Everything you need to know about the fertility drug letrozole

Trying to get pregnant? If you’re having trouble, your doctor may prescribe a drug called letrozole. Sold under the brand name Femara, letrozole was originally created to treat breast cancer. However, doctors found that it also induces ovulation, so, since 2000, it has been used off-label to help women with fertility issues.

The drug is used as a first-line treatment for women with polycystic ovary syndrome (PCOS), a condition where they ovulate irregularly or don’t ovulate at all, and most other ovulatory disorders, says Clifford Librach, director of the Create Fertility Centre in Toronto and president-elect of the Canadian Fertility and Andrology Society. It can also be used to treat unexplained infertility.

How does letrozole work?

Letrozole is typically taken once a day for five days. When you take the drug, it stops androgens in your body from converting into estrogen. When estrogen is blocked, the pituitary gland gets a message that it needs to produce follicle-stimulating hormone (FSH), which stimulates the ovary to produce an egg. Some women on letrozole actually release more than one egg because they produce more FSH while on letrozole than a woman produces when ovulating naturally. 

Typically, Librach says patients who ovulate begin a course of letrozole on day three or four of their cycles and then ovulate about four to seven days after taking the last of five pills. Librach advises patients to have sex about one to three days before they ovulate.  

For decades, clomiphene citrate (commonly known as Clomid or Serophene) was the drug that doctors prescribed to patients who had PCOS or unexplained fertility. But manufacturers stopped producing clomiphene citrate last year (though compounding pharmacists can still make it and your doctor may prescribe it). According to a statement released by the Canadian Fertility and Andrology Society, letrozole is more effective in achieving live births in patients with ovulatory disorders than clomiphene citrate and is equally effective at resulting in births in patients with unexplained fertility.

Who should try letrozole?

Before prescribing letrozole, your doctor should do a consultation and testing, explains Librach. The specific tests vary from case to case, but they can include sperm testing, blood hormone level testing and checking for blockages in your fallopian tubes.

If you’re diagnosed with an ovulatory disorder like PCOS and your doctor decides that letrozole is a good fit for you, they will likely have you try it for up to six months, says Bob Casper, a reproductive endocrinologist and senior scientist at the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital who led the team that worked out the drug’s use for ovulatory disorders.

Even if you haven’t been diagnosed with an ovulatory disorder but are experiencing unexplained infertility, your doctor may try letrozole because it increases your chances of releasing more than one egg, which, in turn, improves your odds of getting pregnant. Librach says that letrozole can regulate and shorten long cycles, which can help boost your chances of conceiving. “If your cycles are once every three or four months, it will be very difficult to pinpoint when you are ovulating and this will reduce your chances of timing things correctly,” he explains.

“Generally speaking, we would try letrozole with timed intercourse or intrauterine insemination [where] for a few months,” says Casper. “If the woman doesn't get pregnant, the next step is to go to in vitro fertilization.”

Trying letrozole before other fertility treatments makes sense for a few reasons. “It’s cheaper, and there’s less risk of multiple pregnancies,” explains Librach. That’s because other options would typically involve an injection of FSH, which is more likely to cause the release of multiple eggs (though there is still an increased chance of multiples with letrozole). A 2014 study published in the New England Journal of Medicine that tracked women with PCOS found that the twin rate for those in the study who took letrozole was 3.4 percent (Librach says the twin rate is about one percent in the general population). There’s also less time-consuming monitoring involved with taking these pills than with injections.

But there are certain circumstances where letrozole isn’t the right fertility choice, notes Librach. “If your husband has a really low sperm count, it wouldn’t make sense to take letrozole,” he says. “Or, if your tubes are blocked, it’s not going to work.” In both cases, you’d want to start with in vitro fertilization (IVF). He also says it may not be a good fit for people with severe endometriosis or those who are not ovulating because they are underweight. He says there are other drugs that are a better choice for the latter situation.

How effective is letrozole?

Togas Tulandi, a reproductive endocrinology and infertility specialist and chief of the obstetrics and gynaecology department at the McGill University Health Centre in Montreal, says that letrozole has a decent rate of inducing ovulation. The same 2014 study from the New England Journal of Medicine showed that, among participants with PCOS who used letrozole, 27.5 percent got pregnant within five cycles and went on to have live births. The study also found that the drug induced ovulation in 61.7 percent of women with PCOS.

What are the side effects of letrozole?

Letrozole has a few side effects, including headaches, fatigue and dizziness. “Anything will have side effects, but the number of patients with complaints is very low,” says Tulandi.

Casper says that about 1 percent of people who take letrozole get leg cramps and headaches, but the good news is that these symptoms go away once you stop taking the pills. Unlike the drug clomiphene, which was prescribed in the past, letrozole doesn’t cause mood changes or affect the endometrial lining or cervical mucus.

Letrozole will interact with other hormone drugs, like birth control pills, but you’re unlikely to be taking those at the same time. Librach also mentions that women who are breastfeeding shouldn’t take letrozole because it will affect the baby’s hormones.

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