Premenstrual dysphoric disorder

Abstract

An estimated 8-out-of-10 women experience physiological premenstrual symptoms, 3–30% of these women suffer with symptoms of premenstrual syndrome (PMS) that interfere with daily life, with 1–10% of women suffering from severe PMS symptoms meeting the DSM-5 criteria for diagnosis of premenstrual dysphoric disorder (PMDD). PMDD can be considered a subdivision of PMS and is a combination of psychological, behavioural and physical symptoms that can vary in intensity and presents cyclically during the luteal phase of ovulatory menstrual cycles. The diagnosis of PMDD and PMS depends on the timing of symptoms, the severity of symptoms and their impact on quality of life. Physiological symptoms (feeling bloated, headache, acne, mood changes and constipation) that do not impact on daily activities and quality of life are considered to be physiological premenstrual symptoms rather than PMS. There is no association with age, educational status or employment for PMS or PMDD.

Clinical case scenario

A 20-year-old woman and her boyfriend, present to her GP surgery, where she complains of generalised fatigue, abdominal cramps, bloating, headache and difficulty in concentrating. She admits her work has been affected by these symptoms for the last few months. The symptoms are worse around the same time each month and symptoms clear up after menstruation. The boyfriend reveals that: ‘She is very touchy and sensitive, if I say anything it kicks her off during those days and it affects our relationship’. He also mentions that after her periods she is a different person, but he denies detecting any other changes in her mood.

Definitions

Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) affect women during the luteal phase of the menstrual cycle, with symptoms improving with the onset of menstruation. Typically, there is a symptom-free spell of 1–2 weeks each month. In 2011, more than 150 psychological, behavioural and physical symptoms were linked to PMS by the International Society for Premenstrual Disorder (ISPMD). The common psychological symptoms include feeling low and mood swings, accompanied by loss of confidence, anxiety, and oversensitivity. In addition, physical symptoms, for example, abdominal bloating, breast engorgement and discomfort are common. The commonly encountered behavioural symptoms are aggression and reduced cognitive ability.

PMS is not defined as a mental disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), however, PMDD is considered a mental health disorder. PMDD is diagnosed when 5-out-of-11 psychological and physical symptoms including one behaviour symptom are affecting daily activities during the luteal phase are observed and when symptoms ease off within a few days of menstruation (American Psychiatric Association, 2013; Ismaili et al., 2016). These symptoms are listed in Box 1.

Box 1.

Summary of diagnostic symptoms for PMDD.

• Feeling low

• Emotionally labile

• Feeling irritable

• Feeling aggressive

• Feeling anxious and stressed

• Poor concentration

• Loss of interest in usual tasks

• Disturbed sleep

• Eating habits (cravings or overeating)

• Feeling tired, drained, overwhelmed or out of control (exaggerated response or no response)

• Breast discomfort

• Weight gain

• Feeling bloated

PMS is subdivided into core premenstrual disorder, variant premenstrual disorders, and the severe presentation of PMDD acting as a further subgroup (Ismaili et al., 2016).

Core premenstrual disorders

In core premenstrual disorders (PMDs) the symptoms are nonspecific and usually recur in ovulatory cycles. They are significant enough to affect the woman’s quality of life, daily routine and interpersonal relationships during the luteal phase, but disappear with the onset of menstruation. Symptom presentation is variable. In some women symptoms are predominantly psychological and in others mostly physiological, but in all are a mixture of both.

Variant PMDs

Variant PMDs are divided further into four sub types:

Premenstrual exacerbation of a pre-existing condition. For example, migraine, epilepsy, depression, anxiety, diabetes or asthma during the pre-menstrual period

Anovulatory PMDs occur in anovulatory menstrual cycles with nonspecific symptoms and no specific relationship with the luteal phase. The mechanism is not fully understood and ovarian follicular activity is considered to be responsible for the symptoms.

Progesterone-induced PMDs: Exogenous progesterone in the form of hormone replacement therapy (HRT), combined oral contraceptive (COC) pills or progesterone-only pills can cause symptoms resembling PMS. There is no cyclical presentation of symptoms and symptoms occur as a side effect of the hormone treatments.

PMDs with absent menstruation: Patients still have symptoms even when their menstruation is stopped either with endometrial ablation, hysterectomy or the levonorgesterol intrauterine system (LNG-IUS). These symptoms are thought to be due to continuous ovarian activity in response to luteinising hormone and follicle stimulating hormone

PMDD

PMDD is the most severe form of PMS and classified in DSM-5 as a mental illness. Diagnosis depends on the presence of at least 5-out-of-11 psychological, physical and behavioural symptoms (including one behaviour/cognitive problem in the luteal phase) and alleviation with onset of menstruation (DSM-5).

