Low Exposure to Testosterone in the Womb May Increase Men's Health Risks in Adulthood

New research may explain how and why low in utero testosterone exposure reduces testosterone levels in adult men and increases their consequent risks of obesity, diabetes, and heart disease.

Scientists from the University of Edinburgh found that the action of androgens in the womb dramatically affects a particular type of stem cell that appears to develop into the Leydig cells that produce testosterone in adult men.

The findings, which the research team believes to be the first of their kind, were published in April in the Proceedings of the National Academy of Sciences of the United States of America.

“This suggested connection has widespread implications,” wrote the authors of the study.

“Our findings provide a pathway through which fetal growth and birth weight could influence testosterone in adult men… No explanation for this association is currently available.”

Other studies of both animals and humans had already shown that levels of testosterone in a mother’s womb correlate positively with levels of testosterone in her adult male offspring, but researchers had found no clear link between the fetal environment and Leydig cells, which do not differentiate until adulthood.

One study, however, did show that the elimination of chicken ovalbumin upstream promoter transcription factor II (Coup-TFII) in prepubertal male mice resulted in failure of adult Leydig cells to develop.

The Edinburgh team therefore hypothesized that COUP-TFII—expressing non-Leydig interstitial cells in fetal testes may be the stem cells that produce adult Leydig cells. Anything affecting those cells might, therefore, affect adult testosterone production.

The group used ethane dimethane sulfonate (EDS) to induce the ablation of Leydig cells in rats and, as group members traced the subsequent regeneration of the Leydig cells, they found evidence that the new cells were, indeed, developing from the stem cells in question.

The researchers then showed that the manipulation of those stem cells in the wombs of mice could affect both cell levels and testosterone levels in adult males.

Reduction in fetal androgen action by the elimination of androgen receptors found on the stem cells reduced the number of such cells by approximately 40% from birth to adulthood and induced compensated failure in adult Leydig cells.

The same result occurred in rats when dibutyl phthalate (DBP) was used to lower intratesticular testosterone. In DBP-exposed males, this failure was probably explained, the researchers believe, by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation in the proximal promoter.

The research team also noted that its work added further weight to earlier findings about the need for pregnant women to live healthy and the need for further research about what, specifically, such women can do to maintain good androgen levels in the womb.

“There is increasing evidence that a mother's diet, lifestyle and exposure to drugs and chemicals can have a significant impact on testosterone levels in the womb,” said Richard Sharpe, PhD, one of the study’s authors, in a news release. “We need a better grasp of these factors so that we can give reliable advice to pregnant women to protect the health of her unborn child.”