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

162 THE PREMENSTRUAL SYNDROMES
GABAergic neurotransmission have been linked
to epilepsy, anxiety disorders, schizophrenia, and
PMDD. 45,46 Plasma and cortical GABA levels of women
with PMDD have been demonstrated to be lower during
the late-luteal phase of the menstrual cycle, compared
with the mid-follicular phase. 45–48 Data from animal
studies suggest that the GABAergic system is substantially
modulated by menstrual cycle phase. 49 This raises
the possibility of disturbances in cortical GABA neuronal
function and modulation by neuroactive steroids
as potentially important contributors to the pathogenesis
of PMDD. 50,51
Moreover, progesterone is converted to neuroactive
steroids (5�-pregnane steroids) in the brain. Progesterone
metabolites (allopregnanolone and pregnanolone) appear
to have anxiolytic and hypnotic properties via GABA
type A (GABA-A) agonistic activity. Therefore, dysfunction
in the GABA-A/neurosteroid system has been
implicated in the pathogenesis of mood disorders and
premenstrual syndrome. 42,52 Diminished levels of luteal
phase �-endorphin have been shown in women with
PMS/PMDD compared with asymptomatic controls. 53–55
Symptoms such as anxiety, food craving, and physical
discomfort have been associated with a significant
premenstrual decline in �-endorphin levels. 56–58 Other
neurotransmitters may have relevance to PMDD, for
example dopamine and acetylcholine, although the evidence
for these is less convincing.
If the above suppositions are substantiated, it would
seem that PMDD is not caused by an endocrine imbalance
per se, but rather from an increased sensitivity
to normal circulating level of ovarian hormones, particularly
progesterone, secondary to a neuroendocrine
disturbance.
THE SEROTONERGIC PATHWAY
As a result of the impressive therapeutic effects of SSRIs
in up to 60–70% of women with PMS/PMDD, dysregulation
of serotonin neurotransmission is a popular
hypothesis in the pathogenesis of premenstrual dysphoria.
Serotonin is a monoamine neurotransmitter stored
at several sites in the body. The majority (95%) is
located in the enterochromaffin cells of the intestinal
mucosa. Smaller amounts occur in platelets and in
the CNS, where the highest concentrations are found
in the raphe nuclei of the brainstem. Serotonergic
neurons project from the raphe nuclei to various brain
regions, and play a vital role in modulating emotion,
motor function, and cognition, as well as circadian and
neuroendocrine functions such as appetite, sleep, and
sexual activity. Serotonin is synthesized from the amino
acid tryptophan, a reaction catalyzed by tryptophan
hydroxylase (TPH), and is stored in presynaptic vesicles
until required. Upon neuronal firing, serotonin is
released extracellularly and binds to postsynaptic
receptor proteins, thereby transmitting a signal from
one cell to the next (Figure 18.1). It also binds to presynaptic
autoreceptors (5-HT 1A and 5-HT 1B/D ), which
regulate further serotonin release. Synaptic serotonin
concentration is directly controlled by its rapid reuptake
into the presynaptic terminal by a specific transporter
protein (5-hydroxytryptamine transporter, 5-HTT).
Serotonin uptake in platelets occurs by a similar active
transport process. 59 Furthermore, the amino acid
sequences of the two transporter proteins are identical
and are encoded by the same gene. 60,61 Monoamine
oxidase A (MAOA) catalyzes the catabolism of serotonin
to 5-hydroxyindoleacetic acid (5-HIAA) and is
pivotal in the regulation of intracellular serotonin levels
(Figure 18.2).
PMDD and psychiatric disorders share several key
symptoms, such as anxiety, depression, tension, and
affective lability. 3,6–8 In light of this association, and the
myriad of publications linking serotonergic polymorphisms
to depressive disorders, the lack of reported
genetic studies in PMDD is surprising. Below, we
describe potential candidate gene polymorphisms suitable
for study in PMDD, and include relevant evidence
from numerous psychiatric studies.
GENETICS OF THE SEROTONERGIC
SYSTEM IN PMDD
The concept of genetic polymorphisms
The fundamental basis of genetic polymorphism in a
population is variation of the nucleotide sequence of
DNA at homologous locations in the genome. These
differences in sequence can result from mutations
involving a single nucleotide or from deletions or insertions
of variable numbers of contiguous nucleotides. At
many loci within the human genome, two or more
alleles may occur with significant frequency in the same
population. These loci are said to be polymorphic. Their
existence allows for multiple combinations of alleles at
different loci, and is responsible for both the incredible
diversity in populations and the uniqueness of individuals.
However, this very diversity is also thought to
account for genetic susceptibility to many diseases. Thus,
the study of polymorphisms in key candidate genes is a
potentially powerful tool in the investigation of complex
polygenic diseases, in which multiple genes (each of which
may have a relatively minor effect) and environmental
factors collaborate to cause disease. Applying this
concept to PMDD, polymorphisms of genes controlling