Diagnosis and Management of Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD)- A Synopsis

RISK FACTORS FOR PMDD

Age:

• Late 20s to mid-30s. [Kaur G et al., 2004]

Comorbid psychiatric disorders:

• Depression
• Anxiety
• Substance use
• Personality disorders

Genetic factors: [Malvika and Supriya 2019]

• 70% of women with PMS have a history of PMS in their mothers compared to 37% of women without a maternal history of PMS.
• 93% concordance in monozygotic twins vs 44% in dizygotic twins
• A possible role for 5HT1A receptor gene and Estrogen receptor alpha (ESR-1) gene

Low parity: 

• The possible explanation being greater exposure to cyclical hormonal changes of menstruation

Psychosocial stressors:

• Increase in PMDD after major life events, stressors.
• Trauma is associated with PMDD. [Wittchen et al 2003]
• Early life emotional and physical abuse increases the risk of PMS in the middle-to-late reproductive years. [Bertone-Johnson E et al., 2013]

Smoking:

Smoking, especially in adolescence and young adulthood, may increase the risk of moderate to severe PMS. [Bertone-Johnson et al 2008]

Obesity: 

Obesity is strongly associated with PMS although the causal mechanisms are unknown. A complex interaction of hormonal and neurochemical factors are postulated. [Bertone-Johnson et al 2010]

DIAGNOSIS OF PREMENSTRUAL DYSPHORIC DISORDER (PMDD)

The presence of at least five of the following eleven affective, behavioural, or somatic symptoms that are discreetly associated with the menstrual cycle are required for a positive diagnosis [APA, 2013]:

• Cognitive-affective – Affective lability (mood swings, tearfulness, or sensitivity to rejection); irritability or anger; depressed mood, hopelessness, or self-deprecating thoughts; anxiety or tension; inability to concentrate; and a subjective sense of feeling out of control.
• Behavioural – Decreased interest in usual activities; lethargy; changes in appetite or specific food cravings; and changes in sleep (hypersomnia or insomnia).
• Somatic – Breast tenderness, breast swelling, or bloating.

There is a strict set of criteria for PMDD, which states that at least one symptom is mood-related and severe enough to interfere with social, occupational, sexual, or scholastic functioning. In addition, these criteria require confirmation over at least two consecutive menstrual cycles.

AETIOLOGY AND PATHOPHYSIOLOGY OF PMDD

1.Neurotransmitter Dysregulation [Kaur G et al., 2004]

• Abnormal response to central neurotransmitters to normal gonadal ovarian hormones
• Low central serotonin levels. Acute treatment with SSRIs increases synaptic serotonin and can improve mood symptoms of PMDD.
• Altered serotonin sensitivity in response to fluctuations in gonadal hormones – tryptophan, a precursor to serotonin is efficacious in PMDD. Similarly, pyridoxine which is a cofactor in the conversion of tryptophan to serotonin is a treatment modality.
• Serotonin deficiency is postulated to mediate carbohydrate craving which is a feature of PMDD.

2. GABA: 

The reduced GABA-A receptor sensitivity to AlloP during the luteal phase and receptor subunit alterations (upregulation of the α4, β, δ subunits) may be responsible for the symptoms of PMS and PMDD. [Schmidt et al 1998]; [Backstrom et al 2011]

In animal studies, progesterone withdrawal leads to upregulation of the α -4 unit of the GABA -A receptor complex and an increased startle response. This ‘startle response’ may be mediated via allopregnanolone which is a positive allosteric modulator of GABA’s action at GABA_A receptors. [Pinna G., 2020]

Furthermore, women with PMS have low GABA-A  receptor sensitivity to the PROG metabolite, pregNANolone, and the efficacy of citalopram is related to its ability to restore GABA-A receptor sensitivity. [Sundstrom and Backstrom 1998]. 

