Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD) Treatment Protocol

Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD) Treatment Protocol

Definition and Pathophysiology

Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) are common disorders of the luteal phase of the menstrual cycle. Both PMS and PMDD Are characterised by moderate to severe physical, affective, and/or behavioural symptoms impacting daily activities and quality of life.[1]

The causes of PMS and PMDD are complex and involve several factors. Fluctuating ovarian hormones, especially oestradiol and progesterone, influence neurotransmitters, which can lead to a reduction of serotonergic function and altered GABA activity during the luteal phase. Recent research also highlights the impact of genetic and epigenetic changes on hormonal and neurotransmitter pathways, with inflammation likely to amplify the peripheral and neurological responses to stress.[1]

Genetic research suggests a hereditary component in PMDD, though specific genetic factors remain unidentified. Recent studies reveal a cellular vulnerability to sex hormones, but overall, the findings have yet to provide a comprehensive understanding of PMDD's underlying biology.[2]

    Patient Signs and Symptoms

    PMS develops within the luteal phase of the menstrual cycle, affecting normal daily function, and resolve shortly after the onset of menstruation. The patient must report at least one of the following affective/somatic symptoms during the five days prior to menses in each of the three previous menstrual cycles:[3]

    Affective symptoms:

    • Angry outbursts
    • Anxiety
    • Confusion
    • Depression
    • Irritability
    • Social withdrawal

    Somatic symptoms:

    • Abdominal bloating
    • Breast tenderness
    • Headache
    • Joint or muscle pain
    • Swelling of the extremities
    • Weight gain

    PMS/PMDD diagnosis are based on obtaining a detailed history and ruling out the presence of physical or psychiatric disorders, such as anxiety or major depressive disorder, hypothyroidism, diabetes.

    Figure 1: American College of Obstetricians and Gynecologists PMS Criteria

    To diagnose PMDD according to DSM-5 criteria:[3]

    Diagnosis of PMDD is as follows:

    1. Symptoms: At least five symptoms must be present, including one core emotional symptom (as detailed in Figure 1).
    2. Timing: Symptoms should occur most of the time during the week before menstruation, improve for a few days during menstruation, and be absent in the week after.
    3. Impact: Symptoms must significantly disrupt daily activities or relationships.
    4. Exclusion: Symptoms should not be a worsening of another disorder, like major depressive disorder or panic disorder.
    5. Duration: Symptoms must be present for at least two consecutive menstrual cycles.
    Figure 2: Criteria for Premenstrual Dysphoric Disorder [3]

    Risk Factors

    The following factors are associated with development of PMS/PMDD:

    Family history, past traumatic events and preexisting anxiety disorders are all known risks for developing PMDD.[4]


    A strong association exists between cigarette smoking and moderate to severe PMS, and even for former smokers. PMDD risk increases for women who began smoking in adolescence.[5]


    PMS severity is significantly correlated with body fat percentage and BMI. The impact of inflammatory adiposity, as well as the intake of calorie-rich foods, sweets, and fried salted snacks are linked to the increased risk.[6]

      Red Flags:

      • Suicidal ideation: If patient is deemed at risk of self-harm or harm to others, seek immediate guidance from a Crisis Assessment and Treatment Team (CATT) or call Triple Zero (000) Emergency. If risk is suspected, use the Mood and Stress Questionnaire and Depression Anxiety Stress Scales (DASS) form questionnaire to assess patient's mental wellbeing, and referring to a General Practitioner, Psychologist, or Psychiatrist where indicated.
      • Premenstrual exacerbation (PME) of an ongoing disorder: PME occurs when chronic symptoms of an existing psychiatric disorder (e.g. depression, obsessive compulsive disorder, bipolar) are significantly worse in the late luteal phase and show improvement in the mid-to-late follicular phase.

      Screening and investigations

      Clinical Screening

      Rationale

      PMDD Symptom Tracker

      PMDD diagnosis is based on tracking symptoms for a minimum of two menstrual cycles. The International Association for Premenstrual Disorders (IAPMD) provides a free symptom tracker with instructions on how to track PMDD symptoms and severity.

      Monitoring Menstrual Cycle Signs

      A symptom tracker to allow patients to monitor their menstrual cycle and pattern, including changes in body temperature and cervical mucus, which are regarded as ovulation indicators.

