PMDD: Why Normal Hormones Can Feel Anything But Normal

PMDD isn’t caused by “abnormal” hormone levels. It’s a heightened brain sensitivity to the normal rise and fall of ovarian steroids—especially in the late luteal phase. We know this because when researchers temporarily switch off ovarian hormones, PMDD symptoms resolve; when they add estradiol and progesterone back, symptoms reappear in women with PMDD but not in controls.

Think of it as a timing problem in brain chemistry rather than a quantity problem in hormone levels.

The physiology of PMDD (including eveidence)

1) Sensitivity, not excess

The bedrock studies use a “suppress-and-add-back” design: a GnRH agonist pauses ovarian function and symptoms remit; adding back physiologic estradiol/progesterone triggers symptoms only in susceptible women. That pinpoints an abnormal neural response to normal hormonal change.

2) Neurosteroids & the GABA-A “calm system”

Progesterone is converted into allopregnanolone (ALLO), a neurosteroid that normally soothes the brain by positively modulating GABA-A receptors. In PMDD, ALLO’s signal appears to misfire in the late luteal phase—so the expected calming becomes irritability, anxiety, or despair. Two lines of clinical evidence support this:

• Block ALLO’s effect: The GABA-A–modulating steroid antagonist sepranolone (isoallopregnanolone) reduced core PMDD symptoms in randomised trials.

• Prevent ALLO’s rise: The 5-α-reductase inhibitor dutasteride blunted the luteal surge in ALLO and mitigated PMDD symptoms—without changing luteal progesterone—arguing that ALLO dynamics, not raw progesterone, are the key driver. PMCPubMed

  (Translation: when we damp down ALLO’s luteal spike—or block its action—symptoms improve. That’s strong mechanistic support.)

3) Serotonin’s phase-specific role

SSRIs work unusually fast in PMDD—often within days—and can be dosed intermittently (luteal-phase only) or even at symptom onset with clinical benefit. That’s a clue we’re dealing with phase-locked sensitivity of serotonin signalling, not a constant deficiency. A recent PET study also shows cycle-phase–linked increases in serotonin transporter binding in PMDD that track symptom severity.

4) The stress axis (HPA) joins the conversation

Several studies show altered cortisol dynamics in PMDD—most notably a blunted cortisol response to acute psychosocial stress in the late luteal phase—independent of baseline mood. Day-to-day life studies also find higher stress reactivity in the late luteal phase. Together, this suggests the HPA axis interacts with ovarian steroids and ALLO to shape symptom intensity.

5) Inflammation and circadian rhythm (emerging threads)

The inflammation data are mixed: some studies find modest shifts in cytokines (e.g., IL-10, hs-CRP) and antioxidant status around symptomatic days, but conclusions remain cautious. Circadian work—including melatonin profiles—suggests a clock-vulnerability for a subset, which fits with common sleep complaints in the late luteal phase. Promising, but not settled.

Tying it all together: normal ovarian steroid waves can destabilise GABA-A and serotonin signalling in susceptible brains and alter stress-axis reactivity, producing the classic late-luteal mood, energy and cognitive symptoms. (And yes, going to bed on time beats adding a third espresso.)

Where trauma fits (what the research actually shows)

1) Population signal

Large datasets report a dose–response association between adverse childhood experiences (ACEs) and premenstrual disorders (PMS/PMDD). More or more-severe adversities → higher odds of clinically significant premenstrual symptoms. (Cross-sectional evidence is strong; prospective confirmation is still needed.)

2) PMDD-specific cohorts

In women with prospectively diagnosed PMDD, childhood adversity predicts worse premenstrual mood and altered cortisol cyclicity. One clinical series reported early-life trauma in 83% of women with PMDD, with emotional abuse the most common—associations that persist even after controlling for current depression/anxiety.

3) Mechanistic bridge: stress biology and epigenetics

Early trauma can sensitise the HPA axis and leave epigenetic marks on stress-regulatory genes (e.g., NR3C1, the glucocorticoid receptor), shaping stress responses across life. Independently, PMDD shows blunted luteal cortisol responses to acute stress. Put together, a trauma-tuned stress system meeting hormonal switch-gear is a coherent biological pathway from adversity to cycle-tied symptoms.

Take-home: trauma doesn’t “cause” PMDD on its own, but it raises vulnerability and may amplify the luteal-phase brain response to otherwise normal hormonal signals.

Viktor Frankl said, “Between stimulus and response there is a space.” In PMDD, biology shrinks that space for a few days each month. Our job in care is to help widen it—biologically and psychologically.

Clinical implications (why this matters for real life)

• Diagnosis stays cyclical. Symptoms peak in the week before bleeding and lift with menses; outside that window, mood should return to baseline. Prospective daily ratings remain the most reliable way to confirm the pattern. (No crystal balls—just good data.)

• Treatment can target timing. Because the biology is phase-sensitive, approaches that respect timing—e.g., luteal-phase or symptom-onset SSRI dosing; targeted ALLO-pathway interventions in research settings; and sleep/light routines—often punch above their weight.

• Trauma-informed support is justified. Given the ACEs signal and HPA-axis findings, integrating safe, trauma-aware psychological care alongside medical/nutritional strategies is not “soft”—it’s biologically sensible.
  

Quick FAQ

Is PMDD just depression?
No. PMDD is cycle-tied. The same person can feel fine in the follicular phase and unwell in the late luteal phase. (That pattern is the point.)

If hormones are normal, why would SSRIs help?
Because the issue is timing and sensitivity in serotonin pathways. Short, well-timed SSRI dosing can stabilise that window.

What’s the deal with progesterone and ALLO?
Progesterone’s metabolite ALLO usually calms the brain; in PMDD, the ALLO–GABA-A signal can flip. Blocking ALLO’s action (sepranolone) or preventing its luteal rise (dutasteride) reduces symptoms in trials.

Where does trauma come in?
Trauma can “tune” the stress system. Later, the normal hormonal shift meets a primed HPA axis and sensitive GABA/serotonin networks—so symptoms surge right before a period.

References

• Ovarian suppression/add-back: Schmidt & Rubinow, NEJM 1998; Schmidt et al., Am J Psychiatry 2017. New England Journal of MedicinePsychiatry Online

• ALLO/GABA-A pathway: Bixo et al., sepranolone RCTs; Martinez et al., dutasteride crossover. PubMed+1PMC

• SSRIs’ rapid/intermittent efficacy & symptom-onset dosing: Freeman/Steiner and later RCTs; 2016 JAMA Psychiatry paper. PMC+1

• Serotonin transporter PET: Sacher et al., Biological Psychiatry 2023. Biological Psychiatry JournalPubMed

• HPA axis responses: Hamidovic et al. 2024 (TSST); Beddig et al. 2019 (daily-life stress). PMCPubMed

• ACEs & PMDs: Yang et al. 2022 (dose-response); Nayman et al. 2023; Kulkarni et al. 2022 (83% trauma prevalence in PMDD).PMCPubMed+1