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When clomiphene is no longer available…

      Clomiphene citrate has been the most widely used oral agent for ovulation induction for many decades. However, EMD Serono recently issued a statement that its clomiphene product will be discontinued as of June 2017. It could leave practitioners with injectable gonadotropins as their only choice for ovarian stimulation and ovulation induction. Another alternative is the off-label use of letrozole. Health Canada approved letrozole is an adjuvant treatment of hormone receptor–positive early breast cancer in postmenopausal women and as extended adjuvant treatment of hormone receptor–positive early breast cancer in postmenopausal women who have received the standard adjuvant therapy with tamoxifen. However, it is not approved for ovarian stimulation. This is despite mounting evidence that letrozole is effective and safe.
      As an aromatase inhibitor, letrozole works by blocking the conversion of androgen to estrogen. As a response to a low estrogen level, the pituitary gland increases FSH secretion that results in stimulation of ovarian follicle development. Early studies compared the effect of letrozole to clomiphene citrate in normal female volunteers,
      • Fisher S.A.
      • Reid R.L.
      • Van Vugt D.A.
      • et al.
      A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women.
      and letrozole was also studied for ovulation induction in clomiphene citrate failures.
      • Mitwally M.F.
      • Casper R.F.
      Use of an aromatase inhibitor for induction of ovulation in cases of inadequate response to clomiphene citrate.
      Since then, many authors subsequently reported the results of ovulation induction with letrozole with or without comparison to clomiphene.
      • Holzer H.
      • Casper R.
      • Tulandi T.
      A new era in ovulation induction.
      In 2014, Legro et al. published the results of a multicentre randomized trial comparing letrozole versus clomiphene in 750 women with polycystic ovarian syndrome (PCOS). Letrozole (starting dose 2.5 mg daily) or clomiphene (50 mg daily) was administered from day 3 to day 7 of the cycle or induced cycle for 5 days for up to 5 treatment cycles.
      • Legro R.S.
      • Brzyski R.G.
      • Diamond M.P.
      • et al.
      Letrozole versus clomiphene for infertility in the polycystic ovary syndrome.
      The dose was increased to 7.5 mg for letrozole and to 150 mg daily for clomiphene if needed. The cumulative live birth in the letrozole group (25.5%) was significantly higher than in the clomiphene group (19.1%; 95% CI 1.1–1.87). Of interest, the results were independent of the BMI of the patients. The ovulation rates were also higher in the letrozole group (61.7% vs. 48.3%). The rate of twin pregnancy in was 3.4% the letrozole group and 7.4% in the clomiphene group. The overall congenital malformations in both groups were similar. A meta-analysis compiling the results of 5 randomized trials in patients with PCOS
      • Roque M.
      • Tostes A.C.
      • Valle M.
      • et al.
      Letrozole versus clomiphene citrate in polycystic ovary syndrome: systemic review and meta-analysis.
      confirmed that letrozole was associated with a higher live birth rate than clomiphene (risks ratio 1.55, 95% CI 1.26–1.9).
      A large comparative randomized study using letrozole, clomiphene, or gonadotropin among 900 women with unexplained infertility was subsequently published in 2015.
      • Diamond M.P.
      • Legro R.S.
      • Coutifaris C.
      • et al.
      Letrozole, gonadotropin, or clomiphene for unexplained infertility.
      The rate of live birth up to 4 treatment cycles in the gonadotropin group (32.2%) was significantly higher than in the clomiphene (23.3%) and letrozole groups (18.7%). Gonadotropin treatment was associated with increased rate of multiple pregnancy (32%) compared to clomiphene (5.7%) or letrozole (14.3%). However, the live birth rate and multiple pregnancy rate between clomiphene and letrozole were comparable. The frequencies of congenital malformation among the 3 groups were similar.
      A possible risk of congenital malformation is indeed an important issue. Tatsumi et al.
      • Tatsumi T.
      • Jwa S.C.
      • Kuwahara A.
      • et al.
      No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole use in assisted reproductive technology.
      recently reported the results of 3136 natural cycles and 792 letrozole-induced cycles associated with fresh, single-embryo transfer and resulting in a clinical pregnancy. The overall risk of congenital malformation in the natural cycle was 1.5% and in the letrozole group was 1.9% (adjusted OR 1.24, 95% CI 0.64–2.40, P = 0.52).
      • Tatsumi T.
      • Jwa S.C.
      • Kuwahara A.
      • et al.
      No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole use in assisted reproductive technology.
      This report supports previous studies showing that letrozole is not associated with increased birth defects.
      • Tulandi T.
      • Martin J.
      • Al-Fadhli R.
      • et al.
      Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate.
       It is certainly a viable alternative to clomiphene for inducing ovulation or ovarian stimulation, and practitioners looking for an oral agent to use for ovulation induction should feel comfortable using letrozole for this purpose.
      We conclude the following: In women with PCOS, the use of letrozole is associated with a higher live birth rate than clomiphene. Accordingly, it could be used as a first-line treatment, especially in women with high BMI (>30 kg/m2). The live birth rate and multiple pregnancy rate after ovarian stimulation in women with unexplained infertility either with clomiphene or letrozole are comparable. The starting dose of letrozole is 2.5 mg daily for 5 days from day 3 to day 7. It can be increased up to 7.5 mg daily. The main side effects of letrozole are fatigue and dizziness; however, in general, letrozole is well-tolerated. The overall risks of congenital malformation after treatment with letrozole are similar to those in natural cycles. Finally, the use of letrozole for ovulation induction and ovarian stimulation is considered off-label in Canada.

      References

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        • Reid R.L.
        • Van Vugt D.A.
        • et al.
        A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women.
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        Letrozole versus clomiphene for infertility in the polycystic ovary syndrome.
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      Linked Article

      • Quand le clomiphène ne sera plus offert…
        Journal of Obstetrics and Gynaecology Canada Vol. 39Issue 9
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          Le citrate de clomiphène est depuis des dizaines d'années le médicament oral le plus utilisé pour déclencher l'ovulation. Or, EMD Serono a récemment annoncé qu'elle cesserait la vente de son médicament à base de clomiphène dès juin 2017. Ainsi, les praticiens pourraient n'avoir d'autre choix que d'utiliser des gonadotrophines injectables pour la stimulation ovarienne et le déclenchement de l'ovulation. Un autre traitement possible serait l'administration hors indication du létrozole. Ce médicament, approuvé par Santé Canada, est indiqué comme traitement adjuvant chez les femmes ménopausées atteintes d'un cancer du sein précoce avec récepteurs hormonaux positifs et comme traitement adjuvant à long terme chez les femmes ménopausées atteintes d'un cancer du sein précoce avec récepteurs hormonaux positifs et ayant reçu un traitement adjuvant traditionnel de tamoxifène.
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