Best Practice & Research Clinical Endocrinology & Metabolism 38 (2024) 101858

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Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Premenstrual disorders and PMDD - a review

Emily Cary (Honorary Senior Lecturer) , Paul Simpson a,⁎
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⁎
(Consultant Gynaecologist)b,
a
GP Mattishall Surgery, 15 Dereham Road, Mattishall, East Dereham, Norfolk NR20 3QA, United Kingdom
b
Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, United Kingdom

a r t i cl e i nfo
Defining, diagnosing and managing premenstrual disorders (PMDs)
Article history: remains a challenge both for general practitioners and specialists. Yet
Available online 28 December 2023 these disorders are common and can have an enormous impact on
women. PMDD (premenstrual dysphoric disorder), one severe form
Keywords: of PMD, has a functional impact similar to major depression yet re­
premenstrual disorder mains under-recognised and poorly treated. The aim of this chapter
premenstrual dysphoric disorder is to give some clarity to this area, provide a framework for non-
luteal phase specialists to work towards, and to stress the importance of MDT care
impact
for severe PMDs, including PMDD.
prospective
© 2024 The Authors. Published by Elsevier Ltd. This is an open access
rating scale
allopregnanolone article under the CC BY-NC-ND license (http://creativecommons.org/
hormonal licenses/by-nc-nd/4.0/).
consensus

Introduction

Premenstrual symptoms have been recognised since Hippocrates in 370AD when menstrual bleeding
was thought to purge melancholic and choleric humors [1]. They occur to some degree in most women

Abbreviations: PMD, premenstrual disorder; PMDD, premenstrual dysphoric disorder; MDT, multi-disciplinary team; PMT,
premenstrual tension; PMS, premenstrual syndrome; ICD, international classification of diseases; PMTS, premenstrual tension
syndrome; DSM, diagnostic and statistical manual of mental diseases; ISPMD, International Society for Premenstrual Disorders;
HR-QOL, health related quality of life; PME, premenstrual exacerbation; DRSP, The Daily Record of Severity of Problems; IAPMS,
International Association of Premenstrual Disorders; CBT, cognitive behavioural therapy; RCT, randomised controlled trial; SSRI,
selective serotonin reuptake inhibitor; FDA, US Food and Drug Administration; NICE, National Institute for Health and Care
Excellence; COCP, combined oral contraceptive pill; EE, ethinylestradiol; DRSP, drospirenone; FRSH, Faculty of Sexual and
Reproductive Healthcare; GNRH, Gonadotrophin-releasing hormone
⁎
Corresponding authors.
E-mail addresses: emilycary@nhs.net (E. Cary), paul.simpson@nnuh.nhs.uk (P. Simpson).

https://doi.org/10.1016/j.beem.2023.101858
1521-690X/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
E. Cary and P. Simpson Best Practice & Research Clinical Endocrinology & Metabolism 38 (2024) 101858

which has led to hypotheses about past evolutionary benefit. One theory is that for our hunter-gatherer
ancestors PMDs would have conferred a selective advantage; by encouraging males to seek out a more
receptive (and possibly less aggressive) ovulating female the likelihood of productive mating would have
been increased [2]. But what was once perhaps adaptive is now clearly maladaptive for modern women.
Severe premenstrual disorders, including PMDD, which is the main focus of this review, have an en­
ormous impact women’s physical, psychological, social and economic wellbeing. Despite an explosion of
research into PMDs many women are still not being diagnosed accurately and so are not accessing the
support and treatment they need.

