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Menopause International 2012; 18: 5259. DOI: 10.1258/mi.2012.

012014

Review

Pathophysiology of premenstrual
syndrome and premenstrual
dysphoric disorder
Andrea J Rapkin and Alin L Akopians
Department of Obstetrics and Gynecology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Correspondence: Andrea J Rapkin, Department of Obstetrics and Gynecology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
Email: arapkin@mednet.ucla.edu

Abstract
Premenstrual syndrome (PMS) and premenstrual dysphoric disorder are triggered by hormonal events ensuing
after ovulation. The symptoms can begin in the early, mid or late luteal phase and are not associated with
defined concentrations of any specific gonadal or non-gonadal hormone. Although evidence for a hormonal
abnormality has not been established, the symptoms of the premenstrual disorders are related to the production of progesterone by the ovary. The two best-studied and relevant neurotransmitter systems implicated
in the genesis of the symptoms are the GABArgic and the serotonergic systems. Metabolites of progesterone
formed by the corpus luteum of the ovary and in the brain bind to a neurosteroid-binding site on the
membrane of the gamma-aminobutyric acid (GABA) receptor, changing its configuration, rendering it
resistant to further activation and finally decreasing central GABA-mediated inhibition. By a similar mechanism, the progestogens in some hormonal contraceptives are also thought to adversely affect the GABAergic
system. The lowering of serotonin can give rise to PMS-like symptoms and serotonergic functioning seems to
be deficient by some methods of estimating serotonergic activity in the brain; agents that augment serotonin
are efficacious and are as effective even if administered only in the luteal phase. However, similar to the
affective disorders, PMS is ultimately not likely to be related to the dysregulation of individual neurotransmitters. Brain imaging studies have begun to shed light on the complex brain circuitry underlying affect and
behaviour and may help to explicate the intricate neurophysiological foundation of the syndrome.
Keywords: PMS, PMDD, pathophysiology, GABA, serotonin

Introduction
This article will review the current understanding of the
pathophysiological mechanisms underlying the premenstrual disorders (PMDs). A secondary goal is to
provide a neurophysiological foundation upon which to
build an understanding of the current treatment regimens
for the PMDs. The role of progesterone and neurotransmitters gamma-aminobutyric acid (GABA) and serotonin
(5-HT) will be addressed in some detail. Recent brain
imaging studies will also be discussed.

How is a PMD defined?


PMDs are comprised of core PMD and variants of PMDs,
according to a consensus conference sponsored by the
International Society for the Study of Premenstrual
Disorders (ISSPMD).1

52

The consensus definition of PMDs does not specify the


nature or number of symptoms; only the timing of the
symptoms and the presence of functional impairment are
relevant. Symptoms must be linked to the luteal phase,
beginning sometime after ovulation and ending by the
end of the menstrual flow, with a symptom-free interval
before the next subsequent ovulation. Core PMD is analogous to the premenstrual syndrome (PMS) as defined by
the American College of Obstetricians and Gynecologists
(ACOG) and the Royal College of Obstetricians and
Gynecologists (RCOG) and may affect as many as 20% of
ovulatory women.2,3 A severe form of core PMD, noted to
occur in approximately 58% of women, has been defined
by the American Psychiatric Association as premenstrual
dysphoric disorder (PMDD) and requires five premenstrual symptoms including at least one moderate to severely
disabling affective symptom.4 In order to diagnose a core
PMD, it is imperative that individuals demonstrate prospectively the appropriate timing of symptoms; starting
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A J Rapkin and A L Akopians


after ovulation and subsequently increasing in conjunction with the rise in serum progesterone during the luteal
phase, with a peak, severity of symptoms during the last
five premenstrual days, with resolution of symptoms
occurring 34 days following the onset of menstrual
bleeding, and with a period of wellbeing associated with
the rise in follicular phase estradiol levels. A variant
PMD is one in which the symptoms may be related to an
exacerbation of an underlying somatic or mood disorder,
to exogenous progestogens, to ovarian activity in the
absence of ovulation or when cyclic symptoms are present
without menses, as in the setting of a prior hysterectomy
or endometrial ablation.

