Kisspeptin as a test of hypothalamic dysfunction in pubertal and reproductive disorders

The hypothalamic-pituitary-gonadal axis is regulated by the gonadotropin-releasing hormone pulse generator in the hypothalamus. This is comprised of neurons that secrete kisspeptin in a pulsatile manner to stimulate the release of GnRH, and, in turn, downstream gonadotropins from the pituitary gland, and subsequently sex steroids and gametogenesis from the gonads. Many reproductive disorders in both males and females are characterized by hypothalamic dysfunction, including functional disorders (such as age-related hypogonadism, obesity-related secondary hypogonadism, hyperprolactinemia, functional hypothalamic amenorrhea and polycystic ovary syndrome), structural pathologies (such as craniopharyngiomas or radiation or surgery-related hypothalamic dysfunction), and pubertal disorders (constitutional delay of growth and puberty and congenital hypogonadotropic hypogonadism). However, in many of these conditions, the relative contribution of hypothalamic dysfunction to the observed hypogonadism is unclear; as to date, there is no direct method of evaluating hypothalamic reproductive function in humans. Indeed, it is not possible to directly measure gonadotropin-releasing hormone levels in the hypothalamo-pituitary portal vessels, such that secondary (i.e., pituitary dysfunction) and tertiary (i.e., hypothalamic dysfunction) hypogonadism are often conflated as one entity. In this review, we examine the evidence for the use of kisspeptin as a method of directly evaluating hypothalamic reproductive dysfunction, and deliberate its potential future role in the evaluation of pubertal and reproductive disorders.