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UNIVERSITY OF WESTERN AUSTRALIA
SCHOOL OF ANATOMY AND HUMAN BIOLOGY
Investigative Review:
Premenstrual syndrome (PMS)
Name:
Nicole Mosseveld
Student Number:
0220735
Unit Name:
Human Reproduction 316
Unit co-ordinator:
Neville Bruce
Date Submitted:
5pm, 17-10-2005
Pages:
6
Premenstrual syndrome affects women of reproductive age to varying degrees, and
the symptoms include physical, behavioural and emotional. Premenstrual dysphoric
disorder (PMDD) is the more severe form of PMS, and like PMS, occurs during the
last week of the luteal phase of the menstrual cycle. In order to diagnose women with
PMS or PMDD certain criteria must be adhered to, in order to determine the
prevalence of the disorder and most importantly, for the determining of effective
treatment. PMDD can be treated using selective serotonin reuptake inhibitors (SSRIs)
which act by blocking the receptors associated with neurotransmitters, and alleviating
depression, which is associated with PMDD. The depression seen with PMDD
patients may be caused by the fluctuating levels of gonadal hormones. It has been
proposed that the cyclic changes in estrogen and progesterone during the menstrual
cycle will have subsequent affects on the central nervous system (CNS) in regard to
gamma-aminobutyric acid (GABA) and serotonergic systems in susceptible women. It
is also suggested that the dysregulation of GABA due to PMDD may cause
asymmetry in the amygdala resulting in mood changes. Therefore, there are many
neuroendocrine changes that occur in women with PMDD that may result in
depression.
Premenstrual syndrome (PMS) is a generic term which includes a broad group of
emotional, behavioural and physical symptoms, as seen in Table 1, which occur for
several days to several weeks before menses and subside following the menstrual
period4. What makes the symptoms distinct to this syndrome, is their cyclic nature.
Table 1: Common Symptoms of PMS
Physical
Behavioural
Swelling
Breast tenderness
Aches
Headache
Bloating/weight
Sleep disturbances
Appetite changes
Poor concentration
Decreased interest
Social withdrawal
Mood
Irritability
Mood swings
Anxiety/tension
Depression
Feeling out of control
75% of women with regular menstrual cycles will experience some mild PMS
symptoms such as breast tenderness and swelling during their reproductive years but
do not perceive these symptoms as either distressing or debilitating1. Three to 15%
will experience the more severe form known as Premenstrual Dysphoric Disorder
(PMDD). PMDD is a disorder that occurs during the last week of the luteal phase of
the menstrual cycle and is characterised by moderate to severe symptoms such as
depressive mood, self depreciating thoughts, marked anxiety and tension affective
lability, anger and irritability, difficulties in concentration, lack of interest in
activities, lethargy, a sense of being overwhelmed, and suicidal ideation1. Women
with PMDD experience marked disruptions in their relationships, and work and social
activities that are similar to those with major depression1.
Disorders such as PMDD are being treated increasingly by selective serotonin
reuptake inhibitors (SSRIs) 8. SSRIs act by selectively blocking the reuptake of
serotonin, resulting in and immediate increase in synaptic levels of serotonin6.
Subsequent slow adaptive receptor changes in the brain lead to the alleviation of
depression6. This occurs via the down-regulation of inhibitory presynaptic
somatodendritic 5-HT1A receptors and inhibitory presynaptic terminal 5-HT1B which
result in an increase of serotonin release6. The drugs ease of dosing and relatively safe
side effects profile contributed to the SSRIs becoming the number one drug
prescribed by psychiatrists8. However, in contrast to patients with major depression,
PMDD patients respond better to lower doses of SSRIs and also to intermittent
dosing2. Also response to treatment is seen within days compared to 2-4 weeks with
depressive patients2. This suggests that PMDD and major depression are distinct
clinical entities and thus should be diagnosed accordingly.
Diagnostic criteria are important for aspects such as, distinguishing between PMS and
PMDD, determining the prevalence of the disorder and most importantly, for the
determining of effective treatment4. The criterion for the diagnosis of PMDD requires;
five PMDD symptoms to be experiences at a severe level premenstrually, and must be
low or absent postmenstrually4. The symptoms should appear to interfere markedly
with relationships with others, in regard to work or school or other social activities4.
