{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T05:31:38Z","timestamp":1767850298353,"version":"3.49.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T00:00:00Z","timestamp":1581984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100008571","name":"SIU School of Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008571","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,26]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Androgens are essential for penile development and for maintaining penile structural and functional integrity. Loss of androgen levels or function results in a decrease in smooth muscle content, accumulation of adipocytes in the corpora cavernosa, and inhibition of erectile function. Our previous studies with a mouse model (KiLHRD582G) of constitutive luteinizing hormone receptor activity also showed structural abnormalities in the penis caused by a decrease in smooth muscle content, accumulation of chondrocytes, and sexual dysfunction. As KiLHRD582G mice exhibit very high levels of testosterone at all postnatal ages, the goal of this study was to determine if the elevated androgen levels were responsible for the morphological changes in the penis. Implantation of testosterone capsules in wild-type mice at neonatal (2\u00a0weeks) and postpubertal (5\u00a0weeks) ages resulted in the accumulation of chondrocytes in the corpora cavernosa of the adult animals. Mice implanted with testosterone capsules at 2\u00a0weeks of age exhibited a 4-fold increase in serum testosterone with a 1.5-fold loss of smooth muscle at 24\u00a0weeks of age. Collagen content was unchanged. Only 57% of testosterone implanted mice were fertile at 24\u00a0weeks of age. Mice implanted with testosterone capsules at 5\u00a0weeks of age showed no decrease in smooth muscle content at 24\u00a0weeks, although serum testosterone levels were elevated 5-fold. Implantation with dihydrotestosterone also resulted in chondrocyte accumulation and a 2-fold loss in smooth muscle content. Together, these studies demonstrate that supraphysiological levels of androgens cause structural changes in the penile corpora cavernosa and impair fertility.<\/jats:p>","DOI":"10.1093\/biolre\/ioaa023","type":"journal-article","created":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T10:03:09Z","timestamp":1582020189000},"page":"1225-1233","source":"Crossref","is-referenced-by-count":4,"title":["High levels of androgens cause chondrocyte accumulation and loss of smooth muscle in the mouse penile body\u2020"],"prefix":"10.1093","volume":"102","author":[{"given":"Deepak S","family":"Hiremath","sequence":"first","affiliation":[{"name":"Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth C","family":"Geerling","sequence":"first","affiliation":[{"name":"Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Hai","sequence":"first","affiliation":[{"name":"Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prema","family":"Narayan","sequence":"first","affiliation":[{"name":"Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,2,18]]},"reference":[{"key":"2020052802395322000_ref1","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1111\/j.1365-2605.2009.01005.x","article-title":"Androgen action in the masculinization programming window and development of male reproductive organs","volume":"33","author":"Macleod","year":"2010","journal-title":"Int J Androl"},{"key":"2020052802395322000_ref2","doi-asserted-by":"crossref","first-page":"e144","DOI":"10.1111\/j.1365-2605.2009.00978.x","article-title":"Critical androgen-sensitive periods of rat penis and clitoris development","volume":"33","author":"Welsh","year":"2010","journal-title":"Int J Androl"},{"key":"2020052802395322000_ref3","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/j.jsxm.2016.06.004","article-title":"Translational perspective on the role of testosterone in sexual function and dysfunction","volume":"13","author":"Podlasek","year":"2016","journal-title":"J Sex Med"},{"key":"2020052802395322000_ref4","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1111\/j.1743-6109.2005.00094.x","article-title":"The physiological role of androgens in penile erection: Regulation of corpus cavernosum structure and function","volume":"2","author":"Traish","year":"2005","journal-title":"J Sex Med"},{"key":"2020052802395322000_ref5","doi-asserted-by":"crossref","first-page":"363","DOI":"10.2164\/jandrol.108.006007","article-title":"Androgens play a pivotal role