Premenstrual Mood & Anxiety Disorders: Comprehensive Study Notes (PMS, PMDD, PME)

Behavioral Objectives

• Demonstrate familiarity with common and complex premenstrual mood/anxiety phenomena that impact well-being and/or function, including:
  • Premenstrual Syndrome (PMS)
  • Premenstrual Dysphoric Disorder (PMDD)
  • Premenstrual Exacerbation (PME) of other mental health conditions
• Analyze PMS, PMDD and PME experiences within a socio-cultural context
• Apply knowledge of pathophysiology and refined screening, assessment and diagnostic skills in evaluating premenstrual mood and anxiety symptoms
• Recommend a range of behavioral, integrative, psychotherapeutic & medical treatments when caring for people with PMS, PMDD, and PME

Premenstrual Mood & Anxiety Symptoms

• Symptoms occur from ovulation through day 1 to 3 of menses
• Involve physical, psychological, cognitive and behavioral domains
• Range of impact from nuisance to intense suffering with potential functional impairment
• PMDD diagnosis can be delayed; historically reported as requiring up to $12\text{-}\text{years}$ and $6\text{ providers}$ to diagnose

Menstrual-Associated Mood Phenomena

• PMS: impacts $30\% \text{ to } 80\%$ of menstruating people (in studies)
• PMDD: experienced by $3\% \text{ to } 8\%$
• PME: $40\%$ of those seeking PMDD treatment have an underlying mood disorder
• PMDD + mood/anxiety disorder: it’s possible to have both

PMDD Morbidity & Mortality

• Four-fold higher risk of suicidal thoughts $4\text{-fold}$
• Seven-fold higher risk of suicide attempts $7\text{-fold}$
• Higher healthcare utilization
• Increased absenteeism and lower productivity
• Major impacts on interpersonal relationships

PMDD Morbidity & Mortality (Continuation)

• Distress and impairment from PMDD can occupy from 24 days up to 6 months annually
• With symptoms occurring one week per menstrual cycle, the cumulative yield is about $8.6\text{ years}$ of suffering between menarche and menopause

PMDD & PME: Foreshadowing & Shared Biology

• PMDD and PME may foreshadow other mood disturbances such as:
  • Postpartum Mood & Anxiety Disorders
  • Perimenopausal Mood & Anxiety Disorders
• These conditions share at least one biological contributor, which is now a target of treatment

Premenstrual Mood & Anxiety Experiences: PERILS

• The experience can be pathologized, politicized, or misunderstood; the slide emphasizes potential harm in medicalizing normal cyclical changes

Disordering Menstrual Experience: A Socio-Cultural Analysis

• Consider ramifications of “disordering” the menstrual cycle in the context of pervasive sexism
• Are menstrual cycles enabling, disabling — or both?
• Is naming and treating menstrual-associated morbidity empowering or disempowering?

Historically: Medicalization & Social Context

• Patriarchal, colonized, and capitalist societies have diminished seasonal/biological rhythms to support linear order, efficiency, and productivity (birth, menstruation, pregnancy, caregiving, death)
• Modern life structure often clashes with fluctuating life experiences
• Disordering/medicalization can label deviance from expectations and desired outcomes

The Medicalized Shadow of Menstruation

• Historical focus on psychological symptoms of PMS/PMDD/ PME over physical & cognitive symptoms
• Perpetuation of “hysteria” or womb-related emotionality/weakness
• PMS/PMDD/ PME labels attempt to capture extreme suffering related to menstruation

Medical Culture: Light vs Shadow of Menstruation

• Medical culture often emphasizes shadow aspects of menstruation, neglecting positive changes (e.g., higher energy, joyful moods, creativity)
• Emphasized quote:
  • “the medicalization of the menstrual cycle, [is] a position that ignores any positive menstrual changes”
  • Source: King, S. (2020)

Follicular Phase Wellness (Illustrative)

• Follicular phase: estrogen rises, progesterone is suppressed, corresponds to normal mood, increased energy, cognitive clarity
• Graph/illustration cited from a secondary source (no primary data provided in the slide)

Neuron Changes Under Hormones

• First half of cycle: estrogen rises → dendrites branch, synapses added
• Second half of cycle: estrogen falls → dendrites and synapses pruned
• Net effect: brain may be less efficient during certain phases, contributing to PMS/PMDD/PME