Definition and nomenclature

The nomenclature around premenstrual symptoms can be confusing. In lay-speak the terms
Premenstrual Tension (PMT) and Premenstrual Syndrome (PMS) have been widely adopted to cover all
premenstrual symptoms, often being used interchangeably and without regard for severity and impact.
Looking back ‘menstrual moodiness’ was a term coined in the 18th century, and there is also the old-
fashioned term ‘molimina’ referring to common and often non-bothersome symptoms (most frequently
breast tenderness, bloating, constipation) that many women experience before menstruation. The first
formal medical description of Premenstrual Tension ‘PMT’ was made by the American gynaecologist
Frank in 1931 [3] who recognised clustering of more severe emotional premenstrual symptoms. The term
Premenstrual Syndrome (PMS) was coined in 1953 after Greene and Dalton argued that premenstrual
symptoms were far more extensive than just ‘nervous tension’ [4]. In current medical practice the terms
PMS and PMD are both commonly used, with syndrome and disorder used both to de-emphasise the
psychological focus of tension but also to convey impact of symptoms on functioning. Different pro­
fessional bodies however do not use the terms uniformly; the International Association of PMD [5] uses
PMD, the Royal College of Obstetrics and Gynaecology in the UK uses PMS, and ICD uses Premenstrual
Tension Syndrome (PMTS). PMDD has also been known as late-luteal dysphoric disorder. For the re­
mainder of this work, we will use PMD and PMDD.

Prevalence

It is hardly surprising that the prevalence of premenstrual symptoms depends on the definition and
criteria used to define them. Worldwide there seems to be consistency in findings that around 90% of
women experience at least one premenstrual symptom. [6,7]. When limited to look for PMD with an
impact on daily functioning, prevalence falls to between 20–40% [8]. Tightening criteria further to look
for PMDD, using the DSM-V criteria that we will outline later in this review, reduces the prevalence even
further to around 5% [9-11].

Classification (ISPMD consensus)

Despite the very long history of women struggling with premenstrual disorders, universally accepted
criteria for diagnosis and classification of PMDs are a relatively new development. In 2008, an inter­
national multidisciplinary group of experts established as the International Society for Premenstrual
Disorders (ISPMD), convened with the primary aim of providing a unified approach to diagnosis and
management. They produced a classification that was far more comprehensive and inclusive than pre­
vious attempts [5].
The ISPMD classification (Table 1) focuses on the timing rather than the nature of symptoms and
emphasises impact and quality of life. PMDs are divided into ‘Core PMD’, associated with spontaneous
ovulatory cycles, and ‘Variants of PMD’. Core PMD is both more common and more frequently recognised
[12] and can be further categorised into (a) predominantly physical, (b) predominantly emotional and (c)
mixed. It is the proportion of women with severe Core-PMD, subsets (b) and (c) who fulfil the diagnostic
criteria for PMDD, and are the main focus of this review. It must be remembered that non-PMDD severe
PMD can also be devastating in its impact and also deserves careful consideration.

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ISPMD classification.
Table 1

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DSM-V criteria for diagnosis PMDD
Box 1

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DSM-V symptoms of PMDD
Box 2

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Fig. 1. - PMDD diagnostic pathway.

PMDD – definition and classification

It is only in the last decade that PMDD has become clearly defined and included as a distinct diagnosis
in the main body of the two classificatory systems of disease used on both sides of the Atlantic. These
were landmark decisions and warrant explanation.
In 2013, the American Psychiatric Association upgraded PMDD to an official ‘stand-alone’ diagnosis in
the depressive disorders chapter of the Diagnostic and Statistical Manual of Mental Disorders (DSM- V)
[13]. Then in 2019, the World Health Association included PMDD as a distinct disease with its own
classification code GA34.41 in the 11th version of the International Statistical Classification of Diseases
(ICD-11) with the primary location under genitourinary diseases but cross listed in depressive disorders
[14]. The previous DSM-IV, published in 2000, had included PMDD only as a provisional diagnostic ca­
tegory in the appendix [15], and in the previous ICD-10 PMDD, it had been mentioned only indirectly as a
sub-classification under ‘Premenstrual tension syndrome’ [16].
These decisions both proved controversial. On the one hand the DSM-V upgrade was strongly ad­
vocated by patients, psychiatrists and the pharmaceutical industry [17] and was heralded as a break­
through for women’s health [6]. On the other hand, it was criticized by psychologists and generalists
fearing over diagnosis and pathologizing of normal hormonal changes. The disparity in opinions re­
garding introduction of PMDD into ICD-11 were broadly along the same lines, with additional fears that
the agenda had been pushed by pharmaceutical companies for their own gain [18]. What is not in doubt
is that the combined impact of these two decisions has led to an explosion of interest, research and
funding in the last ten years. And that the disparity between placement of PMDD as depressive condition
in DSM-V and primarily a gynaecological condition in ICD-11 has stressed the importance of MDT
management of these women.

