Premenstrual Syndromes : PMS and PMDD - Rutuja :: The site ...

86 THE PREMENSTRUAL SYNDROMES
inaccurately, called ‘non-genomic’), one needs to examine
multiple factors prior to inferring the mechanism of action:
● the duration required to see the effect
● the impact on the effect of inhibitors of transcription
and protein synthesis
● the presence (or absence) of intracellular steroid
hormone receptors
● the stereospecificity of ligand binding (to see if
effects are mediated through a classical receptor)
● the effect of hormone receptor blockers
● the ability of the ligand to initiate the action from
the cell membrane (i.e. when entry into the cell is
blocked).
This last requirement acknowledges the presence on the
membrane of binding sites for gonadal steroids that
increasingly seem to be physiologically relevant. 27
NEUROMODULATORY EFFECTS OF
OVARIAN STEROIDS
The best support for the importance of the neuromodulatory
actions of gonadal steroids is found in their
dramatic and widely ranging effects on the brain. In
fact, gonadal steroids have been shown to play a role in
all stages of neural development, including neurogenesis,
synaptogenesis, neural migration, growth, differentiation,
survival, and death. 28 These effects occur largely
as a consequence of the ability of gonadal steroids to
modulate genomic transcription. As transcriptional
regulators, the receptors for gonadal steroids direct or
modulate the synthesis of the synthetic and metabolic
enzymes as well as receptor proteins for many neurotransmitters
and neuropeptides. 29 The advances of the
past 15 years, however, have demonstrated that the cellular
effects of gonadal steroids are far more complex
and wide-reaching than suggested by their originally
described genomic actions.
Gonadal steroids regulate cell survival. Neuroprotective
effects of E 2 have been described in neurons grown in
serum-free media or those exposed to glutamate, amyloid,
hydrogen peroxide, or glucose deprivation. 14 Some of
these effects appear to lack stereospecificity (i.e. are not
classical receptor-mediated effects) and may be attributed
to the antioxidant properties of E 2 , 30,31 although
data from one report are consistent with a receptormediated
effect. 32 Gonadal steroids may also modulate
cell survival through effects on cell survival proteins
(e.g. Bcl-2, BAX), MAPK, Akt or even amyloid precursor
protein metabolism. 22,23,33,34
Some actions of gonadal steroids on brain appear to
be context- and developmental stage-dependent. Toran-
Allerand 35 has shown that estrogen displays reciprocal
interactions with growth factors and their receptors
(e.g. p51 and neurotrophins, trkA) in such a way as to
regulate, throughout development, the response to estrogen
stimulation: estrogen stimulates its own receptor
early in development, inhibits it during adulthood,
and stimulates it again in the context of brain injury.
Additionally, we have demonstrated that the ability to
modulate serotonin receptor subtype and GABA receptor
subunit transcription in rat brain with exogenous
administration of gonadal steroids or gonadal steroid
receptor blockade is largely dependent on the developmental
stage (e.g. last prenatal week vs fourth postnatal
week) during which the intervention occurs 36 (Zhang et al,
unpublished data).
Finally, the effects of gonadal steroids do not occur
in isolation but, rather, in exquisite interaction with the
environment. Juraska, 37 for example, demonstrated that
the rearing environment (enriched vs impoverished) dramatically
influences sex differences in dendritic branching
in the rat cortex and hippocampus. Further, the size
of the spinal nucleus of the bulbocavernosus and the
degree of adult male sexual behavior in rats is in part
regulated by the amount of anogenital licking they receive
as pups from their mothers, an activity that is elicited
from the dames by the androgen the pups secrete in
their urine. 38
The vicissitudes of gonadal steroids and their receptors,
therefore, both direct neural architecture and provide
the means by which the response of the central nervous
system (CNS) to incoming stimuli may be altered. The
extent to which these effects underlie or contribute to
differential pharmacological efficacy or behavioral differences
observed across individuals is unclear but is of
considerable potential relevance for PMS and other
reproductive endocrine-related mood disorders.
ROLE OF OVARIAN STEROIDS IN
MODULATING THE SYSTEMS INVOLVED
IN AFFECTIVE ADAPTATION AND
PREMENSTRUAL SYNDROME
Neuroregulation
Results from animal studies demonstrate that ovarian
steroids influence several of the neuroregulatory systems
thought to be involved in both the pathophysiology of
affective disorders and PMS. 39–41 Preclinical studies have
documented the myriad of effects of ovarian steroids
on neurotransmitter system activities, including regulation
of synthetic and metabolic enzyme production as well
as receptor and transporter protein activity. The modulatory
effects of ovarian steroids on the serotonin (5hydroxytryptamine;
5-HT) system have been extensively