Original research article| Volume 99, ISSUE 1, P61-66, January 2019

Effects of different progestins on prostaglandin biosynthesis in human endometrial explants



      To compare the effects of chlormadinone acetate (CMA), dienogest (DNG) and drospirenone (DRSP) on prostaglandin biosynthesis in a human endometrial explants model.

      Study design

      Human endometrial explants obtained by aspiration curettage and human endometrial YHES cells were stimulated with interleukin-1β (IL-1β) and exposed to CMA, DNG, DRSP or dexamethasone (DEX; YHES cells). Cellular messenger RNA (mRNA) levels of cyclooxygenase-2 (COX-2) were analyzed by reverse-transcription quantitative real-time polymerase chain reaction. Concentrations of prostaglandin F (PGF) in culture supernatants were measured by enzyme-linked immunosorbent assay.


      CMA exerted after IL-1β stimulation a stronger down-regulation of COX-2 mRNA compared to DNG and DRSP in human explants (−55% vs. −40% and 46%, respectively). The effect of CMA on COX-2 mRNA was significantly stronger (p=.025) than that of DNG. Moreover, the effect of CMA was independent from cycle phase or presence of endometriosis. In order to evaluate the impact of the investigated progestins on effector molecules, PGF release was determined in supernatants. Again, CMA reduced the PGF release significantly by an average of −60% (p<.01). In contrast, no significant reduction was found for DNG and DRSP. In YHES cells, only DEX but not the progestins under study exerted a significant down-regulating effect (−79%, p<.01) on COX-2 mRNA after IL-1β stimulation.


      Among the tested progestins, CMA displayed the most consistent suppression of prostaglandin biosynthesis in human endometrial explants.


      Among three tested progestins, chlormadinone acetate had the most consistent suppressive effect on prostaglandins in endometrial explants. These findings support clinical observations about the efficacy of chlormadinone acetate in dysmenorrhea treatment.


      CMA (chlormadinone acetate), COX-2 (cyclooxygenase-2), DEX (dexamethasone), DNG (dienogest), DRSP (drospirenone), IL-1β (interleukin-1β), PGE2 (prostaglandin E2), PGF2α (prostaglandin F2α)


