Femara (Letrozole) as a Fertility Treatment:
Letrozole is an aromatase inhibitor that is FDA approved for the
treatment of breast cancer. It is not approved as a fertility treatment.
Notwithstanding, many drugs are used quite successfully for treatments
they were not originally approved for. On November 24, 2005 the
Canadian Health Service, search ‘Femara’)
and the drug manufacturer Novartis, Inc., issued a statement reminding
physicians that the medication should not be used in patients attempting
to conceive. At present, the FDA has not made such an announcement. This
announcement was in response to a Canadian study showing increased birth
defects with Letrozole presented in October 2005 at the annual meeting of
the American Society of Reproductive Medicine in Montreal. In the
statement, Canadian researchers found nearly a 3-fold increased risk of
fetal malformations in 150 babies born after Letrozole therapy. There were
7 serious malformations in the group of 150 babies (4.7%), much higher
than expected when compared to a large population of babies born at a
local hospital. Of note, not all researchers are in agreement with these
findings. The data was retrospective. Some question its validity.
Regardless, this is potentially very important and has increased debate
concerning this drug as an infertility treatment. In light of this, the
following discussion will review the drug information presented in the
Physician’s Desk Reference (PDR, ref. 1). We will review the pharmacology
of Letrozole and the studies that have suggested that it may have some
benefit as a fertility treatment. Most studies reported clinical pregnancy
rates (i.e. presence of a fetal heart beat at 6-8 weeks) and not outcome
data on the babies delivered. It should also be noted that all of the
studies were done under Institutional Review Board review at their
respective Universities. This means that they were preliminary and
investigative in nature.
Letrozole is an inhibitor of the enzyme aromatase. Aromatase converts
androgens to estrogen. Estrogen may stimulate breast cancer cells, so it
is obvious for the rationale using it in these patients. Some infertile
patients, like those with PCOS, may have excessive estrogen production and
so it is reasonable to see its potential use as a fertility treatment.
Additionally, in patients that are poor responders to gonadotropin therapy
the addition of an aromatase inhibitor may enhance endogenous FSH
secretion and improve ovarian stimulation. It may be more favorable to the
uterine lining. The PDR (1) gives physicians detailed prescribing and
pharmacologic information, provided by the pharmaceutical industry. The
half-life of Letrozole is about 2 days. This means that it takes about 2
days for the concentration of the drug to drop in one-half in the serum.
In general, a drug will be completely eliminated in 5 half-lives. In the
case of Letrozole, this is about 10 days. The pharmacokinetic studies
which determined the half-life of the drug may not have been done in women
of reproductive age as the drug was to be used in post-menopausal women.
Thus it may be metabolized differently in younger women. In fact, two
unknown metabolites are mentioned in the PDR which may have untoward
biological activity. Most studies used Letrozole until about day 7 of the
cycle. Thus, it is possible that the drug could still be in the system at
the time of conception around day 14 or so if we assume it takes 5
half-lives to be completely excreted and potential metabolites exist that
could have biological activity. Also, the half-life of a drug may be
increased by increasing the dose of the drug. Some use Letrozole at 5.0 mg
or 7.5 mg doses, potentially increasing the half-life of the drug. The
dose in breast cancer patients is 2.5 mg per day. There is more to drug
disposition than simply the half-life. The clearance of the drug is slow
and the volume of distribution is approximately 2 L/kg, indicating that it
is widely distributed in the body (2). This raises the possibility that
the drug or its metabolites could be distributed to the ovary or uterus,
organs vital for reproduction. Letrozole is mainly bound to albumin as a
carrier protein in the blood. The PDR warns of fetal toxicity in rodent
studies at doses of 0.003 mg/kg (about 1/100th the human dose) where
increased intrauterine mortality, increased fetal resorption, increased
post-implantation loss, decreased numbers of live fetuses, fetal anomalies
fetal anomalies including shortening of the renal papilla and ureter
dilation and incomplete ossification of the frontal skull and metatarsal.
In rabbits, Letrozole was embryotoxic at doses of 1/100,000th and
fetotoxic at doses 1/10,000th of the maximal recommended human dose. Thus,
standard experimental models showed that Letrozole is toxic to the fetus.
