The breast cancer drug letrozole takes on a different role in infertility treatment: an ovulation-inducing medicine that helps follicles grow
Lower estrogen makes the brain perceive a hormone shortage and increase FSH secretion; letrozole is recommended as first-line treatment for ovulation induction in PCOS
The same drug suppresses estrogen in cancer treatment, while infertility treatment uses the body’s response to that suppression to stimulate follicle growth
A woman who receives a prescription at a fertility clinic may get a surprise when she returns home and searches for the medicine online. The name is letrozole. Alongside the unfamiliar term “aromatase inhibitor,” the first description that appears is “breast cancer treatment.”
She went to a fertility clinic because she wanted to become pregnant, so why was she prescribed a breast cancer drug? Could the pharmacy have given her the wrong medicine? One doubt leads to another.
The answer is that this is not a prescribing mistake. Rather, infertility treatment makes clever use of the body’s opposite response to the distinctive mechanism through which this drug treats breast cancer.
Understanding how a drug that lowers estrogen can help follicles grow and induce ovulation explains why letrozole appears so often in fertility clinics.
It lowers estrogen in breast cancer treatment—and helps eggs develop in women with infertility
Letrozole was originally developed as an aromatase inhibitor.
The body contains an enzyme called aromatase, which converts androgens into the female sex hormone estrogen. Letrozole blocks this enzyme’s activity and reduces estrogen production.
Because some breast cancer cells use estrogen as a growth signal, reducing estrogen is a treatment strategy for hormone-sensitive breast cancer. Put simply, it reduces the hormonal fuel that cancer cells use.
At first glance, this seems to run in the opposite direction from infertility treatment. A woman preparing for pregnancy needs her follicles to grow and ovulation to occur, so taking a medicine that lowers estrogen may be difficult to understand.
Lowering estrogen actually prompts follicles to start growing
The explanation begins in the brain, before the ovaries.
The female reproductive hormone system works through signals exchanged between the brain and ovaries. It can be understood as a feedback system.
When estrogen is sufficient, the brain recognizes that there is enough hormone and adjusts the signals that stimulate the ovaries. When estrogen falls, the brain instead interprets this as a hormone shortage.
Taking letrozole temporarily lowers estrogen (E2), easing the “brake” that estrogen applies to the hypothalamus and pituitary gland in the brain. This, in turn, increases the secretion of follicle-stimulating hormone, or FSH.
As its name suggests, FSH stimulates follicles in the ovaries to grow. The result is a chain reaction: estrogen decreases → the brain senses a shortage → FSH increases → follicles grow → ovulation is induced.
In breast cancer treatment, lowering estrogen is the goal itself. In infertility treatment, the aim is to use the body’s response to a temporary reduction in estrogen.
“Can someone trying to become pregnant take a cancer drug?”
Even after understanding the mechanism, a woman may still be deeply concerned: “It is a cancer drug, after all. Is it really all right to take it when I am trying to become pregnant?”
Yes. The condition a medicine was originally developed to treat and whether it can be used for another condition are separate questions.
Letrozole’s ability to induce ovulation has been studied for more than 20 years. It has become an important treatment, particularly for polycystic ovary syndrome, hereafter PCOS, in which ovulatory dysfunction is common.
The 2023 International Evidence-based PCOS Guideline recommends letrozole as the first-line pharmacological treatment for ovulation induction in women with anovulatory PCOS who have no other infertility factors. It also recommends letrozole over clomiphene to improve ovulation, clinical pregnancy, and live birth outcomes.
Concerns were raised in the past that using letrozole for ovulation induction might increase the risk of fetal malformations. However, current international guidance explains that evidence has not shown a difference in fetal abnormality rates between ovulation induction with letrozole, ovulation induction with clomiphene, and natural conception.
There is, however, an important rule. Letrozole is used for a defined period early in the menstrual cycle, starting on menstrual day 2–3, to induce ovulation. It must not be administered to a woman who may already be pregnant.
Why does the medicine’s description still say “breast cancer treatment”?
This brings us to the concept of “off-label” use. It means using a medicine for a purpose other than its originally approved indication. It does not mean using an unproven medicine arbitrarily.
There are many instances in which an existing medicine enters clinical use for another condition as medical evidence of its effectiveness accumulates.
The international PCOS guideline also explains that using letrozole to induce ovulation, rather than for its originally approved breast cancer indication, remains off-label in many countries. That is why an online search may first describe it as a breast cancer drug rather than an ovulation-inducing medicine, even when a fertility clinic has prescribed it for ovulation induction.
In fact, letrozole did not suddenly enter infertility treatment one day simply because someone decided to borrow a breast cancer drug.
Research into its ovulation-inducing effects began in earnest in the early 2000s. Its use subsequently broadened as randomized clinical trials and systematic reviews accumulated. Today it is used or being studied not only for ovulation induction in women with PCOS but also in some intrauterine insemination (IUI) cycles and in vitro fertilization procedures.
An even more interesting application: egg freezing for patients with breast cancer
The two roles of letrozole intersect most strikingly when a young patient with breast cancer freezes her eggs before chemotherapy.
Because chemotherapy can affect ovarian function, eggs or embryos may be frozen before treatment to preserve the possibility of a future pregnancy. Retrieving multiple eggs, however, requires ovarian stimulation, which can cause estrogen levels to rise substantially.
This is a concern for patients with estrogen-sensitive breast cancer.
In this situation, letrozole may be used alongside ovarian stimulation to suppress the rise in estrogen while eggs are retrieved. Thus, the very medicine used to lower estrogen because of breast cancer also appears in the egg-retrieval process intended to preserve that patient’s future chance of pregnancy.
From cancer treatment to a medicine that awakens follicles
Letrozole has not suddenly “transformed” from a breast cancer drug into an ovulation-inducing medicine. Medicine has simply put the same action of the same drug to use in two different directions.
Fertility specialists explain: “In one setting, it reduces the hormone used by cancer cells. In the other, it uses the signal that the hormone has fallen to stimulate follicle growth. The prescription says ‘letrozole’ in both cases, but in a breast cancer clinic it interrupts the growth signal to cancer cells, while in a fertility clinic it becomes the start button that awakens resting follicles.”
※ This article is based on the International PCOS Network’s “Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome,” published online in Fertility and Sterility in August 2023. DOI: 10.1016/j.fertnstert.2023.07.025. PMID: 37589624.
※ This article does not replace diagnosis or treatment for any individual. Whether to use letrozole, the dose, and the timing of administration may vary with the cause of infertility, ovulatory status, and other factors. Always follow the evaluation and prescription of your treating medical team.
※ The image used in this article was created with generative artificial intelligence (ChatGPT, OpenAI) and depicts fictional people, not real individuals.
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