Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

Female reproduction relies on a complex balance of hormones that drive the reproductive cycle (menstrual cycle in humans) and influence fertility. A hormone called GnRH, which stands for gonadotropin-releasing hormone, plays a major role in regulating this balance. GnRH is transmitted from the brain and stimulates the release of other hormones from a nearby gland called the pituitary gland, which, in turn, activates the reproductive organs to produce steroid hormones, such as estrogen. Steroids do many things in the body, including regulating the release of GnRH and pituitary hormones through a process called feedback. In the case of negative feedback, steroids maintain the release of GnRH and pituitary hormone within a normal range. Once per reproductive cycle, estrogen will instead positively feed back into the system and activate GnRH, causing pituitary hormone levels to spike, and initiate the release of one or more eggs from the ovary by a process known as ovulation. The neurons that make GnRH do not directly respond to estrogen, but instead receive input from different upstream neurons that contain estrogen receptors. However, it is poorly understood how fertility is regulated by these neurons. To investigate the effects of estrogen on these upstream neurons, Wang et al. genetically removed the estrogen receptors from two separate populations of neurons in mice. Estrogen was found to affect each of these populations differently, inhibiting one and activating the other. Wang et al. showed that these two populations likely have different roles in reproduction: the population inhibited by estrogen regulates negative feedback and generates reproductive cycles, whilst the population activated by estrogen regulates positive feedback and stimulates ovulation. This knowledge furthers our understanding of how the brain regulates fertility, and the genetic approach used to remove the estrogen receptor could be applied to the study of other hormones that act on the brain.