Short answer: Clomiphene (Clomid) and gonadotropins such as Gonal-f, Follistim, Menopur and Ovidrel are FDA approved for ovulation induction or IVF. Letrozole is approved only for breast cancer, yet the 2023 PCOS guideline makes it first-line for ovulation in PCOS, off-label. In a 750-woman trial, live births were 27.5% on letrozole vs 19.1% on clomiphene. Kisspeptin has small IVF studies only and no approval.
| Compound | Best evidence | What it shows |
|---|---|---|
| Clomiphene (Clomid) | FDA-approved for this | Approved for ovulation problems in women who want to conceive. In its trials, about 30% of 7,578 patients became pregnant, and 7.98% of pregnancies were multiples. |
| FSH and menotropins (Gonal-f, Follistim AQ, Menopur) | FDA-approved for this | Injected hormones approved to induce ovulation or grow multiple follicles for IVF. In Gonal-f trials, 20% of live births after ovulation induction and 35.1% after IVF were multiples. |
| hCG (Ovidrel) | FDA-approved for this | Ovidrel is approved to trigger final egg maturation in women having IVF after FSH treatment. |
| Letrozole | Approved for a different use | Approved only for breast cancer. The 2023 PCOS guideline makes it first-line for ovulation in PCOS, noting this is off-label in many countries. |
| Kisspeptin (kisspeptin-54 in studies) | Small or early human studies | Triggered egg maturation in small IVF studies of 53 and 60 women. Not FDA approved. FDA lists compounded kisspeptin-10 as a possible safety risk. |
"Animal or lab studies only" means no published human trial for this goal that we could find. Results in rats or cells often do not carry over to people. Compounds that are not FDA-approved have no tested label for dose, purity or safety.
MedlinePlus defines infertility as not getting pregnant after a year of trying, or after six months if you are 35 or older. A clinician looks for the cause first, because each drug is approved for a specific situation.
The Clomid and Gonal-f labels warn about ovarian hyperstimulation syndrome (OHSS), where the ovaries over-respond and fluid shifts in the body, and about multiple pregnancy. The Clomid label says OHSS can progress within 24 hours to several days and become serious. The Gonal-f label says ultrasound and estradiol blood tests help time the trigger and lower OHSS and multiple-pregnancy risk.
Letrozole is an aromatase inhibitor. Its Femara label lists only breast cancer uses. The 2023 international PCOS guideline still says letrozole should be the first-line drug for ovulation induction in anovulatory women with PCOS and no other infertility factors. It says this use is off-label in many countries and that letrozole should not be given if there is any chance of an existing pregnancy.
The main evidence is a 2014 NIH-funded trial of 750 women with PCOS. Over up to five cycles, live births were 27.5% with letrozole vs 19.1% with clomiphene. Ovulation was 61.7% of cycles vs 48.3%. Twin pregnancies were 3.4% vs 7.4%. Clomiphene caused more hot flushes; letrozole caused more tiredness and dizziness. Overall birth defects did not differ significantly.
Kisspeptin is a natural hormone that strongly stimulates the release of reproductive hormones such as LH. A London group tested kisspeptin-54, the main form in human blood, as an IVF trigger. In a 2014 study of 53 women, one injection matured eggs at every dose tested, and 12 of 53 (23%) had a clinical pregnancy. In a 2015 trial of 60 women at high risk of OHSS, eggs matured in 95% of women, and no woman developed moderate, severe or critical OHSS. Live births were 45% per embryo transfer.
Both studies were small, run by one research group, and had no standard-care comparison arm. Kisspeptin is not FDA approved for any use. Kisspeptin-10 is a shorter form that was not tested in these IVF studies, and FDA lists it as a compounding substance that may pose immune reaction risks with limited safety data.
Terms on this page: Aromatase inhibitor (AI) · International unit (IU) · Reconstitution · Subcutaneous injection (SubQ)