Overview of pathophysiology
Role of progesterone
Since the 1980s, the factor responsible for provoking
symptoms of PMS has been attributed to the progesterone
produced by the corpus luteum.5 During anovulatory
cycles, when a corpus luteum fails to form, the symptoms
of PMS are not observed.6 Premenarchal girls, postmenopausal women and those who have undergone bilateral
oophorectomy also do not experience PMS. Nevertheless,
the role of progesterone in triggering adverse symptomatology is not straightforward. For example, PMS symptoms are absent during pregnancy, in spite of high
progesterone and estrogen concentrations. It is unclear
how long after conception the typical PMS symptoms that
are linked to the luteal phase hormonal complement will
diminish.
Administration of exogenous progesterone or a progestogen can also engender symptoms akin to PMS.
Postmenopausal women receiving hormonal therapy
consisting of both estrogen and a progestogen may
experience PMS-like complaints consisting of negative
mood and somatic symptoms. These undesirable effects
were investigated and have been attributed to the progestogen.7 In addition, PMS-like symptoms often persist
even after anovulation has been induced with a hormonal
contraceptive, and again it has been hypothesized that
the exogenous progestogens are responsible, although the
dose of estrogen may also be relevant. There are a number
of studies suggesting oral contraceptive pills (OCPs),
regardless of the elimination of ovulation, can be associated with PMS-like negative affective and physical
symptoms such as irritability, depression, anxiety, bloating, fatigue and breast tenderness in a subset of women.8
Although compelling evidence points to the role of
progesterone in the pathophysiology of PMDs, it appears
that the classical progesterone receptor is not involved in
this process. This observation is supported by lack of
reduction in physical or behavioural manifestation of
PMS with administration of the progesterone receptor
antagonist, mifepristone.9 In addition, numerous studies
have been unable to provide evidence for progesterone
excess or deficiency in the aetiology of PMDs. In multiple
studies, measurement of serum progesterone in women
with PMS compared with controls failed to show any
significant differences.5 Finally, a series of randomized
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Pathophysiology of PMS and PMDD

double-blinded placebo-controlled trials (RCTs) failed to


show efficacy of progesterone supplementation.10
Other reproductive hormones, estradiol, testosterone,
the adrenal hormones cortisol and dehydroepiandrosterone sulphate and the pituitary and thyroid hormones
including prolactin and thyroxin also fail to distinguish
women with PMDs from controls. Although in one study,
more severe symptoms were found in cycles with higher
concentrations of both estradiol and progesterone.11
It appears that women with PMDs are more sensitive to
developing negative mood and physical symptoms with
the exposure to normal concentrations of ovarian sex
steroids. Women with PMS, but not asymptomatic
women, had a negative affective response to the administration of physiological doses of exogenous estradiol or
progesterone after having achieved a chemical menopause by receiving a gonadotrophin-releasing hormone
(GnRH) agonist.12
The metabolites of progesterone (and corticosterone)
have psychoactive properties and have been known for
almost a century to produce sedation in animals. These
effects are not mediated through the classical progesterone receptor. Given this evidence, researchers have postulated that a metabolite of progesterone may contribute
to the generation of the affective and physical symptoms
of PMDs through the modulation of a different receptor
mechanism.

