The neuroendocrine basis of lactation-induced suppression of GnRH: role of kisspeptin and leptin

Abstract

Lactation is an important physiological model of the integration of energy balance and reproduction, as it involves activation of potent appetitive neuropeptide systems coupled to a profound inhibition of pulsatile GnRH/LH secretion. There are multiple systems that contribute to the chronic hyperphagia of lactation: 1) suppression of the metabolic hormones, leptin and insulin, 2) activation of hypothalamic orexigenic neuropeptide systems NPY, AGRP, orexin (OX) and melanin concentrating hormone (MCH), 3) special induction of NPY expression in the dorsomedial hypothalamus, and 4) suppression of anorexigenic systems POMC and CART. These changes ensure adequate energy intake to meet the metabolic needs of milk production. There is significant overlap in all of the systems that regulate food intake with the regulation of GnRH, suggesting there could be several redundant factors acting to suppress GnRH/LH during lactation. In addition to an overall increase in inhibitory tone acting directly on GnRH cell bodies that is brought about by increases in orexigenic systems, there are also effects at the ARH to disrupt Kiss1/neurokinin B/dynorphin neuronal function through inhibition of Kiss1 and NKB. These changes could lead to an increase in inhibitory auto-regulation of the Kiss1 neurons and a possible disruption of pulsatile GnRH release. While the low levels of leptin and insulin contribute to the changes in ARH appetitive systems, they do not appear to contribute to the suppression of ARH Kiss1 or NKB. The inhibition of Kiss1 may be the key factor in the suppression of GnRH during lactation, although the mechanisms responsible for its inhibition are unknown.

Fig. 1

Summary of the changes in hypothalamic appetitive neuropeptide systems during lactation. Lactation causes an increase in the activity of orexigenic systems (NPY, AGRP, MCH, OX) and a decrease in anorexigenic systems (POMC and CART). The integration of these systems results in a sustained hyperphagic drive at the level of the PVH. The physical suckling stimulus can activate some of these systems and is responsible for the induction of NPY in the DMH, an adaptation of lactation that may be critical for the sustained hyperphagia. The low levels of serum leptin and insulin also provide signals for the alterations in ARH NPY/AGRP and POMC systems. The combination of the suckling stimulus plus low levels of leptin and insulin ensure that a sustained hyperphagia is maintained to meet the energy demands of milk production. The appetitive neuropeptide systems also provide overlapping regulation of GnRH neuronal activity, thus serving as integrating links between energy balance and reproduction.

Fig. 2

Schematic representation of the regulation of GnRH during lactation. GnRH cell bodies coexpress receptors for several of the orexigenic appetitive neuropeptide systems (MCH/MCHR1, NPY/Y5R, OX/OX1) that are increased during lactation. The MCH and NPY inputs have direct inhibitory effects on GnRH activity through actions on postsynaptic receptors (the effects of the OX/OX1 system is unknown). The decrease in Kiss1 drive from the AVPV could also lead to a decrease in excitatory tone on the neurons. Together, these effects could result in a significant inhibitory tone and result in a decrease in basal GnRH neuronal activity. It is unclear whether these same neuropeptide systems also affect GnRH fibers or terminals to inhibit GnRH release. The alterations in ARH KNDy neuronal function could lead to a suppression of Kiss1 and GnRH release from the median eminence. The diagram of the ARH is a representation of the model published by Wakabayashi et al. (2010) and Navarro et al. (2009), in which the changes in Kiss1 and NKB during lactation are depicted. The suppression of NKB mRNA and peptide levels, coupled to no change in DYN levels, would result in an increased inhibitory autofeedback on the KNDy neurons. The decrease in Kiss1 and NKB release on GnRH fibers and terminals could lead to an inhibition of GnRH pulsatile release (Navarro et al., 2009; Wakabayashi et al., 2010). The factors responsible for the suppression of Kiss1 and NKB are unknown, although the low levels of leptin and insulin do not appear to be contributing factors.