in maintaining penile tissue architecture and erection: A review","volume":"30","author":"Traish","year":"2009","journal-title":"J Androl"},{"key":"2020052802395322000_ref6","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1210\/endo.140.4.6655","article-title":"Effects of castration and androgen replacement on erectile function in a rabbit model","volume":"140","author":"Traish","year":"1999","journal-title":"Endocrinology"},{"key":"2020052802395322000_ref7","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1002\/j.1939-4640.2005.tb01091.x","article-title":"Adipocyte accumulation in penile corpus cavernosum of the orchiectomized rabbit: A potential mechanism for veno-occlusive dysfunction in androgen deficiency","volume":"26","author":"Traish","year":"2005","journal-title":"J Androl"},{"key":"2020052802395322000_ref8","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1007\/s11255-015-1011-3","article-title":"Castration impairs erectile organ structure and function by inhibiting autophagy and promoting apoptosis of corpus cavernosum smooth muscle cells in rats","volume":"47","author":"Wang","year":"2015","journal-title":"Int Urol Nephrol"},{"key":"2020052802395322000_ref9","doi-asserted-by":"crossref","first-page":"743.e749","DOI":"10.1016\/j.urology.2013.02.045","article-title":"Long-term oral administration of 5alpha-reductase inhibitor attenuates erectile function by inhibiting autophagy and promoting apoptosis of smooth muscle cells in corpus cavernosum of aged rats","volume":"82","author":"Zhang","year":"2013","journal-title":"Urology"},{"key":"2020052802395322000_ref10","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.juro.2013.11.101","article-title":"Low androgen induced penile maldevelopment involves altered gene expression of biomarkers of smooth muscle differentiation and a key enzyme regulating cavernous smooth muscle cell tone","volume":"192","author":"Okumu","year":"2014","journal-title":"J Urol"},{"key":"2020052802395322000_ref11","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/j.1365-2605.2011.01232.x","article-title":"Exposure of neonatal rats to anti-androgens induces penile mal-developments and infertility comparable to those induced by oestrogens","volume":"35","author":"Simon","year":"2012","journal-title":"Int J Androl"},{"key":"2020052802395322000_ref12","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1210\/endo.136.4.7534702","article-title":"Dihydrotestosterone is the active androgen in the maintenance of nitric oxide-mediated penile erection in the rat","volume":"136","author":"Lugg","year":"1995","journal-title":"Endocrinology"},{"key":"2020052802395322000_ref13","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1095\/biolreprod55.3.567","article-title":"Androgen and pituitary control of penile nitric oxide synthase and erectile function in the rat","volume":"55","author":"Penson","year":"1996","journal-title":"Biol Reprod"},{"key":"2020052802395322000_ref14","doi-asserted-by":"crossref","first-page":"R1572","DOI":"10.1152\/ajpregu.00041.2003","article-title":"Improved erectile function after rho-kinase inhibition in a rat castrate model of erectile dysfunction","volume":"284","author":"Wingard","year":"2003","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2020052802395322000_ref15","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1095\/biolreprod.116.146605","article-title":"Constitutive luteinizing hormone receptor signaling causes sexual dysfunction and Leydig cell adenomas in male mice","volume":"96","author":"Hai","year":"2017","journal-title":"Biol Reprod"},{"key":"2020052802395322000_ref16","doi-asserted-by":"crossref","first-page":"3900","DOI":"10.1210\/en.2012-2179","article-title":"Precocious puberty and Leydig cell hyperplasia in male mice with a gain of function mutation in the LH receptor gene","volume":"154","author":"McGee","year":"2013","journal-title":"Endocrinology"},{"key":"2020052802395322000_ref17","doi-asserted-by":"crossref","first-page":"S34","DOI":"10.1038\/sj.ijir.3900575","article-title":"Molecular mechanisms for the regulation of penile smooth muscle contractility","volume":"12","author":"Tejada","year":"2000","journal-title":"Int J Impot Res"},{"key":"2020052802395322000_ref18","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ajur.2017.02.001","article-title":"Testosterone replacement maintains smooth muscle content in the corpus cavernosum of orchiectomized