Letrozole Shows Promise for Treating Infertility in Obese Men

Fertility Drugs Not Linked to Increased Cancer Risk in Women
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Low-dose letrozole may help treat infertility in men with obesity-related hypogonadotropic hypogonadism.

SAN DIEGO — Low-dose letrozole may be an effective treatment for restoring fertility in men with obesity-related hypogonadotropic hypogonadism. The drug also had an interesting safety profile and significant advantages in terms of route of administration, according to a new Canadian study presented at ENDO 2015.

Moreover, low-dose letrozole may also be much more cost-effective than gonadotropin injections for spermatogenesis induction, one study researcher noted.

The findings from this study are the first to report successful pregnancies with letrozole at a low dose of one tablet of 2.5 mg weekly. 

For the study, Lena Salgado, MD, who is an endocrinology fellow at the Centre Hospitalier de l’Université de Montréal (CHUM) in Canada, and her colleagues studied the medical records of 12 obese men (mean age, 35.3 years; mean BMI, 43) who sought treatment for infertility and received a diagnosis of obesity-related hypogonadotropic hypogonadism (OrHH).

In this retrospective analysis, all the men had total testosterone levels below the lower limit of normal with normal-to-low follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and/or decreased sperm count as defined by the World Health Organization.

On average, the men had been infertile for nearly 3 years. Eight had primary infertility, and four had secondary infertility.

The men received a letrozole 2.5-mg pill every week. Their follow-up ranged from 2 to 21 months. One man did not tolerate the treatment because of headaches and switched treatment to another aromatase inhibitor drug (anastrozole) and was ultimately excluded from the final analysis.

After initiating low-dose letrozole, estradiol decreased from 119.5 nmol/L to 72.2 nmol/L; mean FSH increased from 4.4 IU/L to 8.0 IU/L; mean LH increased from 4.4 IU/L to 6.6 IU/L; and mean total testosterone increased from 7.4 nmol/L to 21.1 nmol/L. Additionally, mean sperm count increased from 14.8 x 109/L to 64.5 x 109/L.

Three couples conceived, one of whom used in vitro fertilization (IVF), and four pregnancies ensued. Two pregnancies resulted in live births, while one ended due to ectopic pregnancy and another ended due to miscarriage, according to study results.

“We did this study for many reasons. The first one is the cost of the standard-of-care treatment, which is human chorionic gonadotropin (hCG) used to help restore fertility. It is administered by injections, which men usually do not like, and they are quite expensive,” said Dr. Salgado.

“The dose is also proportional to the weight of the patient, so this treatment costs more for obese patients. The other options are IVF and ICSI (intra-cytoplasmic sperm injection), which is also very expensive,” Dr. Salgado added.

Recently published studies have suggested low-dose letrozole may normalize testosterone levels in men with obesity-related low testosterone. It is theorized that obesity causes infertility in men because excess fat results in too much estrogen. The body’s aromatase enzyme, which is more prevalent in fat, converts androgens into estrogen. Letrozole inhibits this action of aromatase. 

“Letrozole was very well tolerated. Two patients experienced headaches. One stopped the treatment because of them. The other had a spontaneous remission within a few days. Two patients experienced decreased libido, which is common when estradiol is completely suppressed by the treatment. In those patients, half a tablet per week might suffice,” Dr. Salgado told Endocrinology Advisor.

She said the most effective way to cure obesity-related hypogonadism and associated infertility is weight loss. However, as all endocrinologists know, it is a long and difficult task.

“Letrozole can help restore fertility in those who do not manage to lose weight, at a much lower cost than other fertility treatments. We must bear in mind, however, that long-term effects of estrogen suppression have not been studied. We would advise using letrozole only to restore fertility, not as a long-term treatment for hypogonadism,” Dr. Salgado said.

She also noted more studies are warranted to determine which patients might benefit most from this treatment. Studies should also be conducted to compare it with other treatments such as gonadotropins and clomiphene citrate.  

If validated, letrozole may prove to be a more cost-effective and user-friendly way to help men with obesity-related hypogonadism in conceiving, according to Dr. Salgado.

Letrozole is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of estrogen receptor (ER)-positive breast cancer in postmenopausal women and is used off-label in infertile women to induce ovulation.  


  1. Lavoie H et al. Abstract THR-132. Presented at: The Endocrine Society’s 97th Annual Meeting & Expo (ENDO 2015); March 5-8, 2015; San Diego.