PMDD’s characteristic waxing and waning symptoms (mood lability, anxiety and irritability) reflect suboptimal GABA-A response to fluctuating levels of AlloP across the menstrual cycle resulting in paradoxical anxiogenic activating effects. [Hantsoo & Epperson, 2020.]

3. β- endorphin

Changes in β- endorphin levels between periovulatory and premenstrual phases may alter pain sensitivity. [Straneva P et al., 2002]

4. SERT Density: [Sacher, 2023].

• A study used Positron emission tomography (PET) imaging to examine the interplay between the serotonin system and estradiol in the brain of patients with PMDD, as well as unaffected women, over the course of two menstrual cycles.
• The investigators found increased central serotonergic uptake followed by extracellular serotonin loss underlying the premenstrual onset of depressed mood in patients with PMDD.
• Increased midbrain SERT density correlated with depressive symptom severity across the menstrual cycle.

5. Changes in Estrogen and Progesterone: 

Progesterone and allopregnanolone

• Levels of progesterone (PROG) and its metabolite, allopregnanolone (ALLO), increase during the luteal phase and then rapidly reduce during menses, then remain low during the follicular phase.
• Chronic hormonal exposure followed by rapid withdrawal (i.e. not steady-state) is hypothesised to be a driver of symptoms associated with PMDD. [Yonkers and Simoni 2017]

Estrogen

• Estradiol is the predominant form of estrogen during a woman’s reproductive age and is involved in the regulation of mood, cognition and sleep.
• Low estrogen levels are linked to reduced emotional regulation through its effects on the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex, which result in a negative mood state and an increased risk of depression. [Newhouse and Albert 2015]

6. BDNF

• A neurotrophin that is expressed in multiple brain regions and is involved in synaptic plasticity, neuronal survival, learning, and memory.
• Research into BDNF and its role in neuropsychiatric conditions have shown that it has cyclicity across the menstrual cycle and appears to be important in estrogen’s modulation of PFC-dependent cognitive processes. [Carbone and Handa 2013]

7. Stress

• Stress and trauma are associated with more severe forms of PMS. [Pilver et al 2011]; [Bertone-Johnson et al 2014]
• Chronic stress negatively impacts PFC-dependent cognitive function processes, and this is possibly mediated through the blunting of ALLO and a reduction in GABergic neurotransmission, both of which are linked to depressive and anxiety-like behaviours.

8. Inflammation

• During the luteal phase, there is a notable increase in proinflammatory cytokines such as IL-6 and TNF-alpha as well as a 20% increase in C-reactive protein. [Gaskins et al 2012]
• This increase in inflammatory markers is associated with premenstrual mood symptoms as well as various risk factors for PMS including smoking, depressive symptoms, increasing age, and increased BMI. [Thurston et al 2011]

9. Calcium:

• Low serum levels of calcium and vitamin D during the luteal phase of the menstrual cycle were found to cause or exacerbate the symptoms of PMS. [Abdi F et al., 2019]

10. Magnesium

Low levels of Mg+ in the erythrocytes and leukocytes of women with PMS. [Salamat s et al., 2008]

11. Others:

Alterations in the following have been implicated in the pathogenesis

• Thyroid hormone
• Melatonin
• Cortisol
• Relaxin
• IGF-1

TOOLS FOR ASSESSMENT OF PMDD

Since the diagnosis of PMDD relies on symptoms during specific phases of the menstrual cycle, it is important that the patient tracks symptoms (type, severity and timing) and their effect on daily life for two consecutive menstrual cycles.

