Letrozole: future alternative to methotrexate for treatment of ectopic pregnancy?
2020; Elsevier BV; Volume: 114; Issue: 2 Linguagem: Inglês
10.1016/j.fertnstert.2020.04.063
ISSN1556-5653
AutoresNathalie Auger, Aimina Ayoub, Shu Qin Wei,
Tópico(s)Assisted Reproductive Technology and Twin Pregnancy
ResumoEctopic pregnancy affects approximately 1% of pregnancies and is a leading cause of maternal mortality in the first trimester (1van Mello N.M. Mol F. Ankum W.M. Mol B.W. van der Veen F. Hajenius P.J. Ectopic pregnancy: how the diagnostic and therapeutic management has changed.Fertil Steril. 2012; 98: 1066-1073Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 2Practice Committee of American Society for Reproductive MedicineMedical treatment of ectopic pregnancy: a committee opinion.Fertil Steril. 2013; 100: 638-644Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). Timely and appropriate treatment of ectopic pregnancy is critical. Ectopic pregnancy may be managed surgically, medically, or expectantly (1van Mello N.M. Mol F. Ankum W.M. Mol B.W. van der Veen F. Hajenius P.J. Ectopic pregnancy: how the diagnostic and therapeutic management has changed.Fertil Steril. 2012; 98: 1066-1073Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Surgical treatment with salpingectomy or salpingostomy is required typically for advanced or ruptured ectopic pregnancy, whereas methotrexate is the first-line medical treatment for early unruptured ectopic pregnancy. Methotrexate can be administered as single or multidose regimens, with success rates reaching 93% (2Practice Committee of American Society for Reproductive MedicineMedical treatment of ectopic pregnancy: a committee opinion.Fertil Steril. 2013; 100: 638-644Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). Methotrexate is a folic acid antagonist that inhibits the enzyme dihydrofolate reductase, which converts folic acid to tetrahydrofolate, a cofactor needed in DNA and RNA synthesis (2Practice Committee of American Society for Reproductive MedicineMedical treatment of ectopic pregnancy: a committee opinion.Fertil Steril. 2013; 100: 638-644Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). By inhibiting dihydrofolate reductase, methotrexate interrupts trophoblast proliferation and induces abortion. Methotrexate is as effective as salpingostomy for ectopic pregnancy and does not appear to affect future fertility (2Practice Committee of American Society for Reproductive MedicineMedical treatment of ectopic pregnancy: a committee opinion.Fertil Steril. 2013; 100: 638-644Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). However, methotrexate is a chemotherapeutic agent that can have adverse consequences, including nausea, vomiting, conjunctivitis, stomatitis, gastritis, impaired liver function, bone marrow suppression, and photosensitivity (1van Mello N.M. Mol F. Ankum W.M. Mol B.W. van der Veen F. Hajenius P.J. Ectopic pregnancy: how the diagnostic and therapeutic management has changed.Fertil Steril. 2012; 98: 1066-1073Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar,2Practice Committee of American Society for Reproductive MedicineMedical treatment of ectopic pregnancy: a committee opinion.Fertil Steril. 2013; 100: 638-644Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). Methotrexate is not indicated for patients with ruptured ectopic pregnancy, hemodynamic instability, or β-human chorionic gonadotropin (hCG) levels >5,000 mIU/mL, all signs of more advanced ectopic pregnancy (2Practice Committee of American Society for Reproductive MedicineMedical treatment of ectopic pregnancy: a committee opinion.Fertil Steril. 2013; 100: 638-644Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). Other contraindications include immunodeficiency, anemia, thrombocytopenia, pulmonary disease, peptic ulcer, hepatic or renal dysfunction, and breastfeeding (2Practice Committee of American Society for Reproductive MedicineMedical treatment of ectopic pregnancy: a committee opinion.Fertil Steril. 2013; 100: 638-644Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). Thus, alternate medical treatments are needed. In this issue of Fertility and Sterility, Mitwally et al. (3Mitwally M.F. Hozayen W.G. Hassanin K.M.A. Abdalla K.A. Abdalla N.K. The aromatase inhibitor, letrozole: a novel treatment for ectopic pregnancy.Fertil Steril. 