Diagnosis, pathophysiology and management ofpremenstrual syndromeSally Walsh MBCHB,a,* Elgerta Ismaili MBBS,b Bushra Naheed MBBS DGO,c Shaugn OBrien DSc MD FRCOGd

aFY2, University Hospital North Staffordshire, City General Hospital, Stoke-on-Trent ST4 6QG, UKbSHO, Royal London Hospital, Whitechapel Road, London E1 1BB, UKcPhD student (clinical science), Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent ST4 7QB, UKdProfessor 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 An overview of current information available on premenstrualsyndrome (PMS), which is in accordance with the new RCOG

Green-top Guideline. Definition of PMS and explanation about the different types ofpremenstrual disorders.

How to accurately diagnose PMS. Discussion about various treatment options available inaccordance with the current literature.

Learning objectives Develop an understanding of the pathophysiology behind PMS. How to diagnose PMS accurately and understand the differentclassifications of PMS.

How to treat PMS, including the different treatment optionsavailable and discussion about side effects and benefits.

Ethical issues Discussion about the long-term risks of GnRH analogue use, andthe impact of long-term estrogen deficiency following a

bilateral salpingoophorectomy. Misdiagnosed PMS in patients with underlying psychiatric andmedical conditions.

Keywords: epidemiology / gynaecology / HRT regimens /menopause / pathology / psychiatry

Please cite this paper as: Walsh S, Ismaili E, Naheed B, OBrien S. Diagnosis, pathophysiology and management of premenstrual syndrome. The Obstetrician &

Gynaecologist 2015;17:99104.

Introduction

Premenstrual syndrome (PMS) is defined as a condition with

emotional, physical and behavioural symptoms that increase

in severity during the luteal phase of the menstrual cycle, and

resolve by the end of menstruation. By definition, there must

be a symptom-free interval after menstruation and

before ovulation.1,2

Symptoms are usually up to 14 days before the start of

menses, causing impairment of life, with anger and irritability

being the most severe and longer lasting symptoms.3,4

Studies have shown that 38% of menstruating women areaffected by PMS, and that 1520% of women meet thecriteria for subclinical PMS.5

ClassificationThe International Society for Premenstrual Disorders

(ISPMD) defined precise criteria for diagnosing

premenstrual disorders (PMD), and divided PMS into core

and variant. In all PMD, symptoms should cause impairment

of daily activities at work, social activities and

interpersonal relationships.

Core (or typical) PMD is associated with spontaneous

ovulatory menstrual cycles and may be subdivided into

predominantly physical symptoms, predominantly

psychological or mixed.1,6,7

Women whose symptoms are predominantly psychological

or mixed may also fulfil the criteria for premenstrual

dysphoric disorder.

Variants of PMD encompass more complex features,

divided into the four following categories: premenstrual

exacerbation of an underlying condition; PMS in the absence

of menstruation; progestogen-induced PMS; and PMS with

anovulatory ovarian activity.6,7

For an accurate diagnosis of PMS, symptoms must

occur regularly in ovulating women during the luteal

phase of the cycle, with resolution by the end of

menstruation (Box 1).6

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DOI: 10.1111/tog.12180

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http://onlinetog.org

2015;17:99104 Review

PathologyResearch is yet to find a conclusive pathophysiological

explanation for PMS. Early theories thought there were

abnormalities in ovarian sex steroid levels, however this has

been disproved, as no differences have been demonstrated

between symptomatic and asymptomatic women, and no

study has demonstrated differences in progesterone levels.5,9

It is recognised that aetiology is centred around the ovarian

cycle, and this theory is supported by the lack of symptoms

before puberty, during pregnancy, after menopause, and

during treatment with gonanotrophin-releasing hormone

(GnRH) analogues.

