neuronerdProgesterone in the brain
Image credit: Ionut Stefan
This post is part of our series “Hormone effects on the brain“. If you’re completely new to the topic of hormones, we recommend that you start from there. If you need a refresher on steroids, check out the first part of the article on estrogens.
What is progesterone?
Progesterone is a steroid hormone, same as estrogens. In fact, it shares quite a few similarities with the latter: it’s derived from cholesterol, it’s produced in multiple areas of the body, and it has both direct and indirect mechanisms of action.
There are, of course, some important differences as well. The first one is actually related to the name: we talk about estrogens (plural, as there are four main types), but progesterone (singular). The broader family of molecules that act on the same receptor is called “progestogens“; synthetic members of this family are known as “progestins“.
Estrogens are synthesized in the ovaries, testes, and placenta, as well as in several peripheral tissues such as fat, skin, bone, blood vessels, and even the brain. Progesterone, by contrast, is produced mainly by the corpus luteum in the ovary and by the placenta in females, by the testes and adrenal glands in males, and locally in the nervous system by both neurons and glia.
General effects
Since it’s known as a sex hormone, it should come as no surprise that the most well-known effects of progesterone are related to the reproductive system.
In females, progesterone contributes to the development of breast glands and influences libido. Additionally, it plays a significant role during pregnancy by helping the uterus prepare for implantation, decreasing the immune system response of the mother such that the pregnancy is more likely to be accepted, inhibiting lactation during pregnancy, and helping prevent premature labor. The fetus also uses placental progesterone to produce adrenal steroids (other very important hormones we’ll talk about in a future article).
In males, progesterone helps with the early differentiation of male genitalia. It does so indirectly, by serving as a precursor for testosterone and a more potent hormone called DHT (dihydrotestosterone).
Beyond that, it appears that progesterone contributes to skin elasticity, stimulates respiration, increases body temperature during ovulation, may increase the risk of gingivitis, and act in signaling insulin release, among others.
Neural effects
Progesterone receptors are widely distributed throughout the brain, though not evenly. Some regions and cell types express them more strongly than others, allowing for region- and cell-specific effects. In addition, progesterone acts not only through classical nuclear receptors but also through membrane receptors and metabolites such as allopregnanolone, which themselves influence brain activity.
Two neural effects have been studied most intensively. The first is a potential neuroprotective role. In animal models of traumatic brain injury, stroke, and neuroinflammation, progesterone reduces swelling, limits cell death, and dampens inflammatory responses. While these findings are promising, large clinical trials in humans have not yet shown clear benefits, so its therapeutic value remains under investigation.
The second is a neuromodulatory effect on neurotransmission, particularly through GABA-A receptors. Allopregnanolone, a metabolite of progesterone, acts as a modulator of these receptors, producing anxiolytic (anti-anxiety) and calming effects. This mechanism is clinically relevant, as it helps explain both progesterone’s role in mood regulation and some of the neuropsychiatric side effects of hormonal contraceptives.
Other neural actions of progesterone include promoting dendritic spine remodeling (i.e. reshaping synapses in regions like the hippocampus) and possibly influencing the gut microbiome, which communicates bidirectionally with the nervous system. These latter effects are still emerging areas of research but suggest progesterone’s influence on the brain is both broad and dynamic.
What we still don’t know
Similar to estrogens, there are still many areas where more research needs to be done.
For example, while animal trials and small clinical trials in humans have shown neuroprotective effects of progesterone after brain injury, larger phase III trials have failed to replicate these results. Whether this reflects differences in dosing, timing, or biological complexity is still an open question.
In terms of mood and anxiety, while we know that progesterone and its derivatives play a role here, we still don’t fully understand how synthetic derivatives affect the brain. And with respect to the gut-brain axis, we don’t know yet whether the observed influence translates into any meaningful effects on mood or cognition.
Finally, as with estrogens, it’s uncertain whether progesterone acts in the same way outside reproduction in both males and females.
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References
Brinton, R. D., Thompson, R. F., Foy, M. R., Baudry, M., Wang, J., Finch, C. E., Morgan, T. E., Pike, C. J., Mack, W. J., Stanczyk, F. Z., & Nilsen, J. (2008). Progesterone receptors: Form and function in brain. Frontiers in Neuroendocrinology, 29(2), 313–339. https://doi.org/10.1016/j.yfrne.2008.02.001
Burgraff, N. J. (2024). Keeping breathing in balance through hormonal modulation in respiratory control. Acta Physiologica, 240(4). Portico. https://doi.org/10.1111/apha.14094
Pletzer, B., Winkler-Crepaz, K., & Maria Hillerer, K. (2023). Progesterone and contraceptive progestin actions on the brain: A systematic review of animal studies and comparison to human neuroimaging studies. Frontiers in Neuroendocrinology, 69, 101060. https://doi.org/10.1016/j.yfrne.2023.101060
Tahri, A., Niccolai, E., & Amedei, A. (2025). Neurosteroids, Microbiota, and Neuroinflammation: Mechanistic Insights and Therapeutic Perspectives. International Journal of Molecular Sciences, 26(14), 7023. https://doi.org/10.3390/ijms26147023
Wei, J., & Xiao, G. (2013). The neuroprotective effects of progesterone on traumatic brain injury: current status and future prospects. Acta Pharmacologica Sinica, 34(12), 1485–1490. https://doi.org/10.1038/aps.2013.160
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