The PDR considers Letrozole to be a Category D drug in pregnancy (Positive
evidence of fetal risk). Anytime a drug is Category D, the benefits must
clearly outweigh the risks. Data on the health on the babies would
certainly help to determine this. While the patients are not technically
pregnant at the time they are taking the drug, can we be absolutely
certain that it or one of its metabolites is no longer in the body
especially given the low doses that are toxic in experimental animals?
In order to evaluate published research studies on Letrozole, articles
were obtained from a Medline search with keywords ‘Letrozole and
infertility, Letrozole and ovulation induction”. Several studies were
published over the past few years indicating that Letrozole may be useful
as a fertility treatment. It should be noted that the endpoint was
generally clinical pregnancy rates. Clinical pregnancies are the presence
of fetal cardiac activity via ultrasound exam at about 6 weeks of
pregnancy. It is not delivery of a healthy baby. Most miscarriages occur
between week 6 and week 12 of pregnancy. The Table below summarizes the
Table 1. Research reports utilizing Letrozole as a fertility treatment.
One of the major weaknesses of studies on Letrozole is the lack of
information published in peer-reviewed journals on the health of the
children conceived. Over 1200 cycles were reported from over 500 patients.
From the summary of the published data, we were only able to see
documentation of single baby. Before Letrozole is considered a standard
therapy, studies should document healthy children as the appropriate
end-point. The recent Canadian announcement underscores the caution with
which we should approach this potential new treatment.
1. Femara. Physicians Desk Reference, 2006. Thomson-PDR. Montvale, New
Jersey, pp. 2210-2214.
2. Sioufi A, Gauducheau N, Pineau V, Marfil F, Jaouen A, Cardot JM,
Godbillon J, Czendlik C, Howard H, Pfister C, Vreeland F. 1997. Absolute
bioavailability of Letrozole in healthy postmenopausal women. Biopharm.
Drug Dispos. 18(9):779-89.
3. Mitwally MFM, Casper RF. 2001. Use of an aromatase inhibitor for
induction of ovulation in patients with an inadequate response to
clomiphene citrate. Fertility and Sterility 75(2):305-309.
4. Mitwally MFM, Casper RF. 2002. Aromatase inhibition improves ovarian
response to follicle-stimulating hormone in poor responders. Fertility and
5. Mitwally MFM, Casper RF. 2003. Aromatase inhibition reduces
gonadotropin dose required for controlled ovarian hyperstimulation in
unexplained infertility. Human Reproduction 18(8):1588-1597.
6. Healey S, Tan SL, Tulandi T, Biljan MM. 2003. Effects of Letrozole
on superovulation with gonadotropins in women undergoing intrauterine
insemination. Fertility and Sterility 80(6):1325-1329.
7. Fatemi HM, Kolibianakis E, Tournaye H Camus M, Van Steirteghem,
Devroney P. 2003. Clomiphene citrate versus Letrozole for ovarian
stimulation: a pilot study. RBM Online 7(5):543-546.
8. Al-Fozan H, Al-Khasouri M, Tan SL, Tulandi T. 2004. A randomized
trial of Letrozole versus clomiphene citrate in women undergoing
superovulation. Fertility and Sterility. 82(6):1561-63.
9. Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K,
BN Chakravarty, and Kabir SN. 2004. A randomized single-blind controlled
trial of Letrozole as a low-cost protocol in women with poor ovarian
response: a preliminary report. Hum. Repro. 19(9):2031-35.
10. Mitwally MFM, Casper RF. 2004. Aromatase inhibition reduces the
need for gonadotropins in controlled ovarian hyperstimulation. J. Soc.
Gynecol. Invest. 11:406-415.
11. Garcia-Velasco JA, Moreno L, Pacheco A, Guillen A, Duque L, Requena
A, Pellicer A. 2005. The aromatase inhibitor Letrozole increases the
concentration of intraovarian androgens and improves in vitro
fertilization outcome in low responder patients: a pilot study. Fertility
and Sterility. 84:82-87.
12. Mitwally MF, Bilan MM, Casper RE. 2005. Pregnancy outcome after the
use of an aromatase inhibitor for ovarian stimulation. Am. J. Obstet.