Sex steroids easily pass the bloodbrain barrier, and their

receptors are abundant in many areas of the brain including

the amygdala and hypothalamus.5 It has now been

hypothesised that progesterone is metabolised in the brain

to allopregnanolone and pregnanolone, which stimulates the

gamma-aminobutyric acid (GABA) inhibitory

neurotransmitter system. GABAA receptors are associated

with alterations in mood, cognition, and affect.9

In high concentrations pregnanolone and

allopregnanolone produce anxiolytic, sedative and

anaesthetic effects, however at lower levels allopregnanolone

can cause anxiety, negative mood and aggression. The GABA

receptors become less sensitive to allopregnanolone after

exposure to high concentrations, and hence the worsened

symptoms experienced during the luteal phase.9

Serotonergic activity in the brain is also affected by

estrogen and progesterone. Progesterone increases

monoaimine oxidase (MAO), which decreases the

availability of 5-hydroxytryptamine (5-HT), resulting in a

depressed mood. Whereas estrogen increases the degradation

of MAO, thus increasing the availability of free tryptophan in

the brain, which enhances serotonin transport, and therefore

stimulates 5-HT binding sites in the brain, resulting in an

antidepressant effect.10

Diagnosis

For an accurate diagnosis of PMS, prospective charting of

symptoms over two menstrual cycles is required. The Daily

Record of Severity of Problems (DRSP) is a well-validated

scale used in the diagnosis of PMS (Box 2).11,12 Prospective

documentation should demonstrate a presence of

symptoms during the luteal phase and resolution of

symptoms during menstruation. If there is a discrepancy

over the symptom pattern, then a third cycle of rating

should be carried out.13

The ISPMD first consensus reviewed the diagnostic criteria

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

during the follicular phase, as well accurately recording

symptoms on a symptom chart.

Many patients find conscientious completion of charts

difficult. A new App, PreMentricS is now available (currently

iPhones only [Feb 2015]) which graphically documents

symptoms, provides a diagnosis, and monitors therapy

(Figure 1). It differs from previous charts but has yet to be

scientifically validated.

Patient perspectiveOne woman had been under the care of psychiatrists,

with regular psychiatric admissions premenstrually. Her

diagnoses included bipolar disorder and borderline

personality disorder but PMS was diagnosed through

prospective charting. The womans symptoms were so

persistent (including progestogen-induced PMS when on

estrogen treatment) that she requested a hysterectomy

with bilateral salpingoophorectomy (BSO) at the age of 28

despite not having children. After much debate she

underwent surgery. Post-surgery and estrogen replacement,

the woman commenced a university degree and remained

symptom-free.

A quotation from another woman highlighted how

debilitating PMS can be to social and family life: GnRH

followed by estrogen and Mirena saved my marriage.

Treatment

Management of PMS is usually performed in a step-wise

manner from non-pharmacological strategies, antidepressant

medications, hormonal strategies, with surgical options being

a last resort.

Women should have their symptoms confirmed by

prospective charting, and only when other underlying

medical and psychiatric conditions have been addressed

should treatment be commenced.

Box 1. Criteria for diagnosing core premenstrual disorder6

It is precipitated by ovulation Symptoms are not defined, although typical symptoms exist Any number of symptoms can be present Physical and psychological symptoms are important Symptoms recur in the luteal phase Symptoms disappear by the end of menstruation A symptom-free week occurs between menstruation and ovulation Symptoms must be prospectively rated Symptoms are not an exacerbation of an underlying psychological

or physical disorder Symptoms cause significant distress and impairment of daily

activities, such as work commitments, social interactions andfamily activities.

100 2015 Royal College of Obstetricians and Gynaecologists

An overview of the current management of PMS

Women with presumed PMS should initially be

investigated for other conditions such as depression,

anxiety disorders, and hypothyroidism, with referral to the

appropriate medical specialty, and adequate communication

with their general practitioner. There are links between PMS

and sexual abuse, as well as with post-traumatic stress

disorder, and therefore a full history to assess these aspects

should be obtained.14

Non-pharmacological treatmentA course of cognitive behavioural therapy (CBT) to address

relaxation, stress management, and assertiveness training,

has been reported to be effective in mild PMS, with success

being comparable to treatment with fluoxetine.10 Successful

CBT could avoid the need for pharmacotherapy; studies

have shown a more sustained but less rapid improvement

with the use of selective serotonin reuptake

inhibitors (SSRIs).

Complementary therapiesRigorous research on complementary therapies for the

treatment of PMS is limited, with few well designed

randomised controlled trials. One study on the extract of

the Agnus cactus fruit (Vitex agnus castus) showed

improvement in PMS symptoms in up to 52% of

patients,14 however the trial numbers were small.

