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Femara (Letrozole) as a Fertility Treatment:
Potential Risks

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 studies.

Table 1. Research reports utilizing Letrozole as a fertility treatment.

Reference No. Letrozole/
Letrozole/FSH
# Pt # Cycles #Preg/Cycle(%) Delivery Data
3. L (PCOS)
L (ovulatory)
12
10
12
10
3/12 (75%)
1/10 (10%)
1 delivered
4. L/FSH 12 14 3/14 (21%) NA
5. L/FSH 36 36 8/36 (21%) NA
6. L/FSH 60 60 13/60 (21%) NA
7. L 7 7 2/7 (28%) NA
8. L 74 115 13/115 (11.5%) NA
9. L/FSH 13 13 3/13 (23%) NA
10. L/FSH(PCOS)
L/FSH (ovulatory)
26
63
49
75
16/49 (34%)
10/75 (12%)
NA
NA
11. L/HMG 71 71 29/71 (41%) NA
12. L(2.5 mg)
L(5.0 mg)
L(HMG)
33
70
30
167
432
153
33/167 (19%)
70/432 (16%)
38/153 (9%)
NA
NA
NA
Totals   517 1214 248/1214 (20%) 1

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.

References:

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 Sterility. 77(4):776-780.

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. Gynecol. 192(2):381-386.
 

 

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