From cycling hormones to cycling brains to cycling behavior

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 If we want to take psychoendocrinology seriously we will have to search for brain processes that also somehow follow the menstrual cycle.  We need to understand the precise molecular mechanism by which one or several steroid hormones produce the relevant brain changes.   Circulating hormones could have effects on neuronal metabolism, electrical processes,  or on the neurotransmitters used by neurons to relay information from one to the other.     Have modulations of neurotransmitters been observed to follow (track) the menstrual cycle in mammals ?   You bet they have !   Most of the data comes from research on rodents.   All of the neurotransmitters known to play an important role in cognition show a subtle phasing that is time-locked to the estrous cycle (a term equivalent to the term menstrual cycle  reserved for humans). For example,  the neurotransmitters serotonin and noradrenalin reach their peak at ovulation,  whereas the neurotransmitters dopamine and gamma-aminobutyric acid reach their peak at menstruation.  The evidence for this modulation of neurotransmitters, in humans, comes from studies of body liquids sampled at various stages of the menstrual cycle.  Such liquids provide an indirect estimation of neurotransmitter dynamics in the brain.  We will know a great deal more about the phenomenon when researchers start mapping neurotransmitters with targeted metabolic brain imaging -as a function of the menstrual cycle.  Studies of neuron cultures in vitro have shown that estrogen is a physiological agonist of serotonin and is a dopaminergic antagonist.  There is one piece of the puzzle left to comment.  Why would,  and how could the relative efficiency of the brain's hemispheres change under the influence of hormone cycling ?   The key that will help us unravel that intriguing question,  I think,  could have to do with the fact that brain neurotransmitters are hemispherically asymmetric.    Post mortem assay of serotonin in women's brains has shown that this neurotransmitter is present in different concentrations in the two hemispheres,  more so in women than in men.  Specifically,  there is more of it in the right hemisphere -especially in women.   This helps to explain (or begin to imagine) how a serotonin agonist like estrogen,  which is delivered diffusely to the whole brain through the blood stream could have an asymmetric effect on hemispheric function.  

Aside from hemispheric lateralization,  were brain serotonin to be modulated by cycling female hormones,  then one could expect that modulations of those functions which are well established as being brain serotonin-dependent should track the menstrual cycle.  What are the serotonin-dependent functions ?   They are sleep,  body temperature,  propensity towards inflammation,  mood,  appetite,  hostility (the psychological expression of aggressiveness),  pain sensitivity, sexual receptiveness, and so on.   Low and behold !  All of these have been found to significantly vary as a function of the menstrual cycle in normal cycling women not taking contraceptive pills (women taking contraceptive pills undergo less variation of their steroid hormones).  Such effects are presented in table 9.

Table 9

Findings of significant menstrual modulations of putatively serotonin-dependent behaviors

Behaviors believed to be ersotonin dependent	References
Appetite	Laessle et al, 1990
Sensitivity to pain	Goolkasian, 1985
Mood	Rosen et al, 1989
Agressiveness	Parlee, 1982
Body temperature	Parry et al, 1989
Sexual receptivity	Laessle et al, 1990
Sleep	Dennerstein et al, 1984
Inflammatory response	Zachariasen, 1989

From cycling brain pathology to theoretical models of psychoendocrinology and psychoimmunology.  We can also get further little conceptual handles bearing on this whole issue by searching for evidence of any kind of menstrual tracking of pathology (symptoms) in brain disease.   Let’s start with the auto immune diseases affecting the brain.  Two such diseases are disseminated lupus erythematosis  and multiple sclerosis.  These two female-preponderant diseases sometimes tend to flare up cyclically at ovulation.  Estrogen is a known potentiator of the immune response.   The impact of steroid hormones (especially estrogen) on these two disorders is so important that it has been standard medicine to counsel abstention from pregnancy in afflicted women  -because it was thought that pregnancy causes a major flare-up of the inflammatory condition.  Let me take the opportunity now though of stating that at least ten studies have shown that there is no risk of a permanent aggravation of multiple sclerosis by pregnancy. The same seems to be the case for Crohn's disease.  Pregnancy in patients with disseminated lupus erythematosis puts the fetus at risk for complications,  but the clinical course of the disease for the mother is usually benign.   