Gamma amino butyric acid


Temporal onset of PMS begins with ovulation and is likely
related to progesterone production. The rising concentration of estradiol in the late follicular phase or a hormonal milieu consisting of estrogen alone fails to produce
PMS symptoms. However, progesterone itself did not
seem to be specifically the key, leading researchers to
investigate the role of the neuroactive metabolites of
progesterone that were known to affect mood and behaviour. In the ovary and the brain, progesterone is
metabolized to form the potent neuroactive steroids,
3-alpha-hydroxy-5-alpha-pregnane-20-one (allopregnanolone or ALLO) and 3-alpha-hydroxy-5beta-pregnane20-one ( pregnanolone). These metabolites act as positive
allosteric modulators of the GABA neurotransmitter
system in the brain. The main inhibitory neurotransmitter in the brain, GABA, is a widely distributed neurotransmitter in the central nervous system (CNS) and
evidently is an important regulator of stress, anxiety,
vigilance, alertness and seizures.13
GABA is derived from glutamate, which is synthesized
in series of steps by the Krebs cycle, and is then decarboxylated to GABA by the rate-limiting enzyme, glutamic
acid decarboxylase, exclusively found in GABAergic
neurons. GABA is then stored in vesicles found in the
presynpatic terminal of GABAergic neurons. Three subtypes of GABA postsynaptic receptors have been identified: GABAA, GABAB and GABAC receptors. However, it is
the GABAA receptor that is the site of action of endogenous agents such as neuroactive steroids derived from
progesterone or synthesized de novo in the CNS, as well as
exogenous agents such as progestogens (after metabolism

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Pathophysiology of PMS and PMDD

to reduced steroids), benzodiazepines, barbiturates,


alcohol and anticonvulsants.13
GABAA receptors are transmembrane protein complexes
composed of alpha, beta, delta and gamma subunits that
function as ion channels. For example, when GABA binds
to the GABAA receptor it causes a conformational change
in the protein complex that results in rapid and transient
opening of chloride ion channels. Chloride influx
results in hyperpolarization of the membrane and
decreases the likelihood of depolarization by excitatory
neurotransmitters. This is in contrast to the slow classical
genomic effect of cystosolic activation of steroid hormone
receptors. Binding of alpha reduced progesterone, corticosterone and testosterone metabolites, barbiturates,
benzodiazepines at an allosteric site on the GABAA
receptor results in activation of receptor and increases
neuronal inhibition via a direct and rapid mechanism as
described above.13 Research has shown that ALLO, by
binding GABAA receptors, plays an important physiological modulatory role in changing the sensitivity of
GABAA receptors for GABA.13 This modulatory effect is
accomplished by altering the subunit composition of the
receptor, rending the receptor temporarily insensitive to
modulation by neurosteroids.
These compositional alterations of the GABAA receptor
isoforms are postulated to be important in the aetiology
of PMDs. Initially a deficiency of these neuroactive
steroids was postulated. For example, acute treatment
with ALLO has been shown to have anxiolytic, antidepressive and anticonvulsant effects. Similarly, decreased
neuroactive steroids have been associated with anxious
and depressive behaviour.14 Reduced progesterone
metabolites such as ALLO have been measured in PMS
and asymptomatic women in the luteal phase and some
but not all studies have shown a deficiency or an association with mood in women with PMS.15,16
In addition to the importance of concentration of these
neuroactive metabolites in determining agonistic effect
on GABAA receptor, the duration of exposure also plays a
critical role. For example, whereas acute, very short-term
ALLO exposure decreases stress and anxiety, chronic
exposure has been shown to produce an anxiety-like
reaction.17 Decreased expression and binding to the
GABAA receptor as well as uncoupling of the receptor
from anxiolytic modulators can result in increased
anxiety. GABAA receptor configuration changes after
exposure to ALLO in the luteal phase such that GABAA
receptor function and modulation vary throughout the
menstrual cycle. Studies completed in rodents have
shown that acute and prolonged exposure as well as
withdrawal from ALLO attribute to an increased in
alpha-4,17 gamma-218 and delta19 subunit of GABAA
receptors. This GABAA plasticity subsequently results in
temporarily decreased sensitivity to GABA and GABA
agonists and enhances anxiety-like behavioural changes.
Although the GABA subunit studies were performed in
rats, human studies using saccadic eye velocity as a proxy
for GABAergic activity support the postulate that these
alterations in GABAA subunit configuration and
GABAergic activity likely contribute to the negative
m and
mood symptoms associated with PMS.20 Sundstro
m (1998)21 demonstrated that administration of a
Backstro
selective serotonin reuptake inhibitor (SSRI) in the luteal

54

phase to women with PMS increased the saccadic eye


velocity to that of control women, suggesting a
re-instatement of GABAergic sensitivity by augmenting
serotonin.