Aetiology

PMS and PMDD affect women during the luteal phase of the menstrual cycle, but not pre-pubertal girls, postmenopausal or pregnant women. The individual response of women to the changing hormone levels that interact with neurotransmitters differently in vulnerable patients is thought to be responsible for the symptoms (Schmidt et al., 1998).

There is some relationship between PMS and PMDD and dietary factors, especially vitamin deficiencies and environmental factors (Dadkhah et al., 2016; Siahbazi et al., 2017). The relationship with stress and personality disorders is not supported by evidence as a causative factor, but a high prevalence of obsessive compulsive disorder is noted in women with PMS and PMDD (Sassoon et al., 2011).

Pathophysiology

The female hormones are considered to play a major role in the symptoms of both PMS and PMDD. This theory is supported by the cyclical presentation of symptoms in menstruating women and improvement in symptoms by suppressing ovaries with gonadotrophin-releasing hormone (GnRH) agonists or surgical removal of ovaries (Cronje et al., 2004). The interaction between hormonal levels and central neurotransmitters (importantly serotonin, beta endorphin, gamma aminobutyric acid (GABA) as well as the autonomic nervous system) is noted to differ in PMS and PMDD patients when compared with women without PMS (Erikson et al., 1994). The hormone levels are thought to alter serotonin response, transforming the sensitivity of GABA receptors to allopregnanolone, which in turn then modifies emotional and cognitive function in the brain (Lanza di Scalea and Pearlstein, 2019). The serotonin levels are thought to play the most significant role in PMS and PMDD. The studies support the progesterone- and oestrogen-induced changes in GABA and serotonin levels in women suffering with PMS, but do not explain why some women have a symptomatic response and others not. One theory suggests that the abnormal response to progesterone influx or abjuration is through GABA receptors (Yonkers and Simoni, 2018).

Diagnostic approach

The diagnosis of PMS and PMDD is a diagnosis of exclusion. Before starting any treatment, a careful history must be taken to elicit risk factors including a family history of PMS or PMDD, a family history of severe depression, bipolar affective disorder and any past psychiatry history. Asking detailed questions about past use of contraceptive pills and their relationship to symptoms reported and other mental illnesses such as depression or mood disorders is essential. Surgical history should consider hysterectomy and/or salpingo-ophorectomy and their subsequent impact on quality of life.

An important component of diagnosis is analysis of a symptoms diary recorded for at least two menstrual cycles. There are several apps and calendars available to record the daily severity of problems. This daily record of severity of problems (DRSP) is validated and commonly used in clinical practice www.aafp.org/afp/2011/1015/afp20111015p918-fig1.pdf. There are 17 common symptoms including 11 from the DSM-5 and symptoms are rated on a scale of 1–5 where 5 is the most severe form (Endicott et al., 2006).

The symptoms timing with the luteal phase of the menstrual cycle and alleviation at the onset of menstruation for one week or so are important to note. A careful interpretation of the symptoms diary can identify symptoms of anxiety and depression that can be further evaluated using the Patient Health Questionnaire-9 (PHQ-9). If the symptoms do not appear to be cyclical other causes such as mood disorders, hypothyroidism, anaemia, irritable bowel syndrome, interstitial cystitis, chronic fatigue syndrome, dysmenorrhoea, endometriosis, and systemic lupus erythematosus should be considered, further evaluated and managed accordingly, where appropriate, in primary care.

In secondary care if the diagnosis is still inconclusive from examination of the DRSP, a 3 month trial of GnRH agonists can be helpful. If the ovarian suppression improves symptoms this supports the diagnosis of PMS/PMDD (RCOG, 2016). It is noteworthy that GnRH agonist use is not licensed for PMS.

Management pathway

The definition of PMS as mild, moderate or severe usually depends on the severity of symptoms, the effect on quality of life and clinician judgement. The management of cases entails general advice for all, symptomatic treatment and specific treatment for moderate and severe PMS/PMDD accordingly.

General advice is for all women

Healthy life-style advice, regular light exercise, and regular (every 2 to 3 hours) light meals rich in complex carbohydrates should be used. Advice on cutting alcohol intake, smoking cessation and management of stress should help to improve sleep patterns (Daley, 2009). Treatment strategies will be based on severity of symptoms.

Mild PMS/PMDD

If the main complaint is pain, discuss options, such as paracetamol, or non-steroidal anti-inflammatories (NSAIDs). Always consider other drug interactions when prescribing medication, such as stomach protection with NSAIDs. Naproxen 250–500 mg twice daily can be used up to the maximum dose of 1250 mg in 24 hours or ibuprofen 400 mg/6–8 hours to the maximum dose of 2400 mg per 24 hours for pain relief (Armour et al., 2018).

