The Role of Kisspeptin Neurons in Mediating Prolactin-Induced Suppression of LH Secretion

Abstract

Hyperprolactinaemia is one of the major causes for infertility. It is well-established that elevated prolactin levels suppress the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, and therefore cause a reduction in pulsatile luteinizing hormone (LH) secretion from the pituitary gland. However, the exact mechanism by which prolactin suppresses fertility remains largely unknown. With only less than a hundred GnRH neurons express prolactin receptors, it was proposed that prolactin would act indirectly in the underlying neural circuitry that regulates GnRH pulsatile secretion. In this report, we have tested the hypothesis that prolactin-induced inhibition of LH secretion is mediated by kisspeptin neurons that are known to be one of the major excitatory inputs to GnRH neurons. To evaluate pulsatile LH secretion, serial blood samples from diestrous mice were collected and LH measured using an ultrasensitive enzyme-linked immunosorbent assay (ELISA). We demonstrated that acute prolactin administration decreases LH pulses and mean LH secretion in wildtype mice. This prolactin-induced suppression on LH secretion was lost in mice with a conditional knock-out of prolactin receptors (PRLRs) specifically in kisspeptin neurons. To locate the kisspeptin neurons responsible, immunohistochemistry was used to examine prolactin responses in kisspeptin neurons by using prolactin-induced phosphorylation of signal transducer and activator of transcription 5 as a marker of PRLR-mediated signal transduction.