Testosterone production depends on a four-step signal chain
Why does testosterone decline in men as they age? A newly mapped molecular mechanism in the hormone-producing cells of the testis sheds light on that question.
Leydig cells are the cells in the testis that produce testosterone. They are essential for male fertility and play a broader role in muscle maintenance, bone density and energy levels. As men age, the number of properly functioning Leydig cells declines. The molecular reasons for this were only partially understood.
A four-step signal chain
Researchers identified a complete chain of molecular signals that determines whether Leydig cell precursors (stem Leydig cells) mature into fully functional, hormone-producing cells. The study, published in eLife, identified a four-step chain: the protein Desert Hedgehog (Dhh) signals through the receptor Patched 2 (Ptch2) to activate the transcription factor Gli1, which in turn switches on the gene Sf1. Sf1 is indispensable for the final maturation of stem Leydig cells into testosterone-producing cells.
The researchers used CRISPR/Cas9 to knock out each component of this chain individually in Nile tilapia, a fish model commonly used for reproductive biology research. Disrupting Dhh caused severe defects in Leydig cell development and a drop in androgen levels. Rescue experiments confirmed which step in the chain is the critical one.
What this means for male aging
The finding is relevant to understanding why testosterone declines with age. If stem Leydig cells receive insufficient signalling through this pathway, they cannot mature into functional cells. This could contribute to the gradual testosterone decline that many men experience after the age of forty.
This research was conducted in fish, not humans. Translation to human physiology requires further study. However, the signalling chain is highly conserved across evolution, suggesting that comparable mechanisms may operate in mammals, including humans. For the science of hormonal aging, this provides a concrete new target.
Search terms: Leydig cell differentiation androgen production, Desert Hedgehog signalling pathway stem cells, testosterone decline male aging