Serotonin
Serotonin (5-HT, 5-hydroxytryptamine) has been implicated in the modulation of mood, eating, arousal and
circadian rhythms. Serotonin depletion through dietary
or pharmacological means leads to anxiety and depressive
like symptoms.
The role of serotonin in PMS has been supported by
various lines of evidence. PMS symptoms overlap symptoms associated with reduction in serotonin transmission.22 These symptoms include depression, mood
swings, irritability, self-deprecation, poor impulse control,
sleep disturbance, anxiety, aggression, decreased pain
threshold, carbohydrate cravings and difficulty in concentrating. In addition, serotonergic function has been
shown to be altered during the luteal phase of the menstrual cycle in women with PMS. For example, decreased
platelet uptake of serotonin,23 decreased baseline whole
blood serotonin24 and decreased platelet monoamine
oxidase (MAO) activity25 have all been shown to occur
during the luteal phase of the menstrual cycle.
Tryptophan loading tests in women with PMS are abnormal compared with the results for asymptomatic women.
Serotonin metabolism is also modulated in part by
ovarian sex steroids. Ovarian sex steroids have also been
implicated in serotonin uptake, turnover, binding and
transport.25
Finally, administration of drugs augmenting serotonergic neurotransmission is effective for treatment of PMDs.
The role of serotonin is further supported by lack of
significant improvement of PMS symptoms with antidepressants that only augment norepinephrine and not
serotonin. Taken together, the evidence suggests that
serotonergic dysregulation may play an important role in
symptomatology of PMS and that serotonin in concert
with other neurotransmitters such as GABA are important
in the pathophysiology underlying the disorder.
5-HT is synthesized in serotonergic neurons.
Specifically, the amino acid, tryptophan, is sequentially
altered by two enzymes in the CNS. First, tryptophan
hydroxylase, the rate-limiting enzyme, produces 5hydroxytryptophan, then L-aromatic amino acid decarboxylase decarboxylates 5-hydroxytryptophan to 5-HT.
5-HT is then stored in vesicles in the presynaptic terminal,
ready to be released upon arrival of nerve impulses. Once
5-HT is released into the synaptic cleft, it is subsequently
inactivated primarily by reuptake through the highaffinity presynpatic membrane serotonin transporter
(SERT). An important clinical target for therapeutic drugs,
SERT, is the site of action of the SSRIs.
Serotonergic activity in the brain is affected by estrogen
and progesterone; specifically sex steroids can modify
serotonin availability at the neuronal synapses. For
example, estrogen has been shown to increase degradation of MAO, enzyme responsible for oxidation of
monoamines, and catechol-o-methyl-transferase (COMT),
enzyme responsible for degradation of cathecolamines.
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Estrogens role in increasing degradation of MAO and
COMT results in augmenting action of serotonin in regulating the availability of free tryptophan in the CNS and
improving clinical effect of SSRIs. In contrast, progesterone increases MAO activity, therefore decreases 5-HT
availability, which may result in depressed mood.

