Age-related differences in the growth hormone secretory response to hGHRH 1-44 in male rats from infancy through puberty

1987 ◽  
Vol 116 (1) ◽  
pp. 138-144 ◽  
Author(s):  
Dorothy I. Shulman ◽  
Margaret Sweetland ◽  
Gregory Duckett ◽  
Allen W. Root
Keyword(s):  
Serum Testosterone ◽  
Pituitary Cell ◽  
Secretory Response ◽  
Male Rats ◽  
Percentage Increase ◽  
Gh Secretion ◽  
Age Related ◽  
Pentobarbital Anaesthesia

Abstract. The GH secretory response to varying doses (15, 30, 60 μg/kg) of sc administered hGHRH 1–44 (or normal saline) was measured in vivo in 10, 20, 30, 40, 50, 60 and 130 days old pentobarbital-anaesthetized, male rats. The 10-min GH level and ΔGH were in general significantly greater in older rats (50, 60, 130 days old) than in younger rats (10, 20 days old) following all doses hGHRH. Ten-day-old animals had no significant GH response to any dose of hGHRH tested. ΔGH correlated significantly with age (r = 0.36; P < 0.0001) and Sm-C level (r = 0.29; P < 0.01) but not with serum testosterone concentrations. Monolayer pituitary cell cultures were established in rats aged 10 to 130 days and were incubated with varying concentrations of hGHRH 1–44 (0.05, 0.5, 5.0, 50 nmol/l or incubation medium). Cultures from 10- and 20-day-old animals had a greater percentage increase over basal GH secretion than other groups at all concentrations of hGHRH tested (P < 0.05). Age-related differences in the GH secretory response to hGHRH are present in male rats from 10 to 130 days. The in vitro results reported here suggest that the increase in magnitude and sensitivity of the GH response to hGHRH observed in pubertal animals in vivo under pentobarbital anaesthesia is likely due to influences above the level of the somatotrope receptor.

Mechanism of action of Hexarelin. I. Growth hormone-releasing activity in the rat

1996 ◽  
Vol 135 (4) ◽  
pp. 481-488 ◽  
Author(s):  
Antonio Torsello ◽  
Roberta Grilli ◽  
Marina Luoni ◽  
Margherita Guidi ◽  
Maria Cristina Ghigo ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Mechanism Of Action ◽  
Direct Action ◽  
Male Rats ◽  
Surgical Ablation ◽  
Adult Rats ◽  
Gh Secretion ◽  
Plasma Gh

Torsello A, Grilli R, Luoni M, Guidi M, Ghigo MC, Wehrenberg WB, Deghenghi R, Müller EE, Locatelli V. Mechanism of action of Hexarelin. I. Growth hormone-releasing activity in the rat. Eur J Endocrinol 1996;135:481–8. ISSN 0804–4643 We have reported Hexarelin (HEXA), an analog of growth hormone-releasing peptide 6 (GHRP-6), potently stimulates growth hormone (GH) secretion in infant and adult rats. This study was undertaken to further investigate Hexarelin's mechanisms of action. In 10-day-old pups, treatments with HEXA (80 μg/kg, b.i.d.) for 3–10 days significantly enhanced, in a time-related fashion, the GH response to an acute HEXA challenge. Qualitatively similar effects were elicited in pups passively immunized against growth hormone-releasing hormone (GHRH) from birth. In adult male rats, a 5-day pretreatment with HEXA (150 μg/kg, b.i.d.) did not enhance the effect of the acute challenge, and the same pattern was present after a 5-day pretreatment in male rats with surgical ablation of the mediobasal hypothalamus (MBH-ablated rats). In addition, in adult sham-operated rats, Hexarelin (300 μg/kg, iv) induced a GH response greater (p < 0.05) than that induced by GHRH (2 μg/kg, iv). However, in MBH-ablated rats 7 days after surgery, GHRH was significantly (p < 0.05) more effective than HEXA, and 30 days after surgery HEXA and GHRH evoked similar rises of plasma GH. Finally, the in vitro Hexarelin (10−6 mol/l) effect was transient while GHRH (10−8 mol/l) induced a longer lasting and greater GH release. Three different mechanisms, not mutually exclusive, are postulated for Hexarelin stimulation of GH secretion in vivo: a direct action on the pituitary, though of minor relevance; an indirect