Premenstrual Syndrome and Dysphoric Disorders
It is estimated that 80-90% of women develop some
premenstrual symptoms, mainly emotional (1), during their reproductive years
which indicate imminent start of menstruation. They are usually referred to as
premenstrual moliminal symptoms, which can be physical, psychological or
behavioural. They cause transient discomfort in the majority of cases, and are
relieved by the onset of menstruation. Conversely, 30-40% of these women are
significantly affected and need to seek medical advice. A diagnosis of
premenstrual syndrome (PMS) is made in these cases. A definition suggested by
Magos and Studd for PMS in 1984 (2) was: ‘a
condition which manifests with distressing physical, behavioural and
psychological symptoms in the absence of organic or underlying psychiatric
disease, which regularly recurs during the luteal phase of each menstrual
(ovarian) cycle and which disappears or significantly regresses by the end of
menstruation’. Traditionally, these patients were considered to have abnormal
or excessive reaction to the normal premenstrual withdrawal of oestrogen and
progesterone. They almost always have used different remedies including evening
primrose for many months, before seeking medical
advice. The symptoms may be severe enough to affect quality of life in 2-9% of
menstruating women (3). These are
mainly in the form of major mood disorders which completely disrupt every
day-to-day activity; hence the name premenstrual dysphoric disorder (PMDD) has been introduced. This name replaced
the term ‘late luteal phase dysphoric disorder (LLPDD)’ in 1993, on the
recommendation of the American Psychiatric Association. Obese women who
performed less exercise, and had lower academic achievement were thought to be
more at risk. A lower prevalence is usually seen in women who use hormonal
contraception (4). The most frequent PMDD symptoms
include anger/irritability, anxiety/tension, feeling tired and
lethargic, mood swings, feeling sad and depressed, and increased interpersonal
conflicts. Such premenstrual problems are not a creation of present day women,
as they have been known since the times of Hippocrates who wrote ‘shivering,
lassitude and heaviness of the head denote the onset of menstruation’. Most
likely with delayed childbirth pattern and smaller family size nowadays, more
women are exposed to repeated menstruations than their ancestors who were more
likely to be pregnant or breast feeding more frequently at the same age group.
Accordingly, they were less exposed to a similar predicament. It is usually
forgotten that 5-15% of women have positive changes premenstrually, with
improved physical activity and sexuality (5).
are no known criteria to distinguish this group from those who usually suffer
The range of premenstrual symptoms is wide and
includes physical, psychological, and behavioural problems. Headaches,
forgetfulness, lack of concentration, insomnia or hypersomnia, fatigue, apathy,
hot flushes, irritability, anger, panic attacks, mood swings and loss of self
control are common. Other symptoms include clumsiness, being tearful and over
sensitive, food cravings, breast tenderness, bloating sensation, swelling,
constipation and diarrhoea. It is noticeable that almost >90% of the
symptoms are psychological or behavioural, which may be a reflection of some
chemical changes in the brain during that period of the cycle.
Two different major endocrine theories have been put
forward over the years as possible causes of PMS and PMDD:
- The ovarian
hormones theory hypothesised that lack of progesterone or reduced
progesterone / oestrogen ratio during the late luteal phase are
responsible for these adverse symptoms. This was the basis why
progesterone medication has been used for many years and in different
forms in an attempt to control these premenstrual symptoms. Evidence from
meta-analysis of randomised controlled studies showed that progesterone
was not more effective than placebo in this respect, and did not support
the use of progesterone in the management of patients with premenstrual
serotonin theory is more plausible, as lower
platelets serotonin content and maximum velocity (Vmax) of serotonin
uptake by platelets have been shown during the luteal phase in women
affected by PMS than a normal control group, as reported by Ashby et al in
The importance of this finding relates to the fact that platelets are
believed to be a peripheral model for central serotoninergic neurones, as
stated by the same authors. Furthermore, the serotonin theory has been
supported by good clinical response after medical treatment with selective
serotonin reuptake inhibitors (SSRI) to replenish brain serotonin
activity. According to this theory, normal cyclic fluctuation in the level
of oestrogen and progesterone triggers brain biochemical changes in
susceptible individuals. A relationship has been found between a decline
in oestrogen level and altered serotonin brain activity (8). This concept has been supported by the
observation that 85% of women with PMS had hot flushes at the same time,
compared to 15% of women with no PMS (9, 10).
