Androgens Upregulate Endometrial Epithelial Progesterone Receptor Expression: Potential Implications for Endometriosis

Background Androgenic compounds have been implicated in induction of endometrial atrophy yet the mechanisms of androgen effects on human endometrium have not been well studied. We hypothesized that androgens may promote their endometrial effects via modulation of progesterone receptor (PR) expression.

Proliferative phase endometrial samples were collected at the time of hysterectomy. We evaluated the effect of the potent androgen 5α-dihydrotestosterone (DHT) on endometrial PR expression by treating human endometrial explants, endometrial stromal cells, and Ishikawa cells with DHT. Ishikawa cells were also treated with DHT ± the androgen receptor (AR) blocker flutamide. The PR-B, total PR messenger RNA (mRNA), and PR protein expression were assessed. Expression of cyclin D1 and D2 was checked as markers of cell proliferation.

As expected, estradiol induced PR expression in isolated stromal cells, endometrial epithelial cells, and tissue explants. The DHT treatment also resulted in increased PR expression in endometrial explants and Ishikawa cells but not in stromal cells. Further, protein levels of both nuclear PR isoforms (PR-A and PR-B) were induced with the DHT treatment. Although flutamide treatment alone did not affect PR expression, flutamide diminished androgen-induced upregulation of PR in both endometrial explants and Ishikawa cells. Although estradiol induced both cyclin D1 and cyclin D2 mRNA, DHT did not induce these markers of cell proliferation.

Androgens may mediate endometrial effects through upregulation of PR gene and protein expression. Endometrial PR upregulation by androgens is mediated, at least in part, through AR. Similar content being viewed by others