The symptoms are found not to be exasperated by another physical or mental disorder,
and the criteria must be confirmed by prospective daily ratings (for example via a
questionnaire) for at least two consecutive menstrual cycles4. As depression is a major
symptom seen in women with PMDD during the luteal phase of the menstrual cycle
the criteria from the diagnostic and statistical manual of mental disorders forth edition
(DSM-IV) is also used for diagnosis6.
Depression is the leading cause of disease-related disability in women9. Studies have
shown that the lifetime prevalence of a major depressive disorder in women is almost
twice that of men9. The sex difference in prevalence first appears around the age of 10
years and persists until midlife, suggesting that women have the greatest risk for a
first episode of depression or developing depressive disorders during their
reproductive years9. These gender-based rates of depression include neuroendocrine
factors specific to women5. Gonadal hormones are stable and low in prepubertal
children; however, with the onset of menarche at puberty, the female brain is exposed
to monthly surges of estrogen and progesterone, which continues until menopause5.
This suggests that in susceptible women hormone fluctuation may contribute to mood
change. Estrogen and progesterone are found in different brain regions and exert a
wide range of actions on different neurons, including serotonergic (5-HT),
noradrenergic (NE), gamma-aminobutyric acid (GABA), dopaminergic (DA) and
anticholinergic neurons. Estrogen and progesterone receptors have also been
identified in multiple brain regions, including the amygdala, hippocampus, and the
midbrain raphe nuclei5. The mechanism by which estrogen and other steroidal
hormones modulate serotonin and other neuronal systems is increasingly understood.
By binding to intracellular receptors estrogen mediates a broad range of cellular
effects; these include the transcription of genes that encode enzymes which regulate
numerous pathways involved in the synthesis and metabolism of neurotransmitters,
their receptors, and neurotransmitter transporters5.
The serotonergic system is complex and involves numerous serotonin postsynaptic
receptors, and dysregulation of postsynaptic serotonergic function has been implicated
in depression5, as a function of serotonin, is to control of mood and emotion6. Clinical
studies suggest that serotonin exerts an inhibitory influence on symptoms such as
irritability, affect lability and depressive mood, suggesting that serotonin deficiency
may lead to depressive symptoms.
Estrogen and progesterone have also been shown to exert their effect on the central
nervous system (CNS) serotonin reuptake transporter10. In humans serotonin is a
neurotransmitter found in platelets and cells of the digestive tract. The reuptake of
serotonin in platelets and the uptake of serotonin in brain transmitter terminals are
similar active transport processes10. As for the serotonin transporter, the 5-HT2A
receptors in platelets are similar to that of the human brain, thus making research into
this area easier10. In studies in has been found that the number of platelet serotonin
transporters (Bmax) is significantly lower in PMDD patients compared to normal
subjects7,10. Bmax was at its lowest during the mid-luteal phase, when progesterone
concentrations reach their peak10. On the other hand Bmax reached its maximum
during the late follicular phase during the pre-ovulatory estrogen peak10. This suggests
that the high and fluctuating endogenous concentrations of steroid hormones in
reproductive women affect these serotonergic measures.
The fluctuating concentration of estrogen and progesterone may also have an affect on
the amygdala brain region. In women without PMDD the neurotransmitters GABA
and serotonin peak premenstrually, during the luteal phase, and decline during the
follicular phase of the cycle1. In contrast the normal premenstrual peak serum levels
of these neurotransmitters are absent during the late luteal phase of the cycle for
women with PMDD1. Thus clarifying (as above) that serotonin deficiency may lead to
depressive symptoms. Both serotonin and GABA mediate inhibitory input to the
amygdala, a structure known to connect to the frontal cortical areas of the brain 1.
Recent studies have shown that asymmetry in the activity of neurons in frontal
cortical areas is a correlate of affect1. Meaning that the affect is mediated by a
combined action of a positive emotion/approach system in the left frontal cortex, and
a negative emotion/avoidance system in the right frontal cortex1. Thus if right frontal
activity exceeds left frontal activity, a depressive affect results. It was found that with
PMDD, which is associated with profound affective psychopathology and
characterised clinically by extreme negative effect, there were changes in the
prefrontal cortex during the luteal phase, in the direction of greater right that left
cortical activation.