2020; 114: 361-366Scopus (7) Google Scholar) assessed the use of letrozole for treatment of ectopic pregnancy. Letrozole is a third-generation aromatase inhibitor that suppresses estrogen production (4Palomba S. Aromatase inhibitors for ovulation induction.J Clin Endocrinol Metab. 2015; 100: 1742-1747Crossref PubMed Scopus (39) Google Scholar). Aromatase is an enzyme involved in estrogen biosynthesis that converts androstenedione to estrone and testosterone to estradiol (4Palomba S. Aromatase inhibitors for ovulation induction.J Clin Endocrinol Metab. 2015; 100: 1742-1747Crossref PubMed Scopus (39) Google Scholar). Letrozole blocks the action of aromatase, preventing a critical step in the production of estrogens. Letrozole is used for estrogen-dependent breast cancer in postmenopausal women and ovulation induction in women with polycystic ovary syndrome (4Palomba S. Aromatase inhibitors for ovulation induction.J Clin Endocrinol Metab. 2015; 100: 1742-1747Crossref PubMed Scopus (39) Google Scholar). Because progesterone is considered more essential than estrogen to establish and maintain pregnancy (1van Mello N.M. Mol F. Ankum W.M. Mol B.W. van der Veen F. Hajenius P.J. Ectopic pregnancy: how the diagnostic and therapeutic management has changed.Fertil Steril. 2012; 98: 1066-1073Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar), it is not immediately evident why letrozole would interrupt ectopic pregnancy. Mitwally et al. (3Mitwally M.F. Hozayen W.G. Hassanin K.M.A. Abdalla K.A. Abdalla N.K. The aromatase inhibitor, letrozole: a novel treatment for ectopic pregnancy.Fertil Steril. 2020; 114: 361-366Scopus (7) Google Scholar) hypothesized that the role of estrogen in early pregnancy may be underestimated, and that inhibition of estrogen production with letrozole may disrupt the physiological functions of progesterone needed to maintain pregnancy. Mitwally et al. (3Mitwally M.F. Hozayen W.G. Hassanin K.M.A. Abdalla K.A. Abdalla N.K. The aromatase inhibitor, letrozole: a novel treatment for ectopic pregnancy.Fertil Steril. 2020; 114: 361-366Scopus (7) Google Scholar) designed a nonrandomized trial of 42 Egyptian women with tubal ectopic pregnancy. Women selected their treatment and were divided into three arms of 14 patients administered letrozole, methotrexate, or salpingectomy. The letrozole arm received 5 mg daily for 10 days, whereas the methotrexate arm received a single intramuscular injection at a dose of 50 mg/m2. β-Human chorionic gonadotropin levels were measured on treatment day and 4, 7, and 14 days later. Undetectable β-hCG levels indicated resolution of ectopic pregnancy. The authors monitored hemoglobin levels, blood platelet counts, liver enzymes, renal function, and antimüllerian hormone, a measure of ovarian reserve and fertility. According to their results, letrozole was as effective as methotrexate, with success rates of 86% for both treatment arms. β-Human chorionic gonadotropin levels even appeared to decrease more rapidly for women treated with letrozole than methotrexate, although the difference was statistically nonsignificant. Letrozole did not affect hematologic parameters, whereas methotrexate was associated with an increase in liver enzymes and a decrease in hemoglobin and platelet count. Letrozole had no impact on antimüllerian hormone levels 3 months after treatment. The results are promising, although letrozole was compared with single-dose methotrexate, which is somewhat less effective than the multidose regimen (2Practice Committee of American Society for Reproductive MedicineMedical treatment of ectopic pregnancy: a committee opinion.Fertil Steril. 2013; 100: 638-644Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). The findings should be interpreted with caution considering the limitations of the study. The authors used a nonrandomized design where patients selected their own treatment. Randomization is necessary to avoid confounding-by-indication, which occurs when patients with certain characteristics are more likely to receive a particular treatment (5Sørensen H.T. Lash T.L. Rothman K.J. Beyond randomized controlled trials: a critical comparison of trials with nonrandomized studies.Hepatology. 