Posted by: birdsandsquirrels | August 19, 2009

femara links

I am a big fan of Femara (letrozole). It worked for me after 7 cycles of clomid and 3 cycles of injectables did not. I am so glad that I pushed my RE to let me try it first when he was suggesting IVF with ICSI for the low morphology. I wish I had pushed my OB to let me try it a year ago. Both doctors kind of pooh-poohed it. The RE had said it is “weaker than clomid”. My old OB had said that he sometimes would prescribe it when all else failed. I wonder why the negativity. Neither one refused to prescribe it for “safety” reasons, or at least they didn’t tell me that. Who knows, maybe the only reason it worked for me was because the 3 cycles of injectables did something to my ovaries to whip them into shape. Maybe the doctors are afraid of change. Maybe they wanted to keep me coming back and paying for cycles and getting nowhere. Now I’m just being paranoid. All I really know is that I am nearly 22 weeks pregnant because of it.

Here are the basics about Femara. It works similarly, but slightly differently than clomid. Clomid blocks estradiol receptors, whereas Femara is an aromatase inhibitor and blocks the production of estradiol. A great explanation (and diagram) of this process can be found here. Clomid tends to cause negative effects on the endometrium and cervical mucus. Clomid stays in the body for a long time and builds up the more you take it. It stays in your body for around 45 days, whereas Femara has a half life of 45 hours and is cleared from the body in days. Femara had far fewer side effects than Clomid. Clomid gave me wicked headaches, mood swings from hell, dizziness, and those bizarre tracing lights that you read about on the pharmacy sheet but never imagine you’ll get. I may have had a headache or two while taking Femara, but it was nothing compared to the crappy Clomid side effects.

By my 4th cycle of Clomid, my lining was shit. I was lucky to get 4 to 5mm at mid cycle, when they want to see at least 8mm. Clomid totally dried up any cervical mucus I had. I stopped ovulating on clomid by the 5th cycle. Still my OB and RE had us try two more cycles. What a waste of time, energy, and money. I only did one cycle of Femara, but my lining was beautiful that month.

So why doesn’t everyone use Femara instead of Clomid?

Femara is fairly new. It’s not approved for use in fertility treatments, so it is used off label. So are many other medications, so that is not unusual. Some doctors are just not aware of its existence. Clomid has been used since the 1960’s, so doctors feel safe prescribing it. In 2005, a very flawed study came out linking the use of Femara during pregnancy to low birth weight and birth defects. Certainly that freaked a lot of people out. However, that study was small, not replicated, and terribly flawed. I won’t tear it apart here, because here are several great resources explaining the flaws of that study.

This is a 15 page document about Femara from http://www.soft-infertility.com, a Canadian infertility clinic.  It is very thorough in explaining how Femara works and discusses in detail the safety issue. They even published the following study concluding that Femara has a lower incidence of birth defects than Clomid:

Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate.Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, Librach C, Greenblatt E, Casper RF.Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada.

OBJECTIVE: To evaluate the incidence of congenital malformations among offspring of mothers who conceived with clomiphene citrate (CC) or with letrozole treatment for infertility. DESIGN: Retrospective study. SETTING: 5 fertility centers in Canada. PATIENTS: 911 newborns from women who conceived following CC or letrozole treatment. INTERVENTIONS: Examination of medical files of both mother and newborn, and cross-checked with the parents by telephone calls. MAIN OUTCOME MEASURES: Identified major and minor congenital malformations, birth weight, age of the mother, and type of treatment that led to the conception. RESULTS: Overall, congenital malformations and chromosomal abnormalities were found in 14 of 514 newborns in the letrozole group (2.4%) and in 19 of 397 newborns in the CC group (4.8%). The major malformation rate in the letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397). One newborn in the letrozole group was found to have a ventricular septal defect (0.2%) compared to 4 newborns in the CC group (1.0%). In addition, the rate of all congenital cardiac anomalies was significantly higher (P: 0.02) in the CC group (1.8%) compared to the letrozole group (0.2%). CONCLUSION: There was no difference in the overall rates of major and minor congenital malformations among newborns from mothers who conceived after letrozole or CC treatments. However, it appears that congenital cardiac anomaly is less frequent in the letrozole group. The concern that letrozole use for ovulation induction could be teratogenic is unfounded based on our data.

