{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T05:46:49Z","timestamp":1761630409535},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[1997,4,1]],"date-time":"1997-04-01T00:00:00Z","timestamp":859852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1997,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Our laboratory has demonstrated that the immunosuppressants Cyclosporin A (CsA) and tacrolimus (FK506), in vivo in the rat, produce a high-turnover osteopenia. CsA is known to decrease serum testosterone (Test) levels both in the rat and in human transplant patients. Less is known of FK506's effect on androgens. CsA-induced hypogonadism may contribute to the aforementioned bone loss because hypogonadism itself is a risk factor for osteoporosis and fracture. The aim of this study was to assess serum androgen levels following CsA and FK506 therapy and to see whether Test replacement therapy, in the form of 28-day controlled release subcutaneous pellet implants, could prevent CsA-induced osteopenia. Two experiments were conducted. In experiment I, four groups of 6-month-old male Sprague-Dawley rats received the following: (A) CsA vehicle and placebo pellet, (B) Test 15 mg pellet and CsA vehicle, (C) CsA 10 mg\/kg and placebo pellet, (D) Test 15 mg pellet and CsA 10 mg\/kg. In experiment II, two groups of rats received (E) FK506 vehicle and (F) FK506 4 mg\/kg. CsA, FK506, and vehicles were given for 28 days by daily oral gavage. The rats were weighed and bled on days 0, 14, and 28. All rats received double fluorescent labeling, and on day 28 the tibiae were removed for histomorphometry. Whole blood was assayed for CsA and FK506 levels. Serum was assayed for total and free Test as well as for osteocalcin (BGP), blood urea nitrogen (BUN), creatinine, and calcium. Whole blood monoclonal CsA levels measured by fluorescent immunoassay were in the therapeutic range, while a drug concentration profile showed good absorption of FK506. Those rats receiving Test and FK506 lost weight, while those receiving CsA remained constant. BUN was only marginally elevated in the CsA-treated groups on day 28 (p &amp;lt; 0.05), while creatinine was unchanged. On day 28, total and free Test was significantly reduced in the CsA-treated rats versus control (p &amp;lt; 0.05), while Test replacement therapy maintained total Test levels above vehicle (p &amp;lt; 0.01) and free Test levels similar to vehicle on day 28. FK506 did not lower total or free Test levels. BGP levels were significantly increased in the CsA (p &amp;lt; 0.01) and FK506 (p &amp;lt; 0.001) groups on day 28. BGP in the groups receiving Test alone and in combination with CsA remained similar to vehicle. Histomorphometry confirmed CsA- and FK506-induced high-turnover osteopenia. The Test alone group marginally increased bone formation. Test replacement failed to prevent the CsA-induced bone loss. In conclusion, immunosuppressive doses of CsA, but not FK506, lowers serum total and free Test. Hypoandrogenemia does not seem to be a major factor in CsA-induced osteopenia because bone loss occurs despite Test replacement.<\/jats:p>","DOI":"10.1359\/jbmr.1997.12.4.607","type":"journal-article","created":{"date-parts":[[2006,4,26]],"date-time":"2006-04-26T22:14:04Z","timestamp":1146089644000},"page":"607-615","source":"Crossref","is-referenced-by-count":53,"title":["The Role of Testosterone in Cyclosporine-Induced Osteopenia"],"prefix":"10.1093","volume":"12","author":[{"given":"A. R.","family":"Bowman","sequence":"first","affiliation":[{"name":"Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. A.","family":"Sass","sequence":"additional","affiliation":[{"name":"Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I. R.","family":"Dissanayake","sequence":"additional","affiliation":[{"name":"Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y. F.","family":"Ma","sequence":"additional","affiliation":[{"name":"Division of Radiobiology, University of Utah, Salt Lake City, Utah, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Liang","sequence":"additional","affiliation":[{"name":"Division of Radiobiology, University of Utah, Salt Lake City, Utah, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Z.","family":"Yuan","sequence":"additional","affiliation":[{"name":"Division of Radiobiology, University of Utah, Salt Lake City, Utah, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. S. S.","family":"Jee","sequence":"additional","affiliation":[{"name":"Division of Radiobiology, University of Utah, Salt Lake City, Utah, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Epstein","sequence":"additional","affiliation":[{"name":"Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024020720020484100_bib1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jbmr.5650110102","article-title":"Post-transplantation bone disease: The role of immunosuppressive agents and the skeleton","volume":"11","author":"Epstein","year":"1996","journal-title":"J Bone Miner Res"},{"key":"2024020720020484100_bib2","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1002\/jbmr.5650100513","article-title":"Rapamycin: