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.
Nerve
discomfort
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
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.
References
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