Low-dose gonadotropin ovulation induction superior to clomiphene

1. Among infertile couples undergoing intrauterine insemination (IUI), those randomized to ovulation induction with low-dose gonadotropins achieved a higher live birth rate than women on clomiphene.

2. Low-dose gonadotropin stimulation was associated with similar incidence of multiple pregnancy and multiple live births compared to clomiphene.

Evidence Rating Level: 1 (Excellent)      

Study Rundown: Infertility, the failure to conceive after one year of regular, unprotected intercourse, impacts roughly 10 percent of couples. The first line treatment for many couples is intrauterine insemination (IUI), which involves introducing sperm directly into the uterus. Pregnancy rates following can be significantly improved with timed ovulation stimulation, termed ovulation induction. Clomiphene citrate, a selective estrogen receptor modulator or SERM, is often used for ovarian induction due to inexpense, ease of use and lower rate of multiples compared with gonadotropin stimulation. Clomiphene works by blocking estrogen receptors in the brain and preventing the negative feedback of estrogen on the hypothalamus, thereby increasing gonadotrophin production and stimulating ovarian follicle growth. The menopausal gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), on the other hand, act directly on ovarian LH and FSH receptors to induce a hypergonadotropic state thus stimulating follicle growth. While some randomized trials have identified improved pregnancy rates with gonadotropin stimulation, others failed to identify this association. Additionally, gonadotropin-IUI is associated with an increased risk of multiple pregnancy, including higher order multiple gestations. In this multi-center, randomized controlled trial, researchers assessed whether ovarian stimulation with low-dose gonadotropin might achieve improved efficacy without increased risk of multiple gestations compared to clomiphene induction.

Compared to clomiphene, low-dose gonadotropin was associated with more clinical pregnancies and a higher live birth rate without an increased incidence of multiples among couples with infertility undergoing IUI. One potential limitation is that couples were allowed to reenter the study for multiple cycles of IUI, which could bias results against couples who achieve early success; however, this was tempered by repeat randomization of couples for each cycle. Given the increased cost and daily injection required with the gonadotropin induction, inclusion of patient satisfaction and healthcare costs in future studies would provide additionally useful clinical information.

Click to read the study in Human Reproduction

Relevant Reading: Effectiveness and treatment for unexplained infertility

In-Depth [randomized controlled trial]: A total of 330 women scheduled to undergo a total of 657 cycles of intrauterine insemination (IUI) were randomized to receive pre-insemination ovarian stimulation with either subcutaneous low-dose human menopausal gonadotropins (n=334) or clomiphene (n=323). Indications for IUI were mild male subfertility, unexplained infertility or minimal-mild endometriosis. The major outcome was clinical pregnancy.

Compared with ovarian stimulation with clomiphene, gonadotropin stimulation resulted in a higher clinical pregnancy rate (14.4% vs. 9.0%, 95%CI 1.1-2.4) and more live births (13.8% vs. 8.7%, 95%CI 1.0-2.4). Rates of multiple pregnancy and multiple births were comparable between groups (p>0.99).

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