by Hudson Institute of Medical Research

L-R: Dr Penny Whiley, Professor Kate Loveland. Credit: Hudson Institute of Medical Research

Correct development of testes in a male fetus—and fertility later in life—depend on a crucial hormone being at just the right level.

It's known that low levels of the growth factor activin A will impair production of testosterone at the time when it is required to masculinize the fetus, but new research now shows that too much activin A can have a similar impact.

Hudson Institute Ph.D. graduate Dr. Penny Whiley and supervisor Professor Kate Loveland led a study using mice to investigate the effects of elevated activin A, which can occur during pregnancy complications. Their findings have been published in Frontiers in Endocrinology.

Cause of male infertility may start in the womb

Dr. Whiley said these are important discoveries, at a time when reproductive health is declining among Australian men. Around 1 in 20 males experience reduced fertility, and testicular cancer is the second most common cancer in young men aged 18–39.

Although these conditions are normally only detected after puberty, the causes are thought to originate from disruptions during fetal life.

"This study is the first to show that elevated activin A bioactivity leads to phenotypes (physical characteristics) similar to those observed in testes exposed to endocrine disruptor chemicals (EDCs)," Dr. Whiley said.

"Baby boys exposed to high levels of EDCs in the womb are at a higher risk of developing cryptorchidism, hypospadias in youth, and infertility as adults."

The team's research has now shown that too much activin A harms both germ cells (sperm precursors) and the Leydig cells (which produce testosterone in adults).

"Unusually, germ cells exposed to high activin A frequently contained more than one nucleus (multinucleated—see image below) and were abnormally localized outside of the testis cords, reducing the number of sperm precursor cells at birth by half," Dr. Whiley said.

Fluorescent image showing multinucleated germ cell (arrows and inset). Credit: Hudson Institute of Medical Research

In other words, exposure to too much of this hormone led to a reduced ability to produce sperm.

"We also discovered that several enzymes necessary for steroid production were lower in Leydig cells in these mice, leading to reduced production of the masculinizing factors."

"Like the Goldilocks story, too much or too little activin A is detrimental to fetal testis development," Dr. Whiley said. "It is important that activin A levels are 'just right' to ensure the correct foundation is built for future reproductive health outcomes."

What should pregnant women be aware of

Importantly, while the conditions described above occur only in males, this research is relevant for pregnant women carrying baby boys.

"Activin A levels are increased in pregnant women who experience conditions such as pre-eclampsia, fetal growth restriction, infections, or who may be taking certain medications such as SSRIs (selective Serotonin reuptake inhibitors) during their pregnancy," she said.

"Our research suggests chronically elevated activin A levels in utero may alter steroid production and severely reduce the number of germ cells present in a newborn boys, with the potential to impair future reproductive health."

More information: Penny A. F. Whiley et al, Testis exposure to unopposed/elevated activin A in utero affects somatic and germ cells and alters steroid levels mimicking phthalate exposure, Frontiers in Endocrinology (2023). DOI: 10.3389/fendo.2023.1234712

Provided by Hudson Institute of Medical Research