Mood changes during the menopause transition share important biological pathways with PMDD, and understanding these connections may help explain why some people are more vulnerable to hormone-driven mood shifts at different life stages.
This review explores how changing levels of estrogen, progesterone, and brain chemicals contribute to depression and anxiety during the transition to menopause. A key focus is allopregnanolone (often called ALLO), a natural brain chemical made from progesterone that normally has a calming effect by boosting the brain's main inhibitory system (called GABA). After menopause, ALLO levels drop, and lower ALLO has been linked to depression. Interestingly, the relationship between ALLO and mood is not straightforward — very low and very high levels seem to be associated with better mood, while levels in between may worsen mood symptoms. This same pattern is thought to play a role in PMDD, where the rise and fall of ALLO during the menstrual cycle can trigger mood symptoms in susceptible individuals.
The review also discusses how estrogen withdrawal affects serotonin, the brain chemical most commonly targeted by antidepressants. During perimenopause specifically, the enzyme that breaks down serotonin appears to become more active, which could contribute to depressed mood. Additionally, the paper covers newer research on kisspeptin and neurokinin B — brain signaling molecules involved in both hot flashes and mood regulation — and highlights emerging treatments like fezolinetant, a recently approved non-hormonal drug for hot flashes that works on these pathways.
For people with PMDD, this research reinforces the idea that sensitivity to normal hormonal fluctuations — not abnormal hormone levels — may be the core issue. The biological mechanisms described here (ALLO, GABA, serotonin changes) overlap significantly with what is understood about PMDD, suggesting these conditions may share a common vulnerability. However, much of the evidence comes from small studies or animal research, and the authors note that the exact interplay between these brain systems is still being worked out.
Key findings
- Postmenopausal women have significantly lower allopregnanolone (ALLO) plasma levels than perimenopausal women (233.8 ± 86.9 pg/mL vs 257.4 ± 80.5 pg/mL in a cohort of 140 women), and levels correlate with years since menopause
- Postmenopausal women with major depression showed reduced plasma ALLO levels compared to healthy postmenopausal controls (4.34 ± 1.14 ng/mL vs 6.00 ± 2.34 ng/mL, N=28)
- A bimodal association exists between ALLO and negative mood: very low and very high levels of ALLO are associated with better mood, while medium (mid-luteal phase) levels are associated with more negative mood and physical symptoms
- Monoamine oxidase A activity in the brain was higher during perimenopause than during reproductive or postmenopausal stages (N=58 women), indicating increased serotonin breakdown during the menopausal transition
- NK3R antagonist (MLE4901) caused a 45% reduction in hot flushes compared to placebo in a phase 2 RCT (N=68 menopausal women), and fezolinetant showed sustained benefits over 52 weeks in phase 3 trials
- Kisspeptin administration in humans caused a 15% decrease in total endogenous GABA levels in brain areas associated with mood control, particularly the anterior cingulate cortex
Methods, briefly
Narrative review of literature from January 1990 to March 2024, searched on PubMed using terms 'menopause' combined with 'mood disorders', 'neurosteroids', 'kisspeptin', or 'neurotransmitters'. Included studies on mechanisms of mood/behavior regulation, estradiol's role in mood disorder pathogenesis, neuroendocrine control of reproduction, and effects of menopausal transition on mood. Exclusion criteria: non-English language, unavailable full texts, dissertations, and correspondence.
Limitations to keep in mind
- Narrative review design without systematic methodology or meta-analytic synthesis
- Most reviewed studies of neuroendocrine changes were conducted in postmenopausal women, often without distinguishing specific perimenopausal stages
- Many cited studies had small sample sizes (e.g., N=10, N=16, N=28)
- Much of the mechanistic evidence is derived from animal models (rodents, primates) with limited direct human data
- The review acknowledges that the precise interplay between the various neuroendocrine systems remains poorly defined
- Sociocultural and psychosocial confounders in mood disorder etiology during menopause were acknowledged but not systematically addressed in the reviewed studies
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