Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility

Tony Sampson, Mercer University College of Pharmacy

Unexplained infertility has occurred in thirty percent of couples who are infertile and is defined as normal test results in tests for ovulation, sperm production, and fallopian tube patency. Initial treatment of unexplained infertility has been three to six cycles of clomiphene along with intrauterine insemination (IUI). [1]

Aromatase inhibitors have been used to induce ovulation and data has shown that pregnancy rates are comparable with use of clomiphene. [2]

Title: Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility [3]
Design Multicenter, randomized, clinical trial; N= 900
Objective To assess whether ovarian stimulation with letrozole, an aromatase inhibitor, as compared with clomiphene or gonadotropin, would result in a lower rate of multiple gestation without lowering the likelihood of pregnancy
Study Groups Gonadotropin (n= 301), clomiphene (n= 300), letrozole (n= 299)
Methods Women received oral clomiphene, oral letrozole or gonadotropin administered subcutaneously.  Medications were started on day three, four, or five of the menstrual cycle, with ovarian stimulation for up to four treatment cycles and intrauterine inseminations.
Duration Unknown
Primary Outcome Measure The rate of multiple gestations among women with clinical pregnancies
Baseline Characteristics Characteristics Gonadotropin (n= 301) Clomiphene (n= 300) Letrozole (n= 299)
Age—years ± SD 32.3 ± 4.1 32.0 ± 4.6 32.2 ± 4.3
Length of time attempting conception—months ± SD 34.8 ± 26.2 34.2 ± 24.1 35.2 ± 26.8
Previous live birth – no.(%) 64 (21.3) 67 (22.3) 52 (17.4)
Results Multiple gestations among clinical pregnancies: gonadotropin (31.8%), clomiphene (9.4%), letrozole (21.9%)
Adverse Events  Event Gonadotropin Clomiphene Letrozole
Common adverse events
Abdominal bloating 27.3 16.8 18.6
Breast pain 21.9 6.4 7.2
Constipation 2.0 9.4 2.7
Headache 30.0 34.9 41.9
Hot flashes 8.4 30.9 16.8
Injection-site reaction 10.8 2.0 3.1
Joint or limb pain 1.7 2.7 5.8
Serious adverse events
Ectopic pregnancy 7.9 4.7 6.0
Emergency cesarean section 0.7 0 0
Congenital anomaly 3.1 4.3 3.6
Neonatal death 0 0 1.8
Study Author Conclusions In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene.

The results of this study demonstrated that letrozole, an aromatase inhibitor, resulted in a lower frequency of multiple gestation compared to gonadotropin and clomiphene.  One limitation of the study was that the gonadotropin group was not blinded.  In conclusion, more trials will be needed to establish the role of aromatase inhibitors in the treatment of unexplained infertility.


  1. Smith S, Pfeifer SM, Collins JA. Diagnosis and management of female infertility. JAMA. 2003;290(13):1767-70.
  2. Ray A, Shah A, Gudi A, Homburg R. Unexplained infertility: an update and review of practice. Reprod Biomed Online. 2012;24(6):591-602.
  3. Diamond MP, Legro RS, Coutifaris C, et al. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. N Engl J Med. 2015;373(13):1230-40.

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