The synthetic progestin, gestodene, affects functional biomarkers in neonatal rat osteoblasts through an estrogen receptor-related mechanism of action

References

• Riggs BL, Khosla S, Melton LJ III. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002;23:279–302.
   PubMed Web of Science ®Google Scholar
• Qu Q, Perälä-Heape M, Kapanen A, et al. Estrogen enhances differentiation of osteoblasts in mouse bone marrow culture. Bone 1998;22:201–209.
   PubMed Web of Science ®Google Scholar
• MacNamara P, Loughrey HC. Messenger RNA transcripts coding for progesterone receptor A and B isoforms are expressed in human osteoblast cells. Biochem Soc Trans 1998;26:1–7.
   PubMed Web of Science ®Google Scholar
• Rickard DJ, Waters KM, Ruesink TJ, et al. Estrogen receptor isoform-specific induction of progesterone receptors in human osteoblasts. J Bone Miner Res 2002; 17:580–592.
   PubMed Web of Science ®Google Scholar
• Scheven BAA, Damen CA, Hamilton NJ, et al. Stimulatory effects of estrogen and progesterone on proliferation and differentiation of normal human osteoblast-like cells in vitro. Biochem Biophys Res Commun 1992;186:54–60.
   PubMed Web of Science ®Google Scholar
• Canalis E, Raisz LG. Effect of sex steroids on bone collagen synthesis in vitro. Calcified Tissue Research. 1978;25:105–110.
   PubMedGoogle Scholar
• Yamamoto Y, Kurabayashi T, Tojo Y, et al. Effects of progestins on the metabolism of cancellous bone in aged oophorectomized rats. Bone 1998:22:533–537.
   PubMed Web of Science ®Google Scholar
• Ikram Z, Dulipsingh L, Prestwood KM. Lack of effect of short-term micronized progesterone on bone turnover in postmenopausal women. J Womens Health Gend Based Med 1999;8:973–978.
   PubMedGoogle Scholar
• Abdalla HI, Hart DM, Lindsay R, et al. Prevention of bone mineral loss in postmenopausal women by norethisterone. Obstet Gynecol 1985;66:789–792.
   PubMed Web of Science ®Google Scholar
• Christiansen C, Riis BJ. 17 Beta-estradiol and continuous norethisterone: a unique treatment for established osteoporosis in elderly women. J Clin Endocrinol Metab 1990; 71:836–841.
   PubMed Web of Science ®Google Scholar
• Horowitz M, Wishart JM, Need AG, et al. Effects of norethisterone on bone related biochemical variables and forearm bone mineral in post-menopausal osteoporosis. Clin Endocrinol (Oxf) 1993;39:649–655.
   PubMed Web of Science ®Google Scholar
• Riis BJ, Christiansen C, Johansen JS, et al. Is it possible to prevent bone loss in young women treated with luteinizing hormone-releasing hormone agonists? J Clin Endocrinol Metab 1990;70:920–924.
   PubMed Web of Science ®Google Scholar
• Di X, Li Y, Zhang C, et al. Effects of levonorgestrel-releasing subdermal contraceptive implants on bone density and bone metabolism. Contraception 1999;60:161–166.
   PubMed Web of Science ®Google Scholar
• Fortherby K, Caldwell ADS. New progestogens in oral contraception. Contraception. 1994;49:1–132.
   PubMed Web of Science ®Google Scholar
• Stanczyk FZ, Archer DF. Gestodene: a review of its pharmacology, potency and tolerability in combined contraceptive preparations. Contraception 2014;89:242–252.
   PubMed Web of Science ®Google Scholar
• Spona J, Huber J. Efficacy of low-dose oral contraceptives containing levonorgestrel, gestodene and cyproterone acetate. Gynecol Obstet Invest 1987;23:184–193.
   PubMed Web of Science ®Google Scholar
• Kuhl H, Jung-Hoffmann C, Wiegratz I. Gestodene-containing contraceptives. Clin Obstet Gynecol 1995;38:829–840.
   PubMed Web of Science ®Google Scholar
• Lewis MA, Heinemann LAJ, MacRae KD, et al. The increased risk of venous thromboembolism and the use of third generation progestogens: role of bias in observational research. Contraception 1996;54:5–13.
   PubMed Web of Science ®Google Scholar
• Farmer RD, Lawrenson RA, Todd JC, et al. A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives. Br J Clin Pharmacol 2000;49:580–590.
   PubMed Web of Science ®Google Scholar
• Dinger J, Shapito S. Combined oral contraceptives, venous thromboembolism, and the problem of interpreting large but imcomplete datasets. J Fam Plann Reprod Health Care 2012;38:2–6.
   PubMed Web of Science ®Google Scholar
• Heinemann LA, Dinger JC. Range of published estimates of venous thromboembolism incidence in young women. Contraception 2007;75:328–336.
   Google Scholar
• Heinemann LA, Dinger JC, Assmann A, et al. Use of oral contraceptives containing gestodene and risk of venous thromboembolism: outlook 10 years after the third-generation “pill scare”. Contraception 2010;81:401–407.
   PubMed Web of Science ®Google Scholar
• Lidegaard Ø, Nielsen LH, Skovlund CW, et al. Risk of veous thromboembolism from use of oral contraceptives containing different progestogens and oestrogens doses: Danish cohort study, 2001–9. BMJ 2011;343: d6423.
