title: Prolonged in vivo administration of testosterone-enanthate, the widely used and abused anabolic androgenic steroid, disturbs prolactin and cAMP signaling in Leydig cells of adult rats.
abstract: This study was designed to systematically analyze and define the effects of 1-day, 2-weeks, 10-weeks intramuscular administration of testosterone-enanthate, widely used and abused anabolic androgenic steroid (AAS), on main regulators of steroidogenesis and steroidogenic genes expression in testosterone-producing Leydig cells of adult rats. The results showed that prolonged (10-weeks) intramuscular administration of testosterone-enanthate, in clinically relevant dose, significantly increased prolactin, but decreased Prlr2 and Gnrhr in pituitary of adult rat. The levels of testosterone, Insl3, cAMP and mitochondrial membrane potential of Leydig cells were significantly reduced. This was followed by decreased expression of some steroidogenic enzymes and regulatory proteins such as Lhcgr, Prlr1/2, Tspo, Star, Cyp11a1, Cyp17a1, Dax1. Oppositely, Hsd3b1/2, Hsd3b5, Hsd17b4, Ar, Arr19 increased. In the same cells, transcriptional milieu of cAMP signaling elements was disturbed with remarkable up-regulation of PRKA (the main regulator of steroidogenesis). Increased prolactin together with stimulated transcription of Jak2/Jak3 could account for increased Hsd3b1/2 and Hsd3b5 in Leydig cells following 10-weeks in vivo treatment with testosterone-enanthate. In vitro studies revealed that testosterone is capable to increase level of Prlr1, Prlr2, Hsd3b1/2, Hsd3b5 in Leydig cells. Accordingly, testosterone-induced changes in prolactin receptor signaling together with up-regulation of PRKA, Hsd3b1/2, Hsd3b5, Ar in Leydig cells, could be the possible mechanism that contribute to the establishment of a new adaptive response to maintain homeostasis and prevent loss of steroidogenic function. Presented data provide new molecular insights into the relationship between disturbed testosterone homeostasis and mammalian reproduction and are important in terms of wide use and abuse of AASs and human reproductive health.
authors.affiliation: Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.
authors.forename: Maja M
authors.initials: MM
authors.lastname: Bjelic
authors.affiliation: Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.
authors.forename: Natasa J
authors.initials: NJ
authors.lastname: Stojkov
authors.affiliation: Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.
authors.forename: Sava M
authors.initials: SM
authors.lastname: Radovic
authors.affiliation: Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.
authors.forename: Aleksandar Z
authors.initials: AZ
authors.lastname: Baburski
authors.affiliation: Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.
authors.forename: Marija M
authors.initials: MM
authors.lastname: Janjic
authors.affiliation: Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.
authors.forename: Tatjana S
authors.initials: TS
authors.lastname: Kostic
authors.affiliation: Reproductive Endocrinology and Signaling Group, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia. Electronic address: silvana.andric@dbe.uns.ac.rs.
authors.forename: Silvana A
authors.initials: SA
authors.lastname: Andric
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D045930:Anabolic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D007986:Luteinizing Hormone / Q000235:genetics / Q000378:metabolism; D008297:Male; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011388:Prolactin / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013739:Testosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D045930:Anabolic Agents; D050791:STAT Transcription Factors; D014157:Transcription Factors; D013739:Testosterone; C004648:testosterone enanthate; D011388:Prolactin; D007986:Luteinizing Hormone; D000242:Cyclic AMP; D015096:3-Hydroxysteroid Dehydrogenases; D053612:Janus Kinases
keywords: Anabolic androgenic steroids; Leydig cells; Prolactin; Transcription factors; cAMP signaling