recombinant FSH + recombinant LH in women undergoing intra-uterine insemination: ovarian response and clinical outcomes. Fertility and Sterility 2007;88:295-6.
    1. Labarta E, Bosch E. Comparative study of highly purified HMG versus recombinant FSH + recombinant LH in ovulation induction for intrauterine insemination: a randomized controlled trial. Medicina Reproductiva y Embriología Clínica 2016;3(1):4-11.
Lambalk 2006 {published data only}
    1. Lambalk CB, Leader A, Olivennes F, Fluker MR, Andersen AN, Ingerslev J, et al. Treatment with the GnRH antagonist ganirelix prevents premature LH rises and luteinization in stimulated intrauterine insemination: results of a double-blind, placebo-controlled, multicentre trial. Human Reproduction 2006;21(3):632-9. - PubMed
Lee 2008 {published data only}
    1. Lee TH, Lin YH, Seow KM, Hwang JL, Tzeng CR, Yang YS. Effectiveness of cetrorelix for the prevention of premature luteinizing hormone surge during controlled ovarian stimulation using letrozole and gonadotropins: a randomized trial. Fertility and Sterility 2008;90(1):113-20. - PubMed
Lin 2008 {published data only}
    1. Lin YH, Seow KM, Chen HJ, Hsieh BC, Huang LW, Tzeng CR, et al. Effect of cetrorelix dose on premature LH surge during ovarian stimulation. Reproductive Biomedicine Online 2008;16(6):772-7. - PubMed
Malhotra 2012 {published data only}
    1. Malhotra N, Karmakar D, Kumar S. Letrozole alone or letrozole gonadotropin combination as first line for superovulation in women with unexplained infertility undergoing intrauterine insemination (IUI): a prospective randomized trial. Fertility and Sterility 2012;98 Suppl 1(3):S258.
Matorras 2000 {published data only}
    1. Matorras R, Recio V, Corcostegui B, Rodriguez-Escudero FJ. Recombinant human FSH versus highly purified urinary FSH: a randomized study in intrauterine insemination with husbands' spermatozoa. Human Reproduction 2000;15(6):1231-4. - PubMed
Moro 2015 {published data only}
    1. Moro F, Scarinci E, Palla C, Romani F, Familiari A, Tropea A, et al . Highly purified hMG versus recombinant FSH plus recombinant LH in intrauterine insemination cycles in women ≥35 years: a RCT. Human Reproduction 2015;30(1):179-85. - PubMed
Nada 2016 {published data only}
    1. Nada AM, El Setohy KA, Banat MM, Shaheen AF. Antagonist protocol versus clomiphene in unexplained infertility: a randomized controlled study. Taiwanese Journal of Obstetrics & Gynecology 2016;55:326-30. - PubMed
Nakajima 1999 {published data only}
    1. Nakajima AK, Smith LL, Wong B, Scott JZ, Cumming DC, Tataryn IV, et al. A randomized trial of clomiphene citrate plus intrauterine insemination versus recombinant follicle-stimulating hormone plus intrauterine insemination for the treatment of unexplained infertility. Fertility and Sterility 1999;72 Suppl 1:S208.
Nayar 2008 {unpublished data only}
    1. Nayar KD, Uniyal S, Sawhney S. Clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility. Fertility and Sterility 2008;90 Suppl 1:S476.
Ozmen 2005 {published data only}
    1. Ozmen B, Salih T, Kaan A, Hakan S, Volkan B, Rusen A. Aromatase inhibitor versus clomiphene citrate in IUI cycles. Human Reproduction 2005;20 Suppl 1:i112.
Parés 2002 {published data only}
    1. Parés P, Bordas JR, Sak MJ, Sunol J, Bassas Ll, Viscasillas P, et al. Recombinant FSH versus urinary FSH in ovarian stimulation for intrauterine insemination with husband's sperm. Prospective and randomised study [FSH recombinante versus FSH urinaria en la estimulación ovárica para inseminaciones artificiales conyugales intrauterinas. Estudio prospectivo y randomizado]. Revista Iberoamericana de Fertilidad y repro Humana 2002;19(2):115-21.
