Somatostatin is required for masculinization of growth hormone–regulated hepatic gene expression but not of somatic growth

Abstract

IntroductionThe episodic release of growth hormone (GH) from pituitary somatotrophs results from a complex interplay primarily between two hypothalamic peptides, the stimulatory GH-releasing hormone (GHRH) and the inhibitory somatostatin (SST) (1). Activation of the GH secretagogue receptor (GHS-R) in hypothalamus and pituitary further modulates the actions of the two classically defined regulators of GH secretion (2). Direct measurement of GHRH and SST in hypophyseal-portal blood of male rats indicates a rhythmic pattern of release of these two neuropeptides at regular 3-to 4-hour intervals about 180°out of phase (3). In contrast, female rats appear to have a different release pattern of the two peptides characterized by continuous secretion of SST and episodic, rather than rhythmic bursts of GHRH. As a result, GH secretory profiles in females are distinct from males and may account for the striking sex difference in somatic growth (4). Male rats exhibit narrow GH pulses with a frequency of about one pulse every 3-4 hours and prolonged nadir values below 1-2 ng/ml. Female rats exhibit relatively broader pulses with an irregular frequency and nadir values of 5-20 ng/ml (4). In humans, a similar sexual diergism (functional dimorphism) of GH secretion exists between men and women, indicating phylogenetic conservation of neuroendocrine hormone rhythms (5).The underlying mechanisms for such a sharp sex-specific difference in GH secretion remain unclear. Periventricular hypothalamic SST peptide and mRNA levels are higher in male compared with female rats and mice (6, 7), leading to the suggestion that sex differences in hypothalamic SST signaling to pituitary somatotrophs play a key role in the sexually diergic GH responses (1). Ontogenic studies have demonstrated that these differences are first evident at postnatal day 5 and continue to develop in an orderly cascade through puberty into adulthood (8, 9). There are five known SST receptors (SSTRs) with distinct cellular distributions and Pulsatile growth hormone (GH) secretion differs between males and females and regulates the sexspecific expression of cytochrome P450s in liver. Sex steroids influence the secretory dynamics of GH, but the neuroendocrine mechanisms have not been conclusively established. Because periventricular hypothalamic somatostatin (SST) expression is greater in males than in females, we generated knockout (Smst -/-) mice to investigate whether SST peptides are necessary for sexually differentiated GH secretion and action. Despite marked increases in nadir and median plasma GH levels in both sexes of Smst -/-compared with Smst +/+ mice, the mutant mice had growth curves identical to their sibling controls and retained a normal sexual dimorphism in weight and length. In contrast, the liver of male Smst -/-mice was feminized, resulting in an identical profile of GH-regulated hepatic mRNAs between male and female mutants. Male Smst -/-mice show higher expression of two SST receptors in the hypothalamus and pituitary than do females. These data ind...

Exploring endocrine GH pattern in mice using rank plot analysis and random blood samples

“…In this study, we have focused on analyzing the distribution of GH concentrations, which is readily affected by mutations and treatments. Data from Low et al (2001) and Yakar et al (2001) on SST and LID mutant mice respectively had shown several-fold increase in average GH levels and absence of nadir values in mutants. In such cases of extreme oversecretion, GH data from spot samples can be directly compared.…”

Treatment ofHelicobactergastritis with IL-4 requires somatostatin

“…To insert the Alzet microosmotic pump (Model 1007D, Durect Corporation, Cupertino, CA) into the peritoneal cavity, wild-type C57BL͞6 mice were anaesthetized at 2 mo of age with xylazine (20 mg͞ml) and ketamine (100 mg͞ml). The SOM null (SOM Ϫ/Ϫ ) mice were bred onto a C57BL͞6 congenic background (26). Both wild-type (SOM ϩ/ϩ ) and SOM Ϫ/Ϫ mice were infused with IL-4 for 7 days, as described above, before inoculation with H. felis (see Supporting Materials and Methods, which is published as supporting information on the PNAS web site, www.pnas.org, for details of bacterial strains, culture conditions and quantification of Helicobacter colonization).…”

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

“…At that time, the effects of E2 and/or gonadectomy on sex-biased drug metabolism and thus on the sex-biased expression of cytochrome P450 (P450 CYP) enzymes were thought to be due solely to direct effects of sex steroid hormones on the hepatocyte (27,31). However, it was shown in 1973 by Colby et al (32), and extensively confirmed by numerous studies since then (27,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43), that the feminizing effect on sex-biased liver gene expression of an injection of E2 into a rat or mouse was indirect and had an absolute dependence on the pituitary ( Figure 1). As explained in detail by Waxman and colleagues over the last 2 decades, this neuroendocrine mechanism of sex bias, working through an axis consisting of the hypothalamic arcuate nucleus-growth hormone releasing hormone (GHRH)-growth hormone (GH)-signal transducer and activator of transcription 5 (STAT5) accounts for sex-biased expression of >1,000 genes in the liver and also of body growth and body weight (27,(41)(42)(43)(44)(45)(46)(47)(48) (Figures 2, 3).…”

“…First, how does administration of exogenous E2 (or similar sex steroid) into an animal produce its effects? As mentioned earlier, it has been shown extensively that effects of exogenously injected E2 depend on generating the "feminine plasma growth hormone pattern" through central hypothalamic/pituitary mechanisms (27,(32)(33)(34)(35)(36)(37)(38)(39)(40) (Figure 1). Specifically, a single injection of E2 into a rodent affects the function of cells in the arcuate and ventromedial nucleus in the hypothalamus and additional nuclei therein (27,(49)(50)(51)(52)(53)(54).…”

“…However, in the female mouse GH levels pulse more frequently and with the same pulse heights as in the male mouse, but still with low levels during the interpulse intervals (27,38,57). In contrast, men show infrequent GH pulses of high magnitude, with very low interpulse levels ( Figure 2); however, women show a more continuous high level of GH (Figure 2) (39,40,56,59,60). Thus, a difference between female humans and female rodents is in the much higher continuous GH levels in women compared with female rodents (Figure 2).…”