This can be challenging and to assist in the process of data gathering, the following tools have been developed

1.Calendar of Premenstrual Experience (COPE)

2. Daily record of severity of problems (DRSP):

Daily Record of Severity of Problems (DRSP) is a validated instrument that can be used prospectively for PMDD as well as other menstrual-related mood disorders. [Endicott et al 2006]

3. Premenstrual Symptoms Screening Tool (PSST)

4. Moos Menstrual distress Questionnaire (MDQ)

5. Premenstrual Assessment Form

6. Prospective Record of impact and Severity of Menstruation (PRISM)

ASSESSMENT AND MANAGEMENT OF PMDD

Key principles in Assessment:

• Rule out organic conditions that can mimic PMS
• Rule out psychiatric disorders
• Establish timing of symptoms

If the patient diary is inconclusive, gonadotrophin-releasing hormone (GnRH) analogues may be administered for 3 months to provide a more definitive diagnosis. [Green L et al., 2016]

MANAGEMENT

Management should follow an integrated and holistic approach. [Green L et al., 2017], [Appleton S., 2018], [Hofmeister S and Bodden S., 2016]

Treatment approaches to PMDD include:

1. Lifestyle changes
2. Nutritional supplements
3. Non-pharmacological treatments
4. Pharmacological treatments
5. Herbal Treatments

Lifestyle Changes: 

• Regular frequent small balanced meals rich in complex carbohydrates are beneficial as they increase brain levels of tryptophan and serotonin.
• Diet low in salt, fat, sugar and caffeine helps decrease fluid retention, irritability and bloating
• Regular exercise
• Smoking cessation
• Alcohol reduction
• Regular sleep
• Yoga, relaxation and stress management

MEDICATION

Serotonergic Antidepressants (SSRIs)

• SSRIs should be considered one of the first-line pharmaceutical management options in  PMS and PMDD. [Green L et al., 2017]
• Initial treatment can begin at low doses e.g escitalopram 10 mg OD. Higher doses e.g 20-40 mg of escitalopram can be trialled if no response to lower doses occurs

Serotonergic agents have shown to have a benefit on the following symptoms:

• Affective: Anxiety, depressed mood, irritability
• Somatic: Bloating, breast tenderness and appetite changes

The onset of action of SSRIs in PMDD is faster than for depression and is linked to increasing serotonergic activity in the synaptic cleft rather than the desensitization of the receptors that underlie the effect of SSRIs in depression. (Learn more on mechanisms of action of SSRIs)

• Improvements are often reported after the first cycle of use.
• All SSRI doses for efficacious and, therefore, can be titrated according to tolerability.

There are 4 dosing strategies: [Appleton S et al., 2018].

Continuous:

• If the patient has a comorbid mood disorder or distressing subsyndromal symptoms in the follicular phase
• Erratic cycles
• Difficulty remembering to take the medication
• SEs with starting or stopping SSRIs

Intermittent:

• Initiation of treatment at ovulation and cessation of medication 1-2 days after the start of menstruation.
• Beneficial for patients with regular cycles but want to limit SE of SSRIs e.g sexual side effects

Semi-intermittent:

• Daily low dose of SSRI with increased dosing during the luteal phase

Symptom onset dosing

• Initiating treatment when symptoms begin and continuing until the onset of menses

Approx 40% of women with PMDD do not respond to SSRIs. [Halbreich U et al., 2008]

SNRIs: 

Venlafaxine has shown a reduction of psychological and physical symptoms beginning from the first cycle.

Quetiapine: 

• Studied as an adjunctive treatment with SSRI and SNRI in patients who did not respond to SSRI or SNRI alone.
• Augmentation (25 mg quetiapine) showed a reduction in luteal phase mood lability, anxiety, irritability.

Anxiolytics: 

• Alprazolam during luteal phase at 0.375 to 1.5 mg may lessen anxiety, tension and irritability symptoms as shown in 2 RCTs.
• Use during the luteal phase only minimises the risk of dependence.

Buspirone: 

• 5HT1A partial agonist which has anxiolytic properties and no risk of dependence.
• 25 mg during the luteal phase was effective in reducing aches and pains, fatigue, cramps, irritability, and impaired personal relationships.

Ibuprofen: 

• 500-1000 mg /day (with food).
• Days 17 through to 28 of the menstrual cycle may relieve mastalgia.

