Pituitary growth hormone network responses are sexually dimorphic and regulated by gonadal steroids in adulthood

Abstract

There are well-recognized sex differences in many pituitary endocrine axes, usually thought to be generated by gonadal steroid imprinting of the neuroendocrine hypothalamus. However, the recognition that growth hormone (GH) cells are arranged in functionally organized networks raises the possibility that the responses of the network are different in males and females. We studied this by directly monitoring the calcium responses to an identical GH-releasing hormone (GHRH) stimulus in populations of individual GH cells in slices taken from male and female murine GH-eGFP pituitary glands. We found that the GH cell network responses are sexually dimorphic, with a higher proportion of responding cells in males than in females, correlated with greater GH release from male slices. Repetitive waves of calcium spiking activity were triggered by GHRH in some males, but were never observed in females. This was not due to a permanent difference in the network architecture between male and female mice; rather, the sex difference in the proportions of GH cells responding to GHRH were switched by postpubertal gonadectomy and reversed with hormone replacements, suggesting that the network responses are dynamically regulated in adulthood by gonadal steroids. Thus, the pituitary gland contributes to the sexually dimorphic patterns of GH secretion that play an important role in differences in growth and metabolism between the sexes. sex hormones | body growth | calcium signaling | systems biology I n most species, males and females display a marked phenotypic divergence in body size, with increased growth rate and body mass being a predominantly masculine trait. Furthermore, in all species examined to date, the growth hormone (GH) axis demonstrates sex-specific differences in hormone contents, secretory outputs, and secretory patterns (1) and their effects on gene expression (2-4). The secretion of GH is controlled by hypothalamic GH-releasing hormone (GHRH) and somatostatin, and there is good evidence for sex-specific imprinting on hypothalamic hypophysiotropic neurons exerted by gonadal steroid exposure early in life (5), with ongoing effects during puberty (6). This has led to the conclusion that the sexually dimorphic control of GH patterns reflects sex differences in GHRH and somatostatin inputs to the pituitary gland. Acute changes in gonadal steroid environment drastically alter the patterns of GH pulsatility in adulthood (7,8); however, although they receive sexually dimorphic inputs (9, 10), GHRH neurons do not display sex-specific electrical characteristics (9, 11). We have previously shown that GH cells in the male mouse pituitary gland form an extensive homotypic cell network with an architecture that exhibits marked plasticity during sexual maturation and that can be altered by gonadectomy (12). Thus, it was important to determine whether male and female pituitary glands would show different responses to the same stimulus in the absence of any hypothalamic influence. To explore this, we assessed the functional activit...

Related pituitary cell lineages develop into interdigitated 3D cell networks

“…Cell shape and network topology are thus adapted to provide equal access of cells to vasculature within the context of the other and more abundant lineages that occupy the bulk of the gland. Whereas cell networks may serve an important role in endocrine function by the rapid exchange of signals, as shown for the GH cell network (6,7,14), their presence may also reflect the developmental program of organogenesis (Fig. 5C).…”

“…The recent discovery of homotypic GH cell networks extending throughout the pituitary has provided the structural basis to explain these types of interactions and differing responsiveness. Indeed, all GH cells of the pituitary maintain adherent junctions with each other to form an extensive cell network that allows extremely rapid exchange of signals between cells and the production of highly synchronized and high amplitude secretory response (6,7). The existence of this 3D web-like GH cell network was not suspected before on the basis of traditional of 2D histological analyses, particularly as GH cells account for the bulk of anterior pituitary cells.…”

Zebrafish pituitary gene expression before and after sexual maturation

“…Therefore, the pulsatory patterns of Gh secretion, and not the transcriptional levels of gh, determine the levels of Gh in the plasma. Thus, gonadal steroids are the main factors that regulate the patterns of GH secretion (Sanchez-Cardenas et al 2010). It has also been reported that sex steroids and some neurotransmitters, such as dopamine and glutamate, regulate Gh levels in fish sera (Wong et al 2006, Canosa et al 2007.…”

“…Profound gender differences exist in several aspects of the endocrine axes (Nishida et al 2005, Sanchez-Cardenas et al 2010. Thus, exploration of sexual dimorphic expression of the major hormones in the pituitary gland may help to understand the physiological regulation of growth metabolism in adult fish.…”

Lipotoxicity disrupts incretin-regulated human β cell connectivity

“…Correlation analyses were performed using a Pearson R coefficient as previously detailed (72). Briefly, individual fluo-2-loaded cells were identified using a region of interest (ROI), and intensity over time traces and Cartesian (x-y) coordinates were extracted.…”