The impact of clomiphene citrate on the endometrium in comparison to gonadotropins in intrauterine insemination cycles: is it thinner and does it matter?

Front Endocrinol (Lausanne). 2024 Jun 24:15:1414481. doi: 10.3389/fendo.2024.1414481. eCollection 2024.

Abstract

Objective: To determine whether endometrial thickness (EMT) differs between i) clomiphene citrate (CC) and gonadotropin (Gn) utilizing patients as their own controls, and ii) patients who conceived with CC and those who did not. Furthermore, to investigate the association between late-follicular EMT and pregnancy outcomes, in CC and Gn cycles.

Methods: Retrospective study. Three sets of analyses were conducted separately for the purpose of this study. In analysis 1, we included all cycles from women who initially underwent CC/IUI (CC1, n=1252), followed by Gn/IUI (Gn1, n=1307), to compare EMT differences between CC/IUI and Gn/IUI, utilizing women as their own controls. In analysis 2, we included all CC/IUI cycles (CC2, n=686) from women who eventually conceived with CC during the same study period, to evaluate EMT differences between patients who conceived with CC (CC2) and those who did not (CC1). In analysis 3, pregnancy outcomes among different EMT quartiles were evaluated in CC/IUI and Gn/IUI cycles, separately, to investigate the potential association between EMT and pregnancy outcomes.

Results: In analysis 1, when CC1 was compared to Gn1 cycles, EMT was noted to be significantly thinner [Median (IQR): 6.8 (5.5-8.0) vs. 8.3 (7.0-10.0) mm, p<0.001]. Within-patient, CC1 compared to Gn1 EMT was on average 1.7mm thinner. Generalized linear mixed models, adjusted for confounders, revealed similar results (coefficient: 1.69, 95% CI: 1.52-1.85, CC1 as ref.). In analysis 2, CC1 was compared to CC2 EMT, the former being thinner both before [Median (IQR): 6.8 (5.5-8.0) vs. 7.2 (6.0-8.9) mm, p<0.001] and after adjustment (coefficient: 0.59, 95%CI: 0.34-0.85, CC1 as ref.). In analysis 3, clinical pregnancy rates (CPRs) and ongoing pregnancy rates (OPRs) improved as EMT quartiles increased (Q1 to Q4) among CC cycles (p<0.001, p<0.001, respectively), while no such trend was observed among Gn cycles (p=0.94, p=0.68, respectively). Generalized estimating equations models, adjusted for confounders, suggested that EMT was positively associated with CPR and OPR in CC cycles, but not in Gn cycles.

Conclusions: Within-patient, CC generally resulted in thinner EMT compared to Gn. Thinner endometrium was associated with decreased OPR in CC cycles, while no such association was detected in Gn cycles.

Keywords: clomiphene; endometrial thickness; gonadotropin; intrauterine insemination; ovarian stimulation.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Clomiphene* / administration & dosage
  • Clomiphene* / therapeutic use
  • Endometrium* / drug effects
  • Endometrium* / pathology
  • Female
  • Fertility Agents, Female* / administration & dosage
  • Fertility Agents, Female* / therapeutic use
  • Gonadotropins*
  • Humans
  • Infertility, Female / drug therapy
  • Infertility, Female / therapy
  • Insemination, Artificial*
  • Ovulation Induction / methods
  • Pregnancy
  • Pregnancy Outcome
  • Pregnancy Rate
  • Retrospective Studies

Substances

  • Clomiphene
  • Gonadotropins
  • Fertility Agents, Female

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Author YL acknowledges the support provided by the National Key Research and Development Program of China (2023YFC2705500, 2023YFC2705501) and Science and Technology Commission of Shanghai Municipality (23Y11901400) for the publication of this study. The funding Institutions haven’t participated in any way in the study design, data collection, analysis and interpretation of data, manuscript preparation and review, or in the decision making of where to submit the manuscript for publication. Authors PC, VJ, ID, KJ, CB, and IS have not received any funding for this study.