Fig. 2.

Regulation of gonadotropin-releasing hormone (GnRH) secretion by kisspeptin, leptin, testosterone, and estradiol. Kisspeptin is the most important stimulator of hypothalamic GnRH secretion. Normal adult serum leptin concentrations induce stimulation of hypothalamic kisspeptin neurons by pre-mamillary ventral neurons (PMV) in men. Leptin is secreted by fat cells, and normal serum adult leptin concentrations depend on adequate nutrition. Thus, anorexia and cachexia are associated with diminished GnRH outflow. Obesity is associated with high serum leptin concentrations is also associated with diminished stimulation of GnRH; this effect might be due to obesity-related leptin resistance or indirect and direct feedback via PMV and hypothalamic kisspeptin neuron cells. Testosterone exerts negative feedback on androgen receptors expressed by hypothalamic kisspeptin cells whereas estradiol may suppress GnRH secretion indirectly via hypothalamic kisspeptin neuron cell estradiol alpha receptors and directly via hypothalamic GnRH receptors