Advertisement

Pituitary suppression with GnRH agonists before ART may be insufficient to treat women with severe adenomyosis

Published:September 30, 2022DOI:https://doi.org/10.1016/j.rbmo.2022.09.023

      Abstract

      Research question

      Does aromatase inhibitor improve IVF outcomes by reducing local oestrogen production in patients with adenomyosis undergoing long-term gonadotrophin-releasing hormone agonist (GnRHa) treatment?

      Design

      Four patients with severe adenomyosis who failed to improve after long-term treatment (≥3 months) with depot GnRHa received treatment with an aromatase inhibitor for 21 days. Blood oestradiol concentrations were monitored after GnRHa treatment both before and after treatment with an aromatase inhibitor. Women received a transfer of IVF autologous or donor oocytes. Pregnancy and ongoing pregnancy rates were the primary outcomes. Blood oestradiol concentration after treatment with an aromatase inhibitor was a secondary outcome.

      Results

      Patients with severe adenomyosis presented with hyperestrogenism due to local production from the lesions even after long-term treatment with GnRHa. Treatment with an aromatase inhibitor reduced hyperestrogenism and improved clinical outcomes in adenomyosis patients who have experienced previous embryo transfer failures.

      Conclusion

      Women with severe adenomyosis would benefit from letrozole or a combination of GnRHa plus letrozole before receipt of treatment with assisted reproductive technology. For women with severe adenomyosis, GnRHa treatment alone may be insufficient to suppress oestrogen production by adenomyotic lesions. Thus, it should be mandatory to test for oestradiol concentrations in patients with severe adenomyosis who have received long-term GnRHa treatment. Also, GnRHa may not always be the sole strategy for medical management of adenomyotic lesions. Letrozole is safe and can improve IVF outcomes for patients with adenomyosis.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Reproductive BioMedicine Online
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Barra F.
        • Lagana A.S.
        • Scala C.
        • Garzon S.
        • Ghezzi F.
        • Ferrero S.
        Pretreatment with dienogest in women with endometriosis undergoing IVF after a previous failed cycle.
        Reprod. Biomed. Online. 2020; 41: 859-868
        • Benagiano G.
        • Brosens I.
        • Habiba M.
        Structural and molecular features of the endomyometrium in endometriosis and adenomyosis.
        Hum. Reprod. Update. 2014; 20: 386-402
        • Bergeron C.
        • Amant F.
        • Ferenczy A.
        Pathology and physiopathology of adenomyosis.
        Best Pract. Res. Clin. Obstet. Gynaecol. 2006; 20: 511-521
        • Bourdon M.
        • Santulli P.
        • Marcellin L.
        • Maignien C.
        • Maitrot-Mantelet L.
        • Bordonne C.
        • Plu Bureau G.
        • Chapron C.
        Adenomyosis: an update regarding its diagnosis and clinical features.
        J. Gynecol. Obstet. Hum. Reprod. 2021; 50102228
        • Bulun S.E.
        • Cheng Y.H.
        • Yin P.
        • Imir G.
        • Utsunomiya H.
        • Attar E.
        • Innes J.
        • Julie Kim J.
        Progesterone resistance in endometriosis: link to failure to metabolize estradiol.
        Mol. Cell. Endocrinol. 2006; 248: 94-103
        • Bulun S.E.
        • Lin Z.
        • Imir G.
        • Amin S.
        • Demura M.
        • Yilmaz B.
        • Martin R.
        • Utsunomiya H.
        • Thung S.
        • Gurates B.
        • Tamura M.
        • Langoi D.
        • Deb S.
        Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment.
        Pharmacol. Rev. 2005; 57: 359-383
        • Bulun S.E.
        • Monsavais D.
        • Pavone M.E.
        • Dyson M.
        • Xue Q.
        • Attar E.
        • Tokunaga H.
        • Su E.J.
        Role of estrogen receptor-beta in endometriosis.
