LETROZOLE

Letrozole is an aromatase inhibitor that is widely used in assisted reproduction. It induces ovulation by reducing estrogen feedback at the pituitary, resulting in increased production of follicle stimulating hormone (FSH). In contrast to clomiphene citrate (another common medication for ovulation induction) it is free from antiestrogenic effects on cervical mucus production and the endometrial lining. In contrast to exogenous gonadotropins, the FSH response is limited, which is a protective factor for multiple ovulation and ovarian hyperstimulation syndrome (OHSS). A single dominant follicle and mono-ovulation should occur in most cases. The half-life of letrozole is short (about 46 hours) and its administration during the early follicular phase allows for it to clear the body prior to fertilization and implantation.

Indications:

Although its use in reproductive medicine is off-label (not FDA approved), Letrozole is routinely utilized in both intrauterine insemination (IUI) and in-vitro fertilization (IVF) treatment protocols, and it is a the first-line medical therapy for anovulatory PCOS. Letrozole is also administered for breast cancer, endometriosis, and other estrogen-modulated conditions.

Letrozole is often prescribed for ovulatory patients undergoing therapeutic donor insemination (TDI) in attempts to limit monetary, emotional, and time-related costs. However, pregnancy rates are not significantly higher in stimulated TDI cycles (up to 3-6 cycles), while multiple pregnancy rates are 4 times higher. Indications for ovulation induction in TDI include:

• AMH < 2
• After 6 unsuccessful IUI cycle attempts
• After 3 unsuccessful IUI cycle attempts at age 40+

Dosage:

• to 0 mg for 5 days, starting on cycle day 3-5.

Clinical parameters:

• Negative pregnancy test prior to administration
• While not required, some patients may opt for mid cycle ultrasound to assess effectiveness and/or withhold insemination if more than two dominant follicles are present at the time of LH surge

Risks:

The primary risk is multiple gestation; however high order multiples are not seen in letrozole cycles. In one large study of ovarian stimulation in cycles of TDI (n=6192), the rate of multiple pregnancy increased from 2.4% in unmedicated cycles to 10.8% in stimulated cycles (however 91.9% of subjects received clomiphene citrate rather than letrozole). In unexplained infertility, a multi-center randomized trial (n=900) showed a multiple gestation rate of 13% with letrozole vs. 9% with clomiphene. In general, both medications typically show a multiple gestation rate of about 10%.

While mild OHSS can occur, moderate or severe OHSS is rare with letrozole. Mild OHSS consists of abdominal bloating and cramping, mild nausea or vomiting, diarrhea, and temporary enlargement of the ovaries. If these symptoms occur, the medication can be discontinued.