One of the specific effects of PMDD is a profound reduction of the GABA
neurotransmitter during the luteal phase of the menstrual cycle. GABA is known to
function as an inhibitory transmitter throughout the nervous system, exerting a tonic
inhibitory effect on many neurons including those in the dorsal and ventral regions of
the amygdala1,3. The amygdala is known to play an important role in the elaboration
of negative emotion, and shows asymmetrical responses to different kinds of emotionrelevant input3. Normal subjects display more actively in the right amygdala in
response to negative stimuli, compared to women with PMDD where the amygdala
showed increased activity in both the left and right amygdala1. This suggests that if
the inhibitory ability of GABA to keep mildly aversive stimuli from overexciting the
amygdala is compromised, as with PMDD, the normally regulated negative emotions
and non-dangerous stimuli may generate an unnecessary amount of fear and anxiety1.
In conclusion, premenstrual syndrome (PMS) and premenstrual dysphoric disorder
(PMDD) are common, but relatively hard to diagnose, as timing, type and severity of
symptoms as well as the prevalence of other mental disorders, can interfere with its
diagnosis. The symptoms occur in a cyclic fashion and the fluctuations in estrogen
and progesterone have a profound effect. Hormonal fluctuations affect the
serotonergic system in susceptible women, such as those with PMDD as serotonin
deficiency and a decreased Bmax lead to depressive symptoms. PMDD can be treated
with SSRIs which selectively block the reuptake of serotonin, resulting in and
immediate increase in synaptic levels of serotonin and alleviating depression. The
decrease in GABA also leads to increased amounts of fear and anxiety in women with
PMDD, and also as a result of decreased GABA the left and right amygdala activity
increases. Therefore, PMDD in particular is considered an important disorder that
involves numerous neuroendocrine factors. Further study may include other women’s
illnesses such as postpartum depression and perimenopausal depression, and perhaps
their linkage to PMDD via common genes.
References
1. Baehr E, Rosenfeld P, Miller L, Baehr R, (2004) Premenstrual dysphoric disorder
and changes in frontal alpha asymmetry. Psychophysiology 52, 159-167.
2. Cohen L, Soares C, Otto M, Sweeney B, Liberman R, Harlow B, (2002)
Prevalence and predictors of premenstrual dysphoric disorder (PMDD) in
older premenopausal women The Harvard Study of Moods and Cycles.
Affective Disorders 70, 125-132.
3. De Ronchi D, Manjola U, Boaron F, Muro A, Piselli M, Quartesan R, (2005)
Symptoms of depression in late luteal phase dysphoric disorder: a variant of
mood disorder? Affective Disorders 86, 169-174.
4. Freeman E, (2003) Premenstrual syndrome and premenstrual dysphoric disorder:
definitions and diagnosis. Psychoneuroendocrinology 28, 25-37.
5. Joffe H, Cohen L, (1998) Estrogen, serotonin, and mood disturbance: where is the
therapeutic bridge? Elsevier Science Inc
6. Lulich KM, (2003) CNS Pharmacology: Antidepressants. Lecture 6. Department
of Medicine and Pharmacology, The University of Western Australia.
7. Melke J, Westburg L, Landen M, Sundblad C, Eriksson O, Baghei F, Rosmond R,
Eriksson E, Ekman A, (2003) Serotonin transporter gene polymorphisms and
platelet [3H]paroxetine binding in premenstrual dysphoria.
Psychoneuroendocrinology 28, 446-458.
8. Metzi J, Angel J (2003) Assessing the impact of SSRI antidepressants in the
popular notions of women’s depressive illness. Department of Psychiatry and
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9. Noble R, (2005) Depression in women. Metabolism Clinical and Experimental 54,
49-52.
10. Wihlback A, Sundtrom Poromaa I, Bixo M, Allard P Mjorndal T, Spigset O,
(2004) Influence of menstrual cycle on platelet serotonin uptake site and
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