Furthermore, oestrogen therapy has been shown to improve clinical
depression by double blind clinical trials in oestrogen deficient patients
Other non-endocrine theories have been put forward as
well, but they are beyond the remit of this chapter. They included
sociocultural, psychosocial, as well as cognitive and learning theories.
Suffice to say that they had related most premenstrual symptoms to
psychological causes, internal conflicts and previous experiences, which could
lead to maladaptive strategies to cope with the onset of menstruation.
A recent breakthrough came with a discovery of
genetic predisposition to PMDD in a preliminary report published by Huo et al
in 2007 (13). A variant of oestrogen receptor
alpha gene, together with a variant form of catechol-o-methyltransferase gene (COMT), were found in women with PMDD. COMT is
an enzyme involved with prefrontal lobe activation, which is an important
regulator of mood. This genetic finding may explain the familial predisposition
to PMDD. About 70% and 36% of the daughters of affected and unaffected women
respectively were similarly inflicted with PMDD (14).
This discovery does not contradict with the general consensus accepting the
serotonin hypothesis as the most credible cause of PMDD.
Women with these genetic variants may be more prone to react badly to CNS
All age groups between menarche and the menopause can
be affected with PMS or PMDD, though they are more common in the third and
fourth decades of life. This can be genuine statistics, but may be a
misrepresentation of reality. Younger women especially teenagers may be
affected, but their symptoms can be related falsely to unstable teenage
hormonal changes and indiscretions. Due to restrictions in medical services,
information is lacking regarding the incidence of PMS and PMDD in developing
countries. Furthermore, talking about menstruation related issues is a taboo
not to be discussed. Most of the research relates to richer societies.
Nevertheless, community studies in these richer nations showed no racial
differences in the prevalence of PMDD, though some differences were reported in
the mode of presentation, and type of symptoms. Food cravings were reported
more frequently by black women (15), whereas
mood changes and weight gain were more common in white women (16).
It is always important to make sure that the
presenting symptoms are not just premenstrual magnification of chronic
depression, or some other psychiatric disorder. PMS and PMDD start after
ovulation and are relieved after the onset of menstruation. Few women may have
different levels of chronic or background psychiatric diseases, which get worse
premenstrually. Accordingly, a prospective diagnostic calendar will be more
appropriate to help in making the right diagnosis. The patient should document
the nature of her symptoms, and rate their severity on daily basis for a period
of at least 2 cycles in relation to menstruation. She should also record their
effects on her personal wellbeing. This will help in excluding patients with
predominantly psychiatric problems including depression, anxiety, panic and bipolar affective
disorders being treated in a gynaecology outpatient clinic. It is also
important to appreciate that all mild forms of these problems are considered to
be risk factors for the development of PMDD. Other predisposing factors include
history of sexual abuse and domestic violence. Medical problems which can
simulate PMS and PMDD should be sought and excluded. Examples of such diseases
include anaemia, thyroid diseases and hyperprolactinaemia. Pelvic endometriosis is another disease which can confound the
picture, as it may be associated with migraine headaches and bloating sensation.
It is not unusual for a patient to see many practitioners
before her symptoms are taken seriously. There was general acceptance at one
time that such symptoms are normal part of menstruation. Retrospective history
may not show the exact extent of the problem, or the range of symptoms suffered
by the patient, hence the need to keep a prospective calendar as mentioned
General history and medical examination can be useful
in directing the diagnosis toward a specific medical problem. Weight loss,
tremors, sweating, shortness of breath, dry skin and excessive or painful
menstruation, premenstrual dyspareunia and dyschezia are helpful symptoms or
signs to elicit. They can direct the clinician to such medical conditions as
thyroid disease, anaemia and endometriosis just as examples. Maternal or family history
of PMDD and history of sexual abuse, infertility, family violence, previous
psychiatric diseases, and alcohol abuse are also important to elucidate.
Imaging techniques are not useful, and there are no
confirmatory endocrine tests pathognomonic of the condition. Nevertheless,
blood tests will be necessary to exclude medical conditions such as anaemia,
thyroid disease and hyperprolactinaemia. Furthermore, serum progesterone level
estimations in women who had a hysterectomy can be used to relate the patients’
symptoms to their ovarian cycle. Transvaginal ultrasound scanning may show a
corpus luteum. Frequently, thorough medical history and a charted calendar of
symptoms may prove to be more diagnostic in this respect. The most important
symptoms are irritability, anxiety, anger and depression. According
to the American Psychiatric Association, the presence of 5 or more of the
following symptoms is necessary to make a diagnosis of PMDD (17), after ruling out other possible causes.