Pattuelli 1996 {published data only}
    1. Pattuelli M, Zanasi P, Seracchioli R, Colombi C, Ferlini F, Fabbri R, et al. Supplementation of GnRH agonist to ovarian stimulation and intrauterine insemination does not improve the pregnancy rate. Human Reproduction 1996;11 Suppl 1:128.
Peeraer 2015 {published data only}
    1. Peeraer K, Debrock S, De Loecker P, Tomassetti C, Laenen A, Welkenhuysen M, et al. Low-dose human menopausal gonadotrophin versus clomiphene citrate in subfertile couples treated with intrauterine insemination: a randomized controlled trial. Human Reproduction 2015;30(5):1079-88. - PubMed
Pourali 2017 {published data only}
    1. Pourali L, Ayati S, Tavakolizadeh S, Soleimani H, Sani FT. Clomiphene citrate versus letrozole with gonadotropins in intrauterine insemination cycles: a randomized trial. International Journal of Reproductive Biomedicine 2017;15(1):49-54. - PMC - PubMed
Pourmatroud 2013 {published data only}
    1. Pourmatroud E, Zargar M, Nikbakht R, Moramazi F. A new look at tamoxifen: co-administation with letrozole in intrauterine insemination cycles. Archives of Gynecology and Obstetrics 2013;287(2):383-7. - PubMed
Ragni 2001 {published data only}
    1. Ragni G, Vegetti W, Baroni E, Colombo M, Arnoldi M, Lombroso G, et al. Comparison of luteal phase profile in gonadotrophin stimulated cycles with or without a gonadotrophin-releasing hormone antagonist. Human Reproduction 2001;16(11):54-8. - PubMed
Ragni 2004 {published data only}
    1. Ragni G, Alagna F, Brigante C, Riccaboni A, Colombo M, Somigliana E, et al. GnRH antagonists and mild ovarian stimulation for intrauterine insemination: a randomized study comparing different gonadotrophin dosages. Human Reproduction 2004;19(1):54-8. - PubMed
Ransom 1996 {published data only}
    1. Ransom MX, Doughman NC, Garcia AJ. Menotropins alone are superior to a clomiphene citrate and menotropin combination for superovulation induction among clomiphene citrate failures. Fertility and Sterility 1996;65(6):1169-74. - PubMed
Rashidi 2013 {published data only}
    1. Rashidi M, Aaleyasin A, Aghahossani M, Loloi S, Kokab A, Najmi Z. Advantages of rFSH over hMG for ovulation stimulation in IUI: a randomised controlled trial in unexplained infertility. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2013;169(2):244-7. - PubMed
Sadaghiani 2012 {published data only}
    1. Sadaghiani M, Hamdi K, Danaii S, Moosapur P. Comparison of the efficacy of letrozole gonadotropins and clomiphene citrate gonadotropins in ovarian hyperstimulation of infertile women undergoing intrauterine insemination procedure. Iranian Journal of Reproductive Medicine 2012;10:14-5.
Sagnella 2011 {published data only}
    1. Sagnella F, Moro F, Lanzone A, Tropea A, Martinez D, Capalbo A, et al. A prospective randomized noninferiority study comparing recombinant FSH and highly purified menotropin in intrauerine insemination cycles in couples with unexplained infertility and/or mild-moderate male factor. Fertility and Sterility 2011;95(2):689-94. - PubMed
Sammour 2001 {published data only}
    1. Sammour A, Biljan MM, Tan SL, Tulandi T. Prospective randomized controlled trial comparing effect of letrozole (LE) and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing superovulation prior to intrauterine insemination (IUI). Fertility and Sterility 2001;76 Suppl 1:S110.
