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

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Genetics of premenstrual dysphoric disorder
Julia L Magnay and Khaled MK Ismail
INTRODUCTION
Males and females differ in their predisposition to
certain clinical disorders. One of the most widely documented
findings in psychiatric epidemiology is that
women have higher rates of major depressive episodes
than men, a phenomenon observed worldwide using a
variety of diagnostic schemes and interview methods. 1,2
The prevalence of depression among women in these
studies was reported to be between 1.5 and 3 times that
of men. Although a genetic predisposition to major
depression has been extensively postulated, the actual
mechanisms involved in this disorder are still being
investigated. Several authors have reported similarities
and associations between the symptoms of affective
disorders such as anxiety, panic disorder, major depression,
and seasonal affective disorder, and premenstrual
syndrome/premenstrual dysphoric disorder (PMS/
PMDD). 3–8 It has also been noted that the incidence of
anxiety, mood disorders, and depression among women
suffering with PMS is greater than that of the general
population. 9–11
Evidence supporting the view that a genetically determined
vulnerability plays a major role in the expression
of PMS/PMDD is derived from twin and family
studies, 12–15 that showed a high correlation between
mothers and daughters and also between mono- and
dizygotic twins. Additionally, a similarity of PMS subtypes
was noted between mothers and daughters. Thus,
genetic factors have been implicated repeatedly in the
pathogenesis of PMS/PMDD, although no specific susceptibility
gene has been identified.
PMDD AND BRAIN NEUROTRANSMITTERS
We have seen in earlier chaperts (Chapter 10) that the
definitive cause of PMS is unknown but it appears to be
directly related to the ovarian cycle trigger. The concept
of a hormonal imbalance has been popular, but there is
no supportive evidence. The hormone status of PMS
patients does not appear to differ from that of asymptomatic
women. 16–21
Several lines of evidence suggest that an underlying
dysregulation of serotonergic neurotransmission
plays a pivotal role in PMDD. 22–32 Data from both
animal and clinical studies indicate that (serotonin; 5hydroxytryptamine,
5-HT) exerts an inhibitory effect
on symptoms such as irritability, affect lability, and
depression, which are core features of premenstrual
dysphoria. 33,34 Ovarian steroids have been shown to
profoundly influence the activity of the serotonergic
system. 35–37 In the central nervous system (CNS), there
is evidence of region-specific effects on serotonin synthesis,
turnover, uptake, and release, and on specific
receptors by estradiol and progesterone. 38,39 Falling
levels of ovarian hormones (e.g. in the late-luteal phase
of the menstrual cycle) have been associated with
decreased serotonergic activity. 40
Low serotonin levels in red blood cells and
platelets 27–29,41 have been demonstrated in PMS patients
compared with controls. This serotonin deficiency has
been proposed to enhance CNS sensitivity to normal
progesterone following ovulation. 42 Further credence
to the potential involvement of serotonin in the pathogenesis
of premenstrual dysphoria is provided by the
effectiveness of selective serotonin reuptake inhibitors
(SSRIs) such as fluoxetine and sertraline 43 in the treatment
of severe PMS/PMDD. Vitamin B 6 (pyridoxine)
is a cofactor in the final step in the synthesis of serotonin
and dopamine from tryptophan. No data have
yet demonstrated consistent abnormalities of either
brain amine synthesis or deficiency of cofactors such as
vitamin B 6 in PMDD. 44
There is also increasing support for the hypothesis
that ovarian hormones modulate �-aminobutyric acid
(GABA) neuronal function. GABA is the primary
inhibitory neurotransmitter in the CNS. Disorders in