Brain serotonin metabolism seems to be particularly gender-specific

 There have been many research findings on links between neurotransmitters, particularly serotonin, and gender differences in aggressiveness.   However,  serotonin is known to play a role in many body functions.  These are temperature regulation, sleep, mood, immune function, appetite,  pain and the metabolic and behavioral response to stress. 

It appears that women have a slightly higher body temperature than men.  One investigation had subjects consume a light non-protein breakfast before 8:00 AM, a cup of tea or coffee after the 10:00 AM temperature collection, and a substantial 3-course lunch at 1:00 PM.  Results showed that female temperatures were higher throughout the sample period.  However, measurement of body temperature is complicated,  especially in women.  Body temperature is influenced by contraceptives and also by the menstrual cycle.  Furthermore,  in women with disturbed hormonal cycling (anorexics, high performance athletes),  body temperature regulation is often disturbed.  As a matter strictly of personal observation,  it seems to me that the women colleagues, students and employees I have frequented are much more prone to complain of air temperature in air conditioned buildings,  whether it be too hot or too cold.  One recent study found that female rats responded with greater body temperature changes to drugs known to mediate hypothalamic control of body temperature than did male rats.  Of course,  everybody knows that body temperature changes as a function of the menstrual cycle:  the thermometer is thus often used to regulate sexual activity so as to favor or avoid fertilization.  In short,  normal men’s and women’s body temperatures seem to be very similar,  but there could be a basic sex difference in the adaptability of body temperature to endogenous (internal) and exogenous (environmental) stimuli. 

One team of investigators studied effects of age, gender, diagnostic status, and psychiatric features on 102 female and 189 male sleep disorder patients' (aged 16-87 years).   Gender had a strong impact, with women reporting more sleep-related distress.   It is noteworthy however that the male clientele was more numerous, overall.  There are many types of sleep disorders.   The most common one,  perhaps also most closely related to serotonin metabolism,  is insomnia.  There seem to be a bit more women than men who suffer from insomnia.  One study surveyed 14,667 subjects (aged 20-54 years) in Norway about sleeplessness and found that 41.7% of the women and 29.9% of the men were sometimes bothered by insomnia.  It has clearly been documented that the proportion of rapid eye movement sleep (one of the phases of sleep during which the eyeballs « jitter ») is modulated in mice as a function of the menstrual cycle. Furthermore,  a few cases of clinical hypersomnia (a sleep disorder consisting of an excessive need for sleep) have been reported to track the menstrual cycle in afflicted women.  However, normal sleep is probably not directly influenced by sex hormones.  Rather, I expect that the effect on sleep is due to an influence of sex hormones on brain neurotransmitters.  Serotonin seems to have a generally facilitatory role in producing the type of deep sleep scientists call “slow wave sleep”.  Indeed,  reserpine,  a non-specific serotonin antagonist,  deprives animals and humans of that type of sleep.  Another possible biological basis for a sex difference in sleep patterns, in humans,  might be found in the pineal gland situated in the center of the brain.  The pineal gland is light-sensitive and secretes melatonin,  a sleep inducing hormone.  One investigation compared blood-melatonin concentrations in normal men and women exposed to hours of darkness or of strong lights.   In the dark condition, no significant differences were observed between men and women in either the timing or the absolute values of melatonin plasma levels, whereas after bright light exposure, the suppression of plasma melatonin was 40% greater in women than in men. These findings suggest that, in humans, there is a sex difference in the nocturnal sensitivity of the pineal to light.   It is nevertheless very difficult (hazardous) to interpret sex differences in sleep disorders biologically:  women have them relatively more in relation to mood disorders,  whereas men have them relatively more in relation to substance abuse.   Finally,  it is of note that variations in some basic parameters of sleep has been found to track the menstrual cycle in normal women.

As I document in chapter 8,  there is a huge sex difference in the immune function -which could be mediated among other things by serotonin.  Very little is known about this eventuality.  Some anti-inflammatory drugs have a marked serotonergic effect.   Metabolic,  physiologic and psychological effects of some of those drugs vary according to sex.   For example,  aspirin has an antithrombotic effect (protects against strokes),  but only in men. The inhibitory effect of aspirin on blood platelets (the antithrombotic effect) was reduced in orchiectomized (castrated) male patients and was restored by the addition of testosterone to blood samples. Estradiol had no detectable influence on the effect of aspirin on platelets.    Tricyclic antidepressants are selective serotonin agonists.   The effect of one of them, desmethylimipramine,  on natural killer lymphocytes (immune cells), is clearly inhibitory.   One investigation went even further than this:  the authors found that in rats, activation of the immune system by a toxin produces anhedonia (loss of the subjective feeling of pleasure) and other depressive-like symptoms, which can be attenuated or completely blocked by chronic treatment with an antidepressant drug.  An investigation of clinically depressed humans found that several blood indicators of immune system activation indicate immunostimulation during depression,  and that this effect is counteracted by tricyclic antidepressants.   Of course,  research on aspirin and antidepressants is tangential to the issue of whether serotonin is a major factor in normal sex differences in immune function,  but it weakly supports the idea. Chronic fatigue syndrome (CFS) is a condition that affects women in disproportionate numbers, and that is often exacerbated in the premenstrual period and following physical exertion. The signs and symptoms, which include fatigue, myalgia (muscle pain), and low-grade fever, are similar to those experienced by patients infused with cytokines such as interleukin-1,  drugs which influence immune function.  A study was recently carried out to test the hypotheses that (1) cellular secretion of interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-1 receptor type II (IL-1sRII) is abnormal in female CFS patients compared to age- and activity-matched controls; (2) that these abnormalities may be evident only at certain times in the menstrual cycle; and (3) that physical exertion (stepping up and down on a platform for 15 minutes) may accentuate differences between these groups. Isolated peripheral blood mononuclear cells from healthy women, but not CFS patients, exhibited significant menstrual cycle-related differences in IL-1 beta secretion that were related to estradiol and progesterone levels. IL-1Ra secretion for CFS patients was twofold higher than controls during the follicular phase, but luteal-phase levels were similar between groups. In both phases of the menstrual cycle, IL-1sRII release was significantly higher for CFS patients compared to controls.  Candidal vaginitis most often recurs during pregnancy and in the late luteal phase just before menstruation. One study recently examined the influence of the stage of the menstrual cycle on the cellular immune response to Candida albicans, the efficiency of Candida albicans germination in blood serum, and the ability of products from activated lymphoid cells (immune cells) to inhibit germination. Candida albicans germination was maximal in blood sera obtained during the luteal phase. During this period the cellular immune response to Candida was reduced as was the inhibition of Candida germination by products of activated peripheral blood mononuclear cells (another type of immune cell). Variations in immune response to Candida were of much lesser magnitude in women who took oral contraceptives, which suggests that it was the marked fluctuation in progesterone or estradiol levels during the menstrual cycle that influenced the changes in the immune response to Candida albicans. Thus the hormonal status of women may influence the pathogenicity of Candida albicans by modulation of immune system activity. The  results of this investigation explain the clinical observation that candidal vaginitis infections most frequently reappear before menstruation.  Several other investigations have found that the strength of the immune response varies as a function of the menstrual cycle.