      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 to Contraception
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Harel Z.
        Dysmenorrhea in adolescents.
        Ann N Y Acad Sci. 2008; 1135: 185-195
        • Proctor M.
        • Farquhar C.
        Diagnosis and management of dysmenorrhoea.
        BMJ. 2006; 332: 1134-1138
        • Wong C.L.
        • Farquhar C.
        • Roberts H.
        • Proctor M.
        Oral contraceptive pill for primary dysmenorrhoea.
        Cochrane Database Syst Rev. 2009; 4CD002120
        • Zahradnik H.P.
        • Hanjalic-Beck A.
        • Groth K.
        Nonsteroidal anti-inflammatory drugs and hormonal contraceptives for pain relief from dysmenorrhea: a review.
        Contraception. 2010; 81: 185-196
        • Marjoribanks J.
        • Ayeleke R.O.
        • Farquhar C.
        • Proctor M.
        Nonsteroidal anti-inflammatory drugs for dysmenorrhea.
        Cochrane Database Syst Rev. 2015; 7CD001751
        • Jabbour H.N.
        • Kelly R.W.
        • Fraser H.M.
        • Critchley H.O.D.
        Endocrine regulation of menstruation.
        Endocr Rev. 2006; 27: 17-46
        • Benedetto C.
        Eicosanoids in primary dysmenorrhea, endometriosis and menstrual migraine.
        Gynecol Endocrinol. 1989; 3: 71-94
        • Zahradnik H.P.
        • Breckwoldt M.
        Contribution to the pathogenesis of dysmenorrhea.
        Arch Gynecol. 1984; 236: 99-108
        • Maybin J.A.
        • Critchley H.O.D.
        • Jabbour H.N.
        Inflammatory pathways in endometrial disorders.
        Mol Cell Endocrinol. 2011; 335: 42-51
        • Pickles V.R.
        • Hall W.J.
        • Best F.A.
        • Smith G.N.
        Prostaglandins in endometrium and menstrual fluid from normal and dysmenorrhoeic subjects.
        J Obstet Gynecol Br Commonw. 1965; 72: 185-192
        • Abel M.H.
        • Baird D.T.
        The effect of 17-beta-estradiol and progesterone on prostaglandin production by human endometrium maintained in organ culture.
        Endocrinology. 1980; 106: 1599-1606
        • Schatz F.
        • Markiewicz L.
        • Gurpide E.
        Hormonal effects of PGF2alpha output by cultures of epithelial and stromal cells in human endometrium.
        J Steroid Biochem. 1986; 24: 297-301
        • Catalano R.D.
        • Wilson M.R.
        • Boddy S.C.
        • Jabbour H.N.
        Comprehensive expression analysis of prostanoid enzymes and receptors in the human endometrium across the menstrual cycle.
        Mol Hum Reprod. 2011; 17: 182-192
        • Maybin J.A.
        • Critchley H.O.D.
        Menstrual physiology: implications for endometrial pathology and beyond.
        Hum Reprod Update. 2015; 21: 748-761
        • Schneider J.
        • Kneip C.
        • Jahnel U.
        Comparative effects of chlormadinone acetate and its 3α- and 3β-hydroxy metabolites on progesterone, androgen and glucocorticoid receptors.
        Pharmacology. 2009; 84: 74-81
        • Schramm G.
        • Steffens D.
        A 12-month evaluation of the CMA-containing oral contraceptive Belara: efficacy, tolerability and anti-androgenic properties.
        Contraception. 2003; 67: 305-312
        • Zahradnik H.P.
        Belara - a reliable oral contraceptive with additional benefits for health and efficacy in dysmenorrhea.
        Eur J Contracept Reprod Health Care. 2005; 10: 12-18
        • Schramm G.
        • Heckes B.
        Switching hormonal contraceptives to a chlormadinone acetate-containing oral contraceptive. The Contraceptive Switch Study.
        Contraception. 2007; 76: 84-90
        • Anthuber S.
        • Schramm G.A.
        • Heskamp M.L.
        Six-month evaluation of the benefits of the low-dose combined oral contraceptive chlormadinone acetate 2mg/ethinylestradiol 0.03 mg in young women: results of the prospective, observational, non-interventional, multicentre TeeNIS study.
        Clin Drug Investig. 2010; 30: 211-220
        • Göretzlehner G.
        • Waldmann-Rex S.
        • Schramm G.A.K.
        Extended cycles with the combined oral contraceptive chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg.
        Clin Drug Investig. 2011; 31: 269-277
        • Sabatini R.
        • Orsini G.
        • Cagiano R.
        • Loverro G.
        Noncontraceptive benefits of two combined oral contraceptives with antiandrogenic properties among adolescents.
        Contraception. 2007; 76: 342-347
        • Machado R.B.
        • Pompei LdM
        • Giribela A.G.
        • Giribela C.G.