Brain neurocircuitry
Neuroimaging studies focusing on hormonally mediated
changes across the menstrual cycle and in women with
PMDs compared with asymptomatic controls can provide
valuable information regarding the underlying neurophysiological abnormalities in PMS and PMDD. For
example, an early positron emission tomography (PET)
study showed that regional cerebral blood flow in the
prefrontal cortex was attenuated by pharmacological
ovarian suppression, and this was subsequently normalized with estrogen or progesterone replacement.26 A study
employing protein magnetic resonance spectroscopy
showed increased cortical GABA concentrations in the
luteal phase of women with PMDD when compared with
follicular phase; however, healthy subjects showed
decreased cortical GABA.27 The authors concluded that
abnormal GABAA receptor functioning could reduce sensitivity to GABA agonists, including neuroactive steroids
such as the pregnane metabolites.27 A PET study looking
at serotonin-1A receptors showed significantly smaller
increment in receptor binding between the follicular and
the luteal phase scans in women with PMDD compared
with controls.28 In one study using functional magnetic
resonance imaging, neural response was evaluated to an
emotional Go/No-Go task designed to provoke negative
emotion.29 Researchers found that women with PMDD
were less able than controls to inhibit incorrect responses
to affectively negative words. Control subjects showed
more activity during the late luteal phase compared with
the follicular phase within the anterior-medial orbitofrontal cortex (OFC) and less activity in the lateral OFC,
insula and posterior cingluate cortex. However, PMDD
subject showed more activity in the amygdale during the
late luteal compared with the follicular phase and less
activity in the OFC.29 This was interpreted as diminished
impulse control via prefrontal top-down modulation of
the limbic system. In a more recent study, investigators
desired to map functional brain abnormalities associated
with negative mood states in PMDD. PET with [18F]
fluorodeoxyglucose was used to assess regional cerebral
metabolism across the menstrual cycle in women with
PMDD and asymptomatic participants. Women with
PMDD showed an increase in cerebellar activity from the
follicular phase to the late luteal phase and this was correlated with worsening of mood.30 The increased activity
was localized primarily to cerebellar regions that have
been previously described as the limbic cerebellum. The
cerebellum is rich in GABAA receptors containing the
delta and alpha subunits and as noted above, animal
models suggest women with PMDs may have deficiencies
in mechanisms regulating GABA subunits. The increased
cerebellar activity could reflect decreased GABA-mediated
inhibition during the symptomatic luteal phase.
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Pathophysiology of PMS and PMDD

Understanding the treatment of PMDs


based on underlying pathophysiology
In this section, treatment studies will be reviewed only as
they pertain to current understanding of the pathophysiology of the PMDs.

Hormonal treatment
A review of symptomatology of PMS highlights a link
between rise and fall of sex steroids associated with
ovulation and PMS.5 As noted above, PMS does not occur
during anovulatory cycles or in women who have
undergone bilateral oopherectomy. Thus, ovulation
suppression is an area of focus for diagnostic and
treatment options. Many treatment studies have focused
on suppression of ovulation with OCPs, but GnRH
agonists (the gonadotrophin inhibitor [danazol]), high
doses of transdermal estrogen and bilateral
salpingo-oophorectomy (BSO) all have positive evidence
as treatment options for prevention of PMS and PMDD.

Combined oral contraceptive pills


Although the combined OCP prevents ovulation, the
complex effects of estrogen and progestogens in the CNS
is underscored by the fact that few RCTs have shown
efficacy for PMDs. A randomized placebo-controlled trial
showed that tri-phasic OCPs reduced physical symptoms
but not mood symptoms associated with PMS.31 A study
comparing tri-phasic formulation to monophasic formulation of OCPs concluded that the mono-phasic regimen
is less likely to cause adverse mood changes.32 In fact,
approximately 16% of women using traditional combined
OCPs reported mood deterioration with only 12.3%
reporting improvement and 71.4% stating that the combined OCP had no effect at all on mood.33
Researchers have studied various formulations of OCPs
in an effort to find one that would not re-introduce or
mimic PMS-like symptoms. Based on the observation that
PMS symptoms are linked to the rise and fall of progesterone and estradiol with ovulation and are absent
during pregnancy when ovarian sex steroids are constant,
one extended active pill OC regimen was subjected to
RCTs for PMS and PMDD. In a recent overview of four
studies evaluating continuous combined oral contraceptive (COC) use with a specific pill containing levonorgestrel (90 mg) and ethinyl estradiol (20 mg) modest but
inconsistent improvements in premenstrual symptoms
were noted.34 Continuous COC regimens or progestogen
only contraceptives that eliminate ovulation are not well
studied but less than optimal efficacy may be due to the
physical and mood symptoms associated with the progestogen, the estrogen dose or the break through
bleeding.
Since the lack of efficacy of standard COCs in PMDs has
been attributed to estrogen dose, progestogen formulation and dosing regimen, novel dosing regimens and
progestogens have been studied. In traditional 21/7 oral
contraceptive regimens, the seven-day hormone-free
interval allows for continued hormonal fluctuation and

