Development and Physiology of Leydig Cells
Testosterone production by Leydig cells in the testis is the critical factor ensuring adequate sperm production and male fertility. Council researchers are identifying components that affect testosterone secretion and may offer new avenues for contraception and male hormone therapy.
Primitive stem cells, largely believed to be of mesenchymal origin and present in the interstitium of the testis at birth, are the points of origin for the postnatal Leydig cell lineage. The embryonic derivation of these stem cells is still unknown, but both mesodermal and ectodermal origins have been proposed. Leydig cells first become recognizable as progenitor Leydig cells by day 14 postpartum when, in contrast to stem cells, they start to express lineage-specific markers.
These include histochemical staining for 3β-hydroxysteroid dehydrogenase (3β-HSD) and androgens. Progenitor Leydig cells, which are small, spindle-shaped, and highly proliferative on day 14 in situ, enlarge, become round, and greatly reduce their rate of cell division over the next 14 days.
For reasons that remain unclear, progenitor Leydig cells do not differentiate directly into cells that secrete testosterone as their predominant steroid product, but exist for the next four weeks (days 28–56) as immature Leydig cells that secrete 5α-reduced androgens. Immature Leydig cells divide a final time before maturing into adult Leydig cells by day 56. Several hormones and growth factors known to affect Leydig cell development include luteinizing hormone (LH, a pituitary hormone) together with local paracrine and autocrine cytokines and growth factors. A reservoir of Leydig stem cells persists in the testis, supporting a slow turnover of the adult Leydig cell population, or repopulating Leydig cells during the regeneration that follows toxic insults.
The focus of these investigations continues to be elucidating the molecular mechanisms that underlie progenitor commitment to a fully steroidogenic-competent Leydig cell in the context of its microenvironment. Studies show that one lineage-specification factor for a testicular progenitor is growth hormone (GH), with effects on transcription of target genes directly mediated by its receptor and downstream signaling components.
Population Council researchers found that in the testicular interstitium, progenitor but not immature or adult Leydig cells express growth hormone receptor (GHR), a member of the class 1-cytokine receptor family. GH rapidly activates the tyrosine kinase JAK2 and phosphorylation of the transcription factor STAT5b in progenitor but not adult Leydig cells; significant p44/42 activation is not observed unless a second growth factor is present. Locally, several cytokines and prostaglandins regulate the hormone responsiveness of the progenitors and presumably their precursor stem cells.
Researchers have shown that hormone binding to GHR transcriptionally directs the commitment of progenitors to the Leydig cell lineage ex vivo. Significantly, GH induces the expression of the START-domain cholesterol transfer protein, StAR. GHR signaling also induces an array of growth factors and their receptors. These findings are consistent with a direct interaction of GH with GHR in progenitors, and one that should not occur in differentiated Leydig cells in situ. While it has long been appreciated that GH potentiates the effects of LH on the testis, the data predict that GH is one of the environmental factors that predisposes the progenitor cell to "commit" to differentiating to an immature Leydig cell. Taken together, these data suggest that final Leydig cell lineage commitment is made in the context of the local growth factors and the cell’s acquisition of responsiveness to LH.
Prostaglandin (PG) FP and EP1 receptors mediate PDF2α and PGE2 regulation of interleukin-1β expression in Leydig cell progenitors (abstract) (HTML)
Walch,Laurence; Clavarino,Emanuela; Morris,Patricia L.
Endocrinology 144(4): 1284-1291
Publication date: 2003
Cyclooxygenase 2 pathway mediates IL-1β regulation of IL-1α, -1β, and IL-6 mRNA levels in Leydig cell progenitors (abstract) (PDF)
Walch,Laurence; Morris,Patricia L.
Endocrinology 143(9): 3276-3283
Publication date: 2002
Growth hormone regulates steroidogenic acute regulatory protein expression and steroidogenesis in Leydig cell progenitors (abstract) (PDF)
Kanzaki,Masanori; Morris,Patricia L.
Endocrinology 140(4): 1681-1686
Publication date: 1999
Lactogenic hormone-inducible phosphorylation and gamma-activated binding site binding activities of STAT5b in primary rat Leydig cells and MA-10 mouse Leydig tumor cells (abstract) (PDF)
Kanzaki,Masanori; Morris,Patricia L.
Endocrinology 139(4): 1872-1882
Publication date: 1998
Location: United States
Duration: 1/1998 - ongoing
Population Council researchers:
Patricia L. Morris
National Institute of Child Health and Human Development