Here is another IVF clinic with an information page on the use and safety of Femara.

And yet another one: Advanced Fertility Center of Chicago also has a helpful page about the safety of Femara.

I told Another Dreamer that I would put together some links to research about Femara for her. Below are some of the journal articles I found on PubMed.gov. If you don’t already know about PubMed, it is a service of the National Institutes of Health and is a free and easy way to access abstracts of journal articles. I encourage everyone going through fertility treatments to do plenty of research themselves and to ask their RE’s lots of questions.  I’m sorry for the odd formatting. WordPress is not easy to work with when copying and pasting and linking a lot of text.

Ann Pharmacother. 2009 Jul;43(7):1338-46. Epub 2009 Jul 7. Aromatase inhibitors for ovulation and pregnancy in polycystic ovary syndrome.

Eckmann KR, Kockler DR. Virginia Commonwealth University Health System/Medical College of Virginia Hospitals, Richmond, VA, USA.

OBJECTIVE: To evaluate evidence for use of aromatase inhibitors for ovulation induction and pregnancy in patients with polycystic ovary syndrome (PCOS). DATA SOURCES: A MEDLINE search (1966-May 2009) was conducted using the search terms anastrozole, aromatase inhibitors, exemestane, letrozole, ovulation, and polycystic ovary syndrome to identify relevant studies. STUDY SELECTION AND DATA EXTRACTION: Prospective clinical trials published in English and conducted in humans were identified. Trials using intrauterine insemination methods for pregnancy were excluded. The resulting articles were separated into 2 groups: aromatase inhibitor use in clomiphene-resistant patients and use in treatment-naïve patients. Eleven trials were reviewed. DATA SYNTHESIS: Accepted pharmacologic treatments for women with PCOS and infertility include clomiphene citrate, gonadotropins, and gonadotropin-releasing hormone (GnRH) analogs. Each medication has variable efficacy rates and adverse effects. Therefore, other treatments are needed for a subset of women with PCOS and infertility. Evidence suggests that nonsteroidal aromatase inhibitors, specifically letrozole and anastrozole, may have ovulation-inducing effects by inhibiting androgen-to-estrogen conversion. Select trials with aromatase inhibitors have demonstrated efficacy for increased endometrium thickness, ovulation rates, and pregnancy rates when used in clomiphene citrate-resistant or treatment-naïve patients. CONCLUSIONS: Further trials comparing aromatase inhibitors with clomiphene citrate are necessary before aromatase inhibitors can be recommended routinely for ovulation induction in women with PCOS and infertility. However, aromatase inhibitors may be considered in a subset of this population, specifically women who are clomiphene citrate resistant or those who, after discussion of risks and benefits, are not candidates for clomiphene citrate, gonadotropins, or GnRH analogs.

Fertil Steril. 2006 Nov;86(5):1428-31. Epub 2006 Sep 14.

Comparison of the efficacy of the aromatase inhibitor letrozole and clomiphene citrate as adjuvants to recombinant follicle-stimulating hormone in controlled ovarian hyperstimulation: a prospective, randomized, blinded clinical trial.

Barroso G, Menocal G, Felix H, Rojas-Ruiz JC, Arslan M, Oehninger S.

