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Pain is a subjective perception influenced by numerous factors. Pain sensitivity can be vastly different from one person to the next. Some influences on pain sensitivity include psychological and neurobiological factors, but gender and sex hormones also play a very particular role. Researchers have found that there are actual differences in how men and women experience severity of pain, because sex hormones are involved in pain transmission and sensitivity. Specifically, estrogen is linked to visceral pain sensitivity. That is, pain that is diffuse and poorly localized. In multiple disorders that involve visceral pain, such as irritable bowel syndrome (IBS) and chronic pelvic pain, women tend to have lower thresholds of pain. We also have been able to link changes in sensitivity with timing of a woman’s menstrual cycle, which is often the case with pain disorders such migraines and headaches.
Estrogen and the nervous system
Serotonin is a neurotransmitter with multiple effects in the body. It can both elicit the sensation of pain and prevent the sensation of pain, depending on which specific type of serotonin receptor it binds to, where in the body that receptor is located, and the duration of exposure.
In general, both serotonin and the opioid system can be affected by ovarian hormones as sex hormones can influence the production, reuptake and break down of these neurotransmitters. Specifically, estrogen plays an important role in the serotonergic system.
There is an ample amount of estrogen receptors throughout the central nervous system and visceral organs. Estrogen is thought to modulate pain through sensory input: It can alter the signal and change the response of neurons to pain receptors. Additionally, in the spinal cord, estrogen may alter the inhibition of certain pain signals. One way estrogen accomplishes this is by modulating serotonin release, as well as the expression (or presence) of serotonin receptors.
Multiple pain disorders tend to be more common in women such as IBS, fibromyalgia and migraines. Most interesting is the connection between pain severity and fluctuating and elevated levels of estrogen throughout the menstrual cycle and even between reproductive, perimenopausal and postmenopausal years.
IBS pain and estrogen
IBS is a disorder described as recurrent abdominal pain, and abnormal stool frequency and/or form. It affects women more than men by a 2:1 ratio. Some studies have shown that symptoms tend to be worse during certain stages of the menstrual cycle, mainly the luteal phase (after ovulation) and during menstruation. This may be due to enhanced expression of serotonin receptors during the late luteal phase when natural estrogen levels are low. Interestingly, IBS pain also tends to be more common in postmenopausal women when estrogen levels are low.
Estrogen receptors are located throughout the gastrointestinal tract and influence the release of serotonin. This could play a major role in the perception of pain in IBS. Additionally, estrogen receptors here can influence movement in the colon and have shown to exert anti-inflammatory and analgesic effects in animal models of IBS.
From these examples of how estrogen influences serotonin and pain, it seems that estrogen may exert a pain-relieving effect in IBS. But on the flip side, estrogen can also have the opposite effect on pain. Studies have shown a link between ovarian hormones and certain inflammatory pathways, notably the stress response and mast cell activity. Both estrogen and progesterone receptors are located in mast cells: one of the types of immune cells involved in inflammatory reactions. When estrogen binds to these receptor sites the mast cells “degranulate,” initiating an inflammatory response. As well, in times of stress, estrogen affects cortisol receptors within the enteric nervous system – the nervous system that connects the gut and the brain. Both of these responses can cause an increase in visceral sensitivity and pain.
As described above, the influence of estrogen and serotonin on pain perception all depend on the specific type of estrogen and serotonin receptor, the site of action, and other factors that influence the release of serotonin.
Fibromyalgia is a disorder characterized by widespread body pain that has been linked to serotonergic dysfunction. It is for this reason that many drug therapies for fibromyalgia focus on altering serotonin reuptake. Similar to IBS, fibromyalgia is predominately a female disorder, suggesting that decreases in estrogen levels may be one factor in the progression of this disease.
Migraine and non-migraine headache
Migraine headaches are more common in women during reproductive years, as well as during perimenopause when estrogen levels can fluctuate relatively rapidly. Many women also find that migraines and headaches occur during certain stages of the menstrual cycle. There are two theories regarding how estrogen is related to the pain associated with migraine headaches: first, the rapid decrease in estrogen levels (such as during the premenstrual and menstrual phases) cause a shift and increase pain; and second, chronically high levels of estrogen can modulate pain pathways and increase migraine pain.
Non-migraine headaches tend to be worse when estrogen levels are low – similar to the visceral pain of IBS. Estrogen in this case activates different serotonin receptors which causes blood vessels in the brain to dilate and elicit pain.
Targeting serotonin and estrogen in treatment
What does this mean as far as using estrogens as treatment? It is clear that when administered exogenously, estrogens can have different effects depending on the protocol and method. Acute, chronic, intravenous, and transdermal administrations all can have different effects on pain perception. As well, not all estrogen receptors are the same, and depending on their location can also mediate different molecular pathways. In some cases, using estrogens as a hormone therapy can help to alleviate headache pain in perimenopausal and menopausal women. However, due to the link between estrogens and serotonin in pain disorders, many pharmaceutical therapies actually look to target serotonin instead of using estrogens. For example, selective serotonin reuptake inhibitors (SSRIs) are often used in fibromyalgia; Serotonin agonists such as triptan drugs are effective for acute migraines; and serotonin antagonists have been used in women with diarrhea-associated IBS. Regardless, it is quite clear that estrogen plays a very influential role on pain and the serotonergic system, and future research may look to target specific receptors.
Paredes S, Cantillo S, Candido KD, Knezevic NN. (2019) An association of serotonin with pain disorders and its modulation by estrogens. Int J Mol Sci. 20(22): pie: E5729
Sun LH, Zhang WX, Xu Q, Wu H, Jiao CC, Chen XZ. (2019) Estrogen modulation of visceral pain. J Zhejiang Univ Sci B. 20(8): 628-36