rats","volume":"4","author":"Halmenschlager","year":"2017","journal-title":"Asian J Urol"},{"key":"2020052802395322000_ref19","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s41443-017-0010-6","article-title":"The effects of testosterone replacement on penile structure and erectile function after long-term castration in adult male rats","volume":"30","author":"Huh","year":"2018","journal-title":"Int J Impot Res"},{"key":"2020052802395322000_ref20","doi-asserted-by":"crossref","first-page":"273.e271","DOI":"10.1016\/j.urology.2017.02.020","article-title":"Effect of testosterone on the phenotypic modulation of corpus cavernosum smooth muscle cells in a castrated rat model","volume":"103","author":"Liu","year":"2017","journal-title":"Urology"},{"key":"2020052802395322000_ref21","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.2164\/jandrol.112.017012","article-title":"Effects of castration and late hormonal replacement in the structure of rat corpora cavernosa","volume":"33","author":"Miranda","year":"2012","journal-title":"J Androl"},{"key":"2020052802395322000_ref22","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1590\/S0102-865020150070000005","article-title":"Morphometric study of the corpus cavernosum after anabolic androgenic steroid administration in pubertal and adult rats","volume":"30","author":"Sena Ade","year":"2015","journal-title":"Acta Cir Bras"},{"key":"2020052802395322000_ref23","first-page":"223","article-title":"A histological study of the development of the penis of wild-type and androgen-insensitive mice","volume":"153","author":"Murakami","year":"1987","journal-title":"J Anat"},{"key":"2020052802395322000_ref24","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/j.1939-4640.2003.tb02686.x","article-title":"Effects of medical or surgical castration on erectile function in an animal model","volume":"24","author":"Traish","year":"2003","journal-title":"J Androl"},{"key":"2020052802395322000_ref25","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S0022-5347(17)36630-2","article-title":"Collagen alterations in the corpus cavernosum of men with sexual dysfunction","volume":"148","author":"Luangkhot","year":"1992","journal-title":"J Urol"},{"key":"2020052802395322000_ref26","first-page":"181","article-title":"Apoptosis in rat erectile tissue induced by castration","volume":"1","author":"Zhang","year":"1999","journal-title":"Asian J Androl"},{"key":"2020052802395322000_ref27","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s00240-003-0358-6","article-title":"Penile apoptosis in association with p53 under lack of testosterone","volume":"32","author":"Yamamoto","year":"2004","journal-title":"Urol Res"},{"key":"2020052802395322000_ref28","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/BF01275152","article-title":"The effects of testosterone on the cavernous tissue and erectile function","volume":"15","author":"Shabsigh","year":"1997","journal-title":"World J Urol"},{"key":"2020052802395322000_ref29","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1093\/toxsci\/kfi233","article-title":"Estrogen-induced abnormal accumulation of fat cells in the rat penis and associated loss of fertility depends upon estrogen exposure during critical period of penile development","volume":"87","author":"Goyal","year":"2005","journal-title":"Toxicol Sci"},{"key":"2020052802395322000_ref30","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.reprotox.2003.12.001","article-title":"Exposure of neonatal male rats to estrogen induces abnormal morphology of the penis and loss of fertility","volume":"18","author":"Goyal","year":"2004","journal-title":"Reprod Toxicol"},{"key":"2020052802395322000_ref31","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/j.1939-4640.2005.tb02869.x","article-title":"Permanent induction of morphological abnormalities in the penis and penile skeletal muscles in adult rats treated neonatally with diethylstilbestrol or estradiol valerate: A dose-response study","volume":"26","author":"Goyal","year":"2005","journal-title":"J Androl"},{"key":"2020052802395322000_ref32","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/sj.ijir.3901060","article-title":"Effect of TCDD on corpus cavernosum histology and smooth muscle physiology","volume":"16","author":"Moon","year":"2004","journal-title":"Int J Impot Res"},{"key":"2020052802395322000_ref33","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/sj.ijir.3900734","article-title":"Bisphenol A inhibits penile erection