Considering the potential of ovarian hormones in rescuing neurological phenotypes in Duchenne muscular dystrophy – it’s time to think beyond the muscles

• Neurological comorbidities in DMD are common but poorly understood and rarely targeted, contributing to reduced quality of life for patients. • Ovarian hormones may improve neurocognitive symptoms in DMD, but research is limited due to stigma and hormonal complexity. • Oestrogen and progesterone jointly regulate the stress axis and may offer broader neuroendocrine benefits in DMD beyond corticosterone suppression alone. • Future DMD trials should include central nervous system assessments to understand how treatments affect both muscle and neurological phenotypes. Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that causes premature mortality in young boys. While muscle degeneration is the central cause of death, a myriad of other comorbidities, including neurological dysfunction, afflict boys with DMD throughout their life − yet addressing these secondary dysfunctions has been largely overlooked. This has contributed to a poor mechanistic understanding of neurological comorbidities, a lack of specific clinical treatments and, therefore, a reduced quality of life for patients with DMD. Despite years of near exclusive focus on both pharmacological and genetic therapies to improve muscular phenotypes, there remains limited treatments for DMD. It is time to broaden the therapeutic scope to address the neurological phenotypes in DMD, which may improve patient and family quality of life. Transdisciplinary literature across the field of DMD and other neurological disorders provides evidence that ovarian hormones (oestrogen and progesterone) could play a role in rescuing aspects of neurobehavioural and cognitive dysfunction. Yet given the complexities of systemic endocrine hormone signalling, and a likely negative bias in treating males with female sex hormones, only rudimentary investigations in this area have been conducted. We propose that neurological comorbidities in DMD may stem not only by the absence of dystrophin in the brain, but also from peripheral endocrine control. This hypothesis explores the potential of these peripheral pathways—specifically through ovarian hormones or their receptor modulators—as a novel strategy to improve neurological dysfunction in DMD.