How do on and off-label female infertility medications compare?

This article reviewed on and off-label drug use in female infertility treatment.

Female infertility affects millions of couples worldwide with many medications available to assist conception. 

Fertility treatments undergo assessment by the Food and Drug Administration (FDA) to gain a license for a particular use. Many of the drugs prescribed to treat female infertility are used in an off-label manner, meaning they have not undergone all of the assessments necessary for approval for a particular purpose. 

The current review examined the many on- and off-label uses 

Clomiphene citrate (CC, Clomid) is licensed for use in anovulation (failure of ovaries to release an egg). It can induce ovulation in 80% and conception in 40% of patients with polycystic ovarian syndrome (PCOS), a hormonal problem often accompanied by infertility.

It is used off-label in unexplained infertility to encourage growth of multiple follicles (eggs maturing in the ovary prior to release). One trial concluded the first line treatment in unexplained infertility should be CC combined with intrauterine insemination (IUI, the injection of sperm into the woman’s uterus). Other reviews, however, have recommended against the use of CC for unexplained infertility.

The on-label use of aromatase inhibitors (AIs) such as letrozole (Femara) are for postmenopausal women with breast cancer. They are used off-label to induce ovulation. One study of infertile women with PCOS reported a live-birth rate of 27.5% when taking letrozole, compared to 19% with CC.

Gonadotropins are FDA-approved hormones to stimulate ovulation in women undergoing assisted reproduction techniques (ART) or anovulation. Multiple birth rates tend to be high with this treatment.

Human chorionic gonadotropin (hCG) is FDA-approved for ovulation induction. It is also used to prevent ovarian hyperstimulation syndrome (painful, swollen ovaries, which can lead to a serious increase in fluid in the abdomen or chest). Gonadotropin-releasing hormone (GnRH) antagonists are also used off-label for this purpose.  

GnRH antagonists are FDA-approved to prevent premature ovulation (which can lead to fertility treatment cancellation) in women undergoing ovarian stimulation and ART.

Dexamethasone, a steroid, has been effective as an off-label add-on to CC in women with PCOS. One study showed dexamethasone combined with CC resulted in 46 (40.5%) pregnancies, compared with only 5 (4.2%) pregnancies in those taking CC alone.

Metformin is an FDA-approved treatment for type 2 diabetes. It is used in an off-label manner to improve cycle regularity in women with PCOS. It has not been shown to improve live-birth rates.

This review concluded that many drugs are used in female infertility with differing results and safety profiles. Care should be taken by physicians to prescribe the most appropriate medication. 

Many of these medications both on and off label are associated with a significant number of side effects which are important to be aware of before use.

This is a review article, which means it incorporates results of many studies, the accuracy of the individual studies cannot be determined. 

Talk to your physician if you would like to discuss infertility medications.