P501 - LBA_ECE_1260 - Androgen sensitivity and hypogonadotropic hypogonadism correlate differently and independently with cardiovascular risk in severe obesity

Abstract

Androgen activity has been variably associated with cardiovascular disease (CVD) in the literature. Obesity is known to be linked to both hypogonadism and an increased risk of CVD. However, evidence regarding the relationship between increased androgen sensitivity and CVD remains heterogeneous and inconclusive. To evaluate, in a large cohort of patients with severe obesity: (I) the length of CAG repeats in the androgen receptor (AR) gene, as a marker of androgen sensitivity, as compared with the general population; and (II) the potential association between gonadal function and androgen sensitivity with CVD. A total of 163 adult male patients (age >18 years) with severe obesity (BMI > 35 kg/m2) were consecutively enrolled in a cross-sectional observational study. Clinical history was collected for each participant, and gonadal function was assessed by calculating free testosterone (cFT) and measuring gonadotropin levels. Hypogonadism was defined as persistent cFT <225 pmol/L and classified as hypogonadotropic (HH) or hypergonadotropic based on LH levels (cut-off ≤9.4 IU/L). Androgen receptor sensitivity was evaluated by analyzing the length of CAG repeats in the AR gene, using PCR amplification followed by DNA fragment analysis. Androgen sensitivity was categorized as reduced (>24 CAG repeats), intermediate (21-24 repeats), or increased (<21 repeats). Funded by the European Union—Next Generation EU—NRRP M6C2—Investment: 1.3.2, Sub-investment 1.3.2.3.3. CUP E43C25005270001 Chi-square analysis assessing androgen sensitivity revealed a significantly higher frequency of AR gene CAG repeats <21 (P < .0001) in our cohort, indicating greater androgen sensitivity than the general population. Logistic regression analysis investigating the association between CVD with gonadal function and androgen sensitivity demonstrated an independent association with both a lower number of CAG repeats (P = .037) and the presence of HH (P = .041), after adjustment for age, BMI, arterial hypertension, type 2 diabetes mellitus, obstructive sleep apnea (OSA), and smoking history (pack-years). We report, for the first time, a higher prevalence of increased androgen sensitivity in patients with severe obesity compared with the general population. Moreover, both increased androgen sensitivity and, conversely, the presence of HH are independently associated with CVD, suggesting the involvement of distinct pathogenic mechanisms: on the one hand, higher androgens are a known risk factor for CVD; on the other, HH may reflect an underlying systemic inflammatory state capable of exerting deleterious effects on both the cardiovascular system and the central regulation of the hypothalamic-pituitary-gonadal axis.