Abstract
Keywords
Dear Editor,
Genital lichen sclerosus is a chronic, inflammatory and fibrosing dermatosis associated with significant sexual and urological morbidity. It confers an increased risk of penile intraepithelial neoplasia, squamous cell carcinoma and melanoma.1–4 Although its precise aetiopathogenesis remains debated, an expanding body of anatomical, clinical and investigative evidence supports a central role for chronic, occluded exposure of susceptible genital epithelium to urine.5,6
We write to report a recurring clinical observation from a busy tertiary penile dermatology service. Over recent years, we have encountered a number of people with penis presenting with florid, extensive and often rapidly progressive genital lichen sclerosus, who were receiving sodium–glucose cotransporter-2 (SGLT2) inhibitor therapy for type 2 diabetes mellitus. While genital mycotic infections are a well-recognised adverse effect of this drug class, lichen sclerosus has not, to our knowledge, been highlighted in this context. Our intention is not to assert causality, but to raise awareness of a plausible and biologically coherent association that warrants further scrutiny.
The urinary occlusion hypothesis proposes that post-micturition micro-incontinence, combined with occlusion by the foreskin or neo-foreskin, creates prolonged contact of susceptible penile epithelium with urine. This leads to inflammatory injury and, ultimately, sclerosis.5,6 The anatomical distribution of disease, its near-exclusive occurrence in uncircumcised people with a penis, the high prevalence of post-void dribbling in affected patients, and the frequent resolution of disease following circumcision or elimination of urinary contact collectively support this mechanism.5–7
SGLT2 inhibitors act by blocking renal glucose reabsorption in the proximal tubule, resulting in persistent glycosuria. This fundamentally alters the biochemical composition of urine, increasing glucose concentration and potentially modifying pH, osmolarity and the local microbial milieu. 8 In uncircumcised people with a penis, even small amounts of post-micturition dribbling may therefore expose the balanopreputial epithelium to urine that is more irritant, more osmotically active, and more conducive to dysbiosis than urine in non-medicated patients. 9 We hypothesise that this altered urinary environment may exacerbate epithelial damage in predisposed individuals, accelerating or exacerbating the development of genital lichen sclerosus in urine-exposed and occluded sites.
Importantly, this proposed mechanism aligns with several established clinical observations, viz. The association of lichen sclerosus with micro-incontinence, the development of lichen sclerosus at urinary stoma sites, recurrence in the circumcised with neo-foreskin formation, and remission following elimination of urinary contact. 5 SGLT2 inhibitor–induced glycosuria may therefore represent a pharmacological modifier or exacerbator of an already recognised pathogenic pathway, rather than an independent or novel cause of disease.
Given the increasing use of SGLT2 inhibitors, heightened awareness of this complication among dermatologists, urologists and prescribing physicians is important. In people with a penis presenting with new-onset or unusually severe genital lichen sclerosus, the medication history should include specific enquiry about SGLT2 inhibitor therapy. Prospective studies examining disease incidence, severity and outcomes in patients receiving these agents would be valuable, as would mechanistic work exploring how altered urinary properties might influence genital epithelial integrity. 10
In summary, our clinical experience suggests that a link between SGLT2 inhibitor therapy and severe penile lichen sclerosus, may plausibly be mediated through exacerbation of urinary exposure and occlusion. We anticipate this brief paper will stimulate discussion and further investigation.