        Semin. Reprod. Med. 2012; 30: 39-45
        • Bulun S.E.
        • Utsunomiya H.
        • Lin Z.
        • Yin P.
        • Cheng Y.H.
        • Pavone M.E.
        • Tokunaga H.
        • Trukhacheva E.
        • Attar E.
        • Gurates B.
        • Milad M.P.
        • Confino E.
        • Su E.
        • Reierstad S.
        • Xue Q.
        Steroidogenic factor-1 and endometriosis.
        Mol. Cell. Endocrinol. 2009; 300: 104-108
        • Bulun S.E.
        • Yildiz S.
        • Adli M.
        • Wei J.J.
        Adenomyosis pathogenesis: insights from next-generation sequencing.
        Hum. Reprod. Update. 2021; 27: 1086-1097
        • Carrarelli P.
        • Yen C.F.
        • Funghi L.
        • Arcuri F.
        • Tosti C.
        • Bifulco G.
        • Luddi A.
        • Lee C.L.
        • Petraglia F.
        Expression of inflammatory and neurogenic mediators in adenomyosis.
        Reprod. Sci. 2017; 24: 369-375
        • Chen Y.J.
        • Li H.Y.
        • Huang C.H.
        • Twu N.F.
        • Yen M.S.
        • Wang P.H.
        • Chou T.Y.
        • Liu Y.N.
        • Chao K.C.
        • Yang M.H.
        Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis.
        J. Pathol. 2010; 222: 261-270
        • Cozzolino M.
        • Basile F.
        • Pontrelli G.
        Effects of adenomyosis on obstetric outcomes.
        Minerva Ginecol. 2019; 71: 146-154
        • Cozzolino M.
        • Tartaglia S.
        • Pellegrini L.
        • Troiano G.
        • Rizzo G.
        • Petraglia F.
        The effect of uterine adenomyosis on IVF outcomes: a systematic review and meta-analysis.
        Reprod. Sci. 2022 Jan 3; (Epub ahead of print. PMID: 34981458)https://doi.org/10.1007/s43032-021-00818-6
        • Elgindy E.A.
        • Abdelghany A.A.
        • Sibai AbdAlsalam H.
        • Mostafa M.I.
        The novel incorporation of aromatase inhibitor in hormonal replacement therapy cycles: a randomized controlled trial.
        Reprod. Biomed. Online. 2022; 44: 641-649
        • Ezaki K.
        • Motoyama H.
        • Sasaki H.
        Immunohistologic localization of estrone sulfatase in uterine endometrium and adenomyosis.
        Obstet. Gynecol. 2001; 98: 815-819
        • Ferenczy A.
        Pathophysiology of adenomyosis.
        Hum. Reprod. Update. 1998; 4: 312-322
        • Galliano D.
        • Bellver J.
        • Diaz-Garcia C.
        • Simon C.
        • Pellicer A.
        ART and uterine pathology: how relevant is the maternal side for implantation?.
        Hum. Reprod. Update. 2015; 21: 13-38
        • Garcia-Solares J.
        • Donnez J.
        • Donnez O.
        • Dolmans M.M.
        Pathogenesis of uterine adenomyosis: invagination or metaplasia?.
        Fertil. Steril. 2018; 109: 371-379
        • Hardy D.B.
        • Janowski B.A.
        • Corey D.R.
        • Mendelson C.R.
        Progesterone receptor plays a major antiinflammatory role in human myometrial cells by antagonism of nuclear factor-kappaB activation of cyclooxygenase 2 expression.
        Mol. Endocrinol. 2006; 20: 2724-2733
        • Huhtinen K.
        • Desai R.
        • Stahle M.
        • Salminen A.
        • Handelsman D.J.
        • Perheentupa A.
        • Poutanen M.
        Endometrial and endometriotic concentrations of estrone and estradiol are determined by local metabolism rather than circulating levels.
        J. Clin. Endocrinol. Metab. 2012; 97: 4228-4235
        • Inoue S.
        • Hirota Y.
        • Ueno T.
        • Fukui Y.
        • Yoshida E.
        • Hayashi T.
        • Takeyama R.
        • Hashimoto T.
        • Kiyono T.
        • Ikemura M.
        • Taguchi A.
        • Tanaka T.
        • Tanaka Y.
        • Sakata S.
        • Takeuchi K.
        • Muraoka A.
        • Osuka S.
        • Saito T.
        • Oda K.
        • Osuga Y.
        • Terao Y.
        • Kawazu M.
        • Mano H.
        Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations.
        Nat. Commun. 2019; 10: 5785