Assisted Reproductive Division, Instituto Nacional de Perinatología, Mexico City, Mexico. asistida@servidor.inper.edu.mx

OBJECTIVE: To study the efficacy of the aromatase inhibitor letrozole as adjuvant to recombinant FSH (rFSH) in controlled ovarian hyperstimulation (COH). DESIGN: Prospective, randomized, and blinded clinical study. SETTING: Academic tertiary institute. PATIENT(S): Forty-one patients with unexplained infertility undergoing intrauterine insemination (IUI) therapy were randomized to receive either letrozole or clomiphene citrate (CC) as adjuvants to rFSH. INTERVENTION(S): From day 3 to 7 of the cycle 2.5 mg/d letrozole or 100 mg/d CC were administrated. All patients received 75 IU rFSH starting on day 7 of stimulation until the day of hCG administration. Ovulation was triggered with recombinant hCG (250 microg) when the leading follicle(s) reached 18 mm in diameter. A single IUI was performed 36 hours later. The luteal phase was supplemented with micronized progesterone vaginally. MAIN OUTCOME MEASURE(S): Ovarian stimulation response (E(2) levels and number of follicles) was our primary outcome. RESULT(S): There were no differences in demographic characteristics between groups. Although there was a significantly lower peak serum E(2) level in the group receiving letrozole + rFSH compared with CC + rFSH (914 +/- 187 vs. 1,207 +/- 309 pg/mL, respectively; P<.007), there were no differences in the number of mature (>16 mm) preovulatory follicles. A significantly higher endometrial thickness was observed at the time of hCG administration in patients that received letrozole (9.5 +/- 1.5 mm vs. 7.3 +/- 1.1 mm; P=.0001). The clinical pregnancy rate was similar between groups (23.8% vs. 20%, respectively). CONCLUSION(S): The aromatase inhibitor letrozole appears to constitute a good alternative to CC in patients with unexplained infertility undergoing gonadotropin-stimulated COH cycles combined with IUI therapy.

Comparison of letrozole with continuous gonadotropins and clomiphene-gonadotropin combination for ovulation induction in 1387 PCOS women after clomiphene citrate failure: a randomized prospective clinical trial.

Ganesh A, Goswami SK, Chattopadhyay R, Chaudhury K, Chakravarty B.

School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, India.

PURPOSE: Letrozole, though reported to be an effective ovulation inducing agent, warrants larger randomized trials. The purpose of this study is to compare the efficacy of letrozole with that of rFSH and clomiphene citrate(CC)/rFSH for ovarian stimulation in IUI cycles. METHODS: Randomized, prospective, single-blinded clinical trial. 1387 PCOS women after CC failure were randomized into three groups: Group A received letrozole, Group B received CC with two doses rFSH and Group C received continuous rFSH day 2 onwards until hCG injection. RESULTS: Group A, B and C had an ovulation rate of 79.30%, 56.95% and 89.89% and cycle cancellation rate of 20.70%, 43.05% and 10.11%, respectively. Pregnancy rates in Group A, B and C were 23.39%, 14.35% and 17.92%, while the miscarriage rates were 13.80%, 16.67% and 14.52%, respectively. CONCLUSION: Letrozole appears to be a suitable ovulation inducing agent in PCOS women with CC failure and is found to be most effective when baseline estradiol level >60 pg/ml.

Pregnancy outcome after ovulation induction with aromatase inhibitors or clomiphene citrate in unexplained infertility.

Badawy A, Shokeir T, Allam AF, Abdelhady H.

Department of Obstetrics and Gynecology, Mansoura University, Egypt. ambadawy@yahoo.com

OBJECTIVE: To evaluate the pregnancy outcome after ovulation induction with aromatase inhibitors or clomiphene citrate (CC). DESIGN: A prospective, randomized, controlled trial. SETTING: A university hospital center and a private practice setting. POPULATION: The study comprised a total of 796 infertile women (1,100 cycles) and 200 spontaneously pregnant women (298 cycles) as a control group. METHODS: Patients were allocated treatment either with 100 mg of CC daily (420 patients, 634 cycles), 5 mg of letrozole daily (269 patients, 323 cycles) or 1 mg of anastrozole daily (107 patients, 143 cycles) for 5 days starting on day 3 of menses. MAIN OUTCOME MEASURES: The occurrence of pregnancy, miscarriage and neonatal condition. RESULTS: Pregnancy occurred in 167/1,398 cycles (11.9%) in total without significant differences between groups. The total miscarriage rate was 16.1% (varied between 14.2% in CC group and 19.9% in anastrozole group) without difference between spontaneous and stimulated pregnancies. There were 129 deliveries in all groups. There were no significant differences between the stimulated and spontaneous pregnancies as regards mean gestational age, premature deliveries, birth weight, SGA<10th percentile or five minutes Apgar score. There was one case of complete cleft palate and one case of major congenital heart problem in the letrozole group. There were two cases of talipus equinovarus in the CC and spontaneous pregnancy group. CONCLUSION: Aromatase inhibitors and CC resulted in favorable pregnancy outcomes and average miscarriage rates. Safety of the drugs for both the mother and fetuses was documented.