Sengoku 1994 {published data only}
    1. Sengoku K, Tamate K, Takaoka Y, Horikawa M, Goishi K, Komori H, et al. A randomized prospective study of gonadotrophin with or without gonadotrophin-releasing hormone agonist for treatment of unexplained infertility. Human Reproduction 1994;9(6):1043-7. - PubMed
Sengoku 1999 {published data only}
    1. Sengoku K, Tamate K, Takaoka Y, Horikawa M, Goishi K, Komori H, et al. The clinical efficacy of low-dose step-up follicle stimulating hormone administration for treatment of unexplained inferility. Human Reproduction 1999;14(2):349-53. - PubMed
Sharma 2011a {published data only}
    1. Sharma S, Rajani S, Kandula L, Sarkar A, Palchaudhuri P, Chakravarty B. Letrozole gonadotrophins combination is inferior to either letrozole or gonadotrophins alone in women with unexplained infertility after clomiphene failure: a prospective randomised clinical trial. Fertility and Sterility 2011;96 Suppl 1:O-5.
Steward 2011 {published data only}
    1. Steward RG, Gill I, Williams DB, Witz CA, Griffith J, Haddad GF. Cetrorelix lowers premature luteinization rate in gonadotropin ovulation induction-intrauterine insemination cycles: a randomized-controlled clinical trial. Fertility and Sterility 2011;95(1):434-6. - PubMed
Taravat 2011 {published data only}
    1. Taravat F, Hamidreza S, Mansour R, Keshavarzi F, Salma H, Sara D. A comparison of anastrozole and clomiphene citrate for ovulation induction in women with unexplained infertility undergoing intrauterine insemination. Pakistan Journal of Medical Sciences 2011;27(5):985-9.
Wadhwa 2016 {published data only}
    1. Wadhwa L, Khanna R, Gupta T, Gupta S, Arora S, Nandwani S. Evaluation of role of GnRH antagonist in intrauterine insemination (IUI) cycles with mild ovarian hyperstimulation (MOH): a prospective randomised study. Journal of Obstetrics and Gynaecology of India 2016;66:459-65. - PMC - PubMed
Wang 2004 {published data only}
    1. Wang CW, Horng SG, Chen CK, Wang HS, Huang Hy, Soon YK. Superovulation with tamoxifen citrate and human menopausal gonadotrophin for patients undergoing intrauterine insemination with a thin endometrium. Human Reproduction 2004;19 Suppl 1:i115.
Williams 2004 {published data only}
    1. Williams RS, Hillard JB, De Vane G, Yeko T, Kipersztok S, Rhoton-Vlasak A, et al. A randomized, multicenter study comparing the efficacy of recombinant FSH vs recombinant FSH with Ganirelix during superovulation/IUI therapy. American Journal of Obstetrics and Gynecology 2004;191(2):648-51. - PubMed
Wu 2007 {published data only}
    1. Wu H, Wang NM, Cheng M, Hsieh J. A randomized comparison of ovulation induction and hormone profile between the aromatase inhibitor anastrozole and clomiphene citrate in women in infertility. Gynaecological Endocrinology 2007;23(2):76-81. - PubMed
Zadehmodares 2012 {published data only}
    1. Zadehmodares S, Niyakan M, Sharafy SA, Yazdi MH, Jahed F. Comparison of treatment outcomes of infertile women by clomiphene citrate and letrozole with gonadotropins underwent intrauterine insemination. Acta Medica Iranica 2012;50(1):18-20. - PubMed

References to studies excluded from this review

Abunaila 2020 {published data only}
    1. Abunaila R, Al-anbari LA, Abbood MS. The effects of adding gonadotropin-releasing hormone antagonist on cycle characteristics and pregnancy rate in stimulated intrauterine insemination (IUI) cycle. International Journal of Research in Pharmaceutical Sciences 2020;11(3):3053-60.
Akbary‐Asbagh 2007 {published data only}
    1. Akbary-Asbagh F, Heidar Z. Evaulation of letrozole therapeutic effect in infertile women. Acta Medica Iranica 2007;45(3):199-203.
