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Estrogen receptor-α immunoreactivity predicts symptom severity and pain recurrence in deep endometriosis

      Objective

      To determine the relationship between steroid receptor expression and pain symptoms in endometriosis.

      Design

      Cross-sectional

      Setting

      University Hospital

      Patient(s)

      Women with endometriosis (N = 92).

      Intervention(s)

      Tissue samples were obtained from patients with surgically diagnosed endometriosis.

      Main Outcome Measure(s)

      A tissue microarray (TMA) was generated from patients with endometriosis. Data were collected on the presence and severity of dysmenorrhea, deep dyspareunia, dyschezia, and nonmenstrual pain by use of a numerical rating scale (NRS) at the time of surgery and after 1 year. The intensity of receptor expression was evaluated through immunohistochemistry and measured according to an immunoreactive score (IRS). Clinical variables were correlated to IRS by multivariate logistic regression analysis.

      Results

      Estrogen receptor-α (ER-α), progesterone receptor (PR), androgen receptor (AR), and aromatase expression differed among study participants. ER-α expression was reduced by progestin therapy, whereas of expressions of PR, AR, and aromatase were unchanged. Higher ER-α expression increased the likelihood of moderate to severe dysmenorrhea and deep dyspareunia in women not receiving hormonal treatment. In women receiving progestin therapy, persistently higher ER-α expression was correlated with greater likelihood of deep dyspareunia, severe dyschezia, and endometriosis-associated pain persistence at 1 year.

      Conclusion(s)

      ER-α, PR, AR, and aromatase were all expressed in deep endometriosis. ER-α levels best correlated with severity of symptoms, which suggests that ER is a key driver of deep endometriosis. Progestin treatment was associated with a reduction of ER-α expression; however, failure of ER suppression by progestins was also a predictor of pain severity and recurrence at 1 year.
      El Receptor-α de Estrógenos con Inmunoreactividad Predice la Severidad de los Síntomas y la Recurrencia del Dolor en la Endometriosis Profunda

      Objetivo

      Determinar la relación entre la expresión del receptor esteroideo y la sintomatología de dolor en endometriosis
      Diseño: Estudio transversal.

      Lugar

      Hospital Universitario.

      Paciente(s)

      Mujeres con endometriosis (N=92).

      Intervención(es)

      Se obtuvieron muestras de tejido de pacientes con endometriosis diagnosticadas quirúrgicamente.

      Medida(s) principal(es) de resultado

      Se generó un microarray tisular (TMA) a partir de pacientes con endometriosis. Los datos fueron recogidos según presencia y gravedad de dismenorrea, dispareunia profunda, disquecia y dolor no menstrual mediante el uso de una escala de calificación numérica (NRS) en el momento de la cirugía y después de 1 año. La intensidad de la expresión del receptor se evaluó mediante inmunohistoquímica y medido de acuerdo con una puntuación inmunorreactiva (IRS). Las variables clínicas se correlacionaron con el IRS por un análisis de regresión logística multivariable.

      Resultado(s)

      El receptor de estrógeno-α (ER-α), el receptor de progesterona (PR), el receptor de andrógenos (AR) y la expresión de aromatasa difirieron entre las participantes del estudio. La expresión de ER-α se redujo con el tratamiento con progestágenos, mientras que la expresión de PR, AR y aromatasa no cambió. La mayor expresión de ER-α aumentó la probabilidad de dismenorrea moderada a severa y de dispareunia profunda en mujeres que no recibieron tratamiento hormonal. En mujeres que recibieron terapia con progestágenos, la expresión de persistentemente más alta de ER-α se correlacionó con una mayor probabilidad de dispareunia profunda, disquecia severa y persistencia del dolor asociado a la endometriosis al año.

      Conclusión(es)

      ER-α, PR, AR y aromatasa se expresaron en endometriosis profunda. Los niveles de ER-α se correlacionaron mejor con la gravedad de los síntomas, lo que sugiere que ER es un factor clave de la endometriosis profunda. El tratamiento con progestágenos se asoció con una reducción de la expresión de ER-α; sin embargo, el fracaso de la supresión de ER por las progestágenos también fue un predictor de la severidad y recurrencia del dolor al cabo de un año.