Furthermore, symptoms should be severe enough to affect the quality of life,
and at least one of the first four symptoms should be included in a 2-months
and marked anger;
interest in usual activities;
change in appetite;
of being overwhelmed or out of control;
Treatment of patients with PMS
and PMDD should start with the recognition of the problem itself by the doctors
involved. Patients do not need to see many practitioners before their problems
can be addressed. PMS and PMDD are not imaginary problems in the heads of the
inflicted patients. In most cases these patients had different medications for
many months if not years, while waiting to find proper medical attention.
Patients should be encouraged to
change their lifestyle. This should involve changes in eating habits, as small
and frequent meals can reduce the risk of
mood swings. It has been shown that intracellular uptake of glucose can
be impaired during the premenstrual period (18). More physical activity, especially aerobic exercising reduces stress
and has temporary favourable effect on mild cases. All these attempts are less
likely to be effective in moderate or severe cases. Historical advice given to
these patients included reduction of caffeine intake and smoking to reduce
irritability and insomnia. Increased consumption of salt and sugars to satisfy
premenstrual cravings can result in bloating sensation and rapid weight gain (19). Accordingly, these items should be avoided and high fibre food used
Definitive medical treatment
All medical problems, mentioned
before, which may be contributing to the patients’ sufferings should be treated
effectively. Excessive menstrual bleeding and dysmenorrhoea should be addressed
as well, as they add to the patients’ sufferings. Endometriosis is one problem
which can demoralise these patients. Waiting in expectation for premenstrual
and menstrual pain may have a negative impact on the patient’s morale in
anticipation of her periods. Changes in most dimensions of quality of
life were significantly associated with pain as reported by Cox et al in 2007 (20). They also found that role limitation due to emotional
problems and mental health were associated with pain during sexual intercourse
and bladder and bowel function. Furthermore, the repeated sense of
disappointment of having a period by an infertile woman who is keen to conceive
should be taken into consideration. This is especially so with the undue family
pressure endured by women in certain circumstances, and after repeated
unsuccessful infertility treatment attempts. The role of counsellors in such
cases is very important, and patients should be encouraged to see one, despite
the common reluctance shown by many patients.
There is enough evidence to treat
patients with PMDD with one of the many selective serotonin reuptake inhibitors
(SSRIs) available. They have direct effect by improving the brain serotonin deficiency. Few patients may not
be agreeable to use antidepressants, because of the stigma attached to them.
Fluoxetine is the most widely used SSRI for PMDD, in a dose of 20 mg/day. It
can be used continuously during the whole month to start with, before being
restricted to the symptomatic luteal phase of the cycle. This later luteal
phase regimen can be effective for many women as a primary protocol from the
start of medication (21). Fluoxetine
has been found to be more effective in patients suffering mainly from
premenstrual depression and fatigue. Patients suffering from irritability,
anxiety and insomnia are better treated
with sertraline. It is evident that SSRIs are not equally effective in all
aspects of PMDD. Accordingly, changing the brand with another one is indicated
if a patient does not respond to the initial medication. The only tricyclic
antidepressant with any benefit in the treatment of PMDD is clomipramine,
because of its potent serotoninergic activity. An important side effect of
SSRIs is loss of libido, which can be a problem for a patient already suffering
from PMDD. This can worsen what is remaining of her marital relationship. An alternative
line of management should be pursued in these cases, and for patients not
agreeable to use antidepressants.
