Summary: New research shows that high prenatal exposure to progesterone can change gene expression in the frontal cortex of male sheep fetuses. Although progesterone is commonly prescribed to reduce miscarriage risk, this animal study indicates possible sex-specific effects on fetal brain development that merit further investigation.
The investigators identified increased accumulation of the SRD5A1 gene in the frontal cortex of male fetuses — a region of the brain important for cognition and behaviour — while female fetuses showed no comparable changes.
Key research findings
- SRD5A1 increase in males: Male fetuses exposed to elevated progesterone levels exhibited higher accumulation of the SRD5A1 gene in the frontal cortex. SRD5A1 encodes an enzyme involved in metabolizing sex steroids that contribute to brain maturation.
- Sex-specific effects: Alterations in gene expression and related biological pathways, including calcium signalling, were detected only in male fetuses. Females in this study did not show the same molecular changes.
- Treatment regimen: Pregnant ewes received 200 mg of progesterone by injection twice weekly from day 20 to day 75 of gestation, a window the authors equate to roughly the first 15 weeks of human pregnancy.
- No change in core receptors: The research did not find differences in key hormone receptors or several related enzymes in either sex, despite the gene-level alterations seen in males.
- Brain plasticity and uncertainty: Researchers emphasise that the fetal brain is highly plastic. Gene-level changes observed in utero may not persist after birth, so the long-term consequences for development, health, or behaviour remain unknown.
- Why sheep were used: Sheep are valued as a model species for developmental and endocrine studies because their organ size and lifespan are more similar to humans than many small laboratory species. Nonetheless, findings from sheep cannot be assumed to directly translate to humans without further research.
Source: European Society of Endocrinology
Study overview
Researchers from Edinburgh Napier University, the University of Edinburgh and Aberdeen University report that excessive progesterone exposure in pregnancy altered a gene involved in steroid processing in the male fetal frontal cortex. Progesterone is a steroid hormone that supports pregnancy and regulates the menstrual cycle, and it is commonly prescribed during early pregnancy for women at elevated risk of miscarriage or undergoing assisted reproduction. While short-term use of progesterone is generally considered safe, the long-term effects on fetal brain development are not well understood.
Earlier work from the same group showed that increased prenatal progesterone can raise fetal progesterone levels in male sheep and affect pituitary and testicular function, as well as the circulating steroid profile. In the current experiment, the team administered 200 mg progesterone twice weekly to pregnant ewes between gestational day 20 and day 75. Examination of fetal brain tissue revealed that male fetuses had increased accumulation of SRD5A1 in the frontal cortex, whereas female fetuses did not exhibit this change.
Although key hormone receptors and many steroid-related enzymes remained unchanged in both sexes, pathway-level analyses indicated alterations in biological processes such as calcium signalling in male fetal brains. The researchers caution that detection of molecular changes does not automatically imply harmful or permanent effects; further longitudinal work is required to determine whether these prenatal differences persist into postnatal life and influence behaviour or health outcomes.
“Our findings suggest that male and female fetuses may respond differently to maternal progesterone treatment, with some effects observed only in males. Because these are gene-level changes, we cannot yet say whether they will have positive, negative or neutral consequences for development, health and behaviour after birth,” said lead author Dr Katarzyna Siemienowicz of Edinburgh Napier University.
She added that sheep are valuable models for this type of research due to their size and developmental parallels with humans, but emphasised that this remains an early-stage animal study and that additional research is needed to establish relevance to human pregnancy.
The team plans follow-up studies to clarify the mechanisms by which progesterone may modify brain development and to determine whether the observed changes have lasting effects. Future work will include more detailed assessment of hormone levels directly within brain tissue and longer-term follow-up into postnatal life.
Key questions answered
A: Not necessarily. Progesterone remains an important treatment for many pregnancies at risk of miscarriage and is generally regarded as safe for short-term use. This study underlines the need for more research into possible long-term and sex-specific effects of prenatal progesterone exposure.
A: Male and female fetuses have different hormonal environments and developmental timing. SRD5A1 participates in the metabolism of sex steroids, so altering progesterone levels may shift the hormonal milieu in ways that particularly impact male brain regional development.
A: It is too early to conclude that. While gene-level differences were observed in utero, the study does not show whether those changes persist after birth or translate into behavioural or health effects.
Editorial notes
- This article was edited by a Neuroscience News editor.
- The underlying journal paper was reviewed in full by the editorial team.
- Additional context was added by staff to clarify methods and implications without changing the original findings.
About this genetics and neurodevelopment research news
Author: Megan Gell
Source: European Society of Endocrinology
Contact: Megan Gell – European Society of Endocrinology
Image: The image is credited to Neuroscience News
Original research: The findings were presented at the 28th European Congress of Endocrinology (ECE) 2026.