PMDD: A Physician’s Perspective
- By Trudie Mitschang
Table of Contents
DAVID R. RUBINOW, MD, is a distinguished professor and chair of psychiatry at the University of North Carolina (UNC) School of Medicine, and founding director of the UNC Center for Women’s Mood Disorders. With more than 25 years of research into the neurobehavioral effects of gonadal steroids, Dr. Rubinow has focused extensively on conditions like premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD).
At A Glance
- Psychiatrist David R. Rubinow, MD, discusses the diagnostic framework and neurobiology of premenstrual dysphoric disorder.
- PMDD diagnosis depends on the timing of symptoms within the menstrual cycle rather than specific symptoms alone.
- Research led by Dr. Rubinow identified genetic variants involving estrogen receptors and the COMT gene that may contribute to PMDD vulnerability.
- Treatments discussed include selective serotonin reuptake inhibitors and ovarian suppression.
- Accurate diagnosis and awareness among clinicians remain essential for effective management of menstrual cycle-related mood disorders.
PMDD diagnosis depends on the timing of symptoms within the menstrual cycle.
BSTQ: Why is the timing of symptoms crucial to understanding and accurately diagnosing PMDD?
Dr. Rubinow: PMDD is a time-oriented not symptom-oriented diagnosis: Symptoms must consistently occur during the luteal phase of the menstrual cycle, after ovulation, and resolve during the follicular phase, after menstruation begins. This cyclical pattern is what defines PMDD more so than any specific symptoms. That said, typical symptoms include depression, sadness or hopelessness; mood swings; concentration problems; fatigue and lethargy; and feelings of being out of control. Breast swelling or tenderness, headaches, joint or muscle aches, weight gain and bloating may also occur.
PMDD Symptoms and Cyclical Diagnostic Pattern
- PMDD symptoms occur during the luteal phase of the menstrual cycle after ovulation.
- Symptoms resolve during the follicular phase once menstruation begins.
- Emotional symptoms may include depression, sadness, mood swings and feelings of being out of control.
- Physical symptoms may include breast tenderness, headaches, joint or muscle aches, bloating and weight gain.
Development of diagnostic criteria for PMDD and luteal phase mood disorders.
BSTQ: How did you help define the criteria for PMDD?
Dr. Rubinow: In the mid-1980s, two key developments in PMDD occurred. First, a national conference aimed to standardize diagnostic procedures for PMS. Around the same time, I organized a National Institute of Mental Health (NIMH) workshop to establish formal criteria for PMS that could be used across studies. These efforts led to the development of what was initially termed late luteal phase dysphoric disorder, which included the same symptoms now recognized as PMDD.
Evolution of PMDD Diagnostic Criteria
- Efforts to standardize diagnostic procedures for PMS began in the mid-1980s.
- A National Institute of Mental Health workshop established research criteria for luteal phase mood disorders.
- Early terminology included late luteal phase dysphoric disorder.
- The condition later became recognized as premenstrual dysphoric disorder.
Genetic research identifies estrogen receptor variants associated with PMDD.
BSTQ: You also led a study identifying genetic variants linked to PMDD. What did you discover?
Dr. Rubinow: We used gene-based haplotyping to study five genes, focusing in particular on estrogen receptors alpha and beta. We analyzed single nucleotide polymorphisms (SNPs) variations in the DNA sequence, selecting representative ones to cover large regions of each gene, which uncovered four SNPs in the fourth intron of the estrogen receptor alpha (ERα) gene that were significantly associated with PMDD. When combined into what’s called a haplotype, the association became even stronger. Interestingly, this genetic link was evident only in women who also carried a specific variant of another gene: catechol-O-methyltransferase (COMT).
Genetic Variants Linked to Hormone Sensitivity in PMDD
- Gene-based haplotyping examined genetic variation in estrogen receptor genes.
- Four SNPs within the estrogen receptor alpha gene were associated with PMDD.
- Combining these variants into a haplotype strengthened the association.
- The genetic relationship appeared only in individuals who also carried a specific COMT gene variant.
Interaction between estrogen signaling, dopamine metabolism and mood regulation.
BSTQ: Why is the COMT gene so significant in this context?