        • Jichan N.
        • Xishi L.
        • Guo S.W.
        Promoter hypermethylation of progesterone receptor isoform B (PR-B) in adenomyosis and its rectification by a histone deacetylase inhibitor and a demethylation agent.
        Reprod. Sci. 2010; 17: 995-1005
        • Juárez-Barber E.
        • Cozzolino M.
        • Corachán A.
        • Alecsandru D.
        • Pellicer N.
        • Pellicer A.
        • Ferrero H.
        Adjustment of progesterone administration after endometrial transcriptomic analysis does not improve reproductive outcomes in women with adenomyosis.
        Reprod. Biomed. Online. 2022 Sep 15; (S1472-6483(22)00700-3)
        • Kimura F.
        • Takahashi K.
        • Takebayashi K.
        • Fujiwara M.
        • Kita N.
        • Noda Y.
        • Harada N.
        Concomitant treatment of severe uterine adenomyosis in a premenopausal woman with an aromatase inhibitor and a gonadotropin-releasing hormone agonist.
        Fertil. Steril. 2007; 87 (e9–12): 1468
        • Kitawaki J.
        Adenomyosis: the pathophysiology of an oestrogen-dependent disease.
        Best Pract. Res. Clin. Obstet. Gynaecol. 2006; 20: 493-502
        • Kitawaki J.
        • Koshiba H.
        • Ishihara H.
        • Kusuki I.
        • Tsukamoto K.
        • Honjo H.
        Progesterone induction of 17beta-hydroxysteroid dehydrogenase type 2 during the secretory phase occurs in the endometrium of estrogen-dependent benign diseases but not in normal endometrium.
        J. Clin. Endocrinol. Metab. 2000; 85: 3292-3296
        • Kossai M.
        • Penault-Llorca F.
        Role of hormones in common benign uterine lesions: endometrial polyps, leiomyomas, and adenomyosis.
        Adv. Exp. Med. Biol. 2020; 1242: 37-58
        • Lazzeri L.
        • Morosetti G.
        • Centini G.
        • Monti G.
        • Zupi E.
        • Piccione E.
        • Exacoustos C.
        A sonographic classification of adenomyosis: interobserver reproducibility in the evaluation of type and degree of the myometrial involvement.
        Fertil. Steril. 2018; 110 (e3): 1154-1161
        • Martinez-Conejero J.A.
        • Morgan M.
        • Montesinos M.
        • Fortuno S.
        • Meseguer M.
        • Simon C.
        • Horcajadas J.A.
        • Pellicer A.
        Adenomyosis does not affect implantation, but is associated with miscarriage in patients undergoing oocyte donation.
        Fertil. Steril. 2011; 96: 943-950
        • Munro M.G.
        Uterine polyps, adenomyosis, leiomyomas, and endometrial receptivity.
        Fertil. Steril. 2019; 111: 629-640
        • Nie J.
        • Lu Y.
        • Liu X.
        • Guo S.W.
        Immunoreactivity of progesterone receptor isoform B, nuclear factor kappaB, and IkappaBalpha in adenomyosis.
        Fertil. Steril. 2009; 92: 886-889
        • Osada H.
        • Silber S.
        • Kakinuma T.
        • Nagaishi M.
        • Kato K.
        • Kato O.
        Surgical procedure to conserve the uterus for future pregnancy in patients suffering from massive adenomyosis.
        Reprod. Biomed. Online. 2011; 22: 94-99
        • Ota H.
        • Tanaka T.
        Stromal vascularization in the endometrium during adenomyosis.
        Microsc Res. Tech. 2003; 60: 445-449
        • Raga F.
        • Casan E.M.
        • Kruessel J.S.
        • Wen Y.
        • Huang H.Y.
        • Nezhat C.
        • Polan L.
        Quantitative gonadotropin-releasing hormone gene expression and immunohistochemical localization in human endometrium throughout the menstrual cycle.
        Biol. Reprod. 1998; 59: 661-669
        • Scioscia M.
        • Noventa M.
        • Lagana A.S.
        Abnormal uterine bleeding and the risk of endometrial cancer: can subendometrial vascular ultrasound be of help to discriminate cancer from adenomyosis?.
        Am. J. Obstet. Gynecol. 2020; 223: 605-606
        • Sharma S.
        • RoyChoudhury S.
        • Bhattacharya M.P.
        • Mitra I.