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Pathophysiology of PMS and PMDD

can be associated with adverse symptoms that can mimic


physical symptoms of PMS. The rise and fall of sex steroids
can precipitate or worsen PMS symptoms in predisposed
individuals. Early studies suggested that the reduction of
PMS symptoms could be significant with a shorter
pill-free interval.35 Lower dosing of ethinyl estradiol may
also be important for preventing PMS-like symptoms.
When two COCs with the same progestogen dosing but
25 versus 35 mg of ethinyl estradiol were compared,
women taking the lower dosage showed greater
improvements in premenstrual mood.
Newer oral contraceptive regimens with longer active
pill administration and novel progestogens can result in
improved PMS symptoms. A regimen involving 24 active
pills and four placebo days, combined with a progestogen
with a longer half-life and a lower estradiol dose, results in
more complete suppression of folliculogenesis and
endogenous estradiol.35 The OCP containing 20 m of
ethinyl estradiol and 3 mg of the progestogen drospirenone, in a regimen containing 24 active followed by four
inactive pills (24/4 regimen), has proven to be effective in
the treatment of PMDD in two prospective RCTs.35,36 On
the basis of these two trials, this COC received US Food and
Drug Administration (FDA) approval for the indication of
PMDD in those who desire hormonal contraception. The
progestogen drospirenone is not derived from
19-nortestosterone but is an analogue of spironolactone
and has antiandrogenic and antimineralocorticoid properties that may contribute to its efficacy for PMDD.
The adverse mood effects of OCPs may be related to the
progestogens used in OCPs that are derivative of testosterone (19-nortestosterone). In addition, physical side-effects
of OCPs including bloating and breast tenderness are in
part attributed to water retention and probably related to
the estrogenic component of the OCPs, possibly mediated
by the renin angiotensin system. The formulation of OCPs
that contain drospirenone and lower ethinyl estradiol
(20 mg), consisting of 24 active pills followed by four
placebo pills, have been proposed to counteract the effect
of progesterone induced symptoms. In addition, OCPs
with drospirenone, instead of 19-nortestosterone derived
progestogens may ameliorate water retention, bloating,
weight gain and breast tenderness.

GnRH analogues
A GnRH analogue is a synthetic peptide that interacts
with a GnRH receptor and subsequently elicits release of
follicle-stimulating hormone and leutinizing hormone
from the anterior pituitary. After the initial surge of production of ovarian steroid production, it then suppresses
ovarian steroid production and therefore results in a
medical menopause with its associated relief of symptoms of PMS. Several randomized controlled trials have
demonstrated the efficacy of GnRH analogues in relieving
symptoms of PMS.37
GnRH analogues have also been proposed to differentiate symptoms of PMS or PMDD from the premenstrual
exacerbation of an underlying affective disorder.1
However, one study reported that some women who
appeared to have pure PMS continue to have symptoms
after GnRH exposure.38 Although these women had