      Menstrual Health Chart

      A period tracker that allows patients to monitor daily signs and symptoms including menses quality, mood and cognition, sleep quality, and general symptoms.

      Mood and Stress Questionnaire (MSQ)

      A questionnaire designed to help Practitioners establish levels of stress, anxiety and mood concerns.

      Depression Anxiety Stress Scales (DASS) form

      A self-report questionnaire designed to measure the three related negative emotional states of depression, anxiety and tension/stress.

      Sleep Assessment Questionnaire (SAQ)

      A questionnaire designed to help Practitioner’s screen patients for sleep disorders andsleep hygiene practices.

      Me v PMDD, Flo and Clue Applications

      Me v PMDD is a digital symptom and treatment tracking application for PMDD that converts daily tracking data into simple graphs for patients and Practitioners to utilise.

      Flo and Clue are evidence-based applications that allow patients to input daily signs and symptoms to gain better understanding menstrual health patterns, including ovulation, PMS and period predictions.

      Pathology Testing

      Rationale

      Vitamin D

      Vitamin D undergoes increased metabolism by ovarian hormones and deficiency may exacerbate psychological symptoms featured in premenstrual disorders.

      Ideal range: At least 50 nmol/L at end of winter, and between 60 to 70 nmol/L during summer.

      Thyroid Stimulating Hormone (TSH)

      Thyroid dysfunction can present with similar symptoms to those of PMS and PMDD and, therefore, must be ruled out as an underlying health condition. TSH concentration is the most reliable indicator of thyroid status at the tissue level to determine thyroid activity.

      Ideal range: 0.4 to 2.0 mlU/L

      Subclinical hypothyroid: 2.0 to 10 mlU/L with normal T4; Overt hypothyroid: >2.0 mlU/L with low T4

      Blood Glucose

      Detection of hyperglycaemia or hypoglycaemia, which can present with similar symptoms to those of PMS and PMDD and, therefore, must be ruled out as an underlying health issue.

      Iron Studies

      Anaemia can present with similar symptoms to those of PMS and PMDD and, therefore, must be ruled out as an underlying health condition.

      A serum ferritin level <30 µg/L for an adult is diagnostic of iron deficiency. Inflammatory disease may elevate serum ferritin.

      Therapeutic targets:

      • Altered stress response in the luteal phase: Under stressful conditions, symptomatic women demonstrate heightened stress reactivity during the luteal phase of the menstrual cycle and worsening PMS/PMDD symptoms.[7]
      • Immune activation and inflammation: Women with significant premenstrual symptoms have elevated levels of inflammatory biomarkers, including IL-4, IL-10, IL-12, and interferon-gamma (IFN-g),[8] and high-sensitivity C-reactive protein (hsCRP) levels above 3 mg/L are significantly associated with PMS symptoms.[9] Inflammation is detrimental to neurotransmission, hippocampal neurogenesis and stress response pathways driving PMS/PMDD pathophysiology.[9]
      • Sleep dysregulation: Data reveals that during the menstrual transition and the premenstrual phase, women are more prone to sleep disturbances, which negatively impact mood and the menstrual cycle and increased the risk and severity of premenstrual disorders.[10] PMS/PMDD patients often experience poorer sleep quality, higher reliance on sleep medications, and greater daytime dysfunction, which exacerbate affective symptoms.[11]

        Treatment Recommendations

        Core Recommendations

        Select from the following to support luteal phase mood symptoms:

        If with low mood:

        BCM-95™ Turmeric and Saffron for Depression

        Dose: Take 1 capsule twice daily with food

        An anti-inflammatory blend of BCM-95™ Turmeric and saffron to provide neurogenic and neuroprotective actions, as well as serotonergic modulation.

        • 30 mg/d of saffron can help reduce PMS mood symptoms over two menstrual cycles.​[12​]
          • In 120 women with PMDD, those taking saffron experienced a 78% reduction in depressive symptoms with an improved safety profile (vs. 61% reduction with fluoxetine) with saffron showing fewer side effects.
        • 100 mg/d of curcumin taken seven days prior to until three days after menstruation improves physical, behavioural and mood symptoms after three cycles.​[13]​
          • 100 mg of curcumin twice daily for three consecutive cycles led to a 53% reduction in PMS symptom severity compared with a 3% reduction in the group placebo.​[14​]

        OR

        If with elevated prolactin and patterns of low progesterone with irritability:

        Vitex, Ginger and Withania to Increase Progesterone

        Dose: Adults: Take 1 tablet once daily with food.

