Differential regulation of rat testicular 5alpha-reductase type 1 and 2 isoforms by testosterone and FSH

Abstract

Testosterone is metabolised to the more potent androgen, dihydrotestosterone, by the 5 -reductase (5 R) enzyme. We previously showed that 5 -reduced androgens are important for maintaining androgen action on rat spermatogenesis when testicular testosterone concentrations are reduced. This study investigated expression and activity of the 5 R isoforms, type 1 (5 R-1) and type 2 (5 R-2), in the rat during hormone manipulation in order to understand the factors that regulate the testicular concentration of 5 R and testicular 5 -reduced androgen biosynthesis. Testicular 5 R-1 and 5 R-2 mRNA and enzyme activity were measured by real-time PCR and specific enzyme assays respectively. Hormone levels were first suppressed using two models of gonadotrophin suppression: testosterone and oestradiol treatment (LH/testosterone deficiency) or GnRH immunisation (LH/testosterone and FSH deficiency). Hormones were then either restored or suppressed for 6 days by a variety of hormonal treatments. 5 R-1 mRNA and enzyme activity increased when testosterone was suppressed, yet restoration of testosterone decreased 5 R-1 mRNA and enzyme activity, suggesting that testosterone negatively regulates 5 R-1. Suppression of FSH decreased 5 R-1 mRNA yet FSH administration increased 5 R-1 mRNA, but no changes in 5 R-1 activity were observed within the 6 day period. In contrast to 5 R-1, testosterone did not affect the testicular concentration of 5 R-2 mRNA or activity, but there was evidence for modulation of 5 R-2 activity by FSH. Measurement of testicular androgens revealed that 5 R-1 was primarily responsible for the production of 5 -reduced metabolites. It is concluded that the 5 R isoforms in rat testis are differentially regulated by testosterone and FSH: testosterone negatively regulated 5 R-1 mRNA and enzyme activity but had no affect on 5 R-2, whereas FSH positively regulated 5 R-1 mRNA and appeared to regulate 5 R-2.

Influence of short-term dietary weight loss on cortisol secretion and metabolism in obese men

“…There are two isozymes of 5a-reductase and both probably contribute to cortisol metabolism, since the type 1 predominates in liver while the type 2 inhibitor finasteride alters urinary cortisol metabolite excretion (49). Information on promoter regulation of these genes remains scanty and relates predominantly to sex steroid regulation (50,51), so it is unclear whether they are transcriptionally controlled by 'nutrient' receptors such as peroxisome proliferator activating receptor (PPARs). Importantly, the present results suggest that abnormalities in cortisol metabolism in obesity are potentially reversible, but apparently only in the short term.…”

Oestrogen does not affect the restoration of spermatogenesis in the gonadotrophin-releasing hormone-immunised adult rat

“…This is consistent with other studies (Chen et al 1994, Singh et al 1995 suggesting that aromatisation is not required to support spermatogenesis; however it has been shown elsewhere that early spermiogenesis is sensitive to oestrogen action . Although testicular testosterone was not measured in the current study due to the limited amount of available tissue, our previous reports have consistently shown that T24 cm treatment of GnRHimmunised rats elevates total testicular testosterone levels to 10% of control levels (Meachem et al 1998, Pratis et al 2003, compared with 3% in the GnRH-immunised control. Using the same rat model, others have demonstrated an elevation in interstitial fluid testosterone to 20% of control following T24 cm treatment (Awoniyi et al 1989(Awoniyi et al , 1992, with this variation most likely to be due to the different assay systems and tissues measured.…”

“…As testicular oestrogen concentrations were a priority and tissue mass limited, testicular testosterone levels were not measured but have been previously well characterised in this model and reported elsewhere (McLachlan et al 1995, Meachem et al 1998, Pratis et al 2003. Details of the testis perfusion procedure with Bouin's fixative, tissue collection, processing, methacrylate embedding, sectioning (25 µm), periodic acid-Schiff's staining have been previously described (Meachem et al 1997).…”

“…Alternative mechanisms for the inhibitory effects of high-dose testosterone on spermatogonial number could include: (i) that testosterone itself acts in this fashion in these specialised settings; (ii) that testosterone treatment results in the production of an additional product arising from elsewhere (e.g. in the liver); or (iii) another metabolite of testosterone, such as its 5-alpha-reduced product DHT, may be involved, noting that the administration of testosterone to GnRH-immunised rats elevated testicular DHT levels (Pratis et al 2003).…”

“…Exogenous testosterone (e.g. 24 cm Silastic s.c. implant) restores spermatogenesis to near normal by partially restoring testicular testosterone levels (to 10-20% of control) and by the restoration of pituitary FSH by GnRH-independent mechanisms (Meachem et al 1998, Pratis et al 2003. This restoration of serum FSH is not always observed (Awoniyi et al 1989).…”