      Key Words

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      References

        • Giudice L.C.
        Clinical practice. Endometriosis.
        N Engl J Med. 2010; 362: 2389-2398
        • Burney R.O.
        • Giudice L.C.
        Pathogenesis and pathophysiology of endometriosis.
        Fertil Steril. 2012; 98: 511-519
        • Vercellini P.
        • Vigano P.
        • Somigliana E.
        • Fedele L.
        Endometriosis: pathogenesis and treatment.
        Nat Rev Endocrinol. 2014; 10: 261-275
        • Lee B.
        • Du H.
        • Taylor H.S.
        Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium.
        Biol Reprod. 2009; 80: 79-85
        • Bulun S.E.
        • Nezhat C.
        Aromatase, microRNA, and inflammation: a complex relationship.
        Fertil Steril. 2016; 106: 552-553
        • Pluchino N.
        • Freschi L.
        • Wenger J.M.
        • Streuli I.
        Innovations in classical hormonal targets for endometriosis.
        Exp Rev Clin Pharmacol. 2016; 9: 317-327
        • Patel B.G.
        • Rudnicki M.
        • Yu J.
        • Shu Y.
        • Taylor R.N.
        Progesterone resistance in endometriosis: origins, consequences and interventions.
        Acta Obstet Gynecol Scand. 2017; 96: 623-632
        • Han S.J.
        • O'Malley B.W.
        The dynamics of nuclear receptors and nuclear receptor coregulators in the pathogenesis of endometriosis.
        Hum Reprod Update. 2014; 20: 467-484
        • Delvoux B.
        • D'Hooghe T.
        • Kyama C.
        • Koskimies P.
        • Hermans R.J.
        • Dunselman G.A.
        • et al.
        Inhibition of type 1 17beta-hydroxysteroid dehydrogenase impairs the synthesis of 17beta-estradiol in endometriosis lesions.
        J Clin Endocrinol Metab. 2014; 99: 276-284
        • Flores V.A.
        • Vanhie A.
        • Dang T.
        • Taylor H.S.
        Progesterone receptor status predicts response to progestin therapy in endometriosis.
        J Clin Endocrinol Metab. 2018; 103: 4561-4568
        • Cho S.
        • Mutlu L.
        • Zhou Y.
        • Taylor H.S.
        Aromatase inhibitor regulates let-7 expression and let-7f-induced cell migration in endometrial cells from women with endometriosis.
        Fertil Steril. 2016; 106: 673-680
        • Hu Z.
        • Mamillapalli R.
        • Taylor H.S.
        Increased circulating miR-370-3p regulates steroidogenic factor 1 in endometriosis.
        Am J Physiol Endocrinol Metab. 2019; 316: E373-E382
        • Dunselman G.A.
        • Vermeulen N.
        • Becker C.
        • Calhaz-Jorge C.
        • D'Hooghe T.
        • De Bie B.
        • et al.
        ESHRE guideline: management of women with endometriosis.
        Hum Reprod. 2014; 29: 400-412
        • Becker C.M.
        • Gattrell W.T.
        • Gude K.
        • Singh S.S.
        Reevaluating response and failure of medical treatment of endometriosis: a systematic review.
        Fertil Steril. 2017; 108: 125-136
        • Fauconnier A.
        • Staraci S.
        • Huchon C.
        • Roman H.
        • Panel P.
        • Descamps P.
        Comparison of patient- and physician-based descriptions of symptoms of endometriosis: a qualitative study.
        Hum Reprod. 2013; 28: 2686-2694
        • Utsunomiya H.
        • Suzuki T.
        • Kaneko C.
        • Takeyama J.
        • Nakamura J.
        • Kimura K.
        • et al.
        The analyses of 17beta-hydroxysteroid dehydrogenase isozymes in human endometrial hyperplasia and carcinoma.
        J Clin Endocrinol Metab. 2001; 86: 3436-3443
        • Weichert W.
        • Boehm M.
        • Gekeler V.
        • Bahra M.
        • Langrehr J.
        • Neuhaus P.
        • et al.
        High expression of RelA/p65 is associated with activation of nuclear factor-kappaB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis.
        Br J Cancer. 2007; 97: 523-530
        • Oystese K.A.
        • Casar-Borota O.
        • Normann K.R.
        • Zucknick M.
        • Berg J.P.
        • Bollerslev J.
        Estrogen receptor alpha, a sex-dependent predictor of aggressiveness in nonfunctioning pituitary adenomas: SSTR and sex hormone receptor distribution in NFPA.
        J Clin Endocrinol Metab. 2017; 102: 3581-3590
        • Weichert W.
        • Roske A.
        • Gekeler V.
        • Beckers T.
        • Ebert M.P.
        • Pross M.
        • et al.
        Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis.
        Lancet Oncol. 2008; 9: 139-148
        • Bland J.M.
