A Neuroendocrine-Immune Model of Hidradenitis Suppurativa: Mechanistic Insights into Pain, Pruritus, and Hormonal Triggers.

Background/Objectives: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease traditionally viewed through a purely dermatologic lens. However, this perspective fails to explain stress-induced flares, menstrual cycle-linked exacerbations, and severe pain and itch disproportionate to visible cutaneous inflammation. This narrative review synthesizes evidence supporting a neuroendocrine-immune model of HS pathogenesis, with emphasis on mechanisms underlying pain and itch. Methods: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases (January 1990-September 2025) with terms including hidradenitis suppurativa, neuroendocrine mechanisms, HPA axis, sex hormones, neuropeptides, pain (including nociceptive and neuropathic pain, burning, and dysesthesia), and pruritus (itch). Eligible studies included peer-reviewed research examining hormonal, stress-related, or neuropeptide mechanisms in HS. Data were synthesized into thematic categories: endocrine influences, HPA axis function, neuropeptide signaling, immune crosstalk, and clinical implications. Results: Sex hormones promote follicular occlusion and modulate immune responses, explaining perimenstrual flares. Prolactin amplifies inflammation during stress through immune cell activation. Insulin resistance and adipokine imbalance create pro-inflammatory conditions. Chronic stress induces HPA axis dysfunction with cortisol resistance, exacerbating inflammation. Neuropeptides released from cutaneous nerves amplify immune activation and directly mediate pain and itch. These pathways establish self-perpetuating feedback loops wherein inflammation drives stress, and neuroendocrine dysfunction amplifies immune responses. Conclusions: HS represents a systemic disorder with a strong neuroendocrine-immune component, rather than a purely dermatologic condition. This framework supports multidisciplinary management integrating hormonal therapies, targeted immunomodulation, and stress reduction. Future research should characterize neuroendocrine biomarkers and test combination therapies targeting multiple system nodes.