Patel B, Elguero S, Thakore S, Dahoud W, Bedaiwy M, Mesiano S. Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update. 2015;21(2):155–173. Cheong YC, Smotra G, Williams AC. Non-surgical interventions for the management of chronic pelvic pain. Cochrane Database Syst Rev. 2014;(3):CD008797. Bukulmez O, Hardy DB, Carr BR, Word RA, Mendelson CR. Inflammatory status influences aromatase and steroid receptor expression in endometriosis. Endocrinology. 2008;149(3):1190–1204. Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR, Bulun SE. Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab. 2000;85(8):2897–2902. Kim JJ, Kurita T, Bulun SE. Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev. 2013;34(1):130–162. Chalmers JA, Shervington PC. Danazol treatment and follow-up of patients with endometriosis. J Int Med Res. 1977;5(suppl 3):72–74. Dmowski WP, Scholer HF, Mahesh VB, Greenblatt RB. Danazol-a synthetic steroid derivative with interesting physiologic properties. Fertil Steril. 1971;22(1):9–18. Liberato MH, Sonohara S, Brentani MM. Effects of androgens on proliferation and progesterone receptor levels in T47D human breast cancer cells. Tumour Biol. 1993;14(1):38–45. Schmidt WN, Katzenellenbogen BS. Androgen-uterine interactions: an assessment of androgen interaction with the testosterone- and estrogen-receptor systems and stimulation of uterine growth and progesterone-receptor synthesis. Mol Cell Endocrinol. 1979;15(2):91–108. Bukulmez O, Hardy DB, Carr BR, et al. Androstenedione up-regulation of endometrial aromatase expression via local conversion to estrogen: potential relevance to the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2008;93(9):3471–3477. Choi YJ, Anders L. Signaling through cyclin D-dependent kinases. Oncogene. 2014;33(15):1890–1903. Hata H, Holinka CF, Pahuja SL, Hochberg RB, Kuramoto H, Gurpide E. Estradiol metabolism in Ishikawa endometrial cancer cells. J Steroid Biochem. 1987;26(6):699–704. Varma VA, Melin SA, Adamec TA, et al. Monolayer culture of human endometrium: methods of culture and identification of cell types. In Vitro. 1982;18(11):911–918. Handwerger S, Harman I, Zeitler P. In Vitro Methods for Studying Secretion. Amsterdam, Netherlands: Elsevier Science Publications; 1987. Dai Q, Shah AA, Garde RV, et al. A truncated progesterone receptor (PR-M) localizes to the mitochondrion and controls cellular respiration. Mol Endocrinol. 2013;27(5):741–753. Schmitt FC, Soares R. TGF-alpha and angiogenesis. Am J Surg Pathol. 1999;23(3):358–359. Higuchi T, Kanzaki H, Iwai M, Narukawa S, Fujita J, Mori T. Expression of messenger ribonucleic acid for gonadal steroid receptors in the human pelvic peritoneum. Fertil Steril. 1995;63(1):52–57. Iwai M, Kanzaki H, Fujimoto M, et al. Regulation of sex steroid receptor gene expression by progesterone and testosterone in cultured human endometrial stromal cells. J Clin Endocrinol Metab. 1995;80(2):450–454. Apparao KB, Lovely LP, Gui Y, Lininger RA, Lessey BA. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome. Biol Reprod. 2002;66(2):297–304. Selak V, Farquhar C, Prentice A, Singla A. Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst Rev. 2007;(4):CD000068. Shamonki MI, Ziegler WF, Badger GJ, Sites CK. Prediction of endometrial ablation success according to perioperative findings. Am J Obstet Gynecol. 2000;182(5):1005–1007. Fedele L, Marchini M, Bianchi S, Baglioni A, Bocciolone L, Nava S. Endometrial patterns during danazol and buserelin therapy for endometriosis: comparative structural and ultrastructural study. Obstet Gynecol. 1990;76(1):79–84. Floyd WS. Danazol: endocrine and endometrial effects. Int J Fertil. 1980;25(1):75–80. Ferrero S, Tramalloni D, Venturini PL, Remorgida V. Vaginal danazol for women with rectovaginal endometriosis and pain symptoms persisting after insertion of a levonorgestrel-releasing intrauterine device. Int J Gynaecol Obstet. 2011;113(2):116–119. Razzi S, Luisi S, Calonaci F, Altomare A, Bocchi C, Petraglia F. Efficacy of vaginal danazol treatment in women with recurrent deeply infiltrating endometriosis. Fertil Steril. 2007;88(4):789–794. Kokko E, Janne O, Kauppila A, Ronnberg L, Vihko R. Danazol has progestin-like actions on the human endometrium. Acta Endocrinol (Copenh). 1982;99(4):588–593. Bukulmez O. Endometriosis and the role of reproductive medicine. Minerva Ginecol. 2009;61(4):299–318. Soares SR, Martinez-Varea A, Hidalgo-Mora JJ, Pellicer A. Pharmacologic therapies in endometriosis: a systematic review. Fertil Steril. 2012;98(3):529–555. Williams KC, Renthal NE, Condon JC, Gerard RD, Mendelson CR. MicroRNA-200a serves a key role in the decline of progesterone receptor function leading to term and preterm labor. Proc Natl Acad Sci U S A. 2012;109(19):7529–7534. Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Hum Reprod Update. 2013;19(4):406–418. Guzick DS, Huang LS, Broadman BA, Nealon M, Hornstein MD. Randomized trial of leuprolide versus continuous oral contraceptives in the treatment of endometriosis-associated pelvic pain. Fertil Steril. 2011;95(5):1568–1573. Lidegaard O, Edstrom B, Kreiner S. Oral contraceptives and venous thromboembolism: a five-year national case-control study. Contraception. 2002;65(3):187–196. Berrevoets CA, Umar A, Brinkmann AO. Antiandrogens: selective androgen receptor modulators. Mol Cell Endocrinol. 2002;198(1-2):97–103. Kemppainen JA, Lane MV, Sar M, Wilson EM. Androgen receptor phosphorylation, turnover, nuclear transport, and transcriptional activation. Specificity for steroids and antihormones. J Biol Chem. 1992;267(2):968–974. Nguyen TV, Yao M, Pike CJ. Flutamide and cyproterone acetate exert agonist effects: induction of androgen receptor-dependent neuroprotection. Endocrinology. 2007;148(6):2936–2943. Wong C, Kelce WR, Sar M, Wilson EM. Androgen receptor antagonist versus agonist activities of the fungicide vinclozolin relative to hydroxyflutamide. J Biol Chem. 1995;270(34):19998–20003. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Babayev, S.N., Park, C.W., Keller, P.W. et al. Androgens Upregulate Endometrial Epithelial Progesterone Receptor Expression: Potential Implications for Endometriosis. Reprod. Sci. 24, 1454–1461 (2017). https://doi.org/10.1177/1933719117691145 Published: Issue date: DOI: https://doi.org/10.1177/1933719117691145