Summary: New research shows that high prenatal exposure to progesterone can change gene expression in the frontal cortex of male sheep fetuses. The study, presented at the 28th European Congress of Endocrinology in Prague, identifies a sex-specific increase in the SRD5A1 gene in males and highlights the need for further investigation into how commonly prescribed progesterone during early pregnancy might affect long-term brain development.
The research team found notable changes in the SRD5A1 gene in the frontal cortex—a brain region critical for cognition and behavior—specifically in male fetuses. SRD5A1 encodes an enzyme involved in processing sex steroids, which play a key role in neural maturation.
Key Research Findings
- SRD5A1 accumulation: Male sheep fetuses exposed to increased progesterone showed an elevated accumulation of the SRD5A1 gene in the frontal cortex. This gene contributes to the metabolism of sex hormones important for brain development.
- Male-specific effects: Genetic alterations and disruptions to pathways such as calcium signaling were observed only in male fetuses. Female fetuses did not show these same changes.
- Exposure regimen: Pregnant ewes received 200 mg of progesterone by injection twice weekly from day 20 to day 75 of gestation, approximating the first 15 weeks of human pregnancy.
- Brain plasticity and uncertainty: The researchers stress that although changes were detected at the gene level in utero, the developing brain is highly plastic, and it remains unclear whether these alterations will persist after birth or influence later health and behavior.
- Value of the sheep model: Sheep are often used in developmental research because their organ size and lifespan more closely resemble humans than smaller lab animals, but findings from animal models require replication and careful translation before applying to human pregnancy care.
Context and importance
Progesterone is a steroid hormone essential for maintaining pregnancy and regulating the menstrual cycle. It is commonly prescribed during early pregnancy, particularly for women at elevated risk of miscarriage or undergoing assisted reproductive techniques. While short-term use of progesterone is widely accepted and considered safe in many clinical settings, the long-term consequences of increased prenatal exposure on fetal brain development are not well understood.
Previous work by researchers at Edinburgh Napier University, the University of Edinburgh and the University of Aberdeen showed that elevated prenatal progesterone can raise circulating progesterone in male sheep fetuses and alter pituitary and testicular function as well as steroid profiles. Building on that work, the current study links prenatal progesterone exposure specifically to altered expression of SRD5A1 in the male frontal cortex and to changes in molecular pathways such as calcium signaling.
Lead author Dr Katarzyna Siemienowicz of Edinburgh Napier University emphasized the sex-specific nature of the findings: “Our results suggest male and female sheep fetuses respond differently to maternal progesterone treatment, with some effects observed only in males. Because these are gene-level changes, we do not yet know whether they have positive, negative, or neutral consequences for development, health, or behavior after birth and with age.”
She added that while sheep are a valuable translational model due to their size and physiology, this is an early-stage animal study. Further research is needed to determine whether similar effects occur in humans and to identify the mechanisms by which progesterone may influence brain development.
The research team plans follow-up studies to examine the precise biological pathways affected by progesterone, to measure hormone levels directly in brain tissue, and to determine whether observed prenatal changes persist into postnatal life or affect behavior and neurological function later on.
Key Questions Answered:
A: Not necessarily. Progesterone remains an important and commonly prescribed treatment in early pregnancy, particularly for those at increased risk of miscarriage. This study highlights the need for more research into potential long-term and sex-specific effects on fetal brain development rather than proving harm in humans.
A: Male and female fetuses develop under different hormonal environments and timelines. Because SRD5A1 is involved in processing sex steroids, excess progesterone may perturb the specific hormonal milieu required for male brain regionalization and maturation.
A: It is too early to draw that conclusion. The researchers observed gene-level differences in utero, but they have not yet demonstrated whether these changes translate into lasting behavioral or health outcomes after birth.
Editorial Notes:
- Edited by a Neuroscience News editor.
- Journal paper reviewed in full by the editorial team.
- Additional contextual information provided by staff to clarify study limitations and implications.
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: Findings were presented at the European Congress of Endocrinology (ECE) 2026. Continued research will be required to explore mechanisms, long-term outcomes, and relevance to human pregnancy and fetal brain development.