Impact

By definition, PMDD needs to have a significant impact on functioning and quality of life. Studies have
confirmed this impact on HR-QOL, hobbies and social activities, and relationships with others [19,20].

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The IAPMD website says that more than 15% of PMDD sufferers will attempt suicide at least once. This
is backed up by a 2021 systematic review and metanalysis which suggested PMDD is a strong risk factor
for suicide attempt and ideation, increasing the likelihood by seven and four-fold, respectively [21].
Osborne’s systematic review similarly concluded that women with PMDD should be considered a high
risk for suicidality [22]. Loss of impulse control and impaired interpersonal functioning are likely to
contribute to the vulnerability to suicide of women with PMDD.

Diagnosis

The key to effective management of PMDD and other PMDs is to achieve a precise diagnosis (with
DSM-V criteria (Boxes 1 and 2) as the benchmark for PMDD) using a prospective rating scale over at least
2 consecutive cycles [5]. This is to confirm:

– cyclicity with relation to luteal phase

– relief of symptoms after onset of menstruation with symptom free period
– impact on daily functioning

Although a presumptive diagnosis of PMDD can be made based upon retrospective history alone this
is subject to recall bias.
If there is discrepancy in symptoms between the two cycles, then a third cycle of rating should be
completed [5]. Cyclicity of symptoms is paramount, and prospective rating is invaluable in ruling out
premenstrual exacerbation of other psychiatric disorders that are present (to some extent) throughout
the menstrual cycle (PME) and non-cyclical disorders.
The Daily Record of Severity of Problems (DRSP) is the most widely used prospective rating tool and
was developed to screen for DSM PMDD criteria. This tool is reliable, validated [23] and easily down­
loaded from IAMPS. Some women prefer to use digital monitoring and the Me v PMDD App is available
on Apple and android phones.
Although a detailed history from the patient is usually enough to make the decision to start the
patient on prospective symptom tracking, some clinicians like to use a screening tool before starting this.
IAMPD https://iapmd.org/self-screen or Premenstrual Screening Tool (Steiner) are both suitable op­
tions here.
Studies have shown that, though crucial to accurate diagnosis, prospective rating scales are often not
carried out in practice. Women are often desperate for help by the time they reach a physician with
awareness of PMDD, and two cycles of prospective symptoms tracking might seem an arduous task for
both patient and physician. Two surveys in USA and Japan in 2014 and 2023 showed that two full
prospective rating scores were used in only 11.9% [24] and 8.4% [25] of diagnoses of PMDD. For some
women with extreme distress or suicidal ideation two months may not be possible before starting
treatment. However, in such circumstances, daily rating scores have also been validated to show a re­
sponse to treatment and it is likely any cyclicity will still be apparent, even on treatment.

Fig. 2. - Aetiology of PMDD.

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Fig. 3. Treatment pathway

Adapted from Briggs [6] and GreenTOP [12].

Distinguishing PMDD from PME seems to cause the most diagnostic difficulty in PMDD. Many pri­
mary mood and anxiety disorders can overlap with PMDD, as can unstable emotional personality and
trauma related disorders. In women with any mental health disorder the late luteal phase is a vulnerable
time and symptoms which might and bearable and manageable at other times of the month may well be
destabilised. The key here is that there should be a symptom free internal after menstruation where
symptoms are minimal or absent. If this is not there or is very brief, treatment should be considered for
the underlying disorder while continuing symptom tracking.
Other medical conditions can mimic some of the symptoms of PMDD and a milder PMD may worsen
the impact of these conditions in the luteal phase. These disorders are worth bearing in mind and include
chronic fatigue, fibromyalgia, autoimmune conditions and thyroid dysfunction.
Another complexity is those patients in which the cycle length is not ‘standard’. Descriptions of the
symptom free week are based on 28-day cycles with a 14-day luteal phase. For women with shorter cycle
lengths there may only be a couple of symptom free days. It is also becoming apparent that PMDD is an
umbrella term for various subsets of PMDD, for example there are a subgroup of woman with PMDD
whose symptoms start a few days AFTER menstruation is complete.
Sometimes when the diagnosis is in doubt a pragmatic trial of full ovarian suppression with GNRH
analogies is a helpful strategy, this will be discussed further in the treatment section. Emerging evidence
highlights the possibility of distinct subtypes of PMDD with unique pathophysiological bases, but
temporal subgroups have yet to be explored in a systematic way.