        • Altman D.G.
        Statistical methods for assessing agreement between two methods of clinical measurement.
        Lancet. 1986; 1: 307-310
        • Tosti C.
        • Pinzauti S.
        • Santulli P.
        • Chapron C.
        • Petraglia F.
        Pathogenetic mechanisms of deep infiltrating endometriosis.
        Reprod Sci. 2015; 22: 1053-1059
        • Lessey B.A.
        • Metzger D.A.
        • Haney A.F.
        • McCarty Jr., K.S.
        Immunohistochemical analysis of estrogen and progesterone receptors in endometriosis: comparison with normal endometrium during the menstrual cycle and the effect of medical therapy.
        Fertil Steril. 1989; 51: 409-415
        • Hayashi A.
        • Tanabe A.
        • Kawabe S.
        • Hayashi M.
        • Yuguchi H.
        • Yamashita Y.
        • et al.
        Dienogest increases the progesterone receptor isoform B/A ratio in patients with ovarian endometriosis.
        J Ovarian Res. 2012; 5: 31
        • Vereide A.B.
        • Kaino T.
        • Sager G.
        • Arnes M.
        • Orbo A.
        Effect of levonorgestrel IUD and oral medroxyprogesterone acetate on glandular and stromal progesterone receptors (PRA and PRB), and estrogen receptors (ER-alpha and ER-beta) in human endometrial hyperplasia.
        Gynecol Oncol. 2006; 101: 214-223
        • Nguyen T.T.
        • Hachisuga T.
        • Urabe R.
        • Ueda T.
        • Kurita T.
        • Kagami S.
        • et al.
        Immunohistochemical analysis of the effect of dienogest on ovarian endometriotic cysts.
        J UOEH. 2016; 38: 271-278
        • Cloke B.
        • Christian M.
        The role of androgens and the androgen receptor in cycling endometrium.
        Mol Cell Endocrinol. 2012; 358: 166-175
        • Whitaker L.H.
        • Murray A.A.
        • Matthews R.
        • Shaw G.
        • Williams A.R.W.
        • Saunders P.T.K.
        • et al.
        Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium.
        Hum Reprod. 2017; 32: 531-543
        • Ichioka M.
        • Mita S.
        • Shimizu Y.
        • Imada K.
        • Kiyono T.
        • Bono Y.
        • et al.
        Dienogest, a synthetic progestin, down-regulates expression of CYP19A1 and inflammatory and neuroangiogenesis factors through progesterone receptor isoforms A and B in endometriotic cells.
        J Steroid Biochem Mol Biol. 2015; 147: 103-110
        • Steiner N.
        • Shrem G.
        • Tannus S.
        • Dahan S.Y.
        • Balayla J.
        • Volodarsky-Perel A.
        • et al.
        Effect of GnRH agonist and letrozole treatment in women with recurrent implantation failure.
        Fertil Steril. 2019; 112: 98-104
        • Pluchino N.
        • Poppi G.
        • Yart L.
        • Marci R.
        • Wenger J.M.
        • Tille J.C.
        • et al.
        Effect of local aromatase inhibition in endometriosis using a new chick embryo chorioallantoic membrane model.
        J Cell Mol Med. 2019; 23: 5808-5812
        • Burns K.A.
        • Rodriguez K.F.
        • Hewitt S.C.
        • Janardhan K.S.
        • Young S.L.
        • Korach K.S.
        Role of estrogen receptor signaling required for endometriosis-like lesion establishment in a mouse model.
        Endocrinology. 2012; 153: 3960-3971
        • Sakr S.
        • Naqvi H.
        • Komm B.
        • Taylor H.S.
        Endometriosis impairs bone marrow-derived stem cell recruitment to the uterus whereas bazedoxifene treatment leads to endometriosis regression and improved uterine stem cell engraftment.
        Endocrinology. 2014; 155: 1489-1497
        • Naqvi H.
        • Sakr S.
        • Presti T.
        • Krikun G.
        • Komm B.
        • Taylor H.S.
        Treatment with bazedoxifene and conjugated estrogens results in regression of endometriosis in a murine model.
        Biol Reprod. 2014; 90: 121
        • Flores V.A.
        • Stachenfeld N.S.
        • Taylor H.S.
        Bazedoxifene-conjugated estrogens for treating endometriosis.
        Obstet Gynecol. 2018; 132: 475-477
        • Hill A.M.
        • Lessey B.
        • Flores V.A.
        • Taylor H.S.
        Bazedoxifene/conjugated estrogens in combination with leuprolide for the treatment of endometriosis.
        Clin Case Rep. 2018; 6: 990-994
        • Kulak Jr., J.
        • Fischer C.
        • Komm B.
        • Taylor H.S.
        Treatment with bazedoxifene, a selective estrogen receptor modulator, causes regression of endometriosis in a mouse model.
        Endocrinology. 2011; 152: 3226-3232