Summary: New research reveals that excessive exposure to progesterone during pregnancy can alter gene expression in the brains of male sheep fetuses. While progesterone is frequently prescribed to prevent miscarriage, this study suggests it may have sex-specific long-term effects on fetal development.
Researchers identified changes in the SRD5A1 gene within the frontal cortex, a region critical for brain function, specifically in males.
Key Research Findings
- SRD5A1 Alteration: Male fetuses exposed to increased progesterone showed an accumulation of the SRD5A1 gene in the frontal cortex. This gene is responsible for processing sex hormones essential for healthy brain maturation.
- Sex-Specific Response: The genetic changes and alterations in biological pathways, such as calcium signaling, were observed only in male fetuses; no such changes were detected in females.
- Mechanism of Exposure: Pregnant ewes were injected with progesterone twice weekly during a period equivalent to the first 15 weeks of human pregnancy.
- Brain Plasticity: While these changes occur at the gene level in the womb, researchers emphasize that the fetal brain is highly plastic, meaning these alterations may or may not persist after birth.
- Animal Model Value: Sheep are used in this research due to their human-like organ dimensions and long lifespans, though further studies are required to confirm if these effects translate to humans.
Source: European Society of Endocrinology
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 signalling.
“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 behaviour after birth and as the offspring age,” said lead author, Dr Katarzyna Siemienowicz of 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.
Key Questions Answered:
A: Not necessarily. Progesterone is considered safe for short-term use and is vital for many at-risk pregnancies. This study highlights the need for more research into long-term effects and potential sex-specific sensitivities during development.
A: Male and female fetuses have different hormonal profiles and developmental timelines. The SRD5A1 gene processes sex hormones, so an influx of progesterone may disrupt the specific “hormonal environment” required for male brain regionalization.
A: It is too early to tell. While researchers see changes at the genetic level, they do not yet know if these result in positive, negative, or negligible consequences for health and behavior after birth.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
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 will be presented at the European Congress of Endocrinology (ECE) 2026