Aetiology

The precise aetiology of PMDD and other PMDs is an area of active research. The influence of luteal
phase hormonal fluctuations is not in doubt – these conditions do not occur before menarche, during
pregnancy or after menopause. Women with PMDD cannot be distinguished from asymptomatic women
in terms of peripheral ovarian hormone levels [26] so it is not hormonal fluctuations per se that are
responsible for PMDD symptoms but the women’s response to them. Simply put, PMDD is an abnormal
brain response to normal menstrual hormonal fluctuations.
The biological mechanism for this heightened sensitivity to physiological hormone changes is an area
of ongoing interest and seems to be multifactorial. Overlapping genetic and environmental factors seem
to feed into a state of neurobiological vulnerability.

– Genetics - PMDD is thought to have a high heritability between 30-80% [13]. Huo et al. found a single
gene polymorphism in the estrogen receptor alpha (ESR1 gene) and speculated that this may confer

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differential sensitivity to hormones in women with PMDD [27]. Studies are also being carried out on
serotonin gene polymorphism and serotonin transporter genotype.
– Dysregulation in the serotonergic system - is one plausible neurobiological cause for PMDD. A PET study
found that serotonin 1 A receptor (5-HT1A) availability in the brainstem increases in the late luteal
phase in controls but not individuals with PMDD [28]. This helps explain the effectiveness of SSRIs in
managing PMDD.
– Allopregnanolone - There has been intense interest in recent years in the role of the main neuroactive
metabolite of progestogen, allopregnanolone (ALLO), in the aetiology of PMDD. Progesterone is
converted to allopregnanolone via 3-and-5 alpha-reductase enzymes. ALLO acts as a neuromodulator
at GABA-A receptors which are mainly found in the amygdala where they help regulate emotional
responses. ALLO modulation of GABA-A receptors usually has an anxiolytic, mood enhancing effect. In
PMDD ALLO appears to have a paradoxical effect on GABA-A receptors [29] producing negative rather
than positive mood symptoms at endogenous luteal phase levels. This is felt to be due to plasticity of
the GABA-A receptors [30].
– Stress and Inflammation – A history of stress and trauma exposure has also been implicated in the
aetiology of PMDD [6,31]. A study of almost 4000 women found that trauma and PTSD were in­
dependently associated with PMDD [32]. Another study of approximately 3000 women found a
strong correlation between physical and emotional abuse and moderate to severe PMS/PMDD [33].
The mechanism linking stress and PMDD remains unclear but may involve allopregnanolone. As well
as stress, inflammation is thought to be another predisposing factor to PMDD. The luteal phase has
been shown to be a pro-inflammatory state [34,35], and one study has shown a relative increase in
inflammatory markers in women with PMDD vs controls [36].

Treatment

PMDD is a chronic condition that, especially given the impact and risk of suicide, needs careful
management to control symptoms until natural menopause is reached. Management should be con­
sidered as a stepwise approach. The main pharmacological approaches involve either cycle suppression
or neuromodulation. Multi-disciplinary team management, ideally with involvement of gynaecology/
psychiatry/psychology and ideally endocrinology is the gold standard though hard to achieve in both
NHS and private care settings. An MDT approach should certainly be put in place as part of third line
management..

Non-pharmacological approaches

– Diet and exercise - Increasing complex carbohydrates is often recommended in the luteal phase
(theorised to increase central serotonin availability via increased tryptophan) and there is some trial
data to support this [37]. Moderate aerobic exercise is often recommended and has some supporting
data though more evidence is needed [38,39].
– CBT - CBT should be offered routinely to women with PMDD. Though some guidelines suggest it
should be reserved for women with mild PMD or who do not meet the full criterial for PMDD our
view is that should be seen as complementary to pharmacological therapy rather than an alternative.
Three randomised controlled trials have shown improvement in functioning and depression scores in
PMDD treated with CBT [40]. In one of these CBT was as effective as fluoxetine (though there was no
added benefit to combining the two) and recurrence rates in the CBT group were reduced at follow up
[41]. A 2009 metanalysis [42] evaluating CBT against a control intervention showed CBT gave sig­
nificant benefits, though the quality of evidence was poor. A more recent (2019) RCT of an internet-
based CBT intervention for women with PMDD showed a significant improvement in symptoms and
functioning that was maintained after six months [43].

