NEW YORK - Why does stress cause a man's sperm count to plummet? Research led by Population Council endocrinologist Matthew Hardy found that stress hormones overpower the enzymes responsible for ensuring that cells in the testes produce testosterone, which is necessary for sperm formation.
Offering the first evidence that stress acts locally within the testes, via the Leydig cells, the report by Hardy and his colleagues is the lead article in the December Endocrinology and is accompanied by an editorial comment.
"It's well known that stress exerts a profound suppression on the male reproductive system, but we really haven't understood until now where or how in the complex process of spermatogenesis it happens," Hardy says. "This is also a new way of understanding how enzymes work in Leydig cells."
While Hardy's work provides insight into male reproduction, it may also aid the design of new male contraceptives. He comments, "I am ultimately interested in the control of testosterone production. Anytime you look at the biosynthesis of testosterone, you are looking at a potential way to regulate sperm production."
Hardy found receptors in adult Leydig cells that mediate the action of glucocorticoid hormone. In small amounts, glucocorticoid helps cells grow and thrive, but in the large amounts produced during times of stress, it disrupts normal body processes. Too much glucocorticoid overwhelms the Leydig cell defense mechanism, which is controlled by an enzyme called, for short, 11ßHSD-1. The cell produces only enough 11ßHSD-1 to cope with normal amounts of glucocorticoid. The surfeit of hormone overwhelms the capacity of 11ßHSD-1 to neutralize it, shortcircuiting testosterone production. Without testosterone, other sperm-making cells do not begin to manufacture sperm.
Enzyme acts as a double agent
11ßHSD-1 assists and neutralizes glucocorticoid as necessary. As Leydig cells develop, the amount of enzyme increases in parallel with the amount of glucocorticoid receptors. In immature Leydig cells of young mammals, 11ßHSD-1 facilitates the action of glucocorticoid, which helps Leydig cells divide. In essence, according to Hardy's data, glucocorticoid does for the developing Leydig cell what it does for other cells in the body. Fully matured Leydig cells retain their glucocorticoid receptors, but when the hormone enters adult cells it interferes with their ability to make testosterone. So the cells flip the catalytic switch: The enzyme inactivates glucocorticoid, allowing them to make testosterone.
Though the enzyme's activity is opposite, its allegiance is constant, now aiding and now inhibiting glucocorticoid always to the Leydig cell's benefit.
Hardy's data on enzymatic activity within Leydig cells also contained clues hinting that the enzyme active in the adult Leydig cell may not be 11ßHSD-1. Two forms of 11ßHSD are known but only 11ßHSD-1 is active in testicular cells. Hardy's data suggest the presence of a third, previously unknown form of the enzyme.
"We don't know exactly what this enzyme is, though it is very similar to 11ßHSD-1. And we can see what it is doing. This enzyme is the one that maintains testosterone production in the Leydig cell," he explains. The current report follows up on two articles published this year in Endocrinology by Hardy and members of his lab. In them, he sets forth the rationale for his research on sperm formation and provides the preliminary evidence for the novel enzyme on which this research is based.
Hardy scrutinized the level and type of enzyme activity in precursor, immature, and adult Leydig cells. He saw that enzyme reactions skyrocketed in the adult cell. Compared to the immature Leydig cell, enzyme activity in the adult cell was ten times more effective at metabolizing glucocorticoid. It was as if one man had gained the strength of ten.
"My theory now is that this more powerful enzyme emerges when the Leydig cells mature. It may be encoded by a gene closely related to the 11ßHSD gene expressed in younger Leydig cells," Hardy explains. Perhaps because it has several hallmarks of the known 11ßHSD-1, no scientist has spotted the novel enzyme during 40 years of research on the 11ßHSD enzymes.
Hardy has other evidence that the enzyme activity changes in response to stress. He and his colleagues found that dominant rats living in stressful conditions, which produce higher levels of testosterone, have higher levels of enzyme activity that counter increased glucocorticoids and ensure that they remain fertile.
The Population Council is an international, nonprofit, nongovernmental institution that seeks to improve the wellbeing and reproductive health of current and future generations around the world and to help achieve a humane, equitable, and sustainable balance between people and resources. The Council conducts biomedical, social science, and public health research and helps build research capacities in developing countries. Established in 1952, the Council is governed by an international board of trustees. Its New York headquarters supports a global network of regional and country offices.