Use of letrozole in assisted reproduction: a systematic review and meta-analysis.

Requena A, Herrero J, Landeras J, Navarro E, Neyro JL, Salvador C, Tur R, Callejo J, Checa MA, Farré M, Espinós JJ, Fábregues F, Graña-Barcia M; Reproductive Endocrinology Interest Group of Spanish Society of Fertility.

IVI-Madrid, Santiago de Compostela 88, E-28035 Madrid, Spain. arequena@ivi.es

BACKGROUND: Letrozole is the third-generation aromatase inhibitor (AI) most widely used in assisted reproduction. AIs induce ovulation by inhibiting estrogen production; the consequent hypoestrogenic state increases GnRH release and pituitary follicle-stimulating hormone (FSH) synthesis. METHODS: A systematic search of the literature was performed for both prospective and retrospective studies. Meta-analyses of randomized clinical trials (RCTs) were performed for three comparisons: letrozole versus clomiphene citrate (CC), letrozole + FSH versus FSH in intrauterine insemination (IUI) and letrozole + FSH versus FSH in IVF. In the absence of RCTs, non-randomized studies were pooled. RESULTS: Nine studies were included in the meta-analysis. Four RCTs compared the overall effect of letrozole with CC in patients with polycystic ovary syndrome. The pooled result was not significant for ovulatory cycles (OR = 1.17; 95% CI 0.66-2.09), or for pregnancy rate per cycle (OR = 1.47; 95% CI 0.73-2.96) or for pregnancy rate per patient (OR = 1.37; 95% CI 0.70-2.71). In three retrospective studies which compared L + FSH with FSH in ovarian stimulation for IUI, the pooled OR was 1.15 (95% CI 0.78-1.71). A final meta-analysis included one RCT and one cohort study that compared letrozole + gonadotrophin versus gonadotrophin alone: the pooled pregnancy rate per patient was not significantly different (OR = 1.40; 95% CI 0.67-2.91). CONCLUSIONS: Letrozole is as effective as other methods of ovulation induction. Further randomized-controlled studies are warranted to define more clearly the efficacy and safety of letrozole in human reproduction.

[Ovulation induction by means of letrozole]

[Article in Norwegian]
Ekerhovd E.

Kvinneklinikken Førde sentralsjukehus 6807 Førde og London Fertility Centre 112A Harley Street London W1G 7JH. erling.ekerhovd@obgyn.gu.se

BACKGROUND: Clomiphene citrate is a first line treatment of infertile anovulatory women. Although the treatment induces ovulation in most women, only one in four achieve uncomplicated pregnancy after treatment over several cycles. During recent years several clinics have started to use letrozole tablets for ovulation induction. This paper gives a short presentation of letrozole, mechanisms of action are explained, and pros and cons of letrozole versus clomiphene citrate are discussed. MATERIAL AND METHODS: The paper is based on more than two years of clinical experience with use of letrozole for ovulation induction before timed sexual intercourse or intrauterine insemination and the use of letrozole during ovarian stimulation for in vitro fertilization. In addition, a non-systematic search in Pubmed has been performed to give an overview of what is known about letrozole for ovulation induction. RESULTS: Use of letrozole is associated with a higher chance of uncomplicated pregnancy and a lower risk of multiple pregnancy than clomiphene citrate. In addition, more than 60 % of the women who are resistant to clomiphene citrate ovulate after treatment with letrozole. Letrozole combined with gonadotropin may also be beneficial in some women during in vitro fertilization. INTERPRETATION: Studies of letrozole use in reproduction have so far been promising. However, large randomized studies are warranted before it can be concluded that letrozole should become a first line treatment for ovulation induction.