via alteration of histology in the rabbit","volume":"13","author":"Moon","year":"2001","journal-title":"Int J Impot Res"},{"key":"2020052802395322000_ref34","doi-asserted-by":"crossref","first-page":"M1103","DOI":"10.1093\/gerona\/58.12.M1103","article-title":"The mechanisms of androgen effects on body composition: Mesenchymal pluripotent cell as the target of androgen action","volume":"58","author":"Bhasin","year":"2003","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"2020052802395322000_ref35","doi-asserted-by":"crossref","first-page":"5081","DOI":"10.1210\/en.2003-0741","article-title":"Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1\/2 pluripotent cells through an androgen receptor-mediated pathway","volume":"144","author":"Singh","year":"2003","journal-title":"Endocrinology"},{"key":"2020052802395322000_ref36","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/j.1432-0436.2004.07205004.x","article-title":"Inhibition of 5-\u03b1-reductase activity induces stromal remodeling and smooth muscle de-differentiation in adult gerbil ventral prostate","volume":"72","author":"Corradi","year":"2004","journal-title":"Differentiation"},{"key":"2020052802395322000_ref37","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1101\/gad.1017802","article-title":"The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6","volume":"16","author":"Akiyama","year":"2002","journal-title":"Genes Dev"},{"key":"2020052802395322000_ref38","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.1242\/jcs.124305","article-title":"Sox9 modulates cell survival and adipogenic differentiation of multipotent adult rat mesenchymal stem cells","volume":"126","author":"Stockl","year":"2013","journal-title":"J Cell Sci"},{"key":"2020052802395322000_ref39","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/ng.722","article-title":"Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine","volume":"43","author":"Furuyama","year":"2011","journal-title":"Nat Genet"},{"key":"2020052802395322000_ref40","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.celrep.2015.12.071","article-title":"Sox9-positive progenitor cells play a key role in renal tubule epithelial regeneration in mice","volume":"14","author":"Kang","year":"2016","journal-title":"Cell Rep"},{"key":"2020052802395322000_ref41","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1073\/pnas.0609217104","article-title":"SOX9 is required for maintenance of the pancreatic progenitor cell pool","volume":"104","author":"Seymour","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2020052802395322000_ref42","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.stem.2008.05.009","article-title":"Hair follicle stem cells are specified and function in early skin morphogenesis","volume":"3","author":"Nowak","year":"2008","journal-title":"Cell Stem Cell"},{"key":"2020052802395322000_ref43","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.biocel.2009.12.011","article-title":"Human circulating fibrocytes have the capacity to differentiate osteoblasts and chondrocytes","volume":"42","author":"Choi","year":"2010","journal-title":"Int J Biochem Cell Biol"},{"key":"2020052802395322000_ref44","doi-asserted-by":"crossref","first-page":"7556","DOI":"10.4049\/jimmunol.166.12.7556","article-title":"Peripheral blood fibrocytes: Differentiation pathway and migration to wound sites","volume":"166","author":"Abe","year":"2001","journal-title":"J Immunol"}],"container-title":["Biology of Reproduction"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/biolreprod\/advance-article-pdf\/doi\/10.1093\/biolre\/ioaa023\/32755641\/ioaa023.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/biolreprod\/article-pdf\/102\/6\/1225\/33317818\/ioaa023.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/biolreprod\/article-pdf\/102\/6\/1225\/33317818\/ioaa023.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T19:04:34Z","timestamp":1722452674000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biolreprod\/article\/102\/6\/1225\/5739833"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,18]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,2,18]]},"published-print":{"date-parts":[[2020,5,26]]}},"URL":"https:\/\/doi.org\/10.1093\/biolre\/ioaa023","relation":{},"ISSN":["0006-3363","1529-7268"],"issn-type":[{"value":"0006-3363","type":"print"},{"value":"1529-7268","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,6]]},"published":{"date-parts":[[2020,2,18]]}}}