Dr. Rubinow: COMT helps metabolize estrogen and breaks down dopamine in the prefrontal cortex. Estrogen influences prefrontal blood flow during cognitive tasks, and other research has confirmed the prefrontal cortex’s importance in mood. The COMT variant we studied is known as Val/Val at position 158 (Valine/Valine). This form breaks down dopamine more rapidly, which may deplete dopamine in the prefrontal cortex. When combined with the identified ERα haplotype, this dopamine depletion could help explain why some women are more vulnerable to hormone-triggered mood disorders like PMDD. In short, we found a receptor for a hormone (estrogen) known to impact mood, and a gene variant (COMT) that alters how the brain processes that hormone and its downstream neurotransmitters.
Neurobiology of Hormone-Triggered Mood Disorders
- COMT plays a role in estrogen metabolism and dopamine breakdown in the prefrontal cortex.
- Estrogen influences blood flow in brain regions involved in cognitive processing.
- The Val/Val COMT variant accelerates dopamine breakdown.
- Interaction between estrogen receptor variants and COMT may increase vulnerability to hormone-related mood disorders.
Molecular insights may inform future PMDD treatment strategies.
BSTQ: Do these genetic insights change how PMDD should be diagnosed or treated?
Dr. Rubinow: These findings could eventually lead to new molecular targets for treatment and deepen our understanding of how mood is regulated — not just in hormone-related disorders but in mood disorders more broadly. Unlike most forms of depression, PMDD has a clear physiologic trigger: hormonal changes during the menstrual cycle. That gives us a unique opportunity to study mood regulation and potentially apply what we learn to broader psychiatric conditions.
Implications for PMDD Research and Treatment
- PMDD has a clear physiologic trigger linked to hormonal fluctuations during the menstrual cycle.
- Genetic findings may help identify new molecular targets for treatment.
- PMDD provides a model for studying hormone-related mood regulation.
- Insights from PMDD research may inform broader understanding of mood disorders.
Clinical treatment strategies for PMDD.
BSTQ: What approach have you used in your clinical practice to treat PMDD?
Dr. Rubinow: Selective serotonin reuptake inhibitors are very effective for some of these disorders. Another form of treatment is ovarian suppression. (It’s not a first-line treatment, but it is a way of determining whether there is a hormonal etiology of the disorder.)
Common Treatment Approaches for PMDD
- Selective serotonin reuptake inhibitors may reduce mood symptoms associated with PMDD.
- Ovarian suppression can be used to evaluate whether symptoms are hormonally driven.
- Treatment approaches focus on reducing symptom severity or stabilizing hormonal triggers.
Importance of clinician awareness and accurate diagnosis.
BSTQ: What do you hope healthcare providers take away from your research?
Dr. Rubinow: Always ask women of reproductive age about mood symptoms. These issues are often dismissed or misunderstood — by both patients and clinicians. Yet effective treatments do exist. The key to successful treatment is accurate diagnosis. Recognizing PMDD and other menstrual cycle-related mood disorders should be standard practice for gynecologists, psychiatrists and primary care providers alike.
Clinical Awareness and Diagnosis of PMDD
- Mood symptoms related to the menstrual cycle are often overlooked in clinical practice.
- Screening for mood changes in women of reproductive age can improve recognition of PMDD.
- Accurate diagnosis is central to effective treatment.
- Gynecologists, psychiatrists and primary care physicians all play roles in identifying menstrual cycle-related mood disorders.
Frequently Asked Questions
Why is the timing of symptoms important for diagnosing PMDD?
PMDD is defined by a recurring pattern in which symptoms appear during the luteal phase of the menstrual cycle and resolve after menstruation begins. This cyclical timing distinguishes PMDD from many other mood disorders.
What symptoms are commonly associated with PMDD?
Common symptoms include depression, sadness, mood swings, fatigue, difficulty concentrating and feelings of loss of control. Physical symptoms such as breast tenderness, headaches, bloating and muscle aches may also occur.
What genetic factors have been linked to PMDD?
Research has identified variants in the estrogen receptor alpha gene that may be associated with PMDD. This association appears stronger in individuals who also carry a specific variant of the COMT gene involved in dopamine metabolism.
How might estrogen and dopamine influence PMDD?
Estrogen affects brain regions involved in mood and cognition. Variations in genes that regulate estrogen signaling and dopamine metabolism may influence how the brain responds to hormonal fluctuations.
What treatments are commonly used for PMDD?
Selective serotonin reuptake inhibitors are frequently used to manage mood symptoms. In some cases, ovarian suppression may be used to determine whether symptoms are triggered by hormonal changes.
Why is PMDD sometimes overlooked in clinical practice?
Mood symptoms related to the menstrual cycle may be misattributed to other psychiatric conditions or not routinely discussed during medical visits. Increased awareness among clinicians can help improve diagnosis and treatment.
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