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

different neuromodulatory profile from that of the parent
hormones: seen, for example, with the conversion of
progesterone to the neurosteroid allopregnanolone or
DHT to the neurosteroid androsterone (by 5�-reductase
and 3�-hydroxysteroid oxidoreductase [3�-HSOR]), both
potent modulators of the �-aminobutyric acid (GABA)
receptor chloride ionophore. 10,11 Since many of the
enzymes have multiple steroid substrates, a single
enzyme’s activity may regulate the relative amounts of
different behaviorally active metabolites: for example,
3�-HSOR both inactivates the androgen DHT (at the
androgen receptor) and produces the neurosteroids allopregnanolone
and androsterone. 12 Not only will different
metabolic profiles activate or inhibit different receptor
systems but also the consequence of the activation of a
given steroid receptor will differ depending upon which
hormones are present. Estradiol and cortisol, for example,
exert opposing effects on AP1-modulated genes through
interactions with the cointegrator CBP/P300. 13 A steroid
hormone, then, may produce markedly different effects,
depending upon its metabolism and the hormonal context
in which it is acting. Finally, abnormalities of these
metabolic enzymes occur secondary to genotypic variation
and, therefore, one metabolic product could be
selectively favored over others. Several genetically based
abnormalities of steroid metabolism exist, and investigators
speculate that similar variants in the enzymes
required for neurosteroid synthesis may underlie behavioral
disorders, including PMS.
Mechanisms of actions
The classic action of steroid hormones occurs after the
steroid binds (activates) its intracellular receptor,
which, after undergoing phosphorylation and release
from heat shock proteins, binds (usually as a dimer) to
a hormone response element on a gene and directs or
modifies transcription of that gene. Once the ligand–
receptor complex binds to the hormone response
element (which is located on or near the promoter of
the gene), the result can be either the initiation or repression
of transcription of messages coding for an array of
proteins, including synthetic and metabolic enzymes
for neurotransmitters, neuropeptides, receptor proteins
(both membranous and intracellular), transporters, and
second messengers.
Several factors may influence the genomic actions of
gonadal steroids and account for their widespread and
variable effects. First, isoforms of both the androgen
and progesterone receptors exist, and each isoform has
different transcriptional effects. Two separate estrogen
receptors, � and �, exist and are coded for by genes on
the 6th and 14th chromosomes, respectively. These estrogen
receptors have different distributions in the brain,
PATHOPHYSIOLOGY I: ROLE OF OVARIAN STEROIDS 85
different transcriptional actions, and even possess additional
isoforms (e.g. insertional and deletional variants
of ER � and �). Secondly, the activated steroid receptor
regulates transcription by binding protein intermediaries
called coregulators (both stimulatory and inhibitory).
Coregulators are expressed in a tissue-specific fashion,
and their differential localization may contribute to functional
variability in the effects of the same hormone in
different tissues despite the presence of similar concentrations
of both ligand and receptor. Thirdly, activated
hormone receptors can influence the transcription of
genes that do not possess hormone response elements
through interactions with other cellular proteins called
cointegrators, which enable hormones to regulate genes
at transcription factor binding elements (e.g. AP-1, SP-1
sites). Fourthly, steroid hormone receptors can be activated
by a variety of neurotransmitters (e.g. dopamine
through D 1 receptor) and growth factors, even in the
absence of steroid hormones. In this fashion environmental
events (e.g. stressors) can impact the response to a
steroid hormone signal. Finally, hormones may influence
each other’s activity by competing for cofactors or by
producing opposing regulatory effects on genes through
integrator proteins.
The relatively slow, ‘genomic’ effects of gonadal steroids
have been expanded in two dimensions: time, with a
variety of rapid (seconds to minutes) effects observed;
and targets, which now include ion channels and a variety
of second messenger systems. For example, estradiol (E 2 ),
in just minutes, increases firing of neurons in the cerebral
cortex and hippocampus (CA1) 14 and decreases firing
in medial preoptic neurons. 15 The activity of membrane
receptors like the glutamate and GABA receptors is
acutely modulated by gonadal steroids (estradiol and the
5�-reduced metabolite of progesterone, allopregnanolone,
respectively). 10,16 Estradiol binds to and modulates the
Maxi-K potassium channel, 17 increases cyclic adenosine
monophosphate (cAMP) levels, 18 regulates membrane G
proteins (G.αi , G. αq ; G.αs )19 (Manji et al, unpublished work),
inhibits L-type calcium channels (via non-classical receptor),
20 and immediately activates the mitogen-activated
protein kinase (MAPK) pathway (albeit in a receptormediated
fashion). 21 The effects observed are tissue- and
even cell-specific (e.g. estradiol increases MAPK in
neurons but decreases it in astrocytes). 22,23 Finally, both
estradiol and progesterone 24,25 phosphorylate dopamineand
cAMP-regulated phosphoprotein-32 (DARPP-32),
which is an important regulator of the phosphorylation
state of many cellular proteins and, therefore, an important
regulator of neural function. 26 The increase in the number
of described mechanisms by which gonadal steroids can
impact on cell function has paralleled the rapid growth in
their observed effects. Consequently, with each of these
newly identified actions (which are usually, but sometimes