A framework for safe estradiol modulation in male bipolar disorder
Theoretical justification for Serm-enabled adjunctive therapy
Bibliographic Data
| ID | 15524308 |
|---|---|
| Authors | John Carlson, J Andrew Carlson (0000-0002-6866-6314, Montana State University, corresponding author) |
| Year | 2025 |
| Volume | 16 |
| Pages | 1644175-1644175 |
| Publication date | 2025-09-09 |
| Open Access | Yes |
| Type | ARTICLE |
| Venue | Frontiers in Psychiatry (JOURNAL) |
| Journal identifiers | ISSN: 1664-0640 • E-ISSN: 1664-0640 |
| Publisher | Frontiers Media (PUBLISHER • CH) |
| DOI | 10.3389/fpsyt.2025.1644175 |
| PMID | 40995073 |
| OpenAlex | W4414218420 |
| Language | EN |
| Citations received | 1 |
| References cited | 75 |
Treatment-resistant bipolar disorder (TR-BD) in males remains a significant clinical challenge, often unresponsive to standard monoaminergic therapies. This paper proposes a novel, sex- informed hypothesis: that adjunctive estradiol, buffered by selective estrogen receptor modulators (SERMs), can therapeutically engage estrogen receptor beta (ER-β) and G protein-coupled estrogen receptor 1 (GPER1) in the male brain, targeting core dysfunctions in TR-BD. Integrating evidence from neuroendocrine, neuroimmune, and synaptic signaling research, we posit that central estrogen receptor activation can restore neuroplasticity, suppress pro- inflammatory cascades, and recalibrate stress responsivity without inducing feminizing systemic effects. Preclinical and translational studies suggest that ER-β and GPER1 activation enhances brain-derived neurotrophic factor (BDNF) expression, modulates CREB and PI3K/Akt pathways, and attenuates interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) signaling-mechanisms dysregulated in TR-BD. We hypothesize that co-therapy with estradiol and a SERMin male TR-BD will reduce affective instability, cognitive impairment, and stress sensitization via selective activation of ER-β/GPER1, without inducing peripheral feminization. This receptor-targeted strategy offers an endocrine-neutral alternative to existing treatments, with implications for mood disorders, schizophrenia-spectrum illnesses, and trauma-related psychopathology. This framework invites translational trials using biomarker-enriched patient stratification. If validated, it could reshape the role of sex hormones in male psychiatry-not as contraindications, but as precision neuromodulators aligned with neurobiological pathology
CREB · Estrogen · Estrogen receptor · GPER · Monoaminergic · Mood · Selective estrogen receptor modulator · Sensitization · Sigma-1 receptor · Bipolar Disorder and Treatment · Maternal Mental Health During Pregnancy and Postpartum · Tryptophan and brain disorders
Bipolar disorder
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The Experience of Symptoms of Depression in Men vs Women
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| Citations per year | 1 |
|---|---|
| Citation span | 2026 - 2026 (1) |
| Highly cited | No |