In patients presenting with mastalgia, consider general advice for other symptoms of PMS and specific advice, for example, on the use of a soft well-fitted support bra and paracetamol (Amin et al., 2013). Consider breast specialist referral if there is no response to the treatment after 3 months (National Institute for Health and Care Excellence (NICE), 2016). A summary of the management of mild PMDD is presented in Box 2.

Box 2.

Summary of management for mild PMDD.

First line:

A: Healthy lifestyle adjustments

B: Symptomatic treatment pain/mastalgia

C: Cognative behavioural Therapy as adjuvant

Second line:

COCs containing drospirenone or norgestimate or gestodene or desogestrel if not acceptable discuss complimentary therapies

Moderate PMS/PMDD

In these cases, evidence supports the continuous use of a COC pill, rather than cyclical use (Royal College of Obstetricians and Gynaecologists (RCOG), 2017). The use of drospirenone 3 mg and ethinylestradiol 0.03 mg (Yasmin®) appears an effective option (Lopez et al., 2012). The new generation of COCs with new progestogens (norgestimate (Cilest®), gestodene (Femodene®), desogestrel (Marvelon®)) can also be considered. It is important to review the risk profile before prescribing COCs. Use of the COC is off licence in PMS alone but not if the patient needs contraception. It should be remembered, second-generation COCs with progesterone (levonorgesterol and norethisterone) can induce PMS-like symptoms in some women. Referral for cognitive behavioural therapy (CBT) can also be considered according to patient preference.

Severe PMS/PMDD

The PMS guidelines from the RCOG recommend SSRIs as a first line treatment option for PMDD. The use of SSRIs is off license for PMS, but the literature supports use in severe cases. SSRIs can be used continuously or only in the luteal phase, day 15–28 of the menstrual cycle. If the diagnosis is uncertain or the patient is under 18 years in age, a specialist opinion is required. Patients treated with SSRIs need regular follow up. Review within a week of starting treatment to assess for side effects and tolerance of treatment. In patients with good tolerance, continue treatment for 3 months and where improvement is noted continue for up to 6–12 months. The outcome of treatment should be assessed at 2 months using the DRSP questionnaire and if no improvement is noted consider other causes or referral to secondary care for further specialist advice (NICE, 2019). The SSRIs are more effective for alleviating behavioural symptoms than physical symptoms. The recommendation is to start at the lowest possible dose and titrate according to the response with close monitoring (Marjoribanks et al., 2013).

It is important to discuss all the possible side effects including fatigue, self-harm ideations, reduced libido, insomnia and somnolence. Always provide leaflets with information on how to taper off continuous SSRIs. It is easier to stop luteal phase use than continuous use. The usual dosage of medication in common clinical practice for PMS/PMDD is shown in Table 1.

Table 1.

Common dosages of medications used in PMS/PMDD.

Name of medication	Starting dosage	High dose
Fluoxetine	20 mg a day	20–60 mg a day
Sertraline	50 mg a day	50–150 mg a day
Citalopram	10 mg a day	20–40 mg a day
Escitalopram	20 mg a day	20–40 mg a day
Paroxetine	5–10 mg a day or 12.5 mg controlled release once daily	10–30 mg a day or 12.5–25 mg controlled release/day
Venlafaxine	25 mg/twice daily	25–100 mg a day

The use of antidepressants other than SSRIs is not covered by RCOG and NICE guidelines. There is limited evidence for the use of venlafaxine (serotonin and noradrenaline reuptake inhibitor) as it is associated with more withdrawal effects due to a relatively shorter half-life. Initiation of venlafaxine for PMS/PMDD is not recommended in primary care (NICE, 2019). A summary of the management options for moderate-to-severe PMS/PMDD is presented in Box 3.

Box 3.

Summary of management options for moderate-tosevere PMS/PMDD.

First line:

1. Low-dose SSRIs in conjunction with CBT OR

2. CBT alone OR

3. COCs containing drospirenone or norgestimate or gestodene or desogestrel

Where hormones unacceptable then consider complimentary therapy

Second line:

Transdermal E2 and Progestogen/high-dose SSRIs

Third line:

GnRH agonists alone after 6 months/+ add therapy for long term use

Fourth line:

Surgical oophorectomy +/− HRT

Cognitive behavior therapy

CBT is recommended by the RCOG for PMS. Couple CBT is more effective than individual CBT (Ussher and Perz, 2017). Couple therapy helps the understanding of partners and benefits subsequent individual therapy. CBT has similar efficacy to Fluoxetine alone or in combination. The effects of CBT are enduring, whereas Fluoxetine shows an accelerated response (Hunter et al., 2002). The RCOG’s PMS guideline recommends secondary care referral when initial measures of life- style modification, COCs and SSRIs fail to improve symptoms or when patients suffer severe PMS/PMDD symptoms (RCOG, 2016).

