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

72 THE PREMENSTRUAL SYNDROMES
contradictory with some 49,50 but not others, 51–53 suggesting
a deficiency of allopregnanolone. However,
analogous to the rodent model of progesterone exposure,
decreased sensitivity to GABA A agonists, including
neuroactive steroids, has been demonstrated in the
luteal phase in women with PMS. 54,55 Women with
PMS demonstrate decreased pregnanolone responsiveness
possibly due to altered sensitivity of GABA A receptors
54 and there is some evidence to suggest that
patients with mood disorders are also insensitive to
modulatory effects of benzodiazepines. 47,48
The length of allopregnanolone exposure thus plays
a critical role in the regulation and function of the
GABA A receptor. Whereas acute, short-term allopregnanolone
exposure decreases anxiety, chronic exposure
to elevated allopregnanolone can produce decreased
expression and binding to the GABA A receptor as well
as uncoupling of the receptor from several anxiolytic modulators,
leading to increased anxiety. 56,57 Progesterone
metabolite effects on mood and behavior also appear to
be biphasic in nature. 37 In high concentrations, pregnanolone
and allopregnanolone produce anxiolytic,
sedative, antiepileptic, and anesthetic effects. 58–60 At
lower physiological levels, though, allopregnanolone
can cause anxiety, aggression, impulsive behavior, and
negative mood in predisposed individuals. 29,61,62 In
sum, GABA A receptor function and modulation probably
varies throughout the menstrual cycle and probably
contributes to the negative mood symptoms experienced
by many women during the luteal phase.
SEROTONIN NEUROTRANSMITTER SYSTEM
Clinical background
Depression is one of the most serious symptoms of
PMS. The monoamine theory of depression posits deficiency
of norepinephrine and also the indole amine,
serotonin (5-HT). Serotonergic dysfunction has been
implicated in the etiology of PMS, and currently, one of
the treatments of first choice for severe PMS/PMDD
(premenstrual dysphoric disorder) is a serotonergic antidepressant.
However, the absence of biological markers
for depression in women with PMS (e.g. failure of dexamethasone
to suppress cortisol), 63,64 reduced platelet
monoamine oxidase (MAO) B, 65 and the rapid response
to serotonergic antidepressants suggest that PMS is not
a subset of depressive or anxiety disorders and that the
neurophysiology is likely to differ. The serotonin
hypothesis is also hampered by incomplete understanding
of the neurophysiology of the serotonergic system,
as well as the lack of a complete response to serotonergic
medications by all women with PMS.
Serotonin physiology
Serotonin (5-HT, 5-hydroxytryptamine) is synthesized
within serotonergic neurons and in several types of
peripheral cells. 66 The brain accounts for about 1% of
the total body stores of 5-HT. The amino acid tryptophan
is transported to the CNS via an active transport
pump. 67 Two enzymes sequentially alter tryptophan:
tryptophan hydroxylase is the rate-limiting step in the
formation of 5-HT, producing 5-hydroxytryptophan
(5-HTP); then the L-aromatic amino acid decarboxylase
decarboxylates the hydroxylated tryptophan,
resulting in serotonin (5-HT). 68,69
5-HT cannot cross the blood–brain barrier; thus,
CNS neurons must synthesize the amine. Tryptophan
is present in high levels in plasma, and changes in
dietary tryptophan can substantially alter brain levels
of 5-HT. 70 The availability of dietary tryptophan is
important in regulating 5-HT synthesis. 71 Since other
large neutral aromatic amino acids compete for transport
into the CNS, brain levels of tryptophan are also
dependent upon plasma concentrations of other competing
neutral amino acids. 67 5-HT is then stored in
vesicles concentrated in the presynaptic terminal until it
is released by a nerve impulse (Figure 9.3).
Impulse-modulating and release-modulating receptors,
designated 5-HT 1A somatodendritic autoreceptor
and 5-HT 1D terminal autoreceptor, are located on the
cell body and the nerve terminal, respectively, and
detect the presence of 5-HT and then regulate the
release and firing rate of 5-HT neurons. 66,72 Drugs that
block the 5HT 1D autoreceptor increase 5-HT release
and are under development. The serotonergic neuron
also has a terminal autoreceptor, the � 2 heteroreceptor,
that, when occupied by norepinephrine, turns off serotonin
release (Figure 9.4), as well as an � 1 heteroreceptor
on the cell body that can enhance serotonin
release. 73 5-HT that is released into the synapse is inactivated
primarily by reuptake through the high-affinity
presynaptic membrane serotonin transporter (SERT) or
‘reuptake pumps’. SERT is an important clinical target
for therapeutic drugs, such as selective serotonin reuptake
inhibitors (SSRIs). 74 The enzymatic degradation of
5-HT is catalyzed by the MAO enzyme located within
the serotonergic neuron, producing 5-hydroxyindoleacetic
acid (5-HIAA). Low cerebrospinal fluid
(CSF) 5-HIAA has been found in patients with antisocial,
borderline, self-destructive personality disorders
and poor impulse control and those who are prone to
aggressive outbursts and violent suicide. 73,75,76
However, as noted above, the MAO inhibitors and
tricyclic antidepressants, both of which increase all
three monoamine neurotransmitters, but particularly
norepinephrine, and which were effective for the