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hyposensitivity or altered circadian cortisol dynamics
(although, see Parry et al 197 and Steiner et al 198 ).
Bancroft et al 63 identified blunted levels across the
menstrual cycle of tryptophan-stimulated cortisol secretion
in women with PMS. Finally, an abnormal response
to (presumed) luteal phase progesterone in women with
PMS was also seen in their failure to manifest the normal
luteal phase alteration in the timing of the cortisol
acrophase. 195 These data, then, suggest the following:
● stimulated cortisol (albeit paradigm specific) is
decreased in women with PMS relative to controls
during the luteal phase
● the adrenal response to ACTH may be blunted in
women with PMS
● women with PMS manifest an abnormal HPA axis
(and mood) response to progesterone
● women with PMS display disturbances of the HPA
axis that are markedly different from those identified
in major depression.
Although the determinants of these observations are
unclear, they provide another compelling example of
differential response to gonadal steroids in women with
PMS and suggest an additional potential source of vulnerability
to affective disturbance.
Serotonin
Serotonin (5-HT) plays a role in the regulation of mood, 199
impulsivity, 200 appetite, 201 sleep, 202 and sexual interest,
203 behaviors that vary during the menstrual cycle in
women with PMS. Studies of serotonin measures and
the efficacy of serotonergic agonists further suggest the
relevance of the serotonin system for PMS and are
reviewed in Chapters 3 and 9.
CONCLUSIONS
In order to identify what the study of PMS may contribute
to our understanding of the effects of gonadal
steroids on brain and behavior, several observations
must be integrated. First, PMS does not reflect a disturbance
of reproductive endocrine function. Secondly,
estrogen and progesterone appear to be capable of triggering
mood disturbances in a susceptible population;
i.e. some pre-existing vulnerability must explain the
capacity of the same biological stimulus (e.g. gonadal
steroids) to elicit a differential behavioral response
across groups of people. Thirdly, perturbations of nonreproductive
endocrine systems may precipitate PMS.
For example, PMS may appear in the context of
hypothyroidism (with symptoms responsive to thyroid
PATHOPHYSIOLOGY I: ROLE OF OVARIAN STEROIDS 93
hormone replacement), 204 and both provocative 61,205
and especially treatment studies 206 suggest the relevance
of the serotonin system to PMS. PMS, then, may represent
a behavioral state that is triggered by a reproductive
endocrine stimulus in those who may be rendered
susceptible to behavioral state changes by antecedent
experiential events (e.g. history of major depression 207
or physical or sexual abuse 208 ) or biological conditions
(e.g. hypothyroidism). 204 Treatment can, therefore, be
directed to either eliminating the trigger (e.g. ovarian
suppression) or correcting the ‘vulnerability’ (e.g. serotonergic
antidepressants). 206 Although the means by
which alterations in gonadal steroids trigger changes in
behavioral state in certain individuals are unclear, it is
nonetheless striking that, in contrast to the pathological
function of other endocrine systems (e.g. adrenal,
thyroid) seen in association with mood disorders, gonadal
steroids may precipitate mood disturbances in the context
of normal ovarian function. This suggests that further
study of the interactions between gonadal steroids and
other neuroactive systems may help elucidate general
mechanisms underlying affective regulation as well as
the physiological substrate that predisposes certain people
to experience reproductive endocrine-related mood
disorders.
ACKNOWLEDGMENT
The research was supported by the Intramural Research
Programs of the NIMH.
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