Complimentary therapies

The use of a variety of therapies (vitamin D, calcium, vitex agnus-castus latifolia, saffron, reflexology, ginkgobiloba, evening primrose oil, acupuncture, lemon balm, curcumin, isoflavones, St. John’s wort, magnesium, vitamin B6 and multivitamins) is not supported by high-quality evidence. The RCOG’s PMS guidelines suggest there is no evidence to support the complimentary therapies in PMS or PMDD, but advise that these may be considered when hormonal use is contraindicated (RCOG, 2016). The RCOG also advise caution with complimentary therapies. For example, calcium supplements can interfere with absorption of other minerals and vitamins and over-dosage can cause constipation and renal stones. In the case of pyridoxine usage, doses of 25–100 mg per day are usually required, but toxicity and sensory neuropathy can occur with high doses of 200 mg/ day (Whelan et al., 2009). There is no strong evidence that acupuncture is beneficial for PMS/PMDD (Armour et al., 2018; Jang et al., 2014). Most of the studies have methodologies with bias and give conflicting results.

Treatment options in secondary care

Some treatment options are more relevant for secondary care, but knowledge of these options can be helpful when advising on treatment within GP consultations. Patients may ask about treatments that are not recommended. For example, the use of progesterone alone for PMS is not recommended. There is no supporting evidence of benefit for the LNG- IUS in PMS. Patients with PMS should be made aware that use of the LNG-IUS for contraception can exacerbate PMS symptoms (RCOG, 2016). The continuous use of oestrogen plus progesterone as either patches or as sub cutaneous implants is not supported by evidence and even luteal phase oral unopposed oestrogen is probably detrimental for PMS (Naheed et al., 2017). Use of an oestrogen patch continuously or during the luteal phase (add progesterone to avoid endometrial hyperplasia) is recommended for PMS (RCOG, 2016). The NICE Clinical Knowledge Summary (CKS) has not recommended their use in primary care, due to a lack of evidence (NICE, 2019).

Use of diuretics such as Spironolactone is off license, but supported by the RCOG for symptomatic patients with PMS. The NICE CKS does not recommend use in primary care, as it is off license. When patients are prescribed diuretics these should be taken in the morning to avoid sleep disturbance, electrolyte imbalance and interaction with other medications (British National Formulary, 2019). Danazole is noted to be helpful in controlling PMS symptoms, but the NICE CKS does not support its use in primary care, due to irreversible virilising effects on the voice and because use in PMS is again, off license. There are also other side effects including weight gain and hirsutism (NICE, 2019; RCOG, 2016).

GnRH agonists

GnRH agonists are very effective in managing severe PMS/PMDD symptoms, but can be used only in secondary care and for a period of up to 6 months. Long term use can be associated with a reduction in bone density. The ISPMD recommends emergency use in secondary care for threatening situations when PMS/PMDD symptoms are not controllable with SSRIs (Ismaili et al., 2016).

Anxiolytics

Currently the ISPMD does not recommend the use of anxiolytics in PMS/PMDD (Nevatte et al., 2013). Use of these for PMS/PMDD is considered to be off license.

Surgical options

Bilateral oophorectomy is the only surgical option and should generally be used as the last resort and only after a 3 month trial of GnRH agonists. Bilateral oophorectomy with or without hysterectomy may be beneficial in severe cases. Patients need careful counselling, especially on use of hormone treatments postoperatively, and of the other risks of surgery.

KEY POINTS

Use of a DRSP is essential to aid diagnosis and assess the severity of symptoms; apps are available to aid recording by patients and interpretation of results

Treatment strategies are based on severity of symptoms, but general advice can be helpful for all patients with premenstrual symptoms

It is important to differentiate physiological premenstrual symptoms from PMS and PMS from PMDD

Careful consideration should be given to the progesterone content of any current or past hormone therapies

Moderate or severe cases of PMS and PMDD need secondary care referral when initial treatment is ineffective, symptoms are severe, the diagnosis is uncertain or the patient is under the age of 18 years

In secondary care, GnRH agonists are used in severe cases and particularly before consideration of surgical options

Footnotes

ORCID iD

Mr Michael Hardway

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