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The enzymatic complex 5α-reductase (5α-R) and 3α/3β-hydroxysteroid oxidoreductase (HSOR) is expressed in the nervous system, where it transforms progesterone (PROG) and testosterone (T) into neuroactive metabolites. These metabolites regulate myelination, brain maturation, neurotransmission, reproductive behavior and the stress response. The expression of 5α-R and 3α-HSOR and the levels of PROG and T reduced metabolites show regional and sex differences in the nervous system and are affected by changing physiological conditions as well as by neurodegenerative and psychiatric disorders. A decrease in their nervous tissue levels may negatively impact the course and outcome of some pathological events. However, in other pathological conditions their increased levels may have a negative impact. Thus, the use of synthetic analogues of these steroids or 5α-R modulation have been proposed as therapeutic approaches for several nervous system pathologies. However, further research is needed to fully understand the consequences of these manipulations, in particular with 5α-R inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Context: The human adrenal gland produces small amounts of testosterone that are increased under pathological conditions. However, the mechanisms through which the adrenal gland produces testosterone are poorly defined., Objective: Our objective was to define the role of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) in human adrenal production of testosterone., Design and Methods: Adrenal vein sampling was used to confirm ACTH stimulation of adrenal testosterone production. Adrenal expression of AKR1C3 was studied using microarray, quantitative real-time RT-PCR, and immunohistochemical analyses. AKR1C3 knockdown was accomplished in cultured adrenal cells (H295R) using small interfering RNA, followed by measurement of testosterone production., Results: Acute ACTH administration significantly increased adrenal vein testosterone levels. Examination of the enzymes required for the conversion of androstenedione to testosterone using microarray analysis, quantitative real-time RT-PCR, and immunohistochemistry demonstrated that AKR1C3 was present in the adrenal gland and predominantly expressed in the zona reticularis. Decreasing adrenal cell expression of AKR1C3 mRNA and protein inhibited testosterone production in the H295R adrenal cell line., Conclusions: The human adrenal gland directly secretes small, but significant, amounts of testosterone that increases in diseases of androgen excess. AKR1C3 is expressed in the human adrenal gland, with higher levels in the zona reticularis than in the zona fasciculata. AKR1C3, through its ability to convert androstenedione to testosterone, is likely responsible for adrenal testosterone production.

Steroidogenesis in the gonad of the protandrous sea bass, Lates calcarifer, was examined in vitro in spermiating testis, previtellogenic ovary, and transitional gonads. Gonadal tissues were incubated with tritiated androstenedione. Metabolites were analyzed by thin-layer chromatography, high-performance liquid chromatography, microchemical reactions, and crystallization to constant specific activity. 17 beta-Hydroxysteroid dehydrogenase, 5 beta-reductase, and 3 alpha-hydroxysteroid dehydrogenase activities were found in all of the sex types. On the other hand, 11 beta-hydroxysteroid dehydrogenase and 11 beta-hydroxylase activities were found only when testicular tissue was present, i.e., in testis and early transitional gonad. A low aromatase activity leading to estrone synthesis was detected in the previtellogenic ovary. In late transitional gonads, a major metabolite (metabolite X) was suggestively identified as a 3-ester of 17 beta-estradiol according to its chemical and immunological characteristics. Levels of 17 beta-estradiol (E2), the metabolite X, testosterone (T), and 11-ketotestosterone (11KT) were also measured by radioimmunoassay in plasma, before (January and February) and during (March and April) the sex inversion process. Plasma E2 was virtually undetectable (means below 25 pg/ml), although higher levels of metabolite X were found in transitional fish (485 +/- 432 pg/ml in March). Throughout this period, plasma levels of T and 11KT and the androgens/estrogens ratio were significantly higher in males than in transitional fish, where these levels decreased during the sex inversion period. The level of in vitro synthesis of metabolite X was high in transitional gonads, but their concentrations were very low (0.07 +/- 0.09 ng of equivalent E2/g in transitional gonads against 0.22 +/- 0.37 ng of equivalent E2/g in testes and 2.16 +/- 2.7 ng of equivalent E2/g in ovaries).

Testosterone secretory capacity of testicular Leydig cells was determined in fetal males of an aggressive and a nonaggressive genetic selection line of wild house mice. They were studied at Days 15-18 of gestation and on the first day after birth. A previously described morphometric method was used to quantify 3 beta-hydroxy steroid dehydrogenase (3 beta-HSD)-stained Leydig cells in testicular sections to determine testosterone secretory capacity, which may be considered to reflect circulating plasma testosterone in the fetus. The results of this study show that the testosterone secretory capacity of Leydig cells in the testis changes differentially during intrauterine development in males of the aggressive and nonaggressive selection lines. The peak secretory capacity is reached at Day 17 of gestation for the males of the aggressive selection line, while the peak for the nonaggressive males is reached on the first neonatal day. The larger anogenital distance observed in aggressive males suggests a higher prenatal testosterone level in these males. The importance of the difference in timing of the perinatal 3 beta-HSD peak top individual variation in adult aggressive behavior is discussed.

We examined the effect of restraint stress (3 hr) on plasma LH and testosterone levels, on the Leydig cell LH/hCG receptor, and on the activity of enzymes in the testicular steroidogenic pathway of the adult rat. Restraint stress caused a 47% reduction in plasma testosterone concentrations, but had no effect on plasma LH levels. The binding capacity and affinity of Leydig cell LH/hCG receptors were not affected by restraint. Stress did not affect the testicular activity of 20,22 desmolase or 3 beta-hydroxysteroid dehydrogenase, but testicular interstitial cells of stressed rats incubated in vitro with progesterone as a substrate produced more 17 alpha-hydroxyprogesterone but less testosterone than control cells, and when incubated with 17 alpha-hydroxypregnenolone, produced 39% less androstenedione and 40% less testosterone than control cells. These results suggest that restraint stress inhibited 17,20 desmolase but not 17 alpha-hydroxylase activity. When the delta 4 pathway was blocked with cyanoketone (3 beta-HSD inhibitor), stress did not alter the production of pregnenolone or 17 alpha-hydroxypregnenolone, but the production of dehydroepiandrosterone by cells from stressed rats was subnormal, suggesting again a reduction of 17,20 desmolase activity. The data suggest that a major site of the inhibitory action of restraint stress on testicular steroidogenesis is the 17,20 desmolase step. The disruption of androgen production by restraint appears to be LH independent since stress did not affect plasma LH levels, the binding capacity or affinity of LH/hCG receptors, or the activity of 20,22 desmolase.