Abnormal Leydig cell development at puberty in the androgen-resistant Tfm mouse.

Abstract

Leydig cells are the major source of androgens in the male, and it is likely that these cells are also targets for androgen action. The role of androgen action in regulating the development of Leydig cell function has been determined using the testicular feminized (Tfm/Y) mouse, which lacks androgen receptors. In Tfm mice, the testes fail to descend at the normal time (25 days), and testicular descent was, therefore, surgically prevented in control (+/Y) animals. The activity of 3 beta-hydroxysteroid dehydrogenase increased during development from 5-40 days in control and Tfm mice, with no significant difference between the groups. In control animals, 17 alpha-hydroxylase activity was low from 5-25 days, at which time there was a 26-fold increase up to 40 days. In the Tfm group, 17 alpha-hydroxylase activity was 4-fold higher than that in controls on day 5, but showed no change in activity after 25 days and remained at neonatal levels up to 40 days. The activity of 17-ketosteroid reductase in the control animals showed a developmental pattern similar to that of 17 alpha-hydroxylase, with a marked increase in activity after 25 days. In the Tfm group, 17-ketosteroid reductase was normal on day 5, but failed to show any significant change thereafter and remained at neonatal levels on day 40. Serum LH levels in control animals increased from 5 days to a peak at 30 days. In Tfm mice, LH levels were significantly increased on days 20 and 40, but did not differ from controls on days 5, 25, and 30. In control +/Y animals, in which normal testicular descent was allowed to proceed at 25 days, the pattern of development was similar to that in the cryptorchid +/Y animals, although the increase in 17 alpha-hydroxylase activity at 30 and 40 days was significantly greater. The results show 1) that fetal Leydig cell steroidogenesis is enhanced in the absence of androgen receptors, but 2) that adult Leydig cells require receptor-mediated androgen activity around day 25 for normal functional development. In addition, 3) the lack of testicular descent at 25 days reduces the pubertal rise in 17 alpha-hydroxylase activity.

The cytosolic aldehyde dehydrogenase gene (Aldh1) is developmentally expressed in Leydig cells

“…Previous studies with human tissues that confined the presence of ALDH1 in testis to genital skin fibroblasts (GSF) [32, 15, 33]failed to explain the specificity of ALDH1 expression. However both cell types, GSF cells [34]and Leydig cells [35], have androgen receptors, although the expression of Aldh1 has not been investigated before in Leydig cells.…”

Insights into the Development of the Adult Leydig Cell Lineage from Stem Leydig Cells

“…The presence of NR3C4 in the LC lineage suggests that androgen produced by FLCs, adrenal glands or the LCs themselves might regulate the development and function of LCs. In NR3C4 mutated mice in which there is an androgen insensitivity, reduced differentiation of LCs and decreased LC numbers have been noted (O'Shaughnessy and Murphy, 1993; Murphy et al, 1994). Consistent with this, when PLCs are cultured in vitro , adding androgen greatly increased the efficiency of the cells to differentiate into androgen-producing cells (Hardy et al, 1990).…”

Regulation of Estrogen Sulfotransferase Expression in Leydig Cells by Cyclic Adenosine 3′,5′-Monophosphate and Androgen1

“…Studies by other investigators have found that although there is an impairment in Leydig cell development at puberty, total Leydig cell numbers in adult Tfm mice are more or less the same as those in normal mice (28). Studies by other investigators have found that although there is an impairment in Leydig cell development at puberty, total Leydig cell numbers in adult Tfm mice are more or less the same as those in normal mice (28).…”