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Effect of GnRH agonist and letrozole treatment in women with recurrent implantation failure

      Objective

      To compare the influence of dual suppression with the use of GnRH agonist plus aromatase inhibitor compared with suppression with the use of GnRH agonist alone or no suppression at all in patients with idiopathic recurrent implantation failure (RIF).

      Design

      Retrospective cohort study.

      Setting

      University-affiliated reproductive center.

      Patient(s)

      A total of 523 infertile women who failed two blastocyst transfers underwent a third frozen blastocyst transfer. Women with known endometriosis were excluded.

      Intervention(s)

      A total of 204 subjects were not pretreated, 143 received 2 months of GnRH agonist (3.75 mg intramuscular leuprolide acetate monthly) only, and 176 received GnRH agonist and aromatase inhibitor (5 mg oral letrozole daily for 60 days). Demographic and stimulation information was collected and cycle outcomes reported.

      Main Outcome Measure(s)

      Clinical pregnancy rates.

      Result(s)

      Age, antral follicle count, basal FSH levels, duration of infertility, previous pregnancies, and full-term deliveries were similar (P>.05). Clinical pregnancy rates were higher among women who received GnRH agonist plus letrozole compared with women who received GnRH agonist only or women without pretreatment (63%, 42%, and 40%, respectively; P<.0001). Live birth rates were higher among women who received GnRH agonist plus letrozole compared with the other groups (56%, 36%, and 34%; P<.0001). No differences in pregnancy outcomes were noted between patients who did not receive pretreatment and those in the GnRH agonist only group.

      Conclusion(s)

      In patients with RIF, treatment with a GnRH agonist plus letrozole may improve live birth rates in subsequent cycles. We hypothesize that this improvement is due to alterations in the endometrium receptivity or treatment of undiagnosed endometriosis.
      Efecto del tratamiento con agonista de la GnRH y letrozole en mujeres con fallo de implantación recurrente

      Objetivo

      Comparar la influencia de la supresión dual con el uso del agonista de la GnRH y el inhibidor de la aromatasa en comparación con la supresión con el agonista de la GnRH solo o sin supresión en pacientes con fallo de implantación recurrente (RIF) idiopática.

      Diseño

      Estudio de cohortes retrospectivo.

      Ámbito

      Centro reproductivo afiliado a la Universidad.

      Paciente(s)

      Un total de 523 mujeres infértiles que fallaron en dos transferencias de blastocisto y se sometieron a una tercera transferencia de un blastocisto congelado. Mujeres con endometriosis conocida fueron excluidas.

      Intervención(es)

      Un total de 204 sujetos no fueron pretratados, 143 recibieron durante 2 meses solo agonista de la GnRH (3,75 mg de acetato de leuprolide intramuscular mensualmente), y 176 recibieron agonistas de GnRH e inhibidor de aromatasa (5 mg de letrozole oral diariamente durante 60 días). Se recogió la información demográfica, así como de la estimulación y los resultados de los ciclos fue reportada.

      Principal(es) medida(s) de resultado

      Tasas clínicas de gestación.

      Resultado(s)

      Edad, número de folículos antrales, niveles de FSH basales, duración de la esterilidad, gestaciones previas, y gestaciones a término fueron similares (p > 0,05). Las tasas clínicas de gestación fueron mayores en las mujeres que recibieron agonista de GnRH junto con letrozole comparado con las mujeres que recibieron sola el agonista de GnRH o las mujeres sin pretratamiento (63%, 42%, y 40%, respectivamente; p < 0,0001). Las tasas de nacido vivo fueron mayores en las mujeres que recibieron agonista de GnRH junto con el letrozole comparado con los otros grupos (56%, 36%, y 34%; p < 0,0001). No se observaron diferencias en cuanto a los resultados de embarazo entre el grupo de pacientes que no recibió pretratamiento y aquellas que recibieron solo el agonista GnRH.

      Conclusión(es)

      En pacientes con RIF, el tratamiento con agonista de la GnRH junto con letrozole puede mejorar las tasas de nacido vivo en ciclos posteriores. Nosotros hipotetizamos que esta mejora se debe a alteraciones en la receptividad endometrial o al tratamiento de la endometriosis no diagnosticada.