56

structured clinical interviews and prospectively documented symptoms consistent with PMS, they did manifest more rapidly cycling mood symptoms throughout the
premenstrual phase and therefore may have had an
underlying affective disorder and not pure PMS. However,
this study highlights some of the gaps in our knowledge
of the role of sex steroids in the disorder.
In managing PMDs with GnRH analogues it is important to keep in mind that the ensuing hypo-estrogenic
state can result in several unfavourable side-effects such as
depression, anxiety, irritability, vasomotor symptoms,
vaginal dryness, insomnia, headache and muscle aches,
and that long-term use can result in osteoporosis and
increased risk of cardiovascular disease. Add-back treatment with estrogen can mitigate all of the above sideeffects and decrease the risks but unopposed estrogen is
contraindicated for extended periods of time due to the
risks of endometrial hyperplasia and carcinoma. A combination of estrogen and low dose of a progestogen or
tibolone, a synthetic anabolic steroid, have been shown to
decrease adverse effects of GnRH without reducing efficacy. However, add-back hormones can contribute to
mood symptoms in women with severe PMS38 and it is
the progestogen that is most poorly tolerated. A
meta-analysis on effects of tibolone has shown that it is
less likely to re-introduce premenstrual symptoms when
compared with cyclical estrogen and progestogen.37 The
lowest systemic exposure to an endometrial protective
progestogen is afforded by the levonorgestrel containing
intrauterine device.

Progestogens
A systematic review of RCTs using progesterone or progestogens (norethisterone, medroxyprogesterone acetate,
levonorgestrel) during the luteal phase or continuously
have shown that their use is ineffective in treatment
of PMS and often re-stimulates the symptoms.39
Progestogen-induced premenstrual disorders are now well
recognized as the direct consequence of progestogen
administration.40 As mentioned above, a plausible explanation for ineffectiveness of progesterone in treatment of
PMS is that progesterone metabolites via modulation of
the GABAA receptor are responsible for reinstating the
symptoms of PMS even if ovulation has been eliminated
with the progestogen. For many years progesterone and
progestogens have been the only preparations available
that are specifically licensed in the UK for managing
premenstrual syndrome. This arose from the very enthusiastic non-evidence-based claims by Katharina Dalton
and surprisingly this licence and their prescription have
continued despite robust negative evidence for their efficacy and scientific research that fails to demonstrate any
evidence of progesterone deficiency in affected women.
This contrasts greatly with the situation in the US where
only evidence-based licensing has occurred (SSRIs and
drospirenone OCs).41

Hysterectomy and BSO


Endometrial ablation or hysterectomy does not eliminate
symptoms of PMS, as the primary result of these
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A J Rapkin and A L Akopians


treatments is the elimination of menstruation and preservation of ovarian function. In order to eliminate
ovarian function, women may desire to proceed with
bilateral oophorectomy. This approach has been shown to
be effective in women with severe PMS.42 If BSO is being
considered as a treatment modality for severe and debilitating symptoms of PMS, it may be beneficial to consider
a trial of GnRH agonist first to establish the relative contributions of endocrine-related pathology as the aetiology
of symptoms versus underlying psychiatric or psychosocial causes of PMS. After BSO, it is important to replace
estrogen until the age of natural menopause in order to
prevent the complications of premature menopause outlined above. It is important to perform a hysterectomy at
the time of BSO in order to allow women to receive
unopposed estrogen replacement and to avoid recurrent
progestogen-induced premenstrual symptoms with the
combination hormonal replacement.

Estradiol
Placebo-controlled studies have indicated the therapeutic
effect of ovulation suppression by increasing plasma
estradiol levels in improving symptoms of PMS. For
example, percutaneous estradiol has been shown to
prevent ovulation and in addition improve PMS symptoms.43 Specifically, high-dose transdermal estradiol
(200 mg) via the patch has been shown to prevent ovulation and reduce symptoms of PMS.43 Unopposed estrogen may lead to endometrial hyperplasia and cancer but
studies have shown that oral progesterone may worsen
symptoms of PMS. An alternative to orally administered
progestogen is use of levonorgestrel releasing intrauterine
system, which circumvents issues associated with oral
progestogen by having a local effect on the endometrium
with minimal serum levels.

