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DOI: 10.1111/tog.

12180 2015;17:99–104
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Diagnosis, pathophysiology and management of


premenstrual syndrome
a, b c d
Sally Walsh MBCHB, * Elgerta Ismaili MBBS, Bushra Naheed MBBS DGO, Shaugn O’Brien DSc MD FRCOG
a
FY2, University Hospital North Staffordshire, City General Hospital, Stoke-on-Trent ST4 6QG, UK
b
SHO, Royal London Hospital, Whitechapel Road, London E1 1BB, UK
c
PhD student (clinical science), Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent ST4 7QB, UK
d
Professor of Obstetrics and Gynaecology, Keele University School of Medicine, Clinical Director Obstetrics and Gynaecology and Consultant
Obstetrician and Gynaecologist University Hospital North Staffordshire NHS Trust, City General Hospital, Newcastle Road, Stoke-on-Trent ST4
6QG, UK
*Correspondence: Sally Walsh. Email: sally.walsh@uhns.nhs.uk

Accepted on 28 January 2015

Key content  How to treat PMS, including the different treatment options
 An overview of current information available on premenstrual available and discussion about side effects and benefits.
syndrome (PMS), which is in accordance with the new RCOG
Ethical issues
Green-top Guideline. 
 Definition of PMS and explanation about the different types of
Discussion about the long-term risks of GnRH analogue use, and
the impact of long-term estrogen deficiency following a
premenstrual disorders.
 How to accurately diagnose PMS.
bilateral salpingoophorectomy.
 Misdiagnosed PMS in patients with underlying psychiatric and
 Discussion about various treatment options available in
medical conditions.
accordance with the current literature.
Keywords: epidemiology / gynaecology / HRT regimens /
Learning objectives

menopause / pathology / psychiatry
Develop an understanding of the pathophysiology behind PMS.
 How to diagnose PMS accurately and understand the different
classifications of PMS.

Please cite this paper as: Walsh S, Ismaili E, Naheed B, O’Brien S. Diagnosis, pathophysiology and management of premenstrual syndrome. The Obstetrician &
Gynaecologist 2015;17:99–104.

Introduction and variant. In all PMD, symptoms should cause impairment


of daily activities at work, social activities and
Premenstrual syndrome (PMS) is defined as a condition with interpersonal relationships.
emotional, physical and behavioural symptoms that increase Core (or typical) PMD is associated with spontaneous
in severity during the luteal phase of the menstrual cycle, and ovulatory menstrual cycles and may be subdivided into
resolve by the end of menstruation. By definition, there must predominantly physical symptoms, predominantly
be a symptom-free interval after menstruation and psychological or mixed.1,6,7
before ovulation.1,2 Women whose symptoms are predominantly psychological
Symptoms are usually up to 14 days before the start of or mixed may also fulfil the criteria for premenstrual
menses, causing impairment of life, with anger and irritability dysphoric disorder.
being the most severe and longer lasting symptoms.3,4 Variants of PMD encompass more complex features,
Studies have shown that 3–8% of menstruating women are divided into the four following categories: premenstrual
affected by PMS, and that 15–20% of women meet the exacerbation of an underlying condition; PMS in the absence
criteria for subclinical PMS.5 of menstruation; progestogen-induced PMS; and PMS with
anovulatory ovarian activity.6,7
Classification For an accurate diagnosis of PMS, symptoms must
The International Society for Premenstrual Disorders occur regularly in ovulating women during the luteal
(ISPMD) defined precise criteria for diagnosing phase of the cycle, with resolution by the end of
premenstrual disorders (PMD), and divided PMS into core menstruation (Box 1).6

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An overview of the current management of PMS