   PubMed Web of Science ®Google Scholar
• Paoletti AM, Orrù M, Floris S, et al. Evidence that treatment with monophasic oral contraceptive formulations containing ethinylestradiol plus gestodene reduces bone resorption in young women. Contraception 2000;61:259–263.
   PubMed Web of Science ®Google Scholar
• Nappi C, Di Spiezio Sardo A, Acunzo G, et al. Effects of a low-dose and ultra-low-dose combined oral contraceptive use on bone turnover and bone mineral density in young fertile women: a prospective controlled randomized study. Contraception 2003;67:355–359.
   Google Scholar
• Nappi C, Di Spiezio Sardo A, Greco E, et al. Effects of an oral contraceptive containing drospirenone on bone turnover and bone mineral density. Obstet Gynecol 2005;105:53–60.
   Google Scholar
• Lemus AE, Santillán R, Damián-Matsumura P, et al. In vitro metabolism of gestodene in target organs: formation of A-ring reduced derivatives with oestrogenic activity. Eur J Pharmacol 2001;417:249–256.
   PubMed Web of Science ®Google Scholar
• Lemus AE, Zaga V, Santillán R, et al. The oestrogenic effects of gestodene, a potent contraceptive progestin, are mediated by its A-ring reduced metabolites. J Endocrinol 2000;165:693–702.
   PubMed Web of Science ®Google Scholar
• Enríquez J, Lemus AE, Chimal-Monroy J, et al. The effects of synthetic 19-norprogestins on osteoblastic cell function are mediated by their non-phenolic reduced metabolites. J Endocrinol 2007;193:493–504.
   PubMed Web of Science ®Google Scholar
• Kaplow LS. A histochemical procedure for localizing and evaluating leukocyte alkaline phosphatase activity in smears of blood and marrow. Blood 1955;10:1023–1027.
   PubMed Web of Science ®Google Scholar
• Arzate H, Alvárez-Pérez MA, Aguilar-Mendoza ME, et al. Human cementum tumor cells have different features from human osteoblastic cells in vitro. J Periodontal Res 1998;33:249–258.
   PubMed Web of Science ®Google Scholar
• Labarca C, Paigen K. A simple, rapid, and sensitive DNA assay procedure. Anal Biochem 1980;102:344–352.
   PubMed Web of Science ®Google Scholar
• Majeska RJ, Ryaby JT, Einhorn TA. Direct modulation of osteoblastic activity with estrogen. J Bone Joint Surg Am 1994;76:713–721.
   PubMed Web of Science ®Google Scholar
• Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248–254.
   PubMed Web of Science ®Google Scholar
• Nibbering PH, Van de Gevel JS, Van Furth R. A cell-ELISA for the quantification of adherent murine macrophages and the surface expression of antigens. J Immunol Methods 1990;131:25–32.
   PubMed Web of Science ®Google Scholar
• Cheng Y-C, Prusoff WH. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 1973;22:3099–3108.
   PubMed Web of Science ®Google Scholar
• Reel JR, Humphrey RR, Shih Y-H, et al. Competitive progesterone antagonists: receptor binding and biologic activity of testosterone and 19-nortestosterone derivatives. Fertil Steril 1979;31:552–561.
   PubMed Web of Science ®Google Scholar
• Bain SD, Lydon JP, Tibbetts T, et al. Mice lacking functional progesterone receptors have no apparent alterations in peak bone mass or bone histomorphometry. J Bone Miner Res 1997;12:S432 (Abstract).
   Google Scholar
• Lemus AE, Enríquez J, Hernández A, et al. Bioconversion of norethisterone, a progesterone receptor agonist into estrogen receptor agonists in osteoblastic cells. J Endocrinol 2009;200:199–206.
   PubMed Web of Science ®Google Scholar
• Enríquez J, Larrea F, Santillán R, et al. Neonatal rat osteoblasts bioconvert testosterone to non-phenolic metabolites with estrogen-like effects on bone cell proliferation and differentiation. Horm Mol Biol Clin Invest 2013;13:41–49.
   PubMedGoogle Scholar
• Shimodaira K, Fujikawa H, Okura F, et al. Osteoblast cells (MG-63 and HOS) have aromatase and 5alpha-reductase activities. Biochem Molec Biol Intern 1996;39:109–116.
   PubMedGoogle Scholar
• Issa S, Schnabel D, Feix M, et al. Human osteoblast-like cells express predominantly steroid 5α-reductase type 1. J Clin Endocrinol Metab 2002;87:5401–5407.
   PubMed Web of Science ®Google Scholar
• Vittek J, Altman K, Gordon GG, et al. The metabolism of 7α-3H-testosterone by rat mandibular bone. Endocrinology 1974;94:325–329.
   PubMed Web of Science ®Google Scholar
• Larrea F, García-Becerra R, Lemus AE, et al. A-ring reduced metabolites of 19-nor synthetic progestins as subtype selective agonists for ER alpha. Endocrinology 2001;142:3791–3799.
   PubMed Web of Science ®Google Scholar
• Gallagher JC, Kable WT, Goldgar D. Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. Am J Med 1991;90:171–178.
   PubMed Web of Science ®Google Scholar
• Liu JH, Muse KN. The effects of progestins on bone density and bone metabolism in postmenopausal women: a randomized controlled trial. Am J Obstet Gynecol 2005;192:1316–1324.
   PubMed Web of Science ®Google Scholar