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

Many other therapeutic areas have been covered in systematic
views but not meta-analysis, which, as we have
said, represents the gold standard for clarity, power,
and precision.
Research into etiology
Much new work on estrogen, progesterone levels, suppression
of the ovarian and cycle, and the investigation
of endocrine cycle paradigms became prominent (see
Chapter 10) during this era, led by the NIMH (National
Institute of Mental Health) group in Washington, DC,
and two groups in Sweden, at the Universities of
Gothenburg and Umea (see Chapters 3 and 13, respectively).
This research was very much cause-driven, not
leading to an immediate therapeutic modality. Landmark
research was undertaken on hypotheses related to neuroanatomy,
ovarian suppression with GnRH and restimulation
paradigms, and neuronal biochemistry; this
work was particularly directed at serotonin and �aminobutyric
acid (GABA) and conducted from the mid
1990s onwards.
Although no excess or deficiency in estrogen or progesterone
levels has ever been demonstrated, the possibility
of differences in progesterone receptors or
progesterone metabolites was considered by the UCLA
(University of California at Los Angeles) group (see
Chapter 9). Because of the affinity of allopregnanolone
for the GABA receptor and the lower measured levels
of allopregnanolone in PMS patients, it became a prominent
recent theory of causation. It has not yet led to
specific treatment recommendations.
As it became clear that ovulation is the trigger for premenstrual
events rather than differences in hormone
levels, attention became focused on the probability that
neural factors permitted an increased sensitivity to
ovarian steroids, particularly progesterone. Therapeutic
research on the SSRIs very convincingly demonstrated
a high level of efficacy, although it was realized that effective
therapy does not automatically imply causality in
PMS (i.e. headache is not due to aspirin deficiency!). Effective
SSRI treatment does not prove serotonin deficiency.
It is not surprising that research thereafter led to the
investigation of most neurotransmitters, including the
genetics of serotonin (5-hydroxytryptamine, 5-HT),
GABA, and PMS/PMDD. The editors of this book (and
several other groups) are currently investigating the
genetic basis of PMS and PMDD. Despite many differences
being found in such disorders as depression,
seasonal affective disorder (SAD), and anxiety, the
exploration of polymorphisms in PMDD appeared initially
unfruitful, although it now seems possible that
differences in polymorphisms for the 5-HT1A receptor
may be present compared with controls, and ultimately
HISTORY OF THE PREMENSTRUAL DISORDERS 7
these may show a linkage to cause and/or therapeutic
response (Vandana Dhingra, pers comm).
The inaccessibility of the brain makes the understanding
of any psychological process or illness a major
challenge. If we analyze what has been available to investigators,
our research tools are found to be sadly lacking.
Certainly, there is no objective test available to make a
diagnosis: peripheral blood tests need not necessarily
reflect central nervous system (CNS) levels or activity
(e.g. platelet and blood serotonin, �-endorphin); no
physical test has been identified; for measurements, we
are limited to patient-completed questionnaires; and
detailed psychiatric interviews have been available to
only a small number of studies.
The challenge of the complex inter-relationships seen
in neurological biochemistry and associated genetics is
made even more exciting by developments in brain
imaging. A greater understanding of this whole field is
poised to be unfolded by the arrival of techniques (see
Chapter 11) such as positron emission tomography
(PET), single-photon emission computed tomography
(SPET), and functional magnetic resonance imaging
(fMRI). These techniques offer a real chance of investigating
and understanding brain function and blood flow,
which may link us to an understanding of premenstrual
disorders.
CONCLUSION
It has taken more than 20 centuries to move from
Hippocrates’ observation that women appeared to have
cerebral ‘agitations’ (which were released from the uterus
at menstruation) to developing the ability to visualize
these ‘agitations’ by modern brain imaging technology.
There seems to be little doubt that the normal ovarian
endocrine cycle provides the trigger in women with
CNS sensitivity to these endocrine changes. We are in
the process of explaining the reason for this sensitivity
incrementally – the more we learn, the more an explanation
points towards specific neurotransmitters in the
CNS. A combination of molecular genetics, endocrinology,
and brain imaging will certainly lead us to this
goal. In the meantime, we have a plethora of therapeutic
approaches to help us manage our patients until scientific
study leads to a cure.
REFERENCES
1. Frank RT. The hormonal causes of premenstrual tension. Arch
Neurol Psychiatry 1931; 26:1053.
2. Dalton Greene. The premenstrual syndrome. BMJ 1953; 1:
1016–17.
3. Farrington B. The Medical Works of Hippocrates by John
Chadwick, W.N. Mann. J Hellen Stud 1952; 72:132–3.