Box 1. Criteria for diagnosing core premenstrual disorder6


Diagnosis
For an accurate diagnosis of PMS, prospective charting of
 It is precipitated by ovulation symptoms over two menstrual cycles is required. The Daily
 Symptoms are not defined, although typical symptoms exist
 Any number of symptoms can be present Record of Severity of Problems (DRSP) is a well-validated
 Physical and psychological symptoms are important scale used in the diagnosis of PMS (Box 2).11,12 Prospective
 Symptoms recur in the luteal phase documentation should demonstrate a presence of
 Symptoms disappear by the end of menstruation
symptoms during the luteal phase and resolution of
 A symptom-free week occurs between menstruation and ovulation
 Symptoms must be prospectively rated symptoms during menstruation. If there is a discrepancy
 Symptoms are not an exacerbation of an underlying psychological over the symptom pattern, then a third cycle of rating
or physical disorder should be carried out.13
 Symptoms cause significant distress and impairment of daily
The ISPMD first consensus reviewed the diagnostic criteria
activities, such as work commitments, social interactions and
family activities. for PMS.1 It highlighted the importance of an accurate
history of symptoms, which should be recorded for a
minimum of 2 months, as stated above. The symptoms
should be present during the premenstrual phase and absent
Pathology during the follicular phase, as well accurately recording
Research is yet to find a conclusive pathophysiological symptoms on a symptom chart.
explanation for PMS. Early theories thought there were Many patients find conscientious completion of charts
abnormalities in ovarian sex steroid levels, however this has difficult. A new App, PreMentricS is now available (currently
been disproved, as no differences have been demonstrated iPhones only [Feb 2015]) which graphically documents
between symptomatic and asymptomatic women, and no symptoms, provides a diagnosis, and monitors therapy
study has demonstrated differences in progesterone levels.5,9 (Figure 1). It differs from previous charts but has yet to be
It is recognised that aetiology is centred around the ovarian scientifically validated.
cycle, and this theory is supported by the lack of symptoms
before puberty, during pregnancy, after menopause, and Patient perspective
during treatment with gonanotrophin-releasing hormone One woman had been under the care of psychiatrists,
(GnRH) analogues. with regular psychiatric admissions premenstrually. Her
Sex steroids easily pass the blood–brain barrier, and their diagnoses included bipolar disorder and borderline
receptors are abundant in many areas of the brain including personality disorder but PMS was diagnosed through
the amygdala and hypothalamus.5 It has now been prospective charting. The woman’s symptoms were so
hypothesised that progesterone is metabolised in the brain persistent (including progestogen-induced PMS when on
to allopregnanolone and pregnanolone, which stimulates the estrogen treatment) that she requested a hysterectomy
gamma-aminobutyric acid (GABA) inhibitory with bilateral salpingoophorectomy (BSO) at the age of 28
neurotransmitter system. GABAA receptors are associated despite not having children. After much debate she
with alterations in mood, cognition, and affect.9 underwent surgery. Post-surgery and estrogen replacement,
In high concentrations pregnanolone and the woman commenced a university degree and remained
allopregnanolone produce anxiolytic, sedative and symptom-free.
anaesthetic effects, however at lower levels allopregnanolone A quotation from another woman highlighted how
can cause anxiety, negative mood and aggression. The GABA debilitating PMS can be to social and family life: “GnRH
receptors become less sensitive to allopregnanolone after followed by estrogen and Mirena saved my marriage”.
exposure to high concentrations, and hence the worsened
symptoms experienced during the luteal phase.9 Treatment
Serotonergic activity in the brain is also affected by
estrogen and progesterone. Progesterone increases Management of PMS is usually performed in a step-wise
monoaimine oxidase (MAO), which decreases the manner from non-pharmacological strategies, antidepressant
availability of 5-hydroxytryptamine (5-HT), resulting in a medications, hormonal strategies, with surgical options being
depressed mood. Whereas estrogen increases the degradation a last resort.
of MAO, thus increasing the availability of free tryptophan in Women should have their symptoms confirmed by
the brain, which enhances serotonin transport, and therefore prospective charting, and only when other underlying
stimulates 5-HT binding sites in the brain, resulting in an medical and psychiatric conditions have been addressed
antidepressant effect.10 should treatment be commenced.