SSRIs and serotonin norepinephrine reuptake


inhibitors
Numerous double-blind placebo-controlled trials have
shown efficacy of serotonergic pharmacological agents for
treatment of severe forms of PMS and PMDD with an on
average response rate of approximately 60% in effectively
controlling PMS symptoms compared with placebo.44
ACOG currently recommends treatment with SSRIs as the
drug of choice for severe PMS/PMDD. Specifically fluoxetine and sertraline have been shown to be effective in
treatment of both the affective and the physical symptoms of PMDD, with improvement of quality of life and
psychosocial functioning.45 Meta-analyses of placebocontrolled trials have demonstrated that either continuous use or luteal phase use of SSRIs and serotonin norepinephrine reuptake inhibitors are effective in reducing
symptoms.46 The fact that treatment during luteal phase
has been shown to be effective for fluoxetine, citalopram,
sertraline and clomipramine underscores the contention
that serotonergic dysregulation in PMDs may be confined
to the luteal phase for fluoxetine, citalopram, sertraline
and clomipramine.
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Pathophysiology of PMS and PMDD

Research on other CNS-acting drugs for treatment of


PMS has not shown to be very effective compared with
serotonergic antidepressants. As noted above, augmenting noradrenergic activity alone has not been shown to be
effective in treatment of PMDD. For example, trials comparing fluoxetine to bupropion,47 sertraline to desipramine48 and paroxetine to maprotiline49 have shown that
augmenting noradrenergic activity alone is not effective.
The exact mechanism of action of SSRIs in ameliorating
symptoms of PMS is unknown; however, researchers have
partially contributed this effectiveness by increasing the
CNS serotonergic activity. An additional possible mechanism of action involves ALLO. GABA has been shown to
regulate the activity of 5-HT neurons through ALLO
modulation of GABAA-mediated inhibition. SSRIs have
been shown to augment the reactions involved in the
formation of ALLO. In one study, L-tryptophan, a precursor of serotonin that crosses the bloodbrain-barrier, was
administered and ALLO and pregnenolone concentrations were assessed. After L-typtophan challenge, the
circulating ALLO concentrations were significantly
increased in both controls and women with PMS during
the luteal phase of the menstrual cycle.50 The relationship
between serotonergic activity and brain neurosteroids
such as ALLO may partially explain the benefit of treatment with SSRIs in women with PMS. Efficacy data on
GABA agonists such as benzodiazepine and alprazolam
are conflicting. Agents that bind GABAA receptors may
not be effective for the same reason that progesterone is
not useful. No other GABAergic agents have been studied
and there are no GABA subunit specific pharmaceuticals
currently available.

Calcium
The ovarian steroids influence calcium, magnesium and
vitamin D metabolism. Specifically, estrogen plays a role
in regulation of calcium metabolism, intestinal absorption and parathyroid gene expression and secretion,
resulting in fluctuation across the menstrual cycle.
Hypocalcaemia has been associated with many affective
disturbances that are similar to the symptoms of PMS.
Some evidence indicates that women with PMS have
underlying calcium dysregulation with a secondary
hyperparathyroidism and vitamin D deficiency. In two
controlled trials, calcium carbonate 1200 mg/day in
divided doses has been shown to decrease PMS symptoms.51 Ghanbari et al. (2009)52 showed that calcium,
500 mg twice daily, reduced fatigability, changes in
appetite and depression in women with PMS.

Summary and future directions


Our conceptualization of the aetiology of the PMDS
incorporates available knowledge regarding the effects of
exposure to the rise and fall of estrogen and in particular,
progesterone on neurotransmitters such as GABA and serotonin. However, current understanding of the neurobiological substrates of mood and behaviour are still in their
infancy. Additional research is clearly needed to understand
the complex effects of the menstrual cycle on the brain in

57

A J Rapkin and A L Akopians

Pathophysiology of PMS and PMDD

asymptomatic women and those with premenstrual mood


and other somatic disorders. Most mood, autoimmune and
pain disorders are exacerbated in the luteal phase. Future
research will continue to shed light on the myriad influences of ovarian sex steroids on the functioning of the
central nervous system in health and disease.

19

20

Competing interests: None declared.

21

Accepted: 9 March 2012

22
23

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