A new era in ovulation induction.

Holzer H, Casper R, Tulandi T.

Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada.

OBJECTIVE: To evaluate the efficacy of aromatase inhibitors in ovulation induction, superovulation, and IVF. DESIGN: A literature search was conducted with the key words “aromatase inhibitor,” “letrozole,” “anastrazole,” “ovulation induction,” “ovulation,” and “superovulation” in MEDLINE, EMBASE, and the Cochrane Database of systematic reviews. RESULT(S): Ovulation induction with letrozole is associated with an ovulation rate of 70%-84% and a pregnancy rate of 20%-27% per cycle. In one study, ovulation and pregnancy rates with letrozole seemed to be higher than those of anastrazole. In superovulation, letrozole is associated with few developing follicles and thick endometrium. The use of letrozole for superovulation is associated with a pregnancy rate higher than with the use of clomiphene citrate (CC) (16.7% vs. 5.6%). The addition of letrozole to FSH treatment leads to a decreased FSH requirement. The pregnancy rate for treatment with letrozole and FSH was similar to that for FSH alone. CONCLUSION(S): Aromatase inhibitors are as effective as or superior to CC in ovulation induction and in superovulation. Unlike CC, they do not carry an antiestrogenic effect on the endometrium. Given the advantages of aromatase inhibitors, they can be used to replace CC as ovulation-inducing drugs. Their role in IVF remains to be determined.

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Responses

  1. You rock!!! Thank you so much for the studies 🙂

  2. Add me to the Femara fan club, too! I did 3 iui’s with Femara after 4 ivi’s using Clomid, and I’m convinced that Femara made all the difference with no side effects to speak of. I’m surprised that some doctors are dismissing it…my RE told me that it often gives better results than Clomid and, like you said, stays in the body for a much shorter time, so there is less of a risk of multiples. No regrets here! 🙂

  3. I was slated to take femara cause I was sure that last clomid cycle wouldn’t work, and I was happily wrong. But I agree with you about a lot of the clomid stuff. I never had more than headaches as visible side effects, but every month my lining measured thinner and thinner (and I was taking off a month every couple rounds to try to clear it out of my system). And had it not been for the IUI’s I’m pretty sure I wouldn’t have had success on it b/c my CM was non existent on it.

    My RE said he likes clomid to femara because it has a longer track record and is more likely to help produce multiple follicles (femara is more likely to only give one). So that seems a little weird of a reason to prefer clomid to femara for a couple with normal sperm since I thought RE’s tried to avoid multiples.

  4. I was just referred to you by Amanda. Glad I read this. My doctor also does not want me to take Femara and it’s so annoying! She’d rather I get surgery or take shots… even though she says I will likely over-respond to shots because I am small. It’s really frustrating. She says she thinks femara won’t work because only my first cycle (of 3) on Clomid worked, she also mentioned birth defects…but I read that study was inaccurate? Gosh, I’m so tempted to try this!

  5. femara works really well for PCOS girls who DON’T do well on clomid.. we are almost 24 weeks with twins because of femara/ fsh combo.. think i told you this back in march.. clomid did NOTHING for me but give me lumpy breasts and hot flashes and depression. Praise God for doctors who are willing to use femara!
    so glad you did press your doc to let you try it! i learned that femara helps with egg quality.. because it also supresses androgens in the ovary.. clomid does not do that!!

  6. I am a Femara supporter! After TTC for a year, including a miscarriage, my doctor prescribed Femara stating “it’s VERY effective”. How could I have imagined that after only ONE cycle I would get pregnant!? I’m 8 weeks along now and so grateful! Thank you for your article. There is a lot of nonsense online that scare women away from this drug.


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