Despite the fact that PMDD is
related to ovulatory cycles, blocking ovulation with oral contraceptive pills
may not cause significant relieve of symptoms in all cases (22, 23). There is even increased incidence of
headaches, pelvic pain, bloating sensation and breast tenderness during the
hormone free intervals, compared to the 21 days while the pill has been taken (24). This negative effect was attributed
to the progestogen fraction of the pill, irrespective of it chemical type. In
fact one community based study published by Joffe et al in
2003 (25) reported mood deterioration in 16.3% of women
who took the pill. Previous history of depression was found to be the only
significant predictor of this effect in this study (odds ratio, 2.0; 95% CI,
1.1-3.8). Shortening the hormone free period can be of benefit in many cases,
as well as using extended or continuous contraceptive regimens. Contraceptive pills with the progestogen fraction changed to
drospirenone, which is a mild diuretic, have been shown to be effective with both
the physical and psychological symptoms (26, 27). Accordingly, they can be used
as the first line of treatment by willing patients, and those who are seeking
contraception as well. Drospirenone also has antimineralocorticoid effect, and
can counteract oestrogen induced aldosterone production. This can potentially
reduce water retention and weight gain. A further option is to insert a mirena
system, and to use
transdermal oestradiol patches or gel continuously. The mirena system liberates
20 µg of levonorgestrel daily into the uterine cavity, and protects the
endometrium against the sustained effect of continuous oestradiol medication.
It has secondary beneficial effects by reducing menstrual blood loss and
improving dysmenorrhoea, and accordingly the patient’s morale.
Vitamin B6 (pyridoxine) is
another medication which has been used for many years for the treatment of PMS.
Conclusions from published randomised placebo controlled trials were limited by
the low quality of most of those trials (28), but in daily doses of 100 mg it is likely to relieve symptoms related
to PMS and premenstrual depression. Nevertheless, it can
lead to peripheral neuropathy, and patients should be advised to stop taking
it, if they had any peripheral tingling sensation or numbness. The routine use
of diuretics in the management of patients with PMDD or PMS is not indicated. Loss of
salt and water stimulates several hormonal systems to compensate for the changes in sodium and water
balance. This includes the renin-angiotensin-aldosterone system,
vasopressin secretion, and
the sympathetic nervous
system which may have important
clinical implications (29). Rebound fluid retention and weight gain may occur when medication is
stopped. The only exception for a useful diuretic is spironolactone which has been shown to affect
both mood swings and physical signs related to PMS or PMDD (30, 31). This
effect was thought to be related to the steroidal structure of the
spironolactone molecule rather than its diuretic effect (26, 27). This
explains the beneficial effect of oral contraceptive pills
containing drospirenone which is a derivative of spironolactone.
Yasmin (Bayer plc) is one pill with 30 mg ethinyloestradiol and 3 mg drospirenone.
There is also a place for
gonadotrophins releasing hormone (GnRH) analogues in downregulation of the
pituitary gonadotrophs, and reducing the production of gonadotrophins, mainly
LH. This leads to anovulation, and a hypoestrogenic state. Prolonged use of
such medication is not recommended, because of its effect on reducing bone
mineralization. When needed for more than 3-6 months, an add-on medication is
necessary to sustain normal oestrogenisation. This can be offered in the form
of continuous oestrogen and progestogen medication, or in the form of livial (Schering-Plough) which is made of oestrogen, progestogen
and androgens. Another disadvantage of this medication is the expensive cost of
repeated GnRH injections, but it can be used for a short period of time to give
another medication, used in parallel, ample time to take effect.
of specific types of symptoms
It is not unusual for women to present with one or
two specific premenstrual problems in repeated months. Dealing with such
patients is occasionally difficult, but success is very rewarding. It is
usually easier to monitor and rank symptoms when dealing with one or two
problems than in patients presenting with vague unrelated symptoms. In most
cases, relapse can occur if medication is suspended. Occasionally, patients may
be symptomatic during few months only for no obvious reasons. The most common
of these problems are premenstrual breast pain, premenstrual migraine headaches, severe anxiety and insomnia, panic attacks, and severe
The help of a fellow psychiatrist may be needed for
patients presenting with anxiety, depression or panic attacks as
they may be part of genuine psychiatric problems not revealed during the
gynaecological clinic interview, or by the symptoms chart filled by the
patient. Different medications other than SSRIs are available, and the patient
may need to stay on one or more of them for a long period of time, rather than
just premenstrually. Buspiron hydrochloride is a useful drug in cases of
anxiety, especially for patients who developed sexual dysfunction on SSRIs
medication (32). It acts on 5-HT1A
receptors, and it usually takes a couple of weeks before response to treatment
It has been
estimated that about 70% of women affected with PMS present with premenstrual
mastalgia as their main symptom. Breast examination usually reveals no
abnormality, except for extreme tenderness. The inflicted patient may not be
able to wear her usual brassier. Different studies showed no specific endocrine
derangement to account for this presentation, including prolactin estimations.