        Drospirenone/ethinylestradiol: a review on efficacy and noncontraceptive benefits.
        Womens Health (Lond Engl). 2011; 7: 19-30
        • Petraglia F.
        • Parke S.
        • Serrani M.
        • Mellinger U.
        • Römer T.
        Estradiol valerate plus dienogest versus ethinylestradiol plus levonorgestrel for the treatment of primary dysmenorrhea.
        Int J Gynaecol Obstet. 2014; 125: 270-274
        • Kim S.A.
        • Um M.J.
        • Kim H.K.
        • Kim S.J.
        • Moon S.J.
        • Jung H.
        Study of dienogest for dysmenorrhea and pelvic pain associated with endometriosis.
        Obstet Gynecol Sci. 2016; 59: 506-511
        • Stavreus-Evers A.
        • Hovatta O.
        • Eriksson H.
        • Landgren B.M.
        Development and characterization of an endometrial tissue culture system.
        Reprod Biomed Online. 2003; 7: 243-249
        • Schäfer W.R.
        • Fischer L.
        • Roth K.
        • Jüllig A.
        • Stuckenschneider J.E.
        • Schwartz P.
        • et al.
        Critical evaluation of human endometrial explants as an ex vivo model system: a molecular approach.
        Mol Hum Reprod. 2011; 17: 255-265
        • Hanjalic-Beck A.
        • Schäfer W.R.
        • Deppert W.R.
        • Fischer L.
        • Stein A.
        • Seebacher L.
        • et al.
        Chlormadinone acetate suppresses prostaglandin biosynthesis in human endometrial explants.
        Fertil Steril. 2012; 98: 1017-1022
        • Bouchard P.
        Chlormadinone acetate (CMA) in oral contraception — a new opportunity.
        Eur J Contracept Reprod Health Care. 2005; 10: 7-11
        • Stanczyk F.Z.
        Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception.
        Rev Endocr Metab Disord. 2002; 3: 211-224
        • Findlay J.W.A.
        • Smith W.C.
        • Lee J.W.
        • Nordblom G.D.
        • Das I.
        • DeSilva B.S.
        • et al.
        Validation of immunoassays for bioanalysis: a pharmaceutical industry perspective.
        J Pharm Biomed Anal. 2000; 21: 1249-1273
        • Viswanathan C.T.
        • Bansal S.
        • Booth B.
        • DeStefano A.J.
        • Rose M.J.
        • Sailstad J.
        • et al.
        Quantitative bioanalytical methods validation and implementation: best practices for chromatographic and ligand binding assays.
        Pharm Res. 2007; 24: 1962-1973
        • Tamura I.
        • Taketani T.
        • Lee L.
        • Kizuka F.
        • Taniguchi K.
        • Maekawa R.
        • et al.
        Differential effects of progesterone on COX-2 and Mn-SOD expressions are associated with histone acetylation status of the promoter region in human endometrial stromal cells.
        J Clin Endocrinol Metab. 2011; 96: E1073-E1082
        • Wiegratz I.
        • Kuhl H.
        Metabolic and clinical effects of progestogens.
        Eur J Contracept Reprod Health Care. 2006; 11: 153-161
        • Hapgood J.P.
        • Africander D.
        • Louw R.
        • Ray R.M.
        • Rohwer J.M.
        Potency of progestogens used in hormonal therapy: toward understanding differential actions.
        J Steroid Biochem Mol Biol. 2014; 142: 39-47
        • Bulun S.E.
        N Engl J Med. 2009; 360: 268-279
        • Banu S.K.
        • Lee J.
        • Speights Jr., V.O.
        • Starzinski-Powitz A.
        • Arosh J.A.
        Cyclooxygenase-2 regulates survival, migration, and invasion of human endometriotic cells through multiple mechanisms.
        Endocrinology. 2008; 149: 1180-1189
        • Chapdelaine P.
        • Kang J.
        • Boucher-Kovalik S.
        • Caron N.
        • Tremblay J.P.
        • Fortier M.A.
        Decidualization and maintenance of a functional prostaglandin system in human endometrial cell lines following transformation with SV40 large T antigen.
        Mol Hum Reprod. 2006; 12: 309-319
        • Stavreus-Evers A.
        • Koraen L.
        • Scott J.E.
        • Zhang P.
        • Westlund P.
        Distribution of cyclooxygenase-1, cyclooxygenase-2, and cytosolic phospholipase A2 in the luteal phase human endometrium and ovary.
        Fertil Steril. 2005; 83: 156-162
        • Huang J.C.
        • Ruan C.H.
        • Tang K.
        • Ruan K.H.
        Prunella stica inhibits the proliferation but not the prostaglandin production of Ishikawa cells.
        Life Sci. 2006; 79: 436-441
        • Kim J.J.
        • Kurita T.
        • Bulun S.E.
        Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer.
        Endocr Rev. 2013; 34: 130-162