Breaking Up the T Party: Short-circuited hormone signal keeps old rats from making testosterone (Sex hormones)
Authors: Davenport R. John 
Published: August 2003

Women haven't cornered the market on hormonal woes. As men age, their blood testosterone concentrations decline, which might contribute to health problems such as osteoporosis (see
"More Than a Hot Flash"
). A new study casts blame on a withered signaling pathway that normally jolts testosterone-producing cells into action.

Scientists don't understand what triggers the fall in testosterone concentration, but the Brown Norway rat, which experiences an ebb in testosterone concentration similar to that in humans, has provided some clues. In old animals, testosterone factories in the testes called Leydig cells lose their capacity to churn out the hormone. Previous studies indicated that supplemental luteinizing hormone (LH), which normally prods Leydig cells into action, couldn't elevate testosterone concentrations in old rats.

To find out why, Chen and colleagues removed Leydig cells from young and old rats and cultured them in the presence of LH. Cells from the youngsters pumped out testosterone, but those from geezer rodents did not. To investigate why old cells fail to respond to LH, the team measured how much LH bound to each type of cell. Old cells glommed onto one-third fewer hormone molecules than young cells did, indicating a decrease in the number of cell surface receptors that bind LH.

But a lack of receptors didn't cause the decline in testosterone production, according to the outcome of an additional experiment. The researchers collected Leydig cells from young animals whose LH output had been artificially lowered. These cells had fewer LH receptors--yet they made much more testosterone in culture than old cells did, a result that takes the number of LH receptors off the hook. Perhaps the pathway through which the LH receptor stimulates testosterone production is defective, the researchers proposed.

After binding LH, the receptor triggers synthesis of a molecule called cyclic AMP (cAMP) inside Leydig cells; cAMP ignites testosterone production. Chen and colleagues found that cells from old rats contained lower cAMP concentrations than did those from either normal young animals or young animals with reduced LH. A general slump in cAMP formation wasn't to blame: Old cells pumped out the molecule when treated with a chemical that directly stimulates the cAMP-producing enzyme. The results suggest that aging short-circuits the LH receptor's ability to trigger cAMP synthesis in Leydig cells.

How this glitch arises is mysterious, but the authors propose that Leydig cells might accrue oxidative damage while making testosterone. Enzymes generate reactive oxygen species as they manufacture testosterone, and previous work by the team suggests that decreasing testosterone output reduces oxidative damage in Leydig cells.

The study provides new evidence for how rat Leydig cells lose their capacity to generate testosterone, says endocrinologist Alvin Matsumoto of the University of Washington, Seattle, but it's uncertain whether humans suffer from the same defect. The idea that free radicals assault Leydig cells is an intriguing one, although not proven, he says. If that's true, antioxidants might help maintain testosterone production. Perhaps the delicate broccoli flower will be the secret to youthful vigor in older men.

--R. John Davenport; suggested by James M. Harper

H. Chen, M. P. Hardy, B. R. Zirkin, Age-related decreases in Leydig cell testosterone production are not restored by exposure to LH
in vitro. Endocrinology
143
, 1637-1642 (2002).
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