INS and obesity due to melanocortin 4 receptor deficiency: The exact mechanism for this inhibitory effect of high BMI/obesity on gonadotropin secretion is unclear but might include insulin resistance, inflammatory mediators, leptin, hypothalamic kisspeptin affecting gonadotropin -releasing hormone (GnRH) secretion and/or increased aromatase activity resulting in elevated estradiol levels which in turn augment negative feed-back regulation [7, 37, 38, 42–44].