        • Hazra S.
        • Chakraborty P.
        • Chaudhury K.
        • Majhi A.K.
        • Baidyanath C.
        Effectiveness of letrozole in symptomatic women with adenomyosis undergoing IVF: an overview of clinical features, sonographic characteristics, and reproductive outcome.
        Hum. Reprod. July 2022; 37
        • Tempest N.
        • Hill C.J.
        • Maclean A.
        • Marston K.
        • Powell S.G.
        • Al-Lamee H.
        • Hapangama D.K.
        Novel microarchitecture of human endometrial glands: implications in endometrial regeneration and pathologies.
        Hum. Reprod. Update. 2022; 28: 153-171
        • Tempest N.
        • Jansen M.
        • Baker A.M.
        • Hill C.J.
        • Hale M.
        • Magee D.
        • Treanor D.
        • Wright N.A.
        • Hapangama D.K.
        Histological 3D reconstruction and in vivo lineage tracing of the human endometrium.
        J. Pathol. 2020; 251: 440-451
        • Uduwela A.S.
        • Perera M.A.
        • Aiqing L.
        • Fraser I.S.
        Endometrial-myometrial interface: relationship to adenomyosis and changes in pregnancy.
        Obstet. Gynecol. Surv. 2000; 55: 390-400
        • Urabe M.
        • Yamamoto T.
        • Kitawaki J.
        • Honjo H.
        • Okada H.
        Estrogen biosynthesis in human uterine adenomyosis.
        Acta Endocrinol. (Copenh). 1989; 121: 259-264
        • Vannuccini S.
        • Luisi S.
        • Tosti C.
        • Sorbi F.
        • Petraglia F.
        Role of medical therapy in the management of uterine adenomyosis.
        Fertil. Steril. 2018; 109: 398-405
        • Vannuccini S.
        • Tosti C.
        • Carmona F.
        • Huang S.J.
        • Chapron C.
        • Guo S.W.
        Pathogenesis of adenomyosis: an update on molecular mechanisms.
        Reprod. Biomed. Online. 2017; 35: 592-601
        • Vercellini P.
        • Bonfanti I.
        • Berlanda N.
        Adenomyosis and infertility: is there a causal link?.
        Expert. Rev. Endocrinol. Metab. 2019; 14: 365-367
        • Vercellini P.
        • Consonni D.
        • Dridi D.
        • Bracco B.
        • Frattaruolo M.P.
        • Somigliana E.
        Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis.
        Hum. Reprod. 2014; 29: 964-977
        • Xiang Y.
        • Sun Y.
        • Yang B.
        • Yang Y.
        • Zhang Y.
        • Yu T.
        • Huang H.
        • Zhang J.
        • Xu H.
        Transcriptome sequencing of adenomyosis eutopic endometrium: a new insight into its pathophysiology.
        J. Cell. Mol. Med. 2019; 23: 8381-8391
        • Yamaguchi M.
        • Yoshihara K.
        • Suda K.
        • Nakaoka H.
        • Yachida N.
        • Ueda H.
        • Sugino K.
        • Mori Y.
        • Yamawaki K.
        • Tamura R.
        • Ishiguro T.
        • Motoyama T.
        • Watanabe Y.
        • Okuda S.
        • Tainaka K.
        • Enomoto T.
        Three-dimensional understanding of the morphological complexity of the human uterine endometrium.
        iScience. 2021; 24102258
        • Yamamoto T.
        • Noguchi T.
        • Tamura T.
        • Kitawaki J.
        • Okada H.
        Evidence for estrogen synthesis in adenomyotic tissues.
        Am. J. Obstet. Gynecol. 1993; 169: 734-738
        • Zhai J.
        • Vannuccini S.
        • Petraglia F.
        • Giudice L.C.
        Adenomyosis: mechanisms and pathogenesis.
        Semin. Reprod. Med. 2020; 38: 129-143

      Biography

      Mauro Cozzolino completed a Fellowship in Reproductive Medicine at IVI Madrid, Spain, in 2017 and began his PhD in 2018. He obtained a Fellowship at the Department of Obstetrics, Gynecology and Reproductive Sciences of Yale School of Medicine from 2018 to 2021. Dr Cozzolino is currently employed at IVIRMA Roma.
      Key message
      Treatment with GnRHa may be ineffective for patients with severe adenomyosis. An inhibitor of aromatase can reduce hyperestrogenism due to local production.