2006; 44: 1075-1082Crossref PubMed Scopus (185) Google Scholar). Confounding-by-indication results in noncomparable treatment arms. In the study by Mitwally et al., women with less advanced ectopic pregnancies may have been more inclined to try a new treatment, knowing that their risk of complications was low and that they would be followed up closely regardless. The opportunity to try letrozole is particularly attractive given the adverse consequences of methotrexate and surgery. It is difficult to determine whether the treatment arms were comparable. Women with advanced ectopic pregnancies who had β-hCG levels >3,000 mIU/mL or signs of fetal cardiac activity were excluded, but data on hemodynamic stability, size of ectopic mass, and presence of peritoneal fluid were not provided. Women treated with letrozole had lower β-hCG levels at baseline than women who received methotrexate or salpingectomy. β-Human chorionic gonadotropin levels on treatment day were only 1,065 mIU/mL in the letrozole group, lower than the 1,415 mIU/mL in the methotrexate group. The investigators included salpingectomy as a control, but salpingostomy is used usually for less-advanced cases and may be more suitable (2Practice Committee of American Society for Reproductive MedicineMedical treatment of ectopic pregnancy: a committee opinion.Fertil Steril. 2013; 100: 638-644Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). Women with early ectopic pregnancies may well have opted for letrozole over methotrexate or salpingectomy. This issue is important because many early ectopic pregnancies with low β-hCG levels resolve spontaneously without treatment (1van Mello N.M. Mol F. Ankum W.M. Mol B.W. van der Veen F. Hajenius P.J. Ectopic pregnancy: how the diagnostic and therapeutic management has changed.Fertil Steril. 2012; 98: 1066-1073Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Therefore, it is possible that some ectopic pregnancies in the letrozole group would have resolved with expectant management (1van Mello N.M. Mol F. Ankum W.M. Mol B.W. van der Veen F. Hajenius P.J. Ectopic pregnancy: how the diagnostic and therapeutic management has changed.Fertil Steril. 2012; 98: 1066-1073Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Compliance with the treatment regimen also needs to be considered. In this study, letrozole was administered orally for 10 days. This regimen may be more difficult to follow than methotrexate, which requires as little as one injection. A randomized controlled trial with an intention-to-treat analysis would be needed to determine whether compliance would limit the effectiveness of letrozole (5Sørensen H.T. Lash T.L. Rothman K.J. Beyond randomized controlled trials: a critical comparison of trials with nonrandomized studies.Hepatology. 2006; 44: 1075-1082Crossref PubMed Scopus (185) Google Scholar). Other limitations that the authors raised include the limited sample size and statistical power, as well as the short follow-up period. Although letrozole had no impact on ovarian reserve 3 months after treatment, longer follow-up would help determine the extent to which letrozole is safe for women and their future offspring. Some researchers have raised questions about the possible teratogenicity of letrozole (4Palomba S. Aromatase inhibitors for ovulation induction.J Clin Endocrinol Metab. 2015; 100: 1742-1747Crossref PubMed Scopus (39) Google Scholar). Overall, the study by Mitwally et al. (3Mitwally M.F. Hozayen W.G. Hassanin K.M.A. Abdalla K.A. Abdalla N.K. The aromatase inhibitor, letrozole: a novel treatment for ectopic pregnancy.Fertil Steril. 2020; 114: 361-366Scopus (7) Google Scholar) provides preliminary support for letrozole as an alternative to methotrexate for ectopic pregnancy. The investigators should be congratulated because their novel findings have potential implications for the future management of ectopic pregnancy. Randomized controlled trials will be needed to determine ultimately the effectiveness and safety of letrozole for ectopic pregnancy. Aromatase inhibitor letrozole: a novel treatment for ectopic pregnancyFertility and SterilityVol. 114Issue 2PreviewTo study the use of the aromatase inhibitor letrozole for treatment of ectopic pregnancy compared with methotrexate. Full-Text PDF
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