      Key Words

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      References

        • Coughlan C.
        • Ledger W.
        • Wang Q.
        • Liu F.
        • Demirol A.
        • Gurgan T.
        • et al.
        Recurrent implantation failure: definition and management.
        Reprod Biomed Online. 2014; 28: 14-38
        • Yang X.
        • Huang R.
        • Wang Y.F.
        • Liang X.Y.
        Pituitary suppression before frozen embryo transfer is beneficial for patients suffering from idiopathic repeated implantation failure.
        J Huazhong Univ Sci Technol Med Sci. 2016; 36: 127-131
        • Timeva T.
        • Shterev A.
        • Kyurkchiev S.
        Recurrent implantation failure: the role of the endometrium.
        J Reprod Infertil. 2014; 15: 173-183
        • Barnhart K.
        • Dunsmoor-Su R.
        • Coutifaris C.
        Effect of endometriosis on in vitro fertilization.
        Fertil Steril. 2002; 77: 1148-1155
        • Gardner D.K.
        • Schoolcraft W.B.
        In vitro culture of human blastocyst.
        in: Jansen R. Mortimer D. Toward reproductive certainty: infertility and genetics beyond 1999. Parthenon Press, Carnforth1999: 378-388
        • Sallam H.N.
        • Garcia-Velasco J.A.
        • Dias S.
        • Arici A.
        • Abou-Setta A.M.
        Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis.
        Cochrane Database Syst Rev. 2006; : CD004635
        • Surrey E.S.
        • Katz-Jaffe M.
        • Kondapalli L.V.
        • Gustofson R.L.
        • Schoolcraft W.B.
        GnRH agonist administration prior to embryo transfer in freeze-all cycles of patients with endometriosis or aberrant endometrial integrin expression.
        Reprod Biomed Online. 2017; 35: 145-151
        • Decleer W.
        • Osmanagaoglu K.
        • Verschueren K.
        • Comhaire F.
        • Devroey P.
        RCT to evaluate the influence of adjuvant medical treatment of peritoneal endometriosis on the outcome of IVF.
        Hum Reprod. 2016; 31: 2017-2023
        • Słopień R.
        • Męczekalski B.
        Aromatase inhibitors in the treatment of endometriosis.
        Menopausal Rev. 2016; 1: 43-47
        • Bilotas M.
        • Meresman G.
        • Stella I.
        • Sueldo C.
        • Barañao R.I.
        Effect of aromatase inhibitors on ectopic endometrial growth and peritoneal environment in a mouse model of endometriosis.
        Fertil Steril. 2010; 93: 2513-2518
        • Lossl K.
        • Loft A.
        • Freiesleben N.L.C.
        • Bangsbøll S.
        • Andersen C.Y.
        • Pedersen A.T.
        • et al.
        Combined down-regulation by aromatase inhibitor and GnRH-agonist in IVF patients with endometriomas—a pilot study.
        Eur J Obstet Gynecol Reprod Biol. 2009; 144: 48-53
        • Khayat S.
        • Elliott B.
        • Dahan M.H.
        Management of recurrent implantation failure by gonadotropin-releasing hormone agonist and aromatase inhibitor suppression, in women without evidence of endometriosis.
        Gynecol Endocrinol. 2019; 35: 267-270
        • Bedaiwy M.A.
        • Mousa N.A.
        • Casper R.F.
        Aromatase inhibitors prevent the estrogen rise associated with the flare effect of gonadotropins in patients treated with GnRH agonists.
        Fertil Steril. 2009; 91: 1574-1577
        • Bulun S.E.
        • Zeitoun K.M.
        • Takayama K.
        • Sasano H.
        Molecular basis for treating endometriosis with aromatase inhibitors.
        Hum Reprod Update. 2000; 6: 413-418
        • Pavone M.E.
        • Bulun S.E.
        Clinical review: The use of aromatase inhibitors for ovulation induction and superovulation.
        J Clin Endocrinol Metab. 2013; 98: 1838-1844
        • Tei C.
        • Maruyama T.
        • Kuji N.
        • Miyazaki T.
        • Mikami M.
        • Yoshimura Y.
        Reduced expression of alphavbeta3 integrin in the endometrium of unexplained infertility patients with recurrent IVF-ET failures: improvement by danazol treatment.
        J Assist Reprod Genet. 2003; 20: 13-20
        • Thomas K.
        • Thomson A.
        • Wood S.
        • Kingsland C.
        • Vince G.
        • Lewis-Jones I.
        Endometrial integrin expression in women undergoing in vitro fertilization and the association with subsequent treatment outcome.
        Fertil Steril. 2003; 80: 502-507
        • Cavagna M.
        • Mantese J.C.
        Biomarkers of endometrial receptivity—a review.
        Placenta. 2003; 24: S39-S47
        • Hoozemans D.A.
        • Schats R.
        • Lambalk C.B.
        • Homburg R.
        • Hompes P.G.
        Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology.
        Reprod Biomed Online. 2004; 9: 692-715
        • Casals G.
        • Ordi J.
        • Creus M.
        • Fábregues F.
        • Carmona F.
        • Casamitjana R.
        • et al.
        Osteopontin and alphavbeta3 integrin as markers of endometrial receptivity: the effect of different hormone therapies.
        Reprod Biomed Online. 2010; 21: 349-359
        • Revel A.
        • Koler D.
        • Prus A.
        • Tsafrir A.
        • Laufer N.
        • Reich R.
        Implementation of integrin beta 3 level as predictor of implantation in IVF program.
        Fertil Steril. 2005; 84: S144-S145
        • Klentzeris L.D.
        • Bulmer J.N.
        • Trejdosiewicz L.K.
        • Morrison L.
        • Cooke I.D.
        Beta-1 integrin cell adhesion molecules in the endometrium of fertile and infertile women.
        Hum Reprod. 1993; 8: 1223-1230
        • Lessey B.A.
        • Castelbaum A.J.
        • Sawin S.W.
        • Sun J.
        Integrins as markers of uterine receptivity in women with primary unexplained infertility.
        Fertil Steril. 1995; 63: 535-542
        • Ruan H.C.
        • Zhu X.M.
        • Luo Q.
        • Liu A.X.
        • Qian Y.L.
        • Zhou C.Y.
        • et al.
        Ovarian stimulation with GnRH agonist, but not GnRH antagonist, partially restores the expression of endometrial integrin beta3 and leukaemia-inhibitory factor and improves uterine receptivity in mice.
        Hum Reprod. 2006; 21: 2521-2529
        • Miller P.B.
        • Parnell B.A.
        • Bushnell G.
        • Tallman N.
        • Forstein D.A.
        • Higdon H.L.
        • et al.
        Endometrial receptivity defects during IVF cycles with and without letrozole.
        Hum Reprod. 2012; 27: 881-888
        • Sagsveen M.
        • Farmer J.E.
        • Prentice A.
        • Breeze A.
        • Duffy J.M.
        • Watson A.
        • et al.
        Gonadotrophin-releasing hormone analogues for endometriosis: bone mineral density.
        Cochrane Database Syst Rev. 2003; : CD001297