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Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición S. Zubirán (INCMNSZ), Mexico City 14000, Mexico
¹ Department of Reproductive Biology, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico
² Institute of Biomedical Research,
³ School of Dentistry and
⁴ School of Chemistry, Universidad Nacional Autónoma de Mexico (UNAM), Mexico City 04510, Mexico
⁵ Department of Nephrology and Mineral Metabolism, INCMNSZ, Mexico City, Mexico
⁶ National Institute of Perinatology and School of Medicine, UNAM/Hospital General de México, Montes Urales No. 800, Col. Lomas Virreyes, Mexico, D.F., C.P. 11000, Mexico City, Mexico

(Requests for offprints should be addressed to G Pérez-Palacios; Email: gperezpal{at}prodigy.net.mx)

The key role of estrogens on osteoblastic cell function is well documented; however, the role of progesterone (P) and synthetic progestins remains controversial. While several reports indicate that P has no significant effects on bone cells, a number of clinical studies have shown that 19-norprogestins restore postmenopausal bone loss. The mechanisms by which 19-norprogestins induce estrogen-like effects on bone cells are not fully understood. To assess whether the actions of 19-norprogestins on osteoblasts are mediated by their non-phenolic metabolites, we studied the effects of norethisterone (NET), levonorgestrel (LNG), and two of their A-ring reduced derivatives upon cell proliferation and differentiation in neonatal rat osteoblasts. Osteoblast function was assessed by determining cell DNA, cell-associated osteocalcin and calcium content, alkaline phosphatase activity, and mineral deposition. P failed to induce changes on osteoblasts, while NET and LNG exerted a number of actions. The most striking finding was that the 3ß,5- and 3,5-tetrahydro derivatives of NET and LNG induced osteoblast proliferation and differentiation with higher potency than those exerted by their parent compounds, mimicking the effects of estradiol. Interestingly, osteoblast differentiation and mineral deposition induced by NET and LNG were abolished by finasteride, a 5-reductases inhibitor, while the potent effect on osteoblast proliferation induced by progestin derivatives was abolished by a steroidal antiestrogen. Results demonstrate that A-ring reduced derivatives of NET and LNG exhibit intrinsic estrogen-like potency on rat osteoblasts, offering a plausible explanation for the mechanism of action of 19-norprogestins in bone restoration in postmenopausal women and providing new insights for hormone replacement therapy research.