Vitamin and mineral supplements

– Vitamin B6 (pyridoxine) has been extensively studied and 100 mg has shown weak superiority to
placebo in a meta-analysis of RCTs [44]. High doses, even of 200 mg daily, may lead to peripheral

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neuropathy and vitamin B6 should be discontinued if tingling or numbness in extremities develops.

IAPMD recommends up to 100 mg a day, and most supplements are limited to a 50 mg daily dose.
– Calcium - there is some support for Calcium supplementation at 600 mg twice daily in randomised
controlled trials [45,46], though larger multi centre trials are needed. It is still easy to recommend Ca
and Vit D supplementation given the proven benefits to bone health.
– Magnesium - one study has suggested that Magnesium supplements may help premenstrual mood
changes [47] and IAMPS recommends a trial of supplementing at 500 mg a day.

Herbal supplements

– there is support from systematic reviews for use of Vitex agnus castus (chasteberry) for decreasing
physical and emotional PMD symptoms. [48-50]. Support in terms of safety data varied in these
reviews and there is no clear dose recommendation.

SSRIs

Systematic reviews [51,52] have repeatedly shown that SSRIs are effective in PMDD and they are
hence a first line treatment [12,53]. Starting doses correspond to those for depression and anxiety,
though anecdotal evidence suggests that sometimes half-doses are equally or more effective. [54].
SSRIs seem to work differently in PMDD than other conditions allowing different methods of dosing.
Whereas the benefit of SSRIs can take a couple of weeks with anxiety and depression, when used for
PMDD, SSRIs seem to have a very rapid onset of action with improvements in affective symptoms seen
even in the first 24 h and peaking around 48 h [55,56].
Systematic reviews show that SSRIs seem to be effective whether taken continuously or just in the
luteal phase [52,57]. Medications and doses shown to be effective with luteal dosing are sertraline
50–100 mg, fluoxetine 20 mg, paroxetine 10–20 mg, and escitalopram 10–20 mg. When evaluating
continuous dosing versus luteal dosing there was no significant difference between the SSRI regimens.
Symptom-onset dosing has also been studied in fluoxetine and escitalopram [58,59] and seems to be
effective. One study also looked at weekly luteal phase dosing for fluoxetine 90 mg [60].
The rapid action of SSRIs in individuals with PMDD is hypothesised to be due to the simultaneous
targeting of 5-HT receptors and interaction with allopregnanolone levels in the brain, thus indirectly
modulating the function of GABAA receptors [61-63].
Adverse effects with SSRIs are relatively frequent and only 50% of patients using SSRIs for PMDD
persist with them for over six months. Common side effects are nausea, insomnia, somnolence, fatigue
and sexual dysfunction with reduced libido or anorgasmia. Loss of libido can be particularly difficult for
some women with PMDD who are already struggling in their relationships. All side effects are dose
dependent and luteal or symptom onset regimens can improve tolerability while maintaining efficacy for
some women. Sexual dysfunction and other side effects rapidly settle on discontinuation.
Discontinuation side effects do not seem to occur with luteal symptom-onset dosing in the same way
that they do for continuous dosing.
Currently, most SSRIs are licensed in the USA for PMDD, but not in the UK. Only Fluoxetine, Sertraline,
and Paroxetine (both continuous and luteal phase administration) are approved by the US Food and Drug
Administration (FDA) for the treatment of PMDD. Whereas, in the UK no SSRIs are approved for this
indication and as such these are all used off-licence.
(NICE https://cks.nice.org.uk/topics/premenstrual-syndrome/management/management/.

COCP

By inhibiting ovulation and eliminating the luteal phase it seems logical that COCPs should help
premenstrual mood symptoms. However, initial studies with second generation COCPs containing nor­
ethisterone and levonorgestrel alongside ethinylestradiol (EE) showed disappointing results [64,65]. This
is perhaps not surprising given the known tendency of some synthetic progestogens to cause PMS-like
side effects. Careful choice of hormones and regimen is needed to get the best chance of benefit and it
makes sense to move away from ‘standard’ second-generation monophasic (21/7) pills.

