ESR1 and obesity due to melanocortin 4 receptor deficiency: Indeed, early studies showed higher estradiol concentrations in young to middle-aged subjects with obesity compared to lean controls [29], and following studies reported the treatment of hypogonadal subjects with obesity with selective estrogen receptor modulators (SERM) or anti-aromatase inhibitors (AI) to be successful in stimulating the HPT axis and in achieving physiological T levels [30,31].