Alternative therapies such as exercise, dietary changes and

relaxation may help reduce PMS symptoms, and can improve

general health, but have not been scientifically proven.15,16

AntidepressantsThe use of selective SSRIs, particularly fluoxetine 2060 mg,paroxetine 2030 mg, citalopram 2040 mg and sertraline50150 mg, has shown a substantial reduction in theemotional, behavioural and physical symptoms in the

treatment of core PMD. The short onset of action of SSRIs

in women with PMS, means that SSRIs can be taken 14 days

Box 2. Item content of the Daily Record of Severity ofProblems (DRSP)11

1a. Felt depressed, sad, down, or blue1b. Felt hopeless1c. Felt worthless, or guilty2. Felt anxious, tense, keyed up or on edge3a. Had mood swings (e.g., suddenly felt sad or tearful)3b. Was more sensitive to rejection or my feelings were easily hurt4a. Felt angry, irritable4b. Had conflicts or problems with people5. Had less interest in usual activities (e.g., work, school, friends,

hobbies)6. Had difficulty concentrating7. Felt lethargic, tired, fatigued, or had a lack of energy8a. Had increased appetite or over-ate8b. Had cravings for specific foods9a. Slept more, took naps, found it hard to get up when intended9b. Had trouble getting to sleep or staying asleep

10a. Felt overwhelmed or that I could not cope10b. Felt out of control11a. Had breast tenderness11b. Had breast swelling, felt bloated, or had weight gain11c. Had headache11d. Had joint or muscle pain

At work, at school, at home, or in daily routine, at least one ofthe problems noted above caused reduction of productivityor inefficiency.

At least one of the problems noted above interfered withhobbies or social activities (e.g., avoid or do less).

At least one of the problems noted above interfered withrelationships with others.

Figure 1. Symptom view and diagnosis of woman with typical (core) premenstrual disorder generated by the PreMentricS App (PermissionGranted by PMS OBrien).

2015 Royal College of Obstetricians and Gynaecologists 101

Walsh et al.

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

on randomised control trials which involved SSRIs in the

management of PMS, showed the efficacy of SSRIs compared

to placebo.1823Many studies suggest that intermittent SSRI

use is as effective as continuous use in reducing irritability

and other mood symptoms, but less effective in reducing

somatic symptoms. It is important to note that the European

Medicines Agency agrees that SSRIs seem to work in PMS,

and certain SSRIs are approved in parts of the world (for

example USA for PMDD). However neither the use of

intermittent nor continuous SSRI treatments are licensed in

the UK and when they are used they are off-licence.12,2427

Patients should be informed of side effects including

nausea, fatigue, insomnia and sexual dysfunction, and that

side effects are less with intermittent use.6 Unfortunately

PMS symptoms recur following discontinuation of SSRIs.38

There can be significant effects if used during the course of

pregnancy even if this is only the initial stages. Women who

have failed two or more SSRI trials should probably try

hormonal treatment.19

The ISPMD second consensus further supports the use of

SSRIs,10 and within the second consensus it was found that

SSRI use as a first-line treatment was the most important

recommendation in the management of PMS, as well as

highlighting the importance of explaining the side effects

associated with the use of SSRIs. In practice this means that a

diagnosis should be accurately ascertained and a systematic

approach to the management of starting with SSRIs should

be utilised.