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– Choice of progestogen. More recently attention has turned to newer oral combined contraceptive pills
especially those containing the anti-mineralocorticoid drospirenone (DRSP). A 2012 Cochrane review
[66] showed significant benefit for both emotional and physical symptoms of PMDD, though a large
placebo effect was noted. Further double blind RCTs [67,68] have also suggested benefit from DRSP
containing COCPs. Cost effective DRSP containing pills in the UK are Yacella®/Dretine® (30 mcg), with
a 20 mcg DRSP containing pill available with the trade name Eloine®.
– Reduced hormone free interval (HFI). It makes sense that a reduced HFI or continuous use of COCP
should be more effective than a standard 21/7 monophasic regimen. Though there will be more days
of progestogen exposure these regimens (UK-FRSH [69] recommend several tailored regimens) in­
crease hormonal stability and reduce chance of escape ovulation. There is evidence for continuous
use for PMD symptoms- a cohort study and its extension [70,71] showed reduced PMD symptoms for
women using a continuous EE/DRSP regimen compared to 21/7 use. Triphasic regimens which aim to
mimic natural menstrual cycle hormonal fluctuations do not make sense and there is no evidence to
support their use.
– Choice of oestrogen. COCPs need to be used safely within the medical eligibility criteria [72]. Most
COCPs contain synthetic ethinyl-estradiol (EE), which has thrombogenic risks and may also adversely
affect mood. There are now some COCPs that use natural estradiol-valerate, and though there are no
long-term epidemiological data to support an increased safety profile they can be considered for
women at higher medical risk. As well as a better safety profile these pills may also benefit mood. A
pilot study [73] suggests that an estradiol containing pill is better tolerated than EE containing pills in
women with PMD and more research is needed in this area. Zoely® is a monophasic estradiol con­
taining COCP available in the UK.

Oestradiol

Inhibition of ovulation and cycle suppression can also be achieved by higher doses of transdermal
oestrogen. This strategy can be used for women who are not eligible for COCP or who have not been able
to tolerate them. Implants [74] and patches have been evaluated, whereas gels have not and so are not
recommended for this purpose. Twice weekly patches (100 mcg/24hrs) have been shown in a RCT to be
just as effective as 200 mcg/24hrs patches at reducing severe PMS symptoms [74-76]. It must be re­
membered that contraceptive efficacy cannot be relied on, and that endometrial protection must also be
ensured. To minimise progestogenic side effects, and in an attempt to give hormonal stability, the
Mirena® IUS can be used to fulfil both of these objectives. Around 10% of women with progestogen
intolerance [77] cannot tolerate progestin-releasing intrauterine devices. However, removal of the device
eliminates symptoms within 24 h [78] which should be offered as reassurance when counselling women
about fitting. An alternative strategy for endometrial protection (though not contraception) is to use
Utrogestan; as this is identical in chemical composition to natural progestogen it is often better tolerated
than synthetic progestogens. A dose of 100 mg, once per night is often used, though in premenopausal
women 200 mg days 1–14 or 100 mg days 1–25 of a 28 day cycle is likely to give better bleeding pre­
dictability. In progestogen sensitive women this can be reduced to 100 mg days 1–7 to minimise ex­
posure [12,79] though there is no long-term safety data for this. Vaginal Utrogestan use is another
alternative, this avoids first pass metabolism to neuroactive allopregnanolone, though again safety data
is lacking [70,80].

GNRH analogues

GNRH analogues induce profound ovarian suppression, effectively inducing medical menopause.
They are widely used in gynaecology for management of endometriosis, fibroids and dysfunctional
uterine bleeding. They have been used since the 1980 s for treatment of severe PMD, however their
usefulness is limited by cost as well as short and long-term hypo-oestrogenic side effects.
A meta-analysis of seven RCTs confirmed their effectiveness for both psychological and physical
symptoms [81]. GNRHs use is usually for severe PMDD cases where surgical management is a con­
sideration. They can also be used (off licence) as a trial to help with diagnosis. If symptoms do not
respond within 12 weeks, the diagnosis of ‘pure’ PMDD should be questioned [12].

