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Susan
C. Conway, MD, MPH, MSc
Georgia Reproductive Specialists
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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.
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