Premenstrual Mood & Anxiety Disorders: PEARLS for Assessment

• PMS: pattern across $3\text{ cycles}$; mild to moderate distress; interferes with activities; lower quality of life

PMS Psychological & Physical Symptoms (Overview)

• Psychological: anger, anxiety, depression, irritability, overwhelm, rejection sensitivity, social withdrawal
• Physical: abdominal bloating, appetite disturbance (usually increased), breast tenderness, headaches, lethargy/fatigue, muscle aches/joint pain, sleep disturbance (hypersomnia), swelling
• Cognitive: forgetfulness, poor concentration
• Affects $30\% \text{ to } 80\%$ of women (ACOG 2021)

PMDD Diagnostic Criteria (Timing & Core Symptoms)

• Timing: symptoms in the late luteal phase, resolving within the first few days of menses for most cycles
• One or more of the following must be present:
  • Marked affective lability (mood swings, sadness/tearfulness, increased sensitivity to rejection)
  • Marked irritability or anger or increased interpersonal conflicts
  • Marked depressed mood, hopelessness, or self-deprecating thoughts
  • Marked anxiety, tension, or feelings of being keyed up or on edge
• Symptoms must cause distress or interfere with function

PMDD Diagnostic Criteria (Extended)

• To reach PMDD diagnosis, one or more of the following additional symptoms must be present along with the core ones:
  1) Decreased interest in usual activities
  2) Subjective difficulty in concentration
  3) Lethargy, easy fatigability, or marked lack of energy
  4) Marked change in appetite; overeating or cravings
  5) Hypersomnia or insomnia
  6) A sense of being overwhelmed or out of control
  7) Physical symptoms such as breast tenderness/swelling, joint/muscle pain, bloating, or weight gain

Pathophysiology: Premenstrual Mood/Anxiety Symptoms (Raffi & Freeman 2017)

• Genetic heritability estimated at $30\% \text{ to } 80\%$
• Brain differences: amygdala and prefrontal cortex involvement
• Altered HPG/HPA function → increased inflammation → greater trauma impact / lower resiliency
• Impaired estrogen-serotonin interactions
• Neurogenic neurotransmitter BDNF: suboptimal levels
• Concept summarized as "5 interwoven pieces" linking hormones, brain, genes, inflammation, and neurochemistry

Progesterone & Allopregnanolone in PMDD/PME

• People with PMDD/PME have heightened sensitivity to allopregnanolone (a metabolite of progesterone) which acts on GABA-A receptors in the brain
• GABA is the major inhibitory neurotransmitter; it modulates activity and can dampen overactivity
• In luteal phase, progesterone and allopregnanolone rise; in susceptible individuals this can amplify PMDD/ PME symptoms

The Role of Allopregnanolone in PMDD/PME

• Rising allopregnanolone levels influence GABA-A receptors in the amygdala (emotional center)
• The result is PMDD/PME symptoms in those with heightened sensitivity
• When menstruation begins and allopregnanolone levels decrease, symptoms rapidly subside
• This mechanism has become a target for new treatments

Differential Diagnosis: Medical Conditions to Rule Out

• Chronic Fatigue Syndrome, Fibromyalgia, Irritable Bowel Syndrome, Migraine, Thyroid disorders

Differential Diagnosis: Psychiatric Conditions to Rule Out

• Major Depression, Generalized Anxiety Disorder, Bipolar Disorder, Intermittent Explosive Disorder

Is It PME or PMDD Superimposed on Another Disorder?

• Distinguish PME vs PMDD superimposed on another disorder
• PMDD: luteal symptoms arise and resolve completely early in menses
• PME: symptoms present most of the cycle and intensify in the luteal phase
• PMDD superimposed on another disorder: different luteal-phase symptoms that resolve with menses

Assessment Challenges

• Different tools emphasize different experiences/symptoms
• PMDD is a culture-bound phenomenon; use open-ended questions to avoid missing symptoms

Premenstrual Experiences Across Cultures

• Prevalence, symptom type, frequency, and severity vary by culture
• Visualization shows darker shades for higher reported premstrual symptoms across countries (Hantsoo et al. 2022)

Assessment Tools

• Prospective mood charting across two cycles
• Premenstrual Symptoms Screening Tool (PSST)
• Calendar of Premenstrual Experiences (COPE)
• Daily Rating of Severity of Problems (DRSP)
• Prospective Record of the Severity of Menstruation (PRISM)