EstrogenEstrogen therapy which inhibits ovulation has been proposed

as a method for management in PMS.28,29 Estrogen is usually

administered as a transdermal patch, or subcutaneous

implant,29 and is an effective agent in the treatment of

PMS. Transdermal patches are more readily available within

the UK, and hence are a frequent choice compared to the

implant. Receiving unopposed estrogen will require

progestogen cover to prevent endometrial hyperplasia,

unless the woman has had a hysterectomy. Progesterone

itself can cause PMS like symptoms, and therefore the lowest

dose possible, for the shortest time is recommended. The side

effects from synthetic progestins can be minimised through

the use of micronised progesterone, which is identical to that

produced by the corpus luteum.30 Alternatively

administration of progesterone directly to the endometrium

using the levonorgestrel-containing intrauterine system may

reduce recurrence of progesterone-induced PMS symptoms

in the long term. A few months after insertion there are

minimal systemic levels of progesterone. Although

excellent endometrial protection is provided, patients

should be advised that initially PMS like symptoms

may occur.12,29

Oral contraceptivesNewer oral contraceptives containing drospirenone 3 mg and

ethinyl estradiol 20 micrograms have shown a positive

improvement in PMS symptoms, when hormones were

administered for 24 days, followed by 4 days of inactive pills,

compared to placebo.3234 However, due to the increased risk

of venous thromboembolism, this group of medication is not

suitable for all women. Unfortunately although this

treatment is licensed in the USA for PMS it is not

in the UK.34

No benefit has been found through the use of progesterone

alone additionally the older combined oral contraceptivepills appear to have no benefit in the treatment of PMS.35,36

Gonadotropin-releasing hormone (GnRH) analoguesLong-acting GnRH analogues suppress ovarian functioning,

reducing the levels of estradiol and progesterone, and

subsequently inhibit the menstrual cycle. Several

randomised controlled trials have demonstrated

improvement of premenstrual symptoms, with a response

rate to GnRH analogue treatment between 60% and 75%. A

meta-analysis concluded that, compared to placebo,

treatment with GnRH analogues resulted in significant

symptom relief in behavioural and physical

PMS symptoms.12,37

Although GnRH analogues seem like a good long-term

option for patients with severe PMS, they induce a hypo-

estrogenic state and eliminate ovulation.6 In the short term

this results in hot flushes, night sweats, low mood and

insomnia. More importantly, in the long term, risks of this

estrogen deficiency include vaginal atrophy, increased

cardiovascular risk and osteoporosis.6,12 Because of these

long-term risks, treatment without addback therapy shouldonly be continued for 6 months. If women are receiving

addback therapy on a long-term basis, they should haveassessment of bone mineral density. Although hormone

replacement therapy can be administered to reduce the effects

of estrogen deficiency, this in itself can re-stimulate PMS

like symptoms.

Due to the long-term risks of GnRH analogue use, they

should be reserved for women with the most severe

symptoms, or where other treatments have failed. In those

who fail to respond to GnRH analogues then the diagnosis of

PMS should be questioned.

Hysterectomy and bilateral salpingo-oophorectomy(BSO)Surgical options should be considered only as a last resort,

and a trial of GnRH with positive effect is advisable before

deciding to perform BSO and hysterectomy.

Hysterectomy with BSO has a beneficial effect on both

mood and physical symptoms. Oophorectomy alone would

stop PMS symptoms, but hysterectomy is required to ensure

102 2015 Royal College of Obstetricians and Gynaecologists

An overview of the current management of PMS

estrogen replacement post-surgery can be unopposed

without the risk of endometrial hyperplasia, and thus

prevent the PMS side effects associated with progestogens.

Success rates of hysterectomy with BSO are high and long-

lasting, and now surgical intervention can usually be

performed laparoscopically, it is less invasive than

previously.38,39 It is important to remember that all surgical

procedures carry an anaesthetic risk, as well as the risk of

surgical complications. Surgery undertaken for a mood

disorder is unique to PMS management.

Surgery will render the woman infertile and induces the

menopause. Estrogen replacement therapy should be

commenced post-surgery to prevent the effects of

long-term estrogen deficiency, and should be continued

until the age when menopause naturally occurs.12

Importantly of course is the absence of endometrium, the

estrogen can be administered without the requirement for

protective progestogen

Ongoing assessment

It is important to remember that if a woman has not

responded to more than one pharmacological treatment, they

should be reassessed for potential underlying psychiatric or

medical disorders, therefore highlighting the importance of

regular patient review following initiation of treatment.

Contribution of authorshipSW: extensive literature search around the topic, and

significant contribution to the writing of the main article,

as well as referencing, and creation of several of the CPD

questions. EI: creation of several of the CPD questions,

appraisal of the article content and construction of the

abstract. BN: contribution into the design of the article, with

contribution in to the content and critical appraisal of the

overall article, as well as creation of several CPD questions.

SO: clinical supervisor who came up with the proposed idea

for the paper, with significant input in to the formatting

and content.

Disclosure of interestsNone

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