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

Estrogen has also been shown to improve the clinical
effect of SSRIs. 94
By contrast, progesterone increases MAO and COMT
enzyme activity, acts as an antiestrogen, and downregulates
estrogen receptors. 93 Exogenously administered
synthetic and natural progestins can induce negative
mood, but this effect is dependent upon relative estrogen
and progesterone dosages. 93,95,96 In summary, progesterone
increases MAO, which decreases 5-HT availability
and depressed mood, whereas estrogen decreases
MAO activity, thus increasing 5-HT availability with
resulting antidepressant effect. 97 It may be that these
inter-relationships of sex steroids and serotonergic function
are an oversimplification of the true picture and
there may be some contradictions that will become
evident as more research becomes available.
Serotonin, affective symptoms and PMS
Clinical substantiation for the role of serotonin in premenstrual
disorders is supported by various lines of evidence,
including:
1. Similarity between symptoms of PMS and those
triggered by serotonin depletion paradigms, 4,98,99
such as depression and impulsive/aggressive behavior,
irritability, anxiety, food cravings, and weight
gain.
2. Decreased luteal phase platelet uptake of serotonin,
100 decreased luteal phase whole blood 5-HT
at baseline, 101 and after either oral 102 or intravenous
L-tryptophan challenge. 103
3. Lack of significant improvement of PMS symptoms
with antidepressants that augment only norepinepherine
but not serotonin.
4. Numerous double-blind placebo-controlled trials
demonstrating the efficacy of serotonergic agents
administered continuously or solely in the luteal
phase for the treatment of the severe form of PMS,
premenstrual dysphoric disorder (PMDD). 104,105
It must be remembered that extrapolation of therapeutic
response to causality must always be viewed with
caution.
SEROTONIN, GABA, AND PMS
There is evidence to support a link between the
GABAergic and serotonergic neurotransmitter systems,
and this link may be relevant to depressive disorders
and PMS. SSRI treatment for major depression
increases GABA concentration, especially in the occipital
cortex. 106,107 GABA has been shown to regulate
NEUROTRANSMITTER PHYSIOLOGY 75
the activity of 5-HT neurons in the dorsal raphe nucleus
through allopregnanolone-potentiated GABA A -mediated
inhibition. 108 Additionally, serotonergic neurons often
terminate at inhibitory GABAergic interneurons in
the hippocampus, suggesting a direct interaction. 109
5-HT1a and 5-HT3 receptors have been localized to
GABA interneurons in the cortex and hippocampus. 110,111
In the piriform cortex, 5-HT1a has been shown to increase
the firing rate of GABAergic neurons. 112 Futhermore,
in-vivo administration of a 5-HT1A receptor agonist
enhances GABA A -stimulated chloride ion influx. 113 In
5-HT1A receptor knock-out mice, there is an alteration
of GABA A receptor subunits, receptor binding is
reduced, and the mice develop benzodiazepine-resistant
anxiety. 114 There clearly is a complex interaction between
GABA and 5-HT neurons that may partially explain
their influence on premenstrual mood and behavior.
ENDOGENOUS OPIOID PEPTIDES
Clinical background
The endorphin hypothesis of PMS was based on the
recognition that some of the symptoms of PMS resembled
those of opiate addiction and withdrawal, i.e. fatigue,
depression, tension, anxiety, irritability, headaches, and
pain sensitivity. It was hypothesized that women could
become addicted to their own endogenous opiate peptides
(EOPs). 115 One study demonstrated prevention of
PMS symptoms with full-cycle treatment with naltrexone,
an opioid antagonist used for opiate addiction. 116
Endogenous opioid peptide physiology
Endogenous opioids include endorphins, enkephalins,
dynorphins, and other peptides. Pro-opiomelanocortin
(POMC) is the 31-kDa glycopeptide precursor that is
cleaved to a number of smaller peptides, including
endorphins, enkephalin, adrenocorticotropic hormone
(ACTH), and melanocyte-stimulating hormone (MSH). 117
Proteolytic processing of POMC to certain small fractions
appears to be tissue-specific, depending on the
region of the brain. 118 POMC has been demonstrated
in the anterior and intermediate lobes of the pituitary
gland, hypothalamus, brain, sympathetic nervous system,
lungs, adrenal medulla, gastrointestinal tract, reproductive
tract, and placenta. 119–121 Proenkephalin A is a precursor
for enkephalins, whereas proenkephalin B is the
precursor for dynorphins. Proenkephalin A has been
found in the adrenal medulla, posterior pituitary
gland, brain, spinal cord, and gastrointestinal tract. 121
Proenkaphalin B is found in the brain and gastrointestinal
tract. 121