A bone sparing immunosuppressant?","volume":"10","author":"Romero","year":"1995","journal-title":"J Bone Miner Res"},{"key":"2024020720020484100_bib3","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1097\/00007890-199404270-00016","article-title":"The deleterious effects of long-term cyclosporin A, cyclosporin G, and FK506 on bone mineral metabolism in vivo","volume":"57","author":"Cvetkovic","year":"1994","journal-title":"Transplantation"},{"key":"2024020720020484100_bib4","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.1210\/endo-123-5-2571","article-title":"Cyclosporin A in vivo produces severe osteopenia in the rat: Effect of dose and duration of administration","volume":"123","author":"Movsowitz","year":"1988","journal-title":"Endocrinology"},{"key":"2024020720020484100_bib5","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1210\/endo-124-5-2179","article-title":"The effect of cyclosporin A administration and its withdrawal on bone mineral metabolism in the rat","volume":"124","author":"Schlosberg","year":"1989","journal-title":"Endocrinology"},{"key":"2024020720020484100_bib6","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/jbmr.5650010307","article-title":"Cyclosporine A inhibits calcemic hormone-induced bone resorption in vitro","volume":"1","author":"Stewart","year":"1986","journal-title":"J Bone Miner Res"},{"key":"2024020720020484100_bib7","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/BF02556041","article-title":"Cyclosporines: Correlation of immunosuppressive activity and inhibition of bone resorption","volume":"45","author":"Stewart","year":"1989","journal-title":"Calcif Tissue Int"},{"key":"2024020720020484100_bib8","first-page":"584","article-title":"Cyclosporin A inhibits bone resorption in cultured neonatal mouse calvaria","volume":"243","author":"Klaushofer","year":"1987","journal-title":"J Pharmacol Exp Ther"},{"key":"2024020720020484100_bib9","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/S0140-6736(88)91862-4","article-title":"Bone histology in renal transplant patients receiving cyclosporin","volume":"1","author":"Aubia","year":"1988","journal-title":"Lancet"},{"key":"2024020720020484100_bib10","first-page":"1048","article-title":"Bone histology in renal transplant patients receiving cyclosporin","volume":"1","author":"Bourbigot","year":"1988","journal-title":"Lancet"},{"key":"2024020720020484100_bib11","first-page":"1740","article-title":"Fracture after cardiac transplantation\u2014A prospective longitudinal study","volume":"81","author":"Shane","year":"1996","journal-title":"JCEM"},{"key":"2024020720020484100_bib12","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/0002-9343(93)90057-V","article-title":"Osteoporosis after cardiac transplantation","volume":"94","author":"Shane","year":"1993","journal-title":"Am J Med"},{"key":"2024020720020484100_bib13","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/BF01623351","article-title":"Mechanisms of rapid bone loss following cardiac transplantation","volume":"4","author":"Sambrook","year":"1994","journal-title":"Osteoporosis Int"},{"key":"2024020720020484100_bib14","first-page":"950","article-title":"Cyclosporine A and prednisone-associated osteoporosis in heart transplant recipients","volume":"11","author":"Rich","year":"1992","journal-title":"J Heart Lung Transplant"},{"key":"2024020720020484100_bib15","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1002\/hep.1840140407","article-title":"Bone loss after liver transplantation","volume":"14","author":"McDonald","year":"1991","journal-title":"Hepatology"},{"key":"2024020720020484100_bib16","first-page":"991","article-title":"Effect of cyclosporin A on male reproduction in rats","volume":"138","author":"Seethalakshmi","year":"1987","journal-title":"Endocrinology"},{"key":"2024020720020484100_bib17","first-page":"190","article-title":"The mechanism of cyclosporine's action in the inhibition of testosterone biosynthesis by rat Leydig cells in vitro","volume":"53","author":"Seethalakshmi","year":"1992","journal-title":"Endocrinology"},{"key":"2024020720020484100_bib18","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1210\/endo-123-2-1069","article-title":"Effects of cyclosporine on the hypothalamic-pituitary-gonadal axis in the male rat: Mechanism of action","volume":"123","author":"Sikka","year":"1988","journal-title":"Endocrinology"},{"key":"2024020720020484100_bib19","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1210\/endo-129-5-2647","article-title":"Cyclosporin-mediated depression of luteinizing hormone receptors and heme biosynthesis in rat testis: A possible mechanism for decrease in serum testosterone","volume":"129","author":"Krueger","year":"1991","journal-title":"Endocrinology"},{"key":"2024020720020484100_bib20","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1210\/endo-121-2-586","article-title":"Cyclosporine inhibits testosterone biosynthesis in the rat testis","volume":"121","author":"Rajfer","year":"1987","journal-title":"Endocrinology"},{"key":"2024020720020484100_bib21","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1159\/000185704","article-title":"Influence