Now let’s look at known serotonin-mediated brain diseases.   Manic-depressive psychosis is thought to involve disturbance of serotonin metabolism -though this is far from providing a full account of the disease.   The best treatment for this disease,  the mineral salt lithium,  has a major influence on serotonin metabolism in the brain.   Only a few cases of manic-depressive psychosis have been reported to cycle with menstruation.   The few cases reported represent unusual portraits for this disease whose cycle is usually annual or seasonal.   Nevertheless,  the few cases reported with a menstrual cycling are telling.  Mania peaks at ovulation and depression peaks at menstruation (when women are hormonally more male-like,  and incidentally,  men have been found to be twice as much at risk for unipolar mania).   Ordinary depression,  the reactive or endogenous types, also seem to involve a  disturbance of brain serotonin metabolism.   The best known treatment for depression consists of the drug class known as tricyclic antidepressants whose mode of action consists of preventing neurons from recovering serotonin released in the synapses.  This has the net effect of increasing synaptic serotonin,  thus mimicking and boosting serotonergic signaling throughout the brain.   Contrary to manic-depressive illness which is not very female-prevalent if at all,  "ordinary" depression  is more common and is very much female-prevalent.   Furthermore,  it is quite common for depressive symptoms to be at their peak in the immediately pre-menstrual phase.   Recall that estrogen is low during this phase,   that estrogen is a serotonin agonist, and that depression is treated by increasing serotonin metabolism.  One data base which lends itself very conveniently to a test of modulation of mood disorder by the menstrual cycle is suicide attempt.   Indeed,  suicide attempts are far more frequent during the paramenstrual week than otherwise.   Successful suicide however,  seems to be most frequent during the luteal phase of the menstrual cycle.  Migraine is another female prevalent (4: 1) brain vascular disorder which we think is serotonin-mediated because the best treatment for migraine has an important effect on serotonin metabolism.   Migraine is believed to be caused,  among other things, by excessive serotonergic activity because serotonin antagonists are quite effective anti-migraine drugs.   Women who have migraine at regular periods in the menstrual cycle have them more often around ovulation.    Furthermore,  it has been noted that migraine seems to often be alleviated or to disappear during pregnancy,  whereas this is not the case for tension headache (headache believed to be caused by muscle tension around the head).

Recall that estrogen is a dopamine antagonist.   Suppose we could find disorders whose symptoms are caused,  among other things,  by excess dopaminergic activity in the brain.  This would be the case of disorders which are effectively treated by neuroleptics whose main action is to inactivate D2 (dopamine) receptors in the brain.   Schizophrenia,  Tourettian tics,  and stuttering are such disorders.   There are several reports of cases of women presenting symptoms which vary in intensity as a function of the menstrual cycle.  Guess when the symptoms are worse!   Yes of course, it is at the approach of menstruation that the symptoms of these disorders get worse.

We have seen in previous sections that aggressiveness is enhanced by dopamine and inhibited by serotonin.   Given what we know about the effects of estrogen on these neurotransmitters,  we would predict that violent assaultive crimes committed by women ought to occur more during menstruation.   A large scale study was carried out long ago on female prison inmates which provides the answer to the prediction.   62% of such assaultive crimes were committed during the paramenstrual week.   

Finally,  several cases of epilepsy in women have been found to present a variation of the frequency of epileptic attacks in synchrony with the menstrual cycle.    The aggravation of the epileptic condition typically takes place in the immediately premenstrual phase.  One neurotransmitter which is important in epilepsy is gamma-aminobutyric acid (GABA).   Several of the more effective anticonvulsant medications are GABA agonists.   So steroid hormones could have a modulatory impact on GABA metabolism,  but this remains to be proven.  The modulation of epilepsy by the menstrual cycle could also be operating via salt channels in the neurons' terminals,  or by some other mechanism.