Sepranolone (IsoallopregNANolone) :

• IsoallopregNANolone (UC1010) is an isomer of allopregnanolone and an allopregnanolone antagonist.
• A study showed that it significantly decreased depressive symptoms in women with premenstrual dysphoric disorder comparable to serotonin reuptake inhibitors and oral contraceptives. [Bixo et al., 2018]

Dutasteride: 

• Dutasteride is a 5α-reductase inhibitor that prevents the conversion of PROG to AlloP.
• It has been shown to decrease symptoms of PMDD.
• Dutasteride was well tolerated, and while it prevented the luteal phase increase in plasma allopregnanolone, it did not significantly change luteal plasma progesterone levels. Stabilisation of AlloP levels from the follicular to the luteal phase of the menstrual cycle by blocking progesterone conversion mitigates PMDD symptoms. [Martinez et al., 2016]

Important:

Safety of medication during pregnancy should be discussed with the physician and an individual risk-benefit analysis is essential.

PSYCHOLOGICAL TREATMENTS

Cognitive Behavioural Therapy:

A meta-analysis showed CBT is beneficial in improving functioning and depression scores in patients with PMS and PMDD.

CBT should be routinely recommended in women with PMS and PMDD. [Green L et al., 2017]

NUTRITIONAL SUPPLEMENTS

Calcium

• 1000-1200 mg daily
• Can alleviate tension, anxiety, fluid retention, pain and food cravings

Vitamin D

• High dose vitamin D supplementation (50000 IU ) can reduce the prevalence of PMS and dysmenorrhea as well as has positive effects on the physical and psychological symptoms of PMS. [Bahrami A et al., 2018]

Magnesium

• 200-400mg /day reduces fluid retention severity of depression, craving, and anxiety symptoms.
• Combination with B6 has better efficacy than Mg alone. [Fatihzadeh N et al., 2010]

Vit B6 (Pyridoxine): 

• Mixed results. Doses of >100 mg /day can increase the risk of peripheral neuropathy.

Vitamin E: 

• 400 IU daily may reduce mood and physical symptoms such as mastalgia.

COMPLEMENTARY AND HERBAL THERAPIES

Evening Primrose Oil

• Derived from American wildflower is a rich source of gamma linoleic acid which is a prostaglandin precursor.
• 3-6 g /day may help mastalgia, irritability and ankle swelling.

Vitex Agnus Castus (Chasteberry)

• Chasteberry binds to dopamine receptors and inhibits prolactin release and thus may relive mastalgia and irritability.
• 20-40 mg /day
• Inadequate safety data to recommend routinely
• Unsafe in pregnancy

Black Cohosh

• Stimulates estrogen receptors and is used to treat premenstrual anxiety and breast pain
• Long term safety is unknown

St John’s Wort

• Useful in mild to moderate comorbid depressive disorder
• May benefit physical and behavioural symptoms
• Significant interactions with other medications
• Avoid use with SSRIs

Saffron (Stigma of Crocus sativus L)

• 30 mg/day showed a reduction in PMS symptoms in one RCT. [Agha-Hosseini M et al., 2008]

Dong Quai

• Chinese herb which is a coumarin derivative and can increase prothrombin time.
• Not safe during pregnancy and contraception advised

Lemon Balm, Curcumin and wheat germ have shown some benefit in single studies.

Other Alternative Therapies:

• Acupressure and Acupuncture
• Vaginal biofeedback
• Homoeopathic Remedies
• Chiropractic and massage therapy
• Reflexology
• Bright Light Therapy (10000 lx cool-white fluorescent light)

HORMONAL TREATMENT

Oral contraceptives

• Drospirenone-containing COCs may represent an effective treatment for PMS and should be considered as a first-line medication intervention
• Drospirenone is a progestin (spironolactone derivative) with antiandrogen and diuretic properties.
•  A Cochrane review of 1920 women showed that the drospirenone-containing OC formulation reduced impairments in productivity and social functioning in women with PMDD. Symptoms of mastalgia, bloating irritability and aggression were also reduced. [Lopez L et al., 2012]
• OC formulation containing Drospirenone 3 mg with ethinylestradiol 20mcg is available as Yaz. (24/4 regime)
• According to the Royal College of Obstetricians and Gynaecologists, emerging data suggest the use of the contraceptive pill continuously rather than cyclically. [Green L et al., 2017]
• It is not known whether COCs are useful for women with milder forms of PMS.

