{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T14:30:53Z","timestamp":1772807453009,"version":"3.50.1"},"reference-count":39,"publisher":"The Endocrine Society","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,9,1]]},"abstract":"<jats:p>After the unexpected findings of the Women\u2019s Health Initiative trial, indicating that traditional cardiovascular risk markers fail to predict the effects of hormone replacement therapy, it is of interest to characterize how steroids act on vascular cells. This is particularly important for tissue-specific drugs such as tibolone, whose actions may differ from other preparations. Because nitric oxide (NO) is a key regulator of vascular tone and atherogenesis, we studied its regulation by tibolone and its metabolites on human endothelial cells. Tibolone and its estrogenic metabolites (3\u03b1- and 3\u03b2-OH tibolone) activate NO synthesis by recruiting functional estrogen receptors, whereas the progestogenic\/androgenic metabolite (\u03944 isomer) has no effect. During prolonged exposures, tibolone and the estrogenic compounds enhance the expression of endothelial NO synthase (eNOS). In addition, tibolone is able to induce rapid activation of eNOS, leading to rapid increases in the release of NO. Relevant for its clinical effects, the sulfated metabolites of tibolone are also effective in activating eNOS. Different from estrogen, rapid activation of eNOS does not rely on recruitment of phosphatidylinositol-3 kinase but rather on MAPK-dependent cascades. These results help to understand the mechanisms of action of tibolone on the cardiovascular system and have relevant clinical implications.<\/jats:p>","DOI":"10.1210\/jc.2003-032189","type":"journal-article","created":{"date-parts":[[2004,9,8]],"date-time":"2004-09-08T03:32:28Z","timestamp":1094614348000},"page":"4594-4600","source":"Crossref","is-referenced-by-count":29,"title":["Tibolone Activates Nitric Oxide Synthesis in Human Endothelial Cells"],"prefix":"10.1210","volume":"89","author":[{"given":"Tommaso","family":"Simoncini","sequence":"first","affiliation":[{"name":"Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa 56100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Mannella","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa 56100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Letizia","family":"Fornari","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa 56100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Caruso","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa 56100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaetano","family":"Varone","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa 56100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Garibaldi","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa 56100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea R.","family":"Genazzani","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa 56100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071617390553000_R1"},{"key":"2020071617390553000_R2","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1056\/NEJM199906103402306","article-title":"The protective effects of estrogen on the cardiovascular system.","volume":"340","author":"Mendelsohn","year":"1999","journal-title":"N Engl J Med"},{"key":"2020071617390553000_R3","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1001\/jama.280.7.605","article-title":"Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. 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