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Endocrinology Vol. 139, No. 9 3787-3795
Copyright © 1998 by The Endocrine Society

ARTICLES

Variation in the End Products of Androgen Biosynthesis and Metabolism during Postnatal Differentiation of Rat Leydig Cells1

Ren-Shan Ge and Matthew P. Hardy

The Population Council and Rockefeller University, New York, New York 10021

Address all correspondence and requests for reprints to: Dr. Matthew P. Hardy, The Population Council, 1230 York Avenue, New York, New York 10021. E-mail: m-hardy{at}popcbr.rockefeller.edu

The amount of testosterone (T) secreted by Leydig cells is determined by a balance between T biosynthetic and metabolizing enzyme activities. It has been established that 5{alpha}-androstan-3{alpha},17ß-diol (3{alpha}-DIOL) is the predominant androgen secreted by the testes of immature rats during days 20–40 postpartum, whereas T is the major androgen by day 56. However, the underlying changes in T biosynthetic and metabolizing enzymes during Leydig cell development and their magnitudes have remained unclear. The aim of the present study was to define the developmental trends for T biosynthetic and metabolizing enzymes in Leydig cells at three distinct stages of pubertal differentiation: mesenchymal-like progenitors on day 21, immature Leydig cells on day 35, and adult Leydig cells on day 90. Production rates for precursor androgen (androstenedione), T, and 5{alpha}-reduced androgens [androsterone (AO) and 3{alpha}-DIOL] were measured in progenitor, immature, and adult Leydig cells in spent medium after 3 h in vitro. Steady state messenger RNA (mRNA) levels and enzyme activities of biosynthetic and metabolizing enzymes were measured in fractions of freshly isolated cells at each of the three stages. Unexpectedly, progenitor cells produced significant amounts of androgen, with basal levels of total androgens (androstenedione, AO, T, and 3{alpha}-DIOL) 14 times higher than those of T alone. However, compared with immature and adult Leydig cells, the capacity for steroidogenesis was lower in progenitor cells, with a LH-stimulated production rate for total androgens of 84.33 ± 8.74 ng/106 cells·3 h (mean ± SE) vs. 330.13 ± 44.19 in immature Leydig cells and 523.23 ± 67.29 in adult Leydig cells. The predominant androgen produced by progenitor, immature, and adult Leydig cells differed, with AO being released by progenitor cells (72.08 ± 9.02% of total androgens), 3{alpha}-DIOL by immature Leydig cells (73.33 ± 14.52%), and T by adult Leydig cells (74.38 ± 14.73%). Further examination indicated that changes in the predominant androgen resulted from differential gene expression of T biosynthetic and metabolizing enzymes. Low levels of type III 17ß-hydroxysteroid dehydrogenase (17ßHSD) mRNA and enzyme activity were present in progenitor cells compared with immature and adult Leydig cells. In contrast, levels of type I 5{alpha}-reductase (5{alpha}R) and 3{alpha}-hydroxysteroid dehydrogenase (3{alpha}HSD) mRNA and enzyme activities were dramatically lower in adult Leydig cells compared with those in progenitor and immature Leydig cells. Several T biosynthetic enzymes attained equivalent levels in immature and adult Leydig cells, but T was rapidly metabolized in the former to 3{alpha}-DIOL by high 5{alpha}R and 3{alpha}HSD activities, which were greatly reduced in the latter. Therefore, declines in 5{alpha}R and 3{alpha}HSD activities are hypothesized to be a major cause of the ascendancy of T as the predominant androgen end product produced by adult Leydig cells. These results indicate that steroidogenic enzyme gene expression is not induced simultaneously, but through sequential changes in T biosynthetic and metabolizing enzyme activities, resulting in different androgen end products being secreted by Leydig cells during pubertal development.




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