Prenatal progesterone exposure alters brain development genes in male fetuses

Excessive exposure to progesterone in the womb can alter a gene in the frontal cortex in male sheep fetuses, which is needed for brain development and function, according to research presented at the 28th European Congress of Endocrinology in Prague. The finding highlights the important role hormones play in fetal development in different sexes and potentially in the predisposition to adult disease.

Progesterone – a steroid hormone that supports and maintains pregnancy, and regulates the menstrual cycle – is commonly prescribed during early pregnancy, particularly for women at an increased risk of miscarriage or during assisted reproduction. While progesterone is widely used and considered safe in the short term, not much is known about its longer-term effects on fetal development and function.

Researchers from Edinburgh Napier University, the University of Edinburgh and Aberdeen University have previously shown that increased prenatal exposure to progesterone can raise progesterone levels in male sheep fetuses and alter their pituitary and testis function, as well as their steroid profile. Now, in this study, the researchers injected pregnant ewes with 200 mg of progesterone, twice a week, from day 20 to 75 (equivalent to 15 weeks of pregnancy in humans) and found that, in male fetuses, progesterone exposure was linked to an increased accumulation of a gene called SRD5A1 in the frontal cortex – a gene whose encoded product is involved in processing sex hormones that are crucial for brain development and function. While no changes were detected in key hormone receptors or related enzymes in either sex, alterations were observed in several important biological pathways in male fetuses, such as calcium signaling.

Our findings suggest that male and female sheep fetuses may respond differently to maternal progesterone treatment, with some effects observed only in males. As we see effects on the gene level, however, we do not know if these have any consequences – either positive or negative – on normal development, health and behavior after birth and as the offspring age."

Dr Katarzyna Siemienowicz, lead author, Edinburgh Napier University, UK

She added: "Though sheep are highly valuable animal models in research due to their human-like size, organ dimensions and long lifespans, this is still an early-stage study in an animal model and further research is needed to understand whether these findings are relevant to humans."

The researchers are now planning to investigate the precise mechanisms by which progesterone may alter brain development and whether these changes have any lasting effects later in life. "Given that the developing brain is responsive to progesterone, this exposure may influence neural development but again the fetal brain is highly plastic and changes observed during fetal life may not persist postnatally. Thus, we aim to better understand how progesterone and related hormones affect the developing brain , including measuring hormone levels directly in brain tissue," said Dr Siemienowicz.