Ovulatory dysfunction is one of the most common causes of reproductive failure in subfertile and infertile couples. Since the first clinical trial was published in 1961, clomiphene citrate (CC) has been the front-line therapy for ovulation induction. Its use quickly expanded to other empiric indications, such as luteal phase defect and the enhancement of fecundity in unexplained infertility. Failure to respond to CC occurs in up to 20% of cases, which may then require the use of injectable gonadotropins. The drawbacks of this approach are its high cost (both for the medication and the extensive monitoring it requires), risk of the potentially life-threatening ovarian hyperstimulation syndrome (OHSS), and, perhaps most importantly, the significant risk of high-order multiple gestations. Clearly, an inexpensive yet equally efficacious oral alternative would be ideal. Recent research has focused on the successful use of aromatase inhibitors, mainly letrozole, for ovulation induction. The Rotunda medical team have begun incorporating letrozole into treatment plans for appropriately selected patients.
CC is an estrogen-receptor (ER) modulator. It binds to nuclear ER in the hypothalamus, mitigating the usual negative feedback of estrogen on GnRH during the follicular phase. This results in augmented FSH stimulation to the ovary from the pituitary as a result of changes in GnRH pulsatility and is the mechanism for ovulation induction or enhancement. Unfortunately, CC can bind nuclear ER for an extended period of time (6-8 weeks) and eventually depletes ER in other estrogen-dependent tissues, such as the endometrium and cervix. This leads to diminished endometrial development and decreased cervical mucus production. When used in the early follicular phase, letrozole inhibits estrogen synthesis, thereby causing enhanced GnRH pulsatility and consequent FSH and inhibin stimulation. This results in normal or enhanced follicular recruitment without the risk of multiple ovulation and OHSS. Letrozole has a very short half-life (~45 hours) and, therefore, is quickly cleared from the body. For this reason, it is less likely to adversely affect the endometrium and cervical mucus.
Letrozole has also been shown to improve outcome in cycles combining injectable FSH with oral ovulation induction. Recent studies report that the combination of letrozole and FSH enhances follicular recruitment while reducing the amount of FSH needed for optimal stimulation, ultimately reducing the cost of the cycle. This approach has also been useful in patients who previously responded poorly to superovulation treatment protocols.
The usual dose for letrozole ovulation induction is 2.5 mg on cycle days 3-7. Ongoing research using a single dose (10-30mg) on cycle day 3 shows similar rates of ovarian stimulation. Single doses as high as 60 mg have been administered without negative effects. Potential side effects of estrogen depletion, including hot flashes, nausea, and vomiting, have been reported in older breast cancer patients who were given the medication on a daily basis for several months. When used in a healthy population for a short time, the medication is much more tolerable. The pregnancy outcomes for letrozole ovulation induction have been very encouraging. The results of several studies show that letrozole and letrozole + FSH cycles had the highest pregnancy rates of studied regimens, and that letrozole cycles had the lowest multiple gestation rate.
Research into the role of aromatase inhibitors in fertility treatment is ongoing. As with any new course of treatment, it will be important to study long-term effects on the patient, the pregnancy and the conceived children. Due to their short half-life, it is unlikely that letrozole or other aromatase-inhibitors will be associated with any significant negative effects.
