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Unexplained Infertility


Robert W. Rebar

, MD, Western Michigan University Homer Stryker M.D. School of Medicine

Last full review/revision Sep 2020| Content last modified Sep 2020
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Infertility is usually considered unexplained when semen in the man is normal and ovulation and fallopian tubes are normal and ovulation is regular in the woman.

Some experts disagree with this definition and recommend continuing to test for other causes even when the man has normal semen and the woman has normal ovulation and fallopian tubes and ovulates regularly. Other experts, who accept the definition above, recommend starting empiric treatments.

Treatment of Unexplained Infertility

  • Controlled ovarian stimulation

  • In vitro fertilization

(See also Evidence-based treatments for couples with unexplained infertility: A guideline, from the Practice Committee of the American Society for Reproductive Medicine.)

Controlled ovarian stimulation (COS) can be used to make pregnancy more likely and to achieve it sooner. This procedure stimulates development of multiple follicles; the goal is to induce ovulation of > 1 oocyte (superovulation). However, COS may result in multifetal pregnancy, which has increased risks and morbidity.

COS involves the following:

  • Giving clomiphene, with human chorionic gonadotropin (hCG) to trigger ovulation, for up to 3 menstrual cycles

  • Intrauterine insemination within 2 days of hCG administration

  • If pregnancy does not result, use of gonadotropins (preparations that contain purified or recombinant follicle-stimulating hormone and variable amounts of luteinizing hormone) with hCG to trigger ovulation, followed by intrauterine insemination (some clinicians begin with gonadotropins rather than clomiphene)

A progestogen may be needed during the luteal phase to maximize the chance of implantation. Gonadotropin dosage depends on the patient’s age and ovarian reserve.

Because multifetal pregnancy is a risk, clinicians are increasingly proceeding directly to in vitro fertilization and avoiding COS.

Prognosis for Unexplained Infertility

The pregnancy rate is the same (about 65%) whether in vitro fertilization is used immediately after unsuccessful treatment with clomiphene plus hCG or whether gonadotropins with intrauterine insemination are used next before trying in vitro fertilization.

However, when in vitro fertilization is done immediately after unsuccessful treatment with clomiphene plus hCG, women become pregnant more quickly and high-order multifetal pregnancies (≥ 3 fetuses) are much less likely than when gonadotropins are used first. Thus, if clomiphene plus hCG is unsuccessful, more clinicians now recommend in vitro fertilization as the next treatment. Recent data indicate that women > 38 with unexplained infertility conceive more quickly and costs are lower when in vitro fertilization is done before controlled ovarian stimulation is tried (1).

Prognosis reference

  • 1. Goldman MB, Thornton KL, Ryley D, et al: A randomized clinical trial to determine optimal infertility treatment in older couples: The forty and over treatment trial (FORT-T). Fertil Steril 101 (6):1574–1581, 2014.

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