Prospective randomized double-blind trial of the correlation between time of administration and antiestrogenic effects of clomiphene citrate on reproductive end organs
Biljan, M. M., Mahutte, N. G., Tulandi, T., & Tan, S. L. (1999). Prospective randomized double-blind trial of the correlation between time of administration and antiestrogenic effects of clomiphene citrate on reproductive end organs. Fertility and Sterility, 71(4), 633-638. https://doi.org/10.1016/s0015-0282(98)00534-2
Biljan MM, Mahutte NG, Tulandi T, Tan SL. Prospective randomized double-blind trial of the correlation between time of administration and antiestrogenic effects of clomiphene citrate on reproductive end organs. Fertil Steril. 1999;71(4):633-638. doi:10.1016/s0015-0282(98)00534-2
Biljan, Marinko M., et al. "Prospective randomized double-blind trial of the correlation between time of administration and antiestrogenic effects of clomiphene citrate on reproductive end organs." Fertility and Sterility, vol. 71, no. 4, 1999, pp. 633-638.
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Day 1 clomiphene was followed by more pregnancies than day 5
In a randomized, double-blind trial of 23 women with unexplained infertility, clomiphene started on cycle day 1 was followed by more pregnancies than a day 5 start. The 45 cycles each ended with insemination. Pregnancy followed 25 out of 100 day 1 cycles and 0 out of 100 day 5 cycles.
Study at a glance, randomized, double-blind trial of 23 women with unexplained infertility: Day 1 clomiphene was followed by more pregnancies than day 5. Source: Biljan MM et al., 1999, PMID 10202871.
Key Findings
23 women with unexplained infertility contributed 45 cycles of clomiphene citrate with intrauterine insemination, randomized to clomiphene on days 1–5 or on days 5–9 of the cycle.
Pregnancy followed 6 of the 24 day 1 cycles (25% per cycle started) and none of the 21 day 5 cycles (odds ratio 15.1; 95% CI 1.1–72.4).
Follicles matured sooner in the day 1 group (median 11 days against 13). The clomiphene-free interval was longer (median 8 days against 6; difference 2 days, 95% CI 1–3).
On cycle day 5, FSH, LH, estradiol and uterine artery pulsatility index were significantly higher in the day 1 group.
On the day of hCG or the spontaneous LH surge, hormone levels and preovulatory follicle counts did not differ significantly. Endometrial thickness did not differ at any observation point.
Interpretation
This randomized, double-blind trial followed 23 women with unexplained infertility through 45 cycles of clomiphene with intrauterine insemination at one academic center. All six pregnancies occurred in the day 1 group. The authors note that the results rest on a relatively small number of patients. The findings support larger studies of clomiphene start timing in unexplained infertility.
RRM Context
Unexplained infertility means a couple's standard tests came back normal. RRM reads it as undiagnosed. These women had normal tubes and partners with normal semen analyses. The introduction cites earlier studies linking clomiphene to poor cervical mucus, delayed endometrial maturation and altered blood flow to the uterus. Cycle charting tracks cervical mucus daily, and restorative clinicians evaluate both partners to find the underlying cause.
Our editorial summary of this paper, not the article's abstract.
Abstract
Objective
To investigate whether the timing of administration of clomiphene citrate (CC) affects hormone levels, follicular recruitment, reproductive end organs, and pregnancy rates.
Design
Prospective, randomized, double-blind trial.
Setting
Academic center.
Patients
Twenty-three patients with unexplained infertility.
Interventions
Twenty-three patients with unexplained infertility underwent 45 cycles of CC and IUI. For each cycle, patients were randomized either to receive 100 mg of CC on days 1-5 and placebo on days 5-9 (study group), or placebo on days 1-5 and CC on days 5-9 (control group).
Main Outcome Measures
The difference in uterine artery PI, number of follicles, endometrial thickness, and pregnancy rates.
Results
Gonadotropins and E2 levels, as well as uterine artery pulsatility index, were significantly higher in the study group on day 5. In addition, in the study group, a longer time interval existed between finishing CC and IUI (8 versus 6 days; MD = 2 days; 95% CI = 1-3) and the pregnancy rate was higher than in the control group (6 versus 0; OR = 15.1; 95% CI = 1.1-72.4).
Conclusions
Clomiphene citrate commenced on day 1 of the menstrual cycle, rather than day 5, results in more rapid follicular growth, a longer CC-free period before IUI, and higher pregnancy rates. Although methodologically sound, our results should be taken with some degree of caution because they are based on a relatively small number of patients.