Premenstrual Mood & Anxiety Disorders: TREATMENT Pearls

• Why treat PMDD & PME?
  • Decrease distress, including suicidality risk
  • Increase empowerment and sense of agency around personal health
  • Improve function: reduce absenteeism, interpersonal conflict, and relationship strain
• The aim is to break the cycle of suffering, support recovery and repair, and instill hope

Building a Premenstrual Treatment Plan

• Collaborate to set achievable treatment goals focused on “Living Well” with a chronic condition present for much of the reproductive years
• Individualize care: consider acuity, self-harm risk, speed of treatment efficacy, comorbid conditions, and treatment side effects
• PMDD treatments exist on a continuum from less invasive to more invasive, and from intermittent to continuous to permanent

Key Behavioral Interventions

• Invoke feminist therapy principles: see individuals across contexts
• Explore home factors where sexism or under-communication may contribute
• Consider societal limitations on menstruators beyond the home; encourage patients to “take up space” around biological rhythms

Clinical Practice Suggestions: Education & Cycle Tracking

• Educate about menstrual physiology and PMDD/PME pathophysiology
• Menstrual suppression is safe; not strictly necessary to have fertile cycles if risks outweigh benefits
• Cycle tracking is increasingly accessible and aids luteal-phase planning for stepped-up self-care
• Cycle tracking may be challenging with irregular cycles

Behavioral Interventions: Practical Strategies

• Stepped-up self-care during luteal and menstrual phases:
  • Slow down, schedule less, and consider more flexible work arrangements
  • Encourage home policy adaptations and rest periods
• Communication: discuss with partners; reduce home demands during PMDD/ PME “hazard zone”
• Create time, space, and privacy for self-care

Quality of Evidence & Evidence Grading (Clinical Practice)

• A = Strong evidence/rationale for efficacy
• B = Limited but promising evidence
• C = No evidence, mixed evidence, or negative evidence
• Important considerations: science is political; funding in capitalist economies influences medical research; integrative, behavioral, and psychotherapeutic approaches often lack large, adequately powered studies

Behavioral Interventions: Lifestyle Factors (Evidence Levels)

• Dietary: (C)
  • Decrease caffeine and alcohol; no definitive PMS diet; potential Mediterranean/DASH patterns
• Exercise: (C)
  • Increase activity; no specific type/frequency universally effective
• Relaxation, bathing & rest: (C)
• Psychotherapy: (A)
  • Cognitive Behavioral Therapy (CBT)
  • Dialectical Behavior Therapy (DBT)
  • Mindfulness practices; interpersonal effectiveness

Integrative Treatments (Evidence Level: C)

• Acupuncture
• Light therapy
• Calcium
• Vitamin B6
• Gingko biloba
• Vitamin E
• Magnesium
• Chasteberry / Vitex

Medical Interventions

• Combined Oral Contraceptives (OCP) with drospirenone – 24/4 dosing schedule (A)
  • Helpful for PMDD; no evidence for PME
• Other OCPs (C)
• Estradiol patch + progestogen add-back for 10 days/month (oral or LNG-IUD) (B)
• Estradiol + progestin vaginal ring (C)
• Note: watch for progestin-triggered mood symptoms with non-drospirenone progestins
• Ovulation suppression is the key therapeutic target

Gonadotropin-Releasing Hormone (GnRH) Analogues (A)

• Monthly injections (Leuprolide acetate, Goserelin)
• +/- estrogen and progesterone add-back at steady daily dose
• Helpful for PMDD; no evidence for PME

Surgical Treatments (A)

• Total Hysterectomy with Bilateral Salpingo-Oophorectomy (THBSO)
• Consider when PMDD/ PME symptoms remit with GnRH analogue and other options; requires estrogen replacement to protect bones

On the Horizon (Level: B)

• Ulipristal Acetate (UPA)
• Isopregnanolone (Sepranolone)
• Both target mechanisms beyond SSRIs; not yet widely ready for routine use

Ulipristal Acetate (UPA) Details (B)

• Progesterone receptor modulator antagonizing progesterone in responsive brain tissues
• Developed to treat uterine fibroids (2012)
• One positive small study for PMDD (B)
• Dosing: 5 mg PO daily across 3 cycles
• Does not induce a low-estrogen state (unlike GnRH agonists)
• Side effects: headaches, fatigue, nausea
• Safety data for use > 3 months is lacking; liver function monitoring may be advised

