60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years

Abstract

At the time of the publication of Geoffrey Harris's monograph on 'Neural control of the pituitary gland' 60 years ago, the pituitary was recognised to produce a growth factor, and extracts administered to children with hypopituitarism could accelerate growth. Since then our understanding of the neuroendocrinology of the GH axis has included identification of the key central components of the GH axis: GH-releasing hormone and somatostatin (SST) in the 1970s and 1980s and ghrelin in the 1990s. Characterisation of the physiological control of the axis was significantly advanced by frequent blood sampling studies in the 1980s and 1990s; the pulsatile pattern of GH secretion and the factors that influenced the frequency and amplitude of the pulses have been defined. Over the same time, spontaneously occurring and targeted mutations in the GH axis in rodents combined with the recognition of genetic causes of familial hypopituitarism demonstrated the key factors controlling pituitary development. As the understanding of the control of GH secretion advanced, developments of treatments for GH axis disorders have evolved. Administration of pituitary-derived human GH was followed by the introduction of recombinant human GH in the 1980s, and, more recently, by long-acting GH preparations. For GH excess disorders, dopamine agonists were used first followed by SST analogues, and in 2005 the GH receptor blocker pegvisomant was introduced. This review will cover the evolution of these discoveries and build a picture of our current understanding of the hypothalamo-GH axis.

Single-Cell RNA-Seq Reveals Hypothalamic Cell Diversity

“…We found that like the expression profile of neuropeptides, the expression profile of neuropeptide receptors mRNA is also very diverse (Figures 6B and S6B). Some receptor genes are expressed in only one or a few neuron subtypes, such as Vipr2 (GABA8) and Ghr (Glu15 and GABA15) (Figures 6B and 6E), which are consistent with previous studies (Harmar et al, 2002; Murray et al, 2015). In contrast, several peptide receptor genes, such as Irs4 , Sstr1 , OPrl1 , and Adcyap1r1 , are broadly expressed in multiple neuron subtypes (Figures 6B and 6E), suggesting extensive regulatory roles of these signaling pathways in the hypothalamus.…”

“…The differentially expressed genes (DEGs) are mainly enriched in Glu5, Glu8, Glu12, GABA1, GABA11, GABA15, and GABA18 clusters (Figures 7D and S7A; Table S6), indicating that these neuronal subtypes are the main cells responding to food deprivation. Identification of the Agrp + (GABA15), Ghrh + (GABA11), and Npvf + (Glu12) neurons as food deprivation-responding cell types are consistent with previous studies (Henry et al, 2015; Murray et al, 2015; Wahab et al, 2015) and thus validate our approach. Importantly, scRNA-seq uncovered cell types, such as MM neurons (Glu5), that were not previously linked to energy homeostasis, exemplifying the ability of our unbiased approach in revealing neuron subtype-specific functions.…”

“…For example, Cartpt and Cck are actively transcribed in the Glu5 cluster ( Foxb1 + neuron in MM), while Prph and Wif1 were co-expressed with Hdc in the Hista cluster (histaminergic neurons in tuberomammillary nucleus), both of which were verified by ISH (Figures S5B and S5C). Additionally, we found that the combined expression of Sst and Prdm8 defines the Sst + neuroendocrine cells (Figure 5C, Glu15) located in PVpo (periventricular hypothalamic nucleus, preoptic part) with known function in regulating growth hormone secretion (Murray et al, 2015), but without a definitive molecular marker. We confirmed the co-expression of Sst and Prdm8 in PVpo, but not in cortex, by immunostaining (Figure S5D).…”

Growth Hormone Response to Oral Glucose Load: From Normal to Pathological Conditions

“…Ghrelin, a gut-derived peptide and a ligand of the GH secretagogue receptor is increasingly recognized as the third regulator of GH secretion with a marked stimulatory action. In addition to its excitatory impact on GHRH release and a weaker inhibitory action on somatostatin, ghrelin directly stimulates GH secretion from pituitary somatotroph cells [4, 5]. IGF-1 has a major inhibitory action on GH release through feedback at both the hypothalamus and the pituitary.…”

60 YEARS OF NEUROENDOCRINOLOGY: Celebrating the brain's other output–input system and the monograph that defined neuroendocrinology

“…Harris' monograph of 1955 consolidated an extensive body of evidence into a coherent model -a model that showed his foresight by incorporating inhibition as well as stimulation of pituitary hormone release (see this issue: Grattan 2015, Murray et al 2015: 'The most likely hypothesis is that nerve fibres from the hypothalamus liberate some humoral substance(s) into the capillaries of the primary plexus in the median eminence, and that this substance is carried by portal vessels to excite or inhibit the secretion of the gland cells in the pars distalis [anterior pituitary]' (Harris 1955).…”