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. Issue 149 (May 2015)

• Record Type: Journal Article
• Authors: Bjelic, Maja M.; Stojkov, Natasa J.; Radovic, Sava M.; Baburski, Aleksandar Z.; Janjic, Marija M.; Kostic, Tatjana S.; Andric, Silvana A.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 149(2015)
• Page Start: 58
• Page End: 69
• Publication Date: 2015-05
• Subjects: AASs anabolic androgenic steroids -- ADCYs/Adcy protein/gene for adenylyl cyclases -- AR/Ar protein/gene for androgen receptor -- ARR19/Arr19 protein/gene for androgen receptor repressor -- Cga gen for common α-subunit of pituitary glycoprotein hormones -- CPA cyproterone-acetate -- CREB/Creb protein/gene for cAMP responsive element-binding protein -- CYP11A1/Cyp11a1 protein/gene for cholesterol side-chain cleavage enzyme -- CYP17A1/Cyp17a1 protein/gene for 17α-hydroxylase/17, 20 lyase -- DAX1/Dax1 protein/gene for dosage – sensitive sex reversal, adrenal hypoplasia critical region -- GATA/Gata protein/gene for GATA-binding factor -- GnRH/Gnrh protein/gene for gonadotropin - releasing hormone -- GnRHR/Gnrhr protein/gene for gonadotropin - releasing hormone receptor -- hCG human chorionic gonadotropin -- HSD17B/Hsd17b protein/gene for 17β-hydroxysteroid dehydrogenase -- HSD3B/Hsd3b protein/gene for 3β-hydroxysteroid dehydrogenase -- INSL3/Insl3 protein/gene for insulin-like factor-3 -- JAK/Jak protein/gene for Janus kinase -- LH luteinizing hormone -- Lhb gen for β-subunit of LH -- LHCGR/Lhcgr luteinizing hormone receptor -- NUR77/Nur77 protein/gene for nerve growth factor IB -- PDEs/Pde protein/gene for phosphodiesterases -- Ppargc1a /bbperoxisome proliferator - activated receptor gamma coactivator 1a/b -- PRKA cAMP-dependent protein kinase A -- PRKAC/Prkac protein/gene for catalytic subunit of PRKA -- PRKAR/Prkar protein/gene for regulatory subunit of PRKA -- PRL/Prl protein/gene for prolactin -- Prlr gene for prolactin receptor -- SF1/Sf1 protein/gene for steroidogenic factor 1 -- StAR/Star protein/gene for steroidogenic acute regulatory protein -- TE testosterone-enanthate -- TSPO/Tspo protein/gene for translocator protein -- Tyk2 gen for tyrosine kinase2 -- ΔΨm mitochondrial membrane potential; Leydig cells -- Anabolic androgenic steroids -- Prolactin -- cAMP signaling -- Transcription factors; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2015.01.012
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: Administration of testosterone-enanthate for 10-weeks increased prolactin in pituitary. Prolactin and increased Jak2 / Jak3 could account for increased Hsd3b1 / 5 in Leydig cells. Elements of cAMP signaling were disturbed with remarkable up-regulation of PRKA. In vitro testosterone addition increase Prlr1, Prlr2, Hsd3b1 / 5 in Leydig cells. Prolactin signaling and PRKA contribute in a new adaptive response of Leydig cells. 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.