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Walsh et al.

with their general practitioner. There are links between PMS


Box 2. Item content of the Daily Record of Severity of and sexual abuse, as well as with post-traumatic stress
Problems (DRSP)11 disorder, and therefore a full history to assess these aspects
should be obtained.14
1a. Felt depressed, sad, ‘down,’ or ‘blue’
1b. Felt hopeless
1c. Felt worthless, or guilty Non-pharmacological treatment
2. Felt anxious, tense, ‘keyed up’ or ‘on edge’ A course of cognitive behavioural therapy (CBT) to address
3a. Had mood swings (e.g., suddenly felt sad or tearful) relaxation, stress management, and assertiveness training,
3b. Was more sensitive to rejection or my feelings were easily hurt
4a. Felt angry, irritable has been reported to be effective in mild PMS, with success
4b. Had conflicts or problems with people being comparable to treatment with fluoxetine.10 Successful
5. Had less interest in usual activities (e.g., work, school, friends, CBT could avoid the need for pharmacotherapy; studies
hobbies)
have shown a more sustained but less rapid improvement
6. Had difficulty concentrating
7. Felt lethargic, tired, fatigued, or had a lack of energy with the use of selective serotonin reuptake
8a. Had increased appetite or over-ate inhibitors (SSRIs).
8b. Had cravings for specific foods
9a. Slept more, took naps, found it hard to get up when intended
9b. Had trouble getting to sleep or staying asleep
Complementary therapies
10a. Felt overwhelmed or that I could not cope Rigorous research on complementary therapies for the
10b. Felt out of control treatment of PMS is limited, with few well designed
11a. Had breast tenderness randomised controlled trials. One study on the extract of
11b. Had breast swelling, felt ‘bloated’, or had weight gain
11c. Had headache
the Agnus cactus fruit (Vitex agnus castus) showed
11d. Had joint or muscle pain improvement in PMS symptoms in up to 52% of
patients,14 however the trial numbers were small.
• At work, at school, at home, or in daily routine, at least one of
the problems noted above caused reduction of productivity Alternative therapies such as exercise, dietary changes and
or inefficiency. relaxation may help reduce PMS symptoms, and can improve
• At least one of the problems noted above interfered with general health, but have not been scientifically proven.15,16
hobbies or social activities (e.g., avoid or do less).
• At least one of the problems noted above interfered with
relationships with others. Antidepressants
The use of selective SSRIs, particularly fluoxetine 20–60 mg,
paroxetine 20–30 mg, citalopram 20–40 mg and sertraline
Women with presumed PMS should initially be 50–150 mg, has shown a substantial reduction in the
investigated for other conditions such as depression, emotional, behavioural and physical symptoms in the
anxiety disorders, and hypothyroidism, with referral to the treatment of core PMD. The short onset of action of SSRIs
appropriate medical specialty, and adequate communication in women with PMS, means that SSRIs can be taken 14 days

Figure 1. Symptom view and diagnosis of woman with typical (core) premenstrual disorder generated by the PreMentricS App (Permission
Granted by PMS O’Brien).

