Figure 7.

The importance of (tuberoinfundibular dopamine) TIDA, (kisspeptin/neurokinin B/dynorphin (KNDγ or KISS1), and gonadotropin-releasing hormone (GnRH)-secreting neurons in the prolactin (PRL)- and kisspeptin (KP)-dependent regulation of the hypothalamic–pituitary–gonadal (HPG) axis in females. TIDA neurons located in the arcuate nucleus (ARC; marked with a dashed green line) send axons towards the median eminence (ME). The tonic release of dopamine (DA) from these neuronal endings provides an appropriate level of inhibition of PRL release from lactotrophs (LTH) under physiological conditions [8]. PRLR expression in TIDA neurons is crucial for the operation of such a short negative feedback loop in the DA/PRL system [270,271,272]. PRL in a sufficiently high concentration causes suppression of GnRH neurons that are scattered between the preoptic area (POA; marked with a dashed red line) and ARC in the shape of an “inverted Y” [82]. Due to the negligible expression of PRLR in GnRH neurons, the inhibitory effect of PRL is exerted indirectly through the participation of KNDy neurons located within the ARC [13,294,295,296,297]. PRLR stimulation of KNDy neurons leads to inhibition of KP secretion, a family of polypeptides that stimulate GnRH secretion via the KP receptor (KISS-1R, also known as GPR54) in GnRH neurons [315,316,317]. PRL-dependent, limited stimulation of GnRH neurons with KP to release GnRH translates into reduced release of gonadotropins from the anterior pituitary gland with the subsequent manifestation of hypogonadotropic hypogonadism [45,314]. Hormones of ovarian origin, mainly estradiol (E₂) and progesterone (P4), operating in a long negative feedback loop, influence the activity of GnRH neurons with a force proportional to their concentration in the blood. Other abbreviations: CNS—central nervous system, DYN—dynorphin, FSH—follicle-stimulating hormone, GABA—gamma-aminobutyric acid, LH—luteinizing hormone, NKB—neurokinin B, “+”—stimulation, “−”—inhibition.