Similarly, different medications have been tried with different effects
including tocopherol (vitamin E), evening primrose, bromocripine and danazol. Despite its popularity as a prime
medication for this specific problem, evening primrose has generally not shown
significant beneficial effects on PMS or PMDD symptoms in controlled clinical
trials (33). A useful drug in this respect is danazol which can be used in a
small daily dose of 50-100 mg during the luteal phase of the cycle. It should
be avoided in women with hyperandrogenic tendency, but it showed no detrimental
effect in normal women. Similarly, bromocripine proved to be useful in treating
premenstrual mastalgia. Paradoxically, luteal phase medication in a dose of
1.25 mg twice daily proved to be more effective in the management of breast
pain than a similar dose given continuously (34).
Premenstrual migraine headaches may be the only problem a woman
presents with. It is occasionally seen in women taking different brands of oral
contraceptive pills. Stopping the pill may or may not resolve the problem, and
the patient may get disheartened in persistent cases. Ultimately, she will have
MRI and other investigations to exclude brain or other intracranial
pathologies. It is not unusual for migraine headache to be a manifestation of
oestrogen withdrawal in many women. Nevertheless, the initial treatment should
be similar to that provided for migraine occurring at other times during the
cycle. This should include lifestyle modifications, and use of appropriate
therapy to reduce the attack symptoms, its duration and disability (35). Eventually a time contingent therapeutic trial of
oestrogen therapy during the luteal phase and menstruation time can relieve the
headache in many women (36-38). Continuous, but not cyclic, use of combined oral
contraceptives reduces the hormonal fluctuations during the cycle, and can
reduce menstrual migraine attacks frequency. This medication has extra hormonal
effects by acting on associated comorbidities like dysmenorrhoea, menorrhagia and endometriosis. A study by Ferrero et al in 2004
(39) showed that women with endometriosis were
twice at risk of having migraine headaches, and at a younger age than a control
group (38.3% vs. 15.1% respectively). In a different study, Tietjen et al (40) looked at women with migraine as the primary study
group, and reported higher prevalence of endometriosis than in non headache
controls. Furthermore, they showed that women with endometriosis and migraine
had more frequent disabling attacks of migraine than women with migraine but no
endometriosis. Additionally they had more menorrhagia, dysmenorrhoea and
infertility than other patients with migraine only and normal controls.
Nonsteroidal anti inflammatory drugs can be used when oestrogen medication is
contraindicated, and can also help with any coexistent dysmenorrhoea. Acute
attacks may be better controlled by a tryptamine based drug, including
sumatriptan and rizatriptan. They can abort an attack within 30-90 minutes in
the majority of patients, but recurrence of the migraine even within the same
day is a possibility. They act by binding to 5-HT1 receptors in
cranial blood vessels and nerve terminals; hence causing vasoconstriction and
reduce pain. For safety reasons, they should not be used at the same time with
SSRIs. Together they can cause the serotonin syndrome (serotonin toxicity). Patients may present with
nausea, diarrhoea, headache, sweating, muscle twitching, tachycardia, high
blood pressure, hyperthermia, tremors, hyperreflexia, mental confusion, hallucinations,
and might end up in coma (41). The main
treatment strategy in such cases is to stop all serotoninergic medication, and
the syndrome will resolve spontaneously. In more severe cases supportive care
should be provided to the patient as necessary, depending on her symptoms and
Premenstrual dysphoric disorders are disabling
medical problems which can affect the quality of life of up to 9% of
menstruating women. They also increase the risk of major depressive disorders
and postpartum depression. They are an important cause of family disruption,
and should be taken seriously. Patients should be followed prospectively with a
symptoms chart for two months, to make a detailed and proper diagnosis.
Normally the symptoms are present only during the second half of the cycle, and
disappear after the onset of menstruation. Patients with symptoms spilling into
the follicular phase suffer from other psychiatric conditions, which should be
managed within that context. Different medications are available for different
symptoms, and supportive counselling should be offered when necessary. Patients
should also be encouraged to change their life style in relation to healthy
dieting, more exercise, and to avoid smoking, caffeine intake, pure sugars and salt.
There is no evidence that most of the alternative therapies taken by many
patients have any benefit more than a placebo effect. It is important not to
neglect the effects of the comorbidities associated with PMDD, and patients
should be treated within a total multidisciplinary management plan.
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