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Significant bone density reduction starts within 6 m use of GNRH analogues, and GNRH analogues are
only licensed for a 6 m continuous use. Add-back hormone replacement must be used if use is extended
beyond this and is usually started much earlier to protect bone density and to stop troublesome vaso­
motor symptoms. Continuous combined HRT with Utrogestan or Tibolone is preferred to prevent pro­
gestogenic PMS-like side effects [82,83]. RCOG guidance suggests that women on long-term therapy
should have DEXA bone density monitoring at least annually.
Women need to be aware that a ‘flare’ of symptoms in the early weeks of GNRH-analogues is not
uncommon. This is due to increased affinity of the agonist for the GnRH receptor and decreased me­
tabolic clearance compared with its natural equivalent. Consequently, after an initial increase in LH and
FSH (flare effect), the continuous exposure of the receptors to the ligand eventually leads to down-
regulation of the receptors with a consequent reduction of the FSH and LH levels and suppression of the
gonadal function [84].

Allopregnanolone modulators

Blockade of allopregnanolone on the GABA-A receptor is a new strategy in PMDD treatment.

Sepranolone is an allopregnanolone antagonist which can be given by subcutaneous injection. In the first
randomised placebo-controlled trial, alternate day subcutaneous injections of Sepranolone showed
significant improvements in PMDD symptom severity scores and functioning in line with SSRIs and
drospirenone containing COCPs [85]. There was no increase in adverse effects, suggesting Sepranolone is
effective and safe. However, in a larger follow up trial in 2022 Sepranolone failed to beat placebo in
reducing PMDD severity hinting at a large placebo effect [86]. More data are needed to clarify the ef­
fectiveness of this group of compounds.

5 -alpha reductase inhibitors

Complementary to Sepranolone trials, one study has looked at the role of the 5-alpha reductase
inhibitor Dutasteride as a treatment for PMDD [87]. 5-alpha reductase inhibitors block the conversion of
progesterone to neuroactive allopregnanolone. The study compared the effectiveness of high dose and
low dose Dutasteride against placebo. High dose Dutasteride appeared to be effective but low dose did
not. More long-term studies are needed here, especially as 5-alpha reductase inhibitors in other po­
pulations have been linked to low mood. Care also needs to be taken in women of childbearing age as
these drugs are linked to birth defects.

Surgery

Hysterectomy with bilateral oophorectomy (TAH BSO) can be used as surgical management for PMDD
and gives permanent ovulation suppression. Blinded randomised control studies are clearly not possible
for this intervention [88] but observational data suggests TAH BSO is a very effective treatment with high
satisfaction rates in the treated women [89]. Oophorectomy is essential to allow oestrogen only hormone
treatment after surgery and thus avoid the potential of PMD symptoms from exogenous progestogens.
Given the young age of many PMDD sufferers, and the fertility implications, surgical management of
PMDD needs careful consideration and MDT team involvement [6]. A trial of ovarian suppression with
GNRH analogies is seen as essential to test the treatment response prior to surgery. Testosterone re­
placement is often required long term in addition to oestrogen replacement in this young cohort of
women.

Research agenda

• Clarification of subtypes of PMDD, understanding of these may help target treatment.

• Alternative, less burdensome means of accurate diagnosis. This could be a biomarker, or new
prospective symptom questionnaires.
• Development of PMDD-specific support for women in crisis.

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• Long term safety data for estradiol-valerate containing COCPs.

• Safety data for vaginal micronized progestogen and for other regimens to minimise progestogen
exposure in sensitive women.

Practice points

• PMDD is a severe PMD which carries a risk of suicide.

• Diagnosis requires prospective symptom tracking for at least two months to confirm cyclicity,
symptom-free interval and impact on daily functioning.
• PMDD is caused by heightened sensitivity to physiological hormone changes.
• The cause of this seems to be multifactorial and includes sensitivity to allopregnanolone.
• The symptom-free interval allows differentiation from PME.
• Long-term management is required ideally within an MDT setting.
• Treatment is targeted at either suppressing hormonal fluctuations or reducing sensitivity to
these fluctuations.

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