of type of immunosuppressive therapy on secretion of somatotropin and function of the pituitary-adrenal and pituitary-gonadal axis in patients with a kidney transplant","volume":"53","author":"Nieszporek","year":"1989","journal-title":"Nephron"},{"key":"2024020720020484100_bib22","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1159\/000186373","article-title":"Cyclosporin-induced alterations in the hypothalamic hypophyseal gonadal axis in transplant patients","volume":"58","author":"Ramirez","year":"1991","journal-title":"Nephron"},{"key":"2024020720020484100_bib23","first-page":"3272","article-title":"Modes of action of FK506, Cyclosporin A, and rapamycin","volume":"26","author":"Morris","year":"1994","journal-title":"Trans Proc"},{"key":"2024020720020484100_bib24","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/0026-0495(94)90191-0","article-title":"Effect of FK506 on rat Leydig cell function\u2014in vivo and in vitro study","volume":"43","author":"Tai","year":"1994","journal-title":"Metabolism"},{"key":"2024020720020484100_bib25","doi-asserted-by":"crossref","first-page":"354","DOI":"10.7326\/0003-4819-106-3-","article-title":"Osteoporosisin men with idiopathic hypogonadotrpic hypogonadism","volume":"106","author":"Finkelstein","year":"1987","journal-title":"Ann Int Med"},{"key":"2024020720020484100_bib26","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1365-2265.1992.tb02910.x","article-title":"Osteoporosis in Klinefelter's syndrome","volume":"36","author":"Horowitz","year":"1992","journal-title":"Clin Endocrinol"},{"key":"2024020720020484100_bib27","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/0002-9343(83)90878-1","article-title":"Risk factors for osteoporosis in men","volume":"75","author":"Seeman","year":"1983","journal-title":"Am J Med"},{"key":"2024020720020484100_bib28","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1111\/j.1532-5415.1991.tb02698.x","article-title":"Does hypogonadism contribute to the occurrence of a minimal trauma hip fracture in elderly men","volume":"39","author":"Stanley","year":"1991","journal-title":"J Am Geriatr Soc"},{"key":"2024020720020484100_bib29","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0169-6009(08)80057-8","article-title":"Time-related increase of biochemical markers of bone turnover in androgen-deficient male rats","volume":"26","author":"Vanderschueren","year":"1994","journal-title":"Bone Miner"},{"key":"2024020720020484100_bib30","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1002\/jbmr.5650101117","article-title":"Early induction of alterations in cancellous and cortical bone histology after orchiectomy in mature rats","volume":"10","author":"Gunness","year":"1995","journal-title":"J Bone Miner Res"},{"key":"2024020720020484100_bib31","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1210\/endo.130.5.1572302","article-title":"Bone and mineral metabolism in aged male rats: Short and long term effects of androgen deficiency","volume":"130","author":"Vanderschueren","year":"1992","journal-title":"Endocrinology"},{"key":"2024020720020484100_bib32","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/jbmr.5650040415","article-title":"Differential effects of gonadal function on bone histomorphometry in male and female rats","volume":"4","author":"Turner","year":"1989","journal-title":"J Bone Miner Res"},{"key":"2024020720020484100_bib33","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1002\/jbmr.5650060403","article-title":"Androgen treatment prevents loss of cancellous bone in the orchidectomized rat","volume":"6","author":"Wakley","year":"1991","journal-title":"J Bone Miner Res"},{"key":"2024020720020484100_bib34","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1002\/jor.1100080418","article-title":"Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats","volume":"8","author":"Turner","year":"1990","journal-title":"J Orthop Res"},{"issue":"Suppl 2","key":"2024020720020484100_bib35","first-page":"61","article-title":"Cyclosporins past, present, and future","volume":"24","author":"Mason","year":"1992","journal-title":"Trans Proc"},{"key":"2024020720020484100_bib36","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1172\/JCI109954","article-title":"New biochemical marker for bone metabolism: Measurement by radioimmunoassay of bone gla protein in the plasme of normal subjects and patients with bone disease","volume":"66","author":"Price","year":"1980","journal-title":"J Clin Invest"},{"key":"2024020720020484100_bib37","first-page":"101","volume-title":"Handbook of Bone Morphology","author":"Jee","year":"1983"},{"key":"2024020720020484100_bib38","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/jbmr.5650020617","article-title":"Bone histomorphometry: Standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Committee","volume":"2","author":"Parfitt","year":"1987","journal-title":"J Bone Miner Res"},{"key":"2024020720020484100_bib39","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/BF00301598","article-title":"Androgens