PARIS — Women experience hormonal fluctuations throughout life that affect mood and may help explain their higher rates of depressive disorders. Premenstrual syndrome (PMS) and its severe form, premenstrual dysphoric disorder (PMDD), affect more than half of women. At the Brain Congress 2026 held in Paris from January 21 to 23, 2026, a session was entirely devoted to answering this question, “Do hormones make people irritable?”

Luteal Phase Onset

In that context, the pathophysiology of PMS and PMDD and potential therapeutic approaches were analyzed at length byAnne-Laure Sutter‑Dallay, MD, PhD, perinatal psychiatrist at Charles Perrens University Hospital in Bordeaux, France.

Premenstrual syndrome was mentioned long ago by Hippocrates, albeit with some rather fanciful hypotheses. In 1953, Greene and Dalton formalized the concept by describing periodic physical and psychological symptoms in women of reproductive age. Later, PMDD was conceptualized to define severe presentations with primarily psychological manifestations, and it is now classified as a depressive disorder in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

PMS and PMDD are characterized by symptoms that appear in the luteal phase after ovulation, improve in the days following the onset of menstruation, and disappear in the follicular phase. PMDD goes undiagnosed in more than half of cases, despite the loss of quality of life it causes, Sutter‑Dallay said.

Prevalence and Severity Data

PMS presents with predominantly physical symptoms such as breast swelling and weight gain, accompanied by mild psychological symptoms like irritability and labile mood. Between 75%-85% of women experience at least one of these symptoms. Moderate-to-severe forms of PMS affect 25%-30% of women, and PMDD affects 2%-9%, with severe manifestations that are primarily psychological. PMDD is defined by the presence of at least five symptoms over two consecutive cycles, including at least one affective symptom and one cognitive, behavioral, or physical symptom such as emotional lability, irritability, depressed mood, feelings of hopelessness or self-deprecation, anxiety, tension, reduced interest in usual activities, subjective difficulty concentrating, lethargy, excessive fatigability, changes in appetite, overeating, strong cravings for certain foods, hypersomnia or insomnia, feeling overwhelmed or out of control, breast tenderness, edema, joint pain, muscle pain, and weight gain.

Women suffering from PMDD more often have psychiatric comorbidities than others, including bipolar disorder, anxiety disorders, and depressive disorders.

Studies have also shown that PMDD is associated with an increased risk for postpartum depression, a fourfold higher risk for suicidal thoughts, and a sevenfold higher risk for suicide attempts. These women also have higher rates of past trauma, smoking, obesity, and are more likely to come from disadvantaged socioeconomic backgrounds.

Progesterone, Estradiol, and Mood

How can PMS, in all its forms including the most severe, be explained? These disorders appear after ovulation, when progesterone rises.Women with PMDD may also have lower luteal phase estradiol levels or an abnormal response to hormonal fluctuations.

These syndromes may result from interactions between cyclical variations in ovarian hormones and central neurotransmitters via GABAergic, serotonergic, and opioid pathways. A metabolite of progesterone, allopregnanolone — which normally has sedative and anxiolytic properties — may be involved in PMDD pathophysiology. Women with PMDD may have lower luteal‑phase allopregnanolone levels or an abnormal response to its cycle‑related variations, Sutter‑Dallay said. There also appears to be an increase in proinflammatory markers during the luteal phase, which is more pronounced in PMDD. Finally, genetic heritability of PMDD is estimated at about 20%-40% in studies comparing monozygotic and dizygotic twins.

Is Serotonin Involved?

What are the treatment options? Because the pathophysiology is not fully elucidated, several therapies have been proposed. In women with severe symptoms, trials have tested antidepressants such as sertraline, fluoxetine, and paroxetine, given either continuously or intermittently during the luteal phase. Results show a reduction in dysphoric symptoms of approximately 40%-60% compared with 20%-30% with placebo.

This effectiveness suggests serotonin may be involved in PMDD pathophysiology, perhaps because selective serotonin reuptake inhibitors increase allopregnanolone levels. Low‑dose combined oral contraceptives containing drospirenone and ethinyl estradiol may be offered, observing their contraindications like overweight and cigarette smoking, although efficacy still needs confirmation, Sutter‑Dallay said. More radical strategies — such as ovulation suppression with gonadotropin‑releasing hormone agonists, danazol, or, more definitively, ovariectomy — eliminate symptom cyclicity but are associated with severe side effects and are not standard treatments. A new therapeutic avenue is the use of allopregnanolone antagonists, such as sepranolone (UC1010).

Finally, lifestyle changes may affect mood in marked PMS or PMDD: dietary changes with reduced caffeine and simple sugars, as well as physical exercise. Psychotherapy, particularly cognitive behavioral therapy, can also help women cope with symptoms.

PMDD therefore remains underrecognized and underdiagnosed, and progress is still needed in management, notably with the development of specific treatments.

This story was translated from Medscape's French edition.