PROJECT
Development and Physiology of Leydig Cells II  

Leydig cells of the testis secrete the male hormone testosterone and are the primary site of synthesis of this androgenic steroid. The chief tropic stimulus of testosterone secretion is luteinizing hormone (LH, a pituitary hormone).

Population Council researchers are developing procedures for purifying the stem cells of Leydig cells using the testes of perinatal rats as source material. The goal of this work is to test the ability of Leydig stem cells to undergo differentiation and acquire steroidogenic capacity when transplanted back into the testis. If successful, this would provide a more physiological means of androgen replacement as a therapeutic intervention for hypogonadal boys or older men suffering from age-related declines in testosterone levels.

Researchers hypothesize that this can be done autologously (that is, with the patient furnishing his own Leydig stem cells) based on a strategy of amplifying stem cell numbers from a biopsy sample and selecting for Leydig stem cells using preparative cell sorting. A cell surface marker such as Kit receptor is one candidate for Leydig stem cells under investigation.

Council scientists are studying the effects of psychosocial and restraint stress on male reproductive function, because stress has been correlated with suppressed fertility. Leydig cells express receptors for the stress hormone glucocorticoid. Researchers have demonstrated that Leydig cells are not only direct targets of glucocorticoid action, but can subtly modulate their responses to glucocorticoid through the metabolizing enzyme type 1 11β-hydroxysteroid dehydrogenase (11βHSD1).

This discovery in turn led to the demonstration that Leydig cells express other steroid metabolizing enzymes previously thought to be localized exclusively in the adrenal gland. For example, the adrenal enzyme 11β-hydroxylase (cyp11B1) was detected in Leydig cells. It is hypothesized that in the testis cyp11B1 is forming 11-hydroxy and 11-keto derivatives of androgens, and that these derivatives act as potent biological regulators. One way they might do that is by competitive inhibition of the 11βHSD1 enzyme.

As a further layer of control, 11-hydroxyandrogens selectively inhibit 11βHSD1 oxidative activity (the enzyme direction that lowers glucocorticoid action) whereas 11-ketoandrogens inhibit the opposing 11βHSD1 reductase, which normally regenerates bioactive glucocorticoid. Having identified these potential pathways of enzymative regulation in the testis, researchers are presently conducting functional studies to understand when the androgen derivatives are made and what controls their synthesis.

---

Population Council researcher
Renshan Ge

Non-Council collaborators

Venkataseshu Ganjam (University of Missouri-Columbia)

Mary M. Lee (Duke University)

Bruce S. McEwen (The Rockefeller University)

David J. Morris (Brown University)

Randall R. Sakai (University of Cincinnati)

Donors

US National Institutes of Health

---

---