Oestrogen and Your Brain’s Own Pain Relief
When aches arrive in midlife without an obvious cause, women are often told the reason is hormonal and left there, with no explanation of what that actually means. Your body makes its own pain relief, a built-in system that quietly dampens everyday aches without you ever noticing it working, and the hormones that shift through perimenopause and menopause help set how much of it you have available. What follows is what the evidence shows for each of the four hormones that matter most, and how strong that evidence is for each.
The body’s own painkillers
Alongside the nerves that carry pain towards the brain, you have a system that works in the other direction, releasing your own natural opioids to turn pain signals down before they fully register. This is why someone in an emergency can act first and feel the injury only later, and why the same knock can barely register on one day and ache on another. This internal relief is always working in the background, and how strongly it responds is not fixed, which is where oestrogen comes in.
Oestrogen, the main regulator
Oestrogen receptors sit throughout the pain system, in the brain, the spinal cord, and the nerves, which means oestrogen is involved in how pain is felt at many points at once.[1] The clearest human evidence comes from a brain-imaging study at the University of Michigan, where healthy women were scanned twice, once when their oestrogen was low and once when it was high, while a steady, controlled muscle pain was maintained, and the brain's own pain-relieving activity was measured as they did.[2] When oestrogen was high, the women's brains released more of their own natural painkillers during the pain, and they rated it as more bearable. When oestrogen was low, that same relief fell in the deep brain regions that handle pain, and the identical pain was felt as worse.
There was a further detail that identifies why women and men can differ. When the women's oestrogen was high, their own pain relief during the pain was as strong as that of a matched group of men. When their oestrogen was low, it dropped below the men's, so the protection was there and low oestrogen took it away. This was a small study of eight women whose oestrogen was adjusted with a patch rather than women moving naturally through menopause, so it shows the mechanism without fully explaining women's midlife pain, but what it does establish is that oestrogen is one of the controls on how much pain relief your own brain can generate.
The effect is not a simple straight line. Higher, steadier oestrogen tends to settle pain, while low or swinging levels tend to amplify it, and researchers are still working out precisely which oestrogen receptor does what, so the mechanism is not fully mapped yet.[1] For everyday life, this reframes the aches that arrive in perimenopause as partly the predictable result of a natural pain-relief system running with less support than it used to have, rather than a sign that your body is failing or that you have become less resilient.
Progesterone, the calming hormone
Progesterone works primarily through a breakdown product called allopregnanolone that boosts GABA, the nervous system's main calming signal, acting on the same braking system as alcohol and benzodiazepines.[3] As progesterone falls across the transition, often earlier and more steeply than oestrogen, some of that calming influence weakens, which for some women shows up as feeling more wired, more sensitive and less able to settle. The current evidence sits in animal studies and no human trial has shown that progesterone treats pain, but it may help to understand your body and be a conversation to have with your GP rather than a treatment to request.[3]
Testosterone, a promising lead
Testosterone is often described as protective against pain, and in animal studies the evidence is fairly strong and consistent, with animals that have normal testosterone showing less pain behaviour, removing it increasing pain sensitivity, and replacing it reducing it again, the plausible mechanism being that testosterone appears to strengthen the descending pathways the brain uses to turn pain down.[4] The human evidence is much weaker and mixed. The one randomised trial is in men, where men with chronic pain and low testosterone had a reduction in pain intensity.[5] Higher natural testosterone is associated with less postoperative pain and lower rates of chronic widespread pain, and in conditions like fibromyalgia lower testosterone tracks with worse pain, but these are correlations rather than proof, and no trial has tested whether testosterone treats pain in women. AndroFeme is approved by the TGA in Australia, but for one thing only, low sexual desire that causes distress, so it is not approved for pain and prescribing it for pain sits outside that licensed indication.[6]
Prolactin, an emerging and female-selective signal
Prolactin is the newest piece of this picture. In laboratory work it makes pain-sensing nerves more excitable in a way that happens in females and not males, and the effect has now been shown across mouse, monkey and human nerve tissue.[7] There is a complication, which is that human prolactin generally falls after menopause, so if prolactin sensitises nerves and prolactin drops, the simple prediction would be less pain after menopause, which is not what most women report.
Putting the four together
The pattern with these four hormones is that when your hormones are steady, your body keeps more of its own pain control regulated, and when they fall and swing, as they do through perimenopause, that control becomes patchy and pain gets through more easily, which is part of why one week can hold both a good day and a difficult one. It is worth saying that perimenopause does not follow one script, and many women's periods remain completely unchanged throughout perimenopause even as other symptoms arrive, so a regular cycle is not evidence that hormonal change is not part of the picture. Easing pain in midlife usually means working on several things at once, steadying oestrogen where that is right for you, protecting your sleep, and taking load off an overstretched nervous system, and taking this to your GP as a pattern, which symptoms, when in your cycle, and what makes them better or worse, turns a rushed appointment into a useful one.
In simple terms
Oestrogen, progesterone, testosterone and prolactin each shape how you feel pain, which is why your pain threshold can change so much across the transition.
Steadier, higher oestrogen tends to settle pain, while falling and swinging hormones tend to turn it up.
Progesterone and prolactin are emerging and animal-based, and testosterone shows a real but unproven link in humans, so treat bold claims with caution.
If your pain tracks your cycle, that pattern is useful clinical information worth writing down and bringing to your GP.
This is not your body failing you. It is your body changing, and the chemistry behind your pain is real.
Medical terms,
Endogenous opioids: the natural painkillers your own nervous system releases to turn pain signals down.
Allopregnanolone: a calming molecule made from progesterone that boosts the brain's main braking signal, GABA.
Descending pathways: the routes the brain uses to send pain-dampening signals down to the spinal cord.
Off-label: prescribing a medicine for a purpose other than the one it is officially approved for.
References
[1] Chen Q, Zhang W, Sadana N, Chen X. Estrogen receptors in pain modulation: cellular signaling. Biology of Sex Differences. 2021;12:22.
[2] Smith YR, Stohler CS, Nichols TE, Bueller JA, Koeppe RA, Zubieta JK. Pronociceptive and antinociceptive effects of estradiol through endogenous opioid neurotransmission in women. Journal of Neuroscience. 2006;26(21):5777–5785. (n=8; oestradiol adjusted by patch; mechanistic, not a menopause cohort.)
[3] Meyer L, Patte-Mensah C, Taleb O, Mensah-Nyagan AG. Allopregnanolone and progesterone in experimental neuropathic pain: former and new insights with a translational perspective. Cellular and Molecular Neurobiology. 2019;39(4):523–537.
[4] Smith AF, Plumb AN, Berardi G, Sluka KA. Sex differences in the transition to chronic pain. Journal of Clinical Investigation. 2025;135(11):e191931.
[5] Kato Y, Shigehara K, Kawaguchi S, et al. Efficacy of testosterone replacement therapy on pain in hypogonadal men with chronic pain syndrome: a subanalysis of a prospective randomised controlled study (EARTH study). Andrologia. 2020;52(10):e13768.
[6] Australasian Menopause Society. Testosterone and the menopause. AMS Information Sheet. (ANNA TO REVIEW — confirm exact AMS reference and year at point of publication.)
[7] Chen Y, Moutal A, Navratilova E, et al. The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females. Science Translational Medicine. 2020;12(529):eaay7550.
This information is educational only and does not constitute personal medical advice. Always consult a qualified health professional about your individual circumstances. © Menopause Hub 2026.
Anna Pattison. Former Registered Nurse, Clinical Myotherapist, Menopause Mentor.
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