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

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Neurotransmitter physiology: the basics for
understanding premenstrual syndrome
Andrea J Rapkin and John Kuo
INTRODUCTION
The concept that severe premenstrual affective, behavioral,
and physical symptoms could be triggered by
ovulation and the rise and fall of ovarian sex steroids in
the luteal phase of the menstrual cycle was an advance
over previous notions that the symptoms resulted from
‘agitated menstrual blood seeking escape from the womb’.
Still, the explicit psychoneuroendocrine etiology of premenstrual
syndrome (PMS) remains unknown, and
more than two decades of research have demonstrated
that a simple alteration of hormones, neuropeptides, or
neurotransmitters cannot completely explain the occurrence
of the symptoms. The purpose of this chapter is
to provide an overview of the three leading hypotheses
that currently attempt to explain the biological basis of
PMS. To this end, we will discuss the monoamine neurotransmitter
serotonin (5-hydroxytryptamine, 5-HT);
the GABAergic neurotransmitter system, in particular, the
GABA A receptor complex; and the pro-opiomelanocortin
(POMC) pathway, in particular, the endogenous opiate
peptide, �-endorphin.
GABA NEUROTRANSMITTER SYSTEM
Clinical background
The symptoms of PMS are more severe in the 5–7 days
before menses, as progesterone levels decline in the late
luteal phase of the menstrual cycle. The first neuroendocrine
hypothesis therefore logically stated that progesterone
deficiency or withdrawal could elicit the
symptoms of PMS. However, the mood deterioration
generally begins in parallel with the rise in the production
of progesterone by the corpus luteum, suggesting
hormone withdrawal cannot explain the symptoms. 1
Progesterone deficiency was also excluded by studies
demonstrating that progesterone concentrations are
not lower in women with PMS compared with controls.
2–4 Furthermore, PMS symptoms were found to be
more severe in cycles with higher concentrations of
both estradiol and progesterone. 5 Finally, a series of
double-blind placebo-controlled treatment trials failed
to demonstrate progesterone supplementation to be
more efficacious than placebo. 6–8
Since ovulation and probably progesterone production
trigger the symptoms of PMS, investigations
proceeded into the neuroactive metabolites of progesterone
and their role in the genesis of PMS symptoms.
Progesterone is metabolized in the ovary and the brain
to form the potent neuroactive steroids, 3�-hydroxy-
5�-pregnan-20-one (allopregnanolone) and 3�-hydroxy-
5�-pregnan-20-one (pregnanolone), positive allosteric
modulators of the �-aminobutyric acid (GABA) neurotransmitter
system in the brain. The contribution of
this receptor system to the genesis of the premenstrual
symptoms is also discussed in further detail in
Chapter 13.
GABA physiology
GABA, the main inhibitory neurotransmitter in the
mammalian brain, is the most widely distributed amino
acid neurotransmitter in the central nervous system
(CNS), crucial for the regulation of anxiety, vigilance,
alertness, stress, and seizures. 9 Most neurons are sensitive
to GABA. GABA is derived from glucose metabolism:
�-ketoglutarate formed by the Krebs (tricarboxylic
acid) cycle is transaminated by GABA-oxoglutarate
transaminase (GABA-T) to the amino acid, glutamate. 10
Found exclusively in GABAergic neurons, glutamic acid
decarboxylase (GAD) catalyzes the rate-limiting decarboxylation
of glutamate to GABA. 11 GABA is then