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 medical team at Georgia Reproductive Specialists
has 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.
©Susan
Conway M.D., M.P.H., M.M.Sc.
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