ª 2015 Royal College of Obstetricians and Gynaecologists 101


An overview of the current management of PMS

before menses, as well as continuously.12,14 A meta-analysis Oral contraceptives


on randomised control trials which involved SSRIs in the Newer oral contraceptives containing drospirenone 3 mg and
management of PMS, showed the efficacy of SSRIs compared ethinyl estradiol 20 micrograms have shown a positive
to placebo.18–23Many studies suggest that intermittent SSRI improvement in PMS symptoms, when hormones were
use is as effective as continuous use in reducing irritability administered for 24 days, followed by 4 days of inactive pills,
and other mood symptoms, but less effective in reducing compared to placebo.32–34 However, due to the increased risk
somatic symptoms. It is important to note that the European of venous thromboembolism, this group of medication is not
Medicines Agency agrees that SSRIs seem to work in PMS, suitable for all women. Unfortunately although this
and certain SSRIs are approved in parts of the world (for treatment is licensed in the USA for PMS it is not
example USA for PMDD). However neither the use of in the UK.34
intermittent nor continuous SSRI treatments are licensed in No benefit has been found through the use of progesterone
the UK and when they are used they are off-licence.12,24–27 alone – additionally the older combined oral contraceptive
Patients should be informed of side effects including pills appear to have no benefit in the treatment of PMS.35,36
nausea, fatigue, insomnia and sexual dysfunction, and that
side effects are less with intermittent use.6 Unfortunately Gonadotropin-releasing hormone (GnRH) analogues
PMS symptoms recur following discontinuation of SSRIs.38 Long-acting GnRH analogues suppress ovarian functioning,
There can be significant effects if used during the course of reducing the levels of estradiol and progesterone, and
pregnancy even if this is only the initial stages. Women who subsequently inhibit the menstrual cycle. Several
have failed two or more SSRI trials should probably try randomised controlled trials have demonstrated
hormonal treatment.19 improvement of premenstrual symptoms, with a response
The ISPMD second consensus further supports the use of rate to GnRH analogue treatment between 60% and 75%. A
SSRIs,10 and within the second consensus it was found that meta-analysis concluded that, compared to placebo,
SSRI use as a first-line treatment was the most important treatment with GnRH analogues resulted in significant
recommendation in the management of PMS, as well as symptom relief in behavioural and physical
highlighting the importance of explaining the side effects PMS symptoms.12,37
associated with the use of SSRIs. In practice this means that a Although GnRH analogues seem like a good long-term
diagnosis should be accurately ascertained and a systematic option for patients with severe PMS, they induce a hypo-
approach to the management of starting with SSRIs should estrogenic state and eliminate ovulation.6 In the short term
be utilised. this results in hot flushes, night sweats, low mood and
insomnia. More importantly, in the long term, risks of this
Estrogen estrogen deficiency include vaginal atrophy, increased
Estrogen therapy which inhibits ovulation has been proposed cardiovascular risk and osteoporosis.6,12 Because of these
as a method for management in PMS.28,29 Estrogen is usually long-term risks, treatment without add–back therapy should
administered as a transdermal patch, or subcutaneous only be continued for 6 months. If women are receiving
implant,29 and is an effective agent in the treatment of add–back therapy on a long-term basis, they should have
PMS. Transdermal patches are more readily available within assessment of bone mineral density. Although hormone
the UK, and hence are a frequent choice compared to the replacement therapy can be administered to reduce the effects
implant. Receiving unopposed estrogen will require of estrogen deficiency, this in itself can re-stimulate PMS
progestogen cover to prevent endometrial hyperplasia, like symptoms.
unless the woman has had a hysterectomy. Progesterone Due to the long-term risks of GnRH analogue use, they
itself can cause PMS like symptoms, and therefore the lowest should be reserved for women with the most severe
dose possible, for the shortest time is recommended. The side symptoms, or where other treatments have failed. In those
effects from synthetic progestins can be minimised through who fail to respond to GnRH analogues then the diagnosis of
the use of micronised progesterone, which is identical to that PMS should be questioned.
produced by the corpus luteum.30 Alternatively
administration of progesterone directly to the endometrium Hysterectomy and bilateral salpingo-oophorectomy
using the levonorgestrel-containing intrauterine system may (BSO)
reduce recurrence of progesterone-induced PMS symptoms Surgical options should be considered only as a last resort,
in the long term. A few months after insertion there are and a trial of GnRH with positive effect is advisable before
minimal systemic levels of progesterone. Although deciding to perform BSO and hysterectomy.
excellent endometrial protection is provided, patients Hysterectomy with BSO has a beneficial effect on both
should be advised that initially PMS like symptoms mood and physical symptoms. Oophorectomy alone would
may occur.12,29 stop PMS symptoms, but hysterectomy is required to ensure

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Walsh et al.

estrogen replacement post-surgery can be unopposed 4 Pearlstein T, Yonkers KA, Fayyad R, Gillespie JA. Pretreatment pattern of
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lasting, and now surgical intervention can usually be the International Society for Premenstrual Disorders. Menopause Int
performed laparoscopically, it is less invasive than 2012;18:43–7.
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significant contribution to the writing of the main article, 17 Royal College of Obstetricians and Gynaecologists. Premenstrual syndrome,
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None blind, placebo-controlled trial. Psychosom Med 2004;66:707–13.
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