Definitions PEA (N-palmitoylethanolamide): an endogenous fatty acid amide synthesized and metabolized by cells that bind to cell receptors. It influences a multitude of physiological functions and has potent effects for a healthy inflammatory response and helps to relieve minor discomfort. Endocannabinoid System: A lipid communication network that has critical physiological functions and serves a vital purpose for our health and well-being through signaling processes, homeostasis and hormone regulation. Lipids and the ECS In 1929, scientists George Oswald Burr and his wife, Mildred Burr, discovered that omega 6 fatty acids were essential for health. This kicked off science’s interest into lipids, and
Discomfort is a subjective perception influenced by numerous factors. Sensitivity to discomfort can be vastly different from one person to the next. Some influences on discomfort sensitivity levels 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 discomfort, because sex hormones are involved in discomfort transmission and sensitivity. Specifically, estrogen is linked to visceral discomfort sensitivity. That is, discomfort that is diffuse and poorly localized. In multiple disorders that involve visceral discomfort, such as gastrointestinal disturbances and pelvic discomfort, women tend to have lower thresholds of discomfort. We also have been able to link changes in sensitivity with timing of a woman’s menstrual cycle, which is often the case with discomfort disorder.
Estrogen and the nervous system
Serotonin is a neurotransmitter with multiple effects in the body. It can both elicit the sensation of discomfort and prevent the sensation of discomfort, 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 discomfort through sensory input: It can alter the signal and change the response of neurons to discomfort receptors. Additionally, in the spinal cord, estrogen may alter the inhibition of certain discomfort signals. One way estrogen accomplishes this is by modulating serotonin release, as well as the expression (or presence) of serotonin receptors.
Multiple discomfort disorders tend to be more common in women. Most interesting is the connection between discomfort severity and fluctuating and elevated levels of estrogen throughout the menstrual cycle and even between reproductive, perimenopausal and postmenopausal years.
Gastrointestinal discomfort and estrogen
Gastrointestinal disturbance leads to abdominal discomfort 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, gastrointestinal issues also tend 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 discomfort in the intestinal tract. Additionally, estrogen receptors here can influence movement in the colon and have shown to promote a healthy inflammatory response and analgesic effects in animals with gastrointestinal distress.
From these examples of how estrogen influences serotonin and discomfort, it seems that estrogen may exert a gastrointestinal discomfort-relieving effect. But on the flip side, estrogen can also have the opposite effect on discomfort. 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 discomfort.
As described above, the influence of estrogen and serotonin on discomfort 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.
Widespread nerve and body discomfort has been linked to serotonergic dysfunction. It is for this reason that many therapies for nerve discomfort focus on altering serotonin reuptake. Nerve discomfort is more common in women, suggesting that decreases in estrogen levels may be one contributing factor.
Cranial discomfort is more common in women during reproductive years, as well as during perimenopause when estrogen levels can fluctuate relatively rapidly. Many women also find that cranial discomfort occurs during certain stages of the menstrual cycle. There are two theories regarding how estrogen is related to cranial discomfort: first, the rapid decrease in estrogen levels (such as during the premenstrual and menstrual phases) cause a shift and increase discomfort; and second, chronically high levels of estrogen can modulate discomfort pathways and increase cranial discomfort.
Sometimes cranial discomfort is worse when estrogen levels are low – similar to visceral gastrointestinal discomfort. Estrogen in this case activates different serotonin receptors, which causes blood vessels in the brain to dilate and elicit discomfort.
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 discomfort perception. As well, not all estrogen receptors are the same, and depending on their location can mediate different molecular pathways. In some cases, using estrogens as a hormone therapy can help to alleviate cranial discomfort in perimenopausal and menopausal women. However, due to the link between estrogens and serotonin in discomfort disorders, many pharmaceutical therapies actually look to target serotonin instead of using estrogens. For example, selective serotonin reuptake inhibitors (SSRIs) are often used in nerve discomfort; serotonin agonists such as triptan drugs are effective for cranial discomfort; and serotonin antagonists have been used in women with diarrhea-associated gastrointestinal discomfort. Regardless, it is quite clear that estrogen plays a very influential role on discomfort 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