        Vitex, zinc, vitamin B6 and withania are blended to relieve affective PMS/PMDD symptoms, support HPA axis function and reduce the physiological impact of stress.

        • Vitex can reduce the symptoms of PMS​[15​] by altering excess levels of stress-induced elevated prolactin secretion, resulting in improved progesterone biosynthesis via dopaminergic action.
          • Compared to fluoxetine, 20 and 40 mg/d of vitex for two months achieved comparable PMDD improvement with reduced premenstrual symptoms and depression scores.[​16]​
        • Vitamin B6 supports biosynthesis of adrenaline, dopamine, and serotonin for stress and mood balance.[​17]​
        • Zinc is a significant element in the central nervous system.​18​ In 100 adolescent female students low serum zinc was correlated with symptoms of anxiety and depression.​[19​]
        • Withania modulates serum cortisol levels, improving resilience towards stress. In 52 patients experiencing chronic stress received, 600 mg/d of withania  reduced in perceived stress after four and eight weeks, as well as lower cortisol levels compared to baseline. [20​]

        OR

        With PMDD tension, low mood and irritability

        Bupleurum Complex for Nervous Tension and Irritability

        Dose: Take 3 capsules twice daily with food.

        A traditional combination of Chinese botanical extracts including bupleurum, Chinese peony and liquorice to relieve stress and nervous tension and support mood in women with premenstrual disorders.

        • When administered to 30 women with PMDD over six months, both depressive-like symptoms and general functioning greatly improved. Additionally, almost half of the PMDD group had complete remission of depressive-like symptoms.[21]
        • In a systematic review of 1,837 patients with depression, the combination of herbs was comparable to antidepressants but with less adverse effects.[22]

        OR

        With heightened anxiousness and HPA activity

        Herbal Support for Hyper HPA and Stress

        Dose: Take 1 tablet three times daily

        A combination of zizyphus, passionflower, kudzu and magnolia that enhance GABA activity, working against glutamate-mediated excitability in the brain to alleviate anxiety, nervous tension and agitation, common to PMS and PMDD.

        • Zizyphus has been shown to modify the GABAA receptors [23], while Passionflower binds to GABAA and GABAB receptors.[24]
          • In n=154 with prolonged nervous tension, 1,020 mg/d of passionflower for 12 weeks improved stress-associated symptoms including restlessness, sleep disturbances, exhaustion and anxiety.[25]
        • Kudzu has demonstrated β-adrenoceptor blocking activity , which may help reduce the physical effects of anxiety and stress such as palpitations, tremor and sweating.[26]
        • Magnolia exhibits muscle relaxing effects via GABAergic mechanisms,as well as neuroprotective properties.[27-28]

        Select from the following to support nutritional health - Magnesium, Calcium and Vitamin D

        Magnesium & Inositol to Support Healthy Female Hormonal Balance & Vitality

        Dose: Add 2 level scoops (9.8 g) to 200ml of water once to twice daily.

        Meta Mag® magnesium bisglycinate, vitamin B6 and zinc are included in this nutritional blend to support women’s hormonal health, improve stress resilience and alleviate the symptoms of PMS.

        • Magnesium, zinc and vitamin B6  supplementation may support mood symptoms symptoms and support PMS remission.[29-31]
          • 250 mg/d of magnesium and 40 mg/d of vitamin B6 for two months were shown to significantly lower mean PMS scores including anxiety and depression.[27]
          • Supplementing 30 mg/d to 50 mg/d of zinc over 12 weeks can significantly improve both physical and psychological symptoms of PMS, including sleep, PMS-related mood presentations such as anger/irritability, anxiety/tension, depressed mood, insomnia, and interference with work productivity.[30,32]
        OR

        Magnesium with Lutein and Zeaxanthin for Sleep Pattern Support

        Dose: Add 1 scoop (5.7 g) in 200 mL of water once daily in the evening.

