Oxandrolone is a 5α-reduced anabolic steroid that is administered for the treatment of short stature disease in children. It is a commonly used substance beginning as early as prepuberty by some individuals who are seeking to enhance athletic performance or personal appearance. Because of the lack of data on the effects of anabolic steroids on the reproductive system, we have examined the effects of oxandrolone treatment on reproductive development in male rats with treatment beginning two days after weaning. Male, Sprague-Dawley rats (N=12) received a daily subcutaneous injection of oxandrolone (32.7 μmol·kg−1·day−1) and the control group (N= 12) received vehicle only (dimethyl sulfoxide). Treatment began at age 23 days and continued to 60 days of age. The weights of the testes, prostate glands, and seminal vesicles in the treatment group were 69%, 50% and 29% below control levels, respectively and were all significantly decreased (p<0.01). Testicular testosterone production in a 3-h incubation was inhibited in the treated animals to 1.3% of control values (p<0.001). Serum FSH (11.7% of control) and LH (undetectable) in the treated animals were both significantly less than controls. Histological findings indicated an arrest of advanced spermatids and a severe depletion of Leydig cells in the interstitial compartment. It was concluded that treatment of immature male rats with oxandrolone results in effects on the adult male reproductive system which are profound and occur at several levels. The most likely affected sites are the hypothalamus, pituitary gland, and the Leydig cells.
Bernard H Grokett, Nazir Ahmad and Dwight W Warren
Yin Lu, Alicia A. McDonough, Robert A. Farley and Dwight W. Warren
Adult Leydig cells respond to LH or hCG with an initial stimulation of testosterone secretion followed by LH receptor down-regulation and blockade of androgen biosynthesis. In contrast, fetal Leydig cells respond with increased LH receptor number and enhanced steroidogenesis. In this study, the molecular mechanisms of high-dose hCG treatment on steroidogenesis in adult and neonatal testes (containing predominantly the fetal generation of Leydig cells) were examined using two recombinant DNA clones specific for enzymes of the rat steroidogenic pathway (P-450 cholesterol side-chain cleavage enzyme, P-450scc and P-450 17α-hydroxylase/C17-20 lyase, P-450c17). We treated adult (60 days of age) and neonatal (2 days of age) rats with a single high dose of hCG (600 IU/kg), sc. The high dose of hCG caused neonatal testicular P450scc and P450c17 mRNA levels to increase, and stimulated adult testicular P450scc mRNA levels, but caused a decrease in adult P450c17 mRNA levels. These studies suggest that high doses of hCG regulate testosterone production differently in adult and fetal Leydig cells at a pretranslational level of the P450c17 enzyme, while mRNA for P450scc is stimulated in both the adult and fetal Leydig cell.
Dwight W. Warren, Ilpo T. Huhtaniemi, Maria L. Dufau and Kevin J. Catt
Abstract. Foetal rats were injected with high doses of hCG or ovine LH (oLH) to determine if LH receptors were down-regulated and steroidogenesis impaired as is seen in the adult animal. Foetuses injected in utero with 52 μg/kg hCG had a prompt increase in intratesticular testosterone, demonstrating that the injected substance reached the foetal testis. Pregnant mothers were laparotomized and each foetus in one uterine horn injected with 52 μg/kg hCG. Twenty-four hours later, the foetal testes from both uterine horns were collected and free LH receptor content measured. In foetuses injected with hCG, free LH receptors were significantly reduced. LH receptors in foetal testes from the contralateral horn were not significantly different from those in controls. Foetuses injected with 52 μg/kg hCG at 17.5 days of gestation showed a delayed response in LH receptor up-regulation when compared with neonatal rats injected with comparable doses of hCG. Injection of foetal and neonatal rats with 400 μg/kg oLH showed no evidence of down-regulation, as is seen in the adult. Testes from foetuses injected with 52 μg/kg hCG 3 days earlier showed an increase in both basal and hCG-stimulated testosterone production during 3 h of incubation when compared with controls. These results show that the rat foetal testis in vivo does not demonstrate down-regulation of LH receptors or steroidogenic lesions of the testosterone synthetic pathway when exposed to high levels of hCG as does the adult rat testis. These results from the foetal testis in vivo are in agreement with results obtained from the foetal testis in vitro and the neonatal testis in vivo.