• 100mg/day can improve symptoms of bloating, swelling, mastalgia, acne, irritability and depression due to its antiandrogen and anti-mineralocorticoid properties.
• Monitoring for hyperkalemia is important as it has potassium-sparing diuretic properties.

SURGERY

• Hysterectomy and bilateral oophorectomy have been shown to be of benefit in women with severe symptoms.
• This can be considered when medical management has failed, long-term GnRH analogue treatment is required or other gynaecological conditions indicate surgery.
• Being a permanent form of ovulation suppression along with the removal of the endometrium, estrogen replacement can be prescribed without the need for a progestogen.

Surgery should not be contemplated without preoperative use of GnRH analogues as a test of cure and to ensure that HRT is tolerated. [Green et al., 2017]

TREATMENT ALGORITHM FOR PMS AND PMDD

If a diagnosis of PMDD is then indicated, lifestyle changes, psychological therapies, and pharmacologic treatments for both somatic and psychological symptoms are recommended. [Green et al 2017]

1. Consider exercise, CBT, and vitamin B6 for the first-line treatment of PMDD. Furthermore, new combined contraceptive pill suppresses ovulation and reduce PMDD symptoms. If necessary, low dose SSRIs (e.g. 10 mg citalopram or escitalopram) can be considered.
2. Second-line therapies include estradiol patches (100 mcg) in addition to micronised progesterone (100 mg or 200 mg on days 17 to 28) or LNG-IUS (52 mg) to minimise progestogenic adverse effects and prevent endometrial hyperplasia. If necessary, higher dose SSRIs (e.g. 20 to 40 mg citalopram or escitalopram) can also be considered.
3. GnRH analogues suppress ovarian steroid production and may only be used for patients with more severe symptoms given their negative effects on bone mineral density. Continuous combined therapy (estrogen and progesterone) or 2.5 mg tibolone should be administered to combat hypoestrogenic symptoms in patients that have used GnRH for ≥6 months.
4. Surgery with or without hormone-replacement therapy may be considered for severe PMDD in those that have had prior use of GnRH analogues to aid in the prediction of the success of an oophorectomy.

According to Prof Kulkarni from Monash Alfred Psychiatry Research Centre (MAPrc) who is a recognised leader in women’s mental health; her group recommends the following:

Suggested 1st line

1. OCP – continuous. Zoely (natural estradiol + nomegestrol acetate) is particularly recommended.
2. OCP + estradiol

2^nd Line treatments

1. SSRI’s – use short half-life drugs, less agitating ones (citalopram, sertraline).
2. Agomelatine to treat depressive symptoms.
3. Pharmacogenomics testing to detect sensitivity and reactivity to medication.

3^rd line treatments

• SSRI+ estradiol
• SSRI + aldosterone

4th line treatments

• GnRH agonist drugs (e.g Synarel) + add back estradiol (chemical menopause)

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CONCLUSION

PMDD is a severe form of PMS that impairs the functioning and quality of life in females of reproductive age.

The symptoms of PMDD can also overlap with other disorders including MDD, GAD, and thyroid disorder (hyperthyroid or hypothyroid).

Depression and anxiety can co-exist with PMDD as the diagnostic criteria are not mutually exclusive, however, PMDD may predate an MDD or GAD diagnosis.

A careful clinical history with a focus on symptomatology during the luteal phase with remission at the beginning of menses is an important differentiator for diagnosing PMDD.

Treatment should be integrative and holistic combining lifestyle modifications, herbal, complementary therapies nutritional supplements, CBT and medications (hormonal and antidepressants).