The drugs most effective for combating mood disorders also operate primarily along the serotoninergic axis, and women are much more at risk for mood disorders.   This issue is reviewed in other chapters of this book.  So to make a long story short,  serotonin-based sex differences seem to include mood. 

As for pain,   there seems to also exist a sex difference.  Women’s thresholds for pain seem to be lower than those of men for most forms of pain.  Women declare pain at lower intensities of stimulation,  and declare higher subjective discomfort or pain at equal levels of stimulation.   One test of pain that has been used to test this sex difference is immersion of the hand into a bucket of ice-water.   It could be argued of course that men just have more bravado...    and it is very hard to judge whether subjective pain is a cultural artifact or not.   One piece of evidence against an exclusively culturalistic interpretation of a sex difference in pain threshold is the finding to the effect that pain killers are reported by women to produce more relief than by men.   However, it might be wise to keep in mind that there are many types of pain.   For example, perhaps the kind of pain encurred during childbirth would not be well tolerated by men...   It is also relevant to think of pain threshold reports of people according to a more fluid concept of sexual identity than simple genotypic sex.   Of course,  what I mean here is the degree of androgyny as measured by the appropriate type of personality scale. One study investigated the relationship between measured levels of masculinity-femininity, social desirability, and responsivity to pain in men and women. A significant interaction was indeed found between masculinity-femininity and sex for pain thresholds. Analysis of this interaction indicated that for men, but not women, there was a significant correlation between masculinity-femininity and pain, where higher masculinity was associated with higher pain thresholds. However, this finding did not account for the sex difference in pain threshold. The sex of the subject remained a significant predictor of both pain thresholds and tolerances after allowing for the influence of masculinity-femininity, social desirability, and their associated interactions.   At least one study has found that women’s sensitivity to painful stimulation varies as a function of the menstrual cycle.

Women are also more often victims of dysregulation of appetite.   Not only are there many more anorexics (self-starvers) and bulimics (binge eaters) of the female sex (see chapter 11),   but women are also more frequently obese.   I suppose it could be argued from a sociocultural perspective that if a person is going to abuse a substance,  if that person is a man,  being acculturated to a position of self-affirmation and of socializing outside the home -he will select disreputable or illegal psychotropic (mind warping) drugs;   if that person is a woman,  she will stick to respectable and perfectly legal abuse of a substance which is close to her social role of housewife:   food.  However there are indications to the effect that female hormones do modulate the brain’s regulation of appetite.  For example,  athletics (particularly long distance running) sometimes disturbs cycling of ovarian hormones.  In some particularly sensitive or fragile women athletes, luteinizing hormone seems to be the first to be reduced,  followed by abnormality of the gonadotropin cycle, and finally by a generalized drop in estrogen.  Then amenorhea (loss of menses) occurs,  followed by loss of appetite (anorexia).    Investigations of normal women have found that food intake varies as a function of the menstrual cycle. 

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Extreme stress is also known to inhibit the menstrual process and prevent pregnancy in several species.  The phenomenon is well known in rodents.  When wild rabbits, for example,  are environmentally stressed,  particularly by food deprivation,  they reproduce less  -a mechanism the adaptiveness of which is quite obvious.   In women,  extreme stress can stop the menstrual process,  make her temporarily infertile,  and disturb her mood,  her thermoregulation, her sleep,  and her appetite.  The phenomenon was observed on a massive scale during the despotic and murderous reign of Pol Pot and Ieng Sary in Cambodia.   Of course,  it cannot be determined precisely to which extent the drop in Cambodian women’s fertility during the years of terror was due to psychocultural factors (less sexual activity,  attempts to avoid pregnancy)  or to psychobiological factors (hormonal imbalance, physiological infertility).   In chapter 5, I argue that men are more sensitive to stress than women (especially around birth),  -except with regard to brain serotonin physiology.