        Meta Mag® magnesium bisglycinate, ornithine, withania, lutein and zeaxanthin to address disrupted sleep cycle patterns and improve sleep quality.

        • Magnesium has been shown to significantly decrease serum cortisol levels, resulting in increased in slow wave sleep(p<0.01).[33]
          • 500 mg/d of magnesium over eight weeks increased sleep time, efficiency, and latency (p<0.03). Serum cortisol levels decreased (p<0.008) in correspondence with increased in melatonin (p<0.007),[34]
        • 400 mg ornithine improves sleep quality, as well as reducing stress markers through the regulation of cortisol and dehydroepiandrosterone sulfate (DHEAS) production.[35]
        • 250 mg/d and 600 mg/d of withania over eight weeks improves perceived stress scores, reduces morning cortisol and enhance sleep quality (p<0.05).[36]
        • Lutein and zeaxanthin support the production and release of melatonin. Supplementation of 20 mg/d of lutein and 4 mg/d of zeaxanthin reduced sleep disturbances and the need for sleep-enhancing medications.[37]

        Vitamin D3
        Dosage: Take 1 capsule daily with food.

        • Low serum 25-hydroxycolecalciferol (25(OH)D3) during the luteal phase has been observed in women with premenstrual disorders.[38]

         

        Hydroxyapatite Complex for Complete Bone Support

        Dosage: Take 1 tablet three times daily with meals.

        Whole bone extract, hydroxyapatite calcium, combined with vitamin D.

        • Hypocalcaemia has been associated with low mood, irritability/restlessness and agitation; calcium supplementation at 500 mg/d over two menstrual cycles.[39]
        • The combination of calcium (500 mg daily) with vitamin B6 (80 mg daily), was more effective than vitamin B6 alone in reducing both general and affective PMS symptoms.[40]

        Diet and Lifestyle Recommendations

        Diet:

        • Western Diet: High in processed foods, trans fats, and sweets; low in fruits and vegetables. Linked to severe PMS.[41]
        • Cravings: Women with PMDD often crave high-fat, sweet foods during the late luteal phase.[42]
        • Healthy Diet: High in fiber, vegetables, whole grains, calcium, vitamin D, and B vitamins can lower PMS risk. A Mediterranean diet promotes balanced macronutrients and moderate portions.[43]
        • Regular Meals: Skipping meals, especially breakfast, is linked to PMDD. Regular meals can help manage symptoms.[44]

        Lifestyle:

          • Exercise: Regular exercise (30-60 minutes, 3-4 times a week) improves mood and sleep. Types include aerobic exercise, yoga, and swimming.[45,46]
          • Barriers: PMS symptoms can reduce motivation for exercise. Exercise during the luteal phase may feel more tiring.[48-49]
          • Boosting Enjoyment: Social activities (team sports, group classes), variety in exercise, and matching intensity to wellbeing can help.[47,49]
          • CBT: Cognitive Behavioral Therapy (60-90 minutes, over 10-24 weeks) reduces mood symptoms. Combining CBT with calcium and vitamin D supplements is more effective.[50,51]
          • Other Tips: Quit smoking, limit alcohol, and maintain regular sleep to reduce symptom severity.[52]

          Pharmaceutical Treatments:

          Contact Metagenics Clinical Support to ensure product recommendations are suitable for use in conjunction with pharmaceutical medications.

          • SSRIs: Medications like fluoxetine, sertraline, paroxetine, and citalopram are first-line treatments for severe mood symptoms.[54]
          • Oral Contraceptives (OCs): OCs can help with symptoms like breast pain, bloating, acne, and appetite, though results for PMS relief are mixed.[55]
          • GnRH Agonists: Effective for PMS and PMDD physical symptoms but can cause bone loss and other side effects. Long-term use requires additional hormone therapy.[55]
          • NSAIDs: Drugs like naproxen can alleviate symptoms such as cramping, aches, diarrhea, and heat intolerance.[55]

            Additional Resources

            Footnotes

            * For the purposes of this treatment protocol, the term ‘woman’ or ‘women’ refers to any individual who has ovaries and therefore may experience PMS and PMDD.

            References

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