Abstract
<title>Abstract</title> <p>Exogenous estrogen, a common component of hormone replacement therapy (HRT) for perimenopausal and menopausal symptoms, has photosensitizing properties hypothesized to augment ultraviolet (UV) induced skin damage. As HRT use increases, clearer evidence is needed regarding its association with premalignant and malignant cutaneous outcomes. This study evaluates associations between combined, estrogen-only, and progesterone-only HRT and incident actinic keratoses (AKs), basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC), as well as AK treatment. This retrospective cohort study utilized the TriNetX US Collaborative Network from January 1, 2010, through January 1, 2025. Female patients aged 40–60 years with menopausal or perimenopausal disorders were categorized into combined HRT, estrogen-only HRT, progesterone-only HRT, or non-HRT control cohorts. HRT exposure required receipt of the corresponding hormone prescription occurring within one year following menopause diagnosis together with documentation of long-term HRT use. Patients with liver disease, cerebral infarction, acute myocardial infarction, venous thromboembolism, or history of estrogen receptor–positive malignancy were excluded. Cohorts were propensity score matched (1:1) based on demographics, nicotine dependence, prior sunburn diagnosis, skin cancer screening encounters, gynecologic surgery history, and systemic contraceptive exposure. Outcomes were assessed at 1 and 3 years following index. Patients with prior diagnoses of these outcomes were excluded. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated, with p < 0.05 considered statistically significant. Compared with matched controls, combined HRT had a greater association with AK at 1 year [RR, 1.45 (1.11–1.91)] and 3 years [RR, 1.31 (1.08–1.59)] and AK destruction at 1 year [RR, 1.64 (1.16–2.32)]. Although statistically significant, the absolute increase in AK incidence was small (0.24% at one year and 0.35% at 3 years). No statistically significant associations were observed for estrogen-only or progesterone-only HRT with AK, AK destruction, BCC, cSCC, or melanoma. Combined HRT was associated with modest short-term increases in AK and AK destruction, while all HRT lacked associated with increased short-term skin cancer risk. Because AK is a well-established precursor to keratinocyte carcinoma, however, prospective studies with longer follow-up are needed to determine whether these AK-related findings indicate earlier manifestations of photocarcinogenesis before skin cancer develops.</p>