Isopregnanolone (Sepranolone) (B)

• Neuroactive steroid that modulates GABA-A receptors
• Inhibits endogenous allopregnanolone effects on receptor activity
• Potential efficacy for Tourette’s and OCD-related compulsions; data in PMDD/PME early
• Initial development as PMDD treatment; dosing: 10 mg subcutaneous every 2 days during luteal phase
• Phase II data show symptom reductions from severe to mild/absent; direct comparison to SSRI outcomes not established
• FDA approval status: unknown

Case Example: Tomiko (PMDD, Pain, Hormonal, and Mental Health Intersections)

• Tomiko: full-time accountant; age 45
• Med history: fluoxetine for generalized anxiety with superimposed PMDD; monthly supportive psychotherapy; stress of caregiving (supporting a teen and ailing mother)
• Symptoms resolved with treatment in 3 months
• At age 46: migraines increased from ~3 days/month to >15 days/month over a year; failed 3 migraine meds in PCP care; no neurology referral
• Increasing fluoxetine dose plus focus on “living well” with chronic pain did not help; depression and anxiety persisted across entire menstrual cycle
• Suffering involved 3 interconnected conditions ignored in women until recently: PAIN CONDITIONS, HORMONALLY-MEDIATED CONDITIONS, MENTAL HEALTH CONDITIONS

Case Example: Sarah (Bipolar II Disorder with PMDD Exacerbation)

• 39-year-old, married, caregiver for 12-year-old son; volunteers at church; supportive psychotherapy twice monthly
• Takes multiple medications for bipolar II with PMDD-related exacerbation (lithium, lamotrigine, extended-release quetiapine)
• Traditional antidepressants (e.g., SSRIs) not suitable due to bipolar disorder
• Trials of cycle-halting strategies (depot progesterone, continuous OCPs, GnRH agonists) not helpful
• Increasing quetiapine XR dose during luteal phase (from 300 mg to 350 mg) showed efficacy for PMDD/ PME symptoms

Hormonal Treatments: Practical Notes

• Combined OCP with drospirenone (A): PMDD-focused; PME lacks strong evidence
• Other OCPs (C)
• Estradiol patch + progestin add-back (B)
• LNG IUD as an option within Estradiol-progestin strategies (monitor for progestin-related mood symptoms)

Ovulation Suppression as a Key Mechanism

• Central theme across hormonal treatments: reducing fluctuations in ovarian hormones can alleviate PMDD/ PME symptoms

Resources for Practice

• MGH Center for Women’s Mental Health: blog-style resources on reproductive mental health
• International Association for Premenstrual Disorders (IAPMD): peer support, education, research, advocacy

Acknowledgements & References

• Acknowledgements: Midwifery Forward 2024 Committee; Pennsylvania ACNM Affiliate; Jessica M. Harrison, PhD, LCSW (UCSF)
• References include: ACOG PMS guidelines; DSM-5; foundational reviews on PMDD; studies on sepranolone and neuroactive steroids; and various reviews on PMDD/PME

Additional Notes on Practice Implications

• Ethical, philosophical, and practical implications of labeling and treating menstrual-related distress require sensitivity to cultural context and patient autonomy
• Consider structural oppression (policy gaps, domestic labor burden, acculturation stress) when assessing psychosocial contributors
• The treatment approach should be personalized: starting with least invasive options and escalating based on acuity, comorbidity, and patient preference

Summary of Key Concepts to Remember

• PMS, PMDD, PME are spectrum-based mood phenomena tied to menstrual cycle biology and brain/gut/neuroendocrine interactions
• PMDD carries higher risk for suicidality and impairment; PME reflects exacerbation of a preexisting disorder during luteal phase
• Allopregnanolone sensitivity and GABA-A receptor modulation are central to PMDD/PME pathophysiology
• Diagnostic criteria require timing, symptom domains, and functional impairment; PMDD diagnosis requires cycle-based confirmation over two cycles
• Assessment requires prospective symptom tracking and culturally sensitive questioning
• Treatments range from lifestyle and psychotherapy to pharmacologic and hormonal strategies, with evolving options on the horizon
• Holistic care benefits from feminist and biopsychosocial approaches that address individual biology, psychology, relationships, and social context