Association between peripheral hsa-miR-4456 expression and plasma oxytocin in men with hypersexual disorder and healthy controls: a secondary cross-sectional analysis

MicroRNAs are candidate regulators and biomarkers of molecular processes relevant to behavior, but their relationships with neuroendocrine signaling in humans remain poorly characterized. Earlier studies in overlapping cohorts identified hypermethylation-associated downregulation of peripheral blood-derived hsa-miR-4456 in men with hypersexual disorder and implicated oxytocin-related pathways through in-silico target prediction; a subsequent study found higher plasma oxytocin in the same clinical context. Whether miR-4456 expression and oxytocin covary within the same individuals had not been examined.

We performed a secondary cross-sectional analysis of baseline, pretreatment measurements from clinically characterized men with hypersexual disorder and healthy male controls. miR-4456 was measured by RT-qPCR in EDTA blood-derived material and plasma oxytocin by radioimmunoassay. The submitted pooled robust regression included 74 paired measurements; revised group-adjusted and interaction models included 73 complete cases (51 hypersexual disorder and 22 controls). miR-4456, but not oxytocin, was rank-based inverse-normal transformed using Blom's method.

In the submitted pooled model, higher miR-4456 was associated with lower plasma oxytocin (β = -4.039 pmol/L, 95% CI -6.149 to -1.930; p < 0.001). After adjustment for diagnostic group, the estimate remained negative but was attenuated (β = -1.522, 95% CI -3.376 to 0.333; p = 0.106). The control-specific estimate was -0.613 (95% CI -3.693 to 2.467; p = 0.696), the hypersexual-disorder estimate was -2.223 (95% CI -4.514 to 0.069; p = 0.057), and the interaction was not significant (p = 0.414). Post hoc sensitivity analyses were directionally consistent but imprecise.

To our knowledge, this is the first human study to directly examine paired peripheral miR-4456 and plasma oxytocin measurements. Although diagnostic-group differences explained part of the pooled association, the paired observation connects previously separate epigenetic, expression, pathway-prediction, and neuroendocrine findings and identifies a focused hypothesis for independent replication. The cross-sectional peripheral measurements do not establish directionality, causation, or central nervous system regulation. Experimental studies are needed to determine whether miR-4456 has any functional influence on oxytocin-related biology.