Sex hormones regulate neuromuscular junction structure, plasticity, and disease vulnerability

The neuromuscular junction (NMJ) is a highly specialized synapse that enables efficient communication between motor neurons and skeletal muscle fibers. Its structural integrity is essential for voluntary movement, yet the NMJ is not static and undergoes continuous remodelling in response to physiological and pathological challenges. Emerging evidence highlights sex and hormonal regulation as critical determinants of NMJ plasticity. Estrogen, testosterone, and progesterone influence neurotransmitter release, postsynaptic receptor clustering, neurotrophic signalling, and glial support. Their fluctuations across puberty, reproductive age, menopause, and aging shape NMJ vulnerability and resilience, offering mechanistic insight into sex-biased patterns of neuromuscular aging and disease. Clinical observations in disorders such as myasthenia gravis and amyotrophic lateral sclerosis reveal sex-linked differences in onset, progression, and therapeutic outcomes, further underscoring the role of endocrine status. Translational strategies are beginning to exploit these mechanisms. Hormone replacement therapy, pharmacological synaptic stabilizers, and lifestyle interventions such as exercise, nutrition, and sleep regulation show potential to modulate NMJ health. In parallel, personalized and sex-specific medicine frameworks incorporating genomics, biomarkers, and endocrine profiling hold promise for precision-based approaches. Despite these advances, significant knowledge gaps remain. Experimental systems underrepresent female biology, clinical trials rarely stratify by sex or hormonal status, and systems biology approaches are only beginning to uncover sex-dependent regulatory networks. Addressing these gaps will require interdisciplinary research integrating endocrinology, neuroscience, and systems medicine. A deeper understanding of sex and hormonal regulation at the NMJ may ultimately enable individualized interventions that preserve synaptic function across aging, disease, and regeneration.