and bone","volume":"56","author":"Vanderschueren","year":"1995","journal-title":"Calcif Tissue Int"},{"key":"2024020720020484100_bib40","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1073\/pnas.86.3.854","article-title":"Identification of androgen receptors in normal human osteoblast-like cells","volume":"86","author":"Colvard","year":"1989","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020720020484100_bib41","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/BF02556115","article-title":"Androgen receptors in osteoblast-like cells","volume":"49","author":"Orwoll","year":"1991","journal-title":"Calcif Tissue Int"},{"key":"2024020720020484100_bib42","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1210\/endo-124-3-1576","article-title":"Androgens directly stimulate proliferation of bone cells in vitro","volume":"124","author":"Kasperk","year":"1989","journal-title":"Endocrinology"},{"key":"2024020720020484100_bib43","doi-asserted-by":"crossref","first-page":"2886","DOI":"10.1172\/JCI117995","article-title":"Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens","volume":"95","author":"Bellido","year":"1995","journal-title":"J Clin Invest"},{"key":"2024020720020484100_bib44","first-page":"1578","article-title":"17\u03b2-estradiol prevents osteopenia in the oophorectomized rat treated with cyclosporin-A","volume":"130","author":"Joffe","year":"1992","journal-title":"Endocrinology"},{"issue":"suppl 1","key":"2024020720020484100_bib45","first-page":"S256","article-title":"The bisphosphonate, alendronate, reverses cyclosporine-induced osteopenia in the aged rat","volume":"10","author":"Sass","year":"1995","journal-title":"J Bone Miner Res"},{"key":"2024020720020484100_bib46","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1210\/endo.137.6.8641176","article-title":"T-lymphocytes play a critical role in the development of cyclosporine A-induced osteopenia","volume":"137","author":"Buchinsky","year":"1996","journal-title":"Endocrinology"},{"key":"2024020720020484100_bib47","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1097\/00007890-199511000-00020","article-title":"Inhibition of intimal hyperplasia in rat aortic allografts with cyclosporine","volume":"60","author":"Stoltenberg","year":"1995","journal-title":"Transplantation"},{"key":"2024020720020484100_bib48","first-page":"1416","article-title":"Toxicity of cyclosporine during treatment with androgens","volume":"28","author":"Broch Moller","year":"1985","journal-title":"New Engl J Med"},{"key":"2024020720020484100_bib49","first-page":"163","article-title":"Selective suppression of rat hepatic microsomal activity by chronic cyclosporine treatment","volume":"8","author":"Brunner","year":"1995","journal-title":"ISSX Proceedings"},{"issue":"Suppl 3","key":"2024020720020484100_bib50","first-page":"1005","article-title":"Cyclosporin-induced testicular dysfunction: A separation of the nephrotoxic component and an assessment of a 60-day recovery period","volume":"3","author":"Seethalakshmi","year":"1988","journal-title":"Trans Proc XX"},{"key":"2024020720020484100_bib51","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1097\/00007890-198804000-00023","article-title":"Reversibility of cyclosporine-induced hypoandrogenism in rats","volume":"45","author":"Sikka","year":"1988","journal-title":"Transplantation"},{"key":"2024020720020484100_bib52","first-page":"959","article-title":"Prevention of loss of vertebral bone density in heart transplant patients","volume":"11","author":"Muchmore","year":"1992","journal-title":"J Heart Lung Transplant"},{"key":"2024020720020484100_bib53","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/j.1939-4640.1992.tb00330.x","article-title":"Changes in the hypothalamic-pituitary-gonadal axis in men after cadaver kidney transplantation and cyclosporin therapy","volume":"13","author":"Samojlik","year":"1992","journal-title":"J Androl"},{"issue":"Suppl 6","key":"2024020720020484100_bib54","first-page":"89","article-title":"Toxicology of FK-506 in the Lewis rat","volume":"XIX","author":"Nalesnik","year":"1987","journal-title":"Trans Proc"},{"key":"2024020720020484100_bib55","volume-title":"The Biology and Medicine of Rabbits and Rodents","author":"Harkness","year":"1989","edition":"3rd Ed."}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1359%2Fjbmr.1997.12.4.607","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/12\/4\/607\/56615279\/5650120413_ftp.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/12\/4\/607\/56615279\/5650120413_ftp.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:54:55Z","timestamp":1710341695000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/12\/4\/607-615\/7514156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,4,1]]},"references-count":55,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2009,12,4]]},"published-print":{"date-parts":[[1997,4,1]]}},"URL":"https:\/\/doi.org\/10.1359\/jbmr.1997.12.4.607","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[1997,4,1]]},"published":{"date-parts":[[1997,4,1]]}}}