Allegra 1990 {published data only}
    1. Allegra A, Volpes A, Coffaro F. Superovulation with buserelin and gonadotropins dramatically improves the success rate of intrauterine insemination with husband's washed semen [Superovulazione con buserelin e gonadotropine in un programma di aid con seme congelato]. Giornale Italiano di Ostetricia E Ginecologia 1990;12:833-7. - PubMed
    1. Allegra A, Voples A, Coffaro F, Guida S, Francofonte R. Superovulation with buserelin and gonadotropins dramatically improves the success rate of intrauterine insemination with husbands' washed semen. Acta Europaea Fertilitatis 1990;21(4):191-5. - PubMed
Alvarez 1999 {published data only}
    1. Alvarez P, Gomez O, Salazar F, Martinez JS, Izquierdo F. Analysis of the follicular stimulation using a low-dose (step-up) protocol with recombinant follicle stimulating hormone (rFSH) and highly purified urinary FSH (FSH-HP) in artificial insemination and directed coitus. Human Reproduction (Oxford, England) 1999;14(Suppl 1):366-7.
Arcaini 1996 {published data only}
    1. Arcaini L, Bianchi S, Baglioni A, Marchini M, Tozzi L, Fedele L. Superovulation and intrauterine insemination vs. superovulation alone in the treatment of unexplained infertility. Journal of Reproductive Medicine 1996;41(8):614-8. - PubMed
Ayaz 2018 {published data only}
    1. Ayaz R, Asoglu MR, Ayas S. Use of clomiphene citrate alone, urinary follicle-stimulating hormone alone, or both combined sequentially in patients with unexplained subfertility undergoing intrauterine insemination: a randomized trial. Turkish Journal of Obstetrics and Gynecology 2018;15(4):243-8. - PMC - PubMed
Azargoon 2013 {published data only}
    1. Azargoon A, Bahrami M, Alavy Toussy J. Comparison of clomiphene citrate plus HMG with clomiphen citrate plus rFSH in IUI cycles in couples with unexplained or male factor infertility: a prospective randomized study. Iranian Journal of Reproductive Medicine 2013;11(3):243-8. - PMC - PubMed
Badawy 2009 {published data only}
    1. 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. Fertility and Sterility 2009;92(4):1355-9. - PubMed
Badawy 2010 {published data only}
    1. Badawy A, Elnashar A, Totongy M. Clomiphene citrate or aromatase inhibitors combined with gonadotropins for superovulation in women undergoing intrauterine insemination: a prospective randomised trial. Journal of Obstetrics and Gynaecology 2010;30(6):617-21. - PubMed
Bakas 2011 {published data only}
    1. Bakas P, Konidaris S, Liapis A, Gregoriou O, Tzanakaki D, Creatsas G. Role of gonadotropin-releasing hormone antagonist in the management of subfertile couples with intrauterine insemination and controlled ovarian stimulation. Fertility and Sterility 2011;95(6):2024-8. - PubMed
Barros Delgadillo 2010 {published data only}
    1. Barros-Delgadillo JC, Trejo-Castaneda H, Ormsby C, Gavino-Gavino F. Differing response to GnRH antagonists in cycles of ovarian hyperstimulation plus intrauterine insemination [Diferencia de respuesta a los antagonistas de GnRH en ciclos de hiperestimulación ovárica más inseminación intrauterina]. Ginecologia y Obstetricia de Mexico 2010;78(1):15-28. - PubMed
Barroso 2006 {published data only}
    1. Barroso G, Menocal G, Feliz H, Rojas-Ruiz JC, Arslan M, Oehninger S. Comparison of the efficacy of the aromatase inhibitor letrozole and clomiphene citrate as adjuvants to recombinant follicle-stimulating hormone in controlled ovarian hyperstimulation: a prospective, randomized, blinded clinical trial. Fertility and Sterility 2006;86(5):1428-31. - PubMed
Bedaiwy 2006 {published data only}
    1. Bedaiwy MA, Forman R, Mousa NA, Al Inany HG, Casper RF. Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation. Human Reproduction 2006;21(1):2838-44. - PubMed
Bejarano Velazquez 2016 {published data only}
    1. Bejarano Velazquez D, De La Perez LO, Trevino Baez JD, Gonzalez Diaz OA. A randomized trial comparing the efficacy and safety of rFSH+rLH vs. rFSH alone and hMG to induce ovulation in cycles for low complexity techniques. Human Reproduction 2016;31:i304.
Bekuretsion 1998 {published data only}
    1. Bekuretsion M, Lundkvist O, Karlström PO. A randomized study comparing low and high dose of HMG/FSH with and without luteal phase support in intrauterine insemination cycles. Human Reproduction (Oxford, England) 1998;13(Suppl 1):199.
Brami 2004 {published data only}
    1. Brami C. Intrauterine insemination for idiopathic infertility [Place des inséminations intra-utérines dans le traitement des infertilités idiopathiques]. La Revue du Praticien Gynécologie et Obstétrique 2004;80:6.
Carrera 2002b {published data only}
    1. Carrera J, Estrada Ll, Rocas A, Francisco E, Sarquella J. Effects of addition of GnRH agonist (triptoreline acetate) to rFSH over intrauterine insemination cycles in patients with polycystic ovary syndrome [Resultados de la adición de un análogo de la GnRH (acetato de triptorelina) a la FSHr en la estimulación ovárica para ciclos de inseminación intrauterine en pacientes con síndrome de ovarios poliquísticos]. Revista Iberoamericana de Fertilidad y Reproducción Humana 2002;19(6):399-405.
Chang 1993 {published data only}
    1. Chang MY, Huang HY, Lee CL, Lai YM, Chang SY, Soong YK. Treatment of infertility using controlled ovarian hyperstimulation with intrauterine insemination: the experience of 343 cases. Journal of the Formosan Medical Association 1993;92(4):341-8. - PubMed
Chaudhury 2013 {published data only}
    1. Chaudhury K, Chaudhury S, Khastgir G, Purakaystha S. An effective alternative to only gonadotrophin for controlled ovarian stimulation in unexplained infertility patients undergoing intra-uterine insemination: a clinical trial. Journal of the Indian Medical Association 2013;111(9):589-92, 594. - PubMed
Check 1992 {published data only}
    1. Check JH, Davies E, Adelson H. A randomized prospective study comparing pregnancy rates following clomiphene citrate and human menopausal gonadotrophin therapy. Human Reproduction 1992;7(6):801-5. - PubMed
Colombi 1996 {published data only}
    1. Colombi C, Pattuelli M, Zanasi P, Seracchioli R, Ferlini F, Magrini O, et al. Small changes in ovarian stimulation protocols do not impair results while largely reducing risks in intrauterine insemination. Human Reproduction (Oxford, England) 1996;(Suppl 1):128.
Crosignani 2005 {published data only}
    1. Crosignani PG, Somigliana E, Colombo M, Riccaboni A, Ragni G, Fahmy I, et al. The current role of intrauterine insemination for the treatment of male factor and unexplained infertility. Middle East Fertility Society Journal 2005;10(1):29-42.
DiMarzo 1992 {published data only}
    1. DiMarzo SJ, Kennedy JF, Young PE, Hebert SA, Rosenberg DC, Villanueva B. Effect of controlled ovarian hyperstimulation on pregnancy rates after intrauterine insemination. American Journal of Obstetrics and Gynecology 1992;166(6):1607-13. - PubMed
Doyle 1991 {published data only}
    1. Doyle MB, DeCherney AH. The value of empiric intrauterine insemination (IUI) with superovulation: a prospective, randomized clinical trial. Fertility and Sterility 1991;56(Abstract book):S34.
Elnashar 2011 {published data only}
    1. Elnashar A, Badawy A, Totongy M. Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Human Reproduction (Oxford, England) 2011;26:i240.
Eskandar 2007 {published data only}
    1. Eskandar MA. Does the addition of a gondadotrophin-releasing hormone agonist improve the pregnancy rate in intrauterine insemination? A prospective controlled trial. Gynaecological Endocrinology 2007;23(10):551-5. - PubMed
Fernandez 2001 {published data only}
    1. Fernandez-Moris J, Viñuela C, Pizarro V, Guerra J. Recombinant human follicle stimulating hormone (r-hFSH) in patients referred to ovulation induction (OI): low dose step up versus step down protocols. Human Reproduction (Oxford, England) 2001;76(3 Suppl 1):S176.
Forghani 2012 {published data only}
    1. Forghani F. Comparison of urinary and recombinant human chorionic gonadotropin during ovulation induction in intrauterine insemination cycles. International Journal of Fertility and Sterility 2012;6:109. - PubMed
Gada 2009 {unpublished data only}
    1. Gada D, Tomar GS, Khare N, Potnis V, Shah V. A randomized trial comparing duration of follicular phase between letrozole and clomiphene citrate when used for superovulation. In: Abstracts of 25th annual meeting ESHRE. Vol. 24. 2009:87.
Gerli 2000 {published data only}
    1. Gerli S. Use of ethinyl estradiol to reverse the anti-oestrogenic effects of clomiphene citrate in patients undergoing IUI; a comparative randomized study. Fertility and Sterility 2000;73(1):85-9. - PubMed
Gerli 2004b {published data only}
    1. Gerli S, Casini ML, Unfer V, Costabile L, Mignosa M, Di Renzo GC. Ovulation induction with urinary FSH or recombinant FSH in polycystic ovary syndrome patients: a prospective randomized analysis of cost-effectiveness. Reproductive Biomedicine Online 2004;9(5):494-9. - PubMed
Graziano 2013 {published data only}
    1. Graziano A, Caserta D, Piva I, Lo Monte G, Bordi G, Martini F, et al. The addition of GnRH antagonist in IUI cycles: a pilot study. European Review for Medical & Pharmacological Sciences 2013;17(12):1604-10. - PubMed
Guzick 2017 {published data only}
    1. Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Litvak P, Steinkampf MP, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. New England Journal of Medicine 2017;340(3):177-83. - PubMed
Hembram 2017 {published data only}
    1. 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. Journal of Human Reproductive Sciences 2017;10(3):173-7. - PMC - PubMed
Ibrahim 2012 {published data only}
    1. Ibrahim MI, Moustafa RA, Abdel-Azeem AA. Letrozole versus clomiphene citrate for superovulation in Egyptian women with unexplained infertility: a randomised controlled trial. Archives of Gynecology & Obstetrics 2012;286(6):1581-7. - PubMed
Isa 2014 {published data only}
    1. Isa AM, Abu-Rafea B, Al-Asiri S, Al-Motawa J, Almady K, Alwaznah R. Ovarian stimulation medications and patients' responses as prognostic factors in IUI-treated infertile Saudi patients. Iranian Journal of Reproductive Medicine 2014;12(7):493-8. - PMC - PubMed
Isaza 2003 {published data only}
    1. Isaza V, Requena A, García-Velasco JA, Remohí J, Pellicer A, Simón C. Recombinant vs urinary follicle-stimulating hormone in couples undergoing intrauterine insemination. Journal of Reproductive Medicine 2003;48(2):112-8. - PubMed
Jacobson 1991 {published data only}
    1. Jacobson A, Galen D, Milani H, Weckstein L, Jacobson J. A novel superovulation regimen: three-day gonadotropin-releasing hormone agonist with overlapping gonadotropins. Fertility and Sterility 1991;56(6):1169-72. - PubMed
Jaroudi 1998 {published data only}
    1. Jaroudi KA, Hollanders H, Sieck U, Zahrani A, Al-Nour A, Atared A. Superovulation and intrauterine insemination for male factor infertility: a controlled randomized study. Middle East Fertility Society Journal 1998;3(3):254-9.
Karande 1995 {published data only}
    1. Karande VC, Rao R, Pratt DE, Balin M, Levrant S, Morris R, et al. A randomized prospective comparison between intrauterine insemination and fallopian sperm perfusion for the treatment of infertility. Fertility and Sterility 1995;64(3):638-40. - PubMed
Karlström 2000 {published data only}
    1. Karlström PO, Bergh T, Lundkvist O. Addition of gonadotrophin-releasing hormone agonist and/or two inseminations with husband's sperm do not improve the pregnancy rate in superovulated cycles. Acta Obstetricia et Gynecologica Scandinavica 2000;79:37-42. - PubMed
Karlström 2002 {published data only}
    1. Karlström PO, Lundkvist O. A randomized comparison of two low dose protocols of Gonal-F during ovarian stimulation for intrauterine insemination. Human Reproduction (Oxford, England) 2002;17(Suppl):20.
Karmon 2015 {published data only}
    1. Karmon AE, Cardozo ER, Petrozza JC. Clomid compared with follicle-stimulating hormone treatment: similar follicle number means different success rates. Obstetrics & Gynecology 2015;125:60S.
Khanna 2013 {published data only}
    1. Khanna SC, Kumar A, Joy SG, Tanwar R, Sharma S, Prasad S. Is letrozole superior to clomiphene for ovarian stimiulation prior to intrauterine insemination? Archives of Gynecology and Obstetrics 2013;287(3):571-5. - PubMed
Kocak 2010 {published data only}
    1. Kocak M, Dilbaz B. Lyophilised HMG versus rFSH in women with unexplained infertility undergoing a controlled ovarian stimulation with intrauterine insemination: a prospective, randomized study. Gynaecolgical Endocrinology 2010;26:429-34. - PubMed
Kotecki 2005 {published data only}
    1. Kotecki JA, Dzik A, Freitas GC, Soares JB, Gahamondes LG, Cavagna M. Comparison of five different ovarian stimulation protocols for intra-uterine insemination. A prospective randomized trial. Fertility and Sterility 2005;84(Suppl 1):S93.
La Cour Freiesleben 2009 {published data only}
    1. La Cour Freiesleben N, Lossl K, Bogstad J, Bredkjaer HE, Toft B, Rosendahl M, et al. Individual versus standard dose of rFSH in a mild stimulation protocol for intrauterine insemination: a randomized study. Human Reproduction 2009;24(10):2523-30. - PubMed
Lorusso 2008 {published data only}
    1. Lorusso F, Palmisano M, Serratì G, Bassi E, Lamanna G, Vacca M, et al. Intrauterine insemination with recombinant or urinary human chorionic gonadotropin: a prospective randomized trial. Gynecological Endocrinology 2008;24(11):644-8. - PubMed
Mahajan 2007 {published data only}
    1. Mahajan NN, Mahajan KN, Soni RN. Effect of GnRH antagonists in FSH mildly stimulated intrauterine insemination cycles: a multicentre randomized trial. Human Reproduction (Oxford, England) 2007;22(10):2795. - PubMed
Malhotra 2015 {published data only}
    1. Malhotra N, Bansal P, Dadhwal V, Deka D, Sharma A. The role of GnRH analogues in improving outcome at superovulation and intra-uterine insemination (IUI) after surgical correction of mild endometriosis: a randomized controlled trial. International Journal of Gynaecology and Obstetrics 2015;131:E126. - PMC - PubMed
Manganiello 1997 {published data only}
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References to studies awaiting assessment

Abu Hashim 2012 {published data only}
    1. Abu Hashim H, El Rakhawy M, Abd Elaal I. Randomized comparison of superovulation with letrozole vs. clomiphene citrate in an IUI program for women with recently surgically treated minimal to mild endometriosis. Acta Obstetricia et Gynecologica Scandinavica 2012;91(3):338-45. - PubMed
IRCT20090912002445N 2019 {unpublished data only}
    1. Keramati P, Zarei A. Effects of prostaglandin and clomiphene citrate on pregnancy outcome. Iranian Registry of Clinical Trials (IRCT) 31 July 2019.
IRCT20180528039878N1 2018 {published data only}
    1. IRCT20180528039878N1. Evaluation of the efficiency of clomiphene citrate plus letrozole gonadotropins for superovulation in patients undergoing intrauterine insemination: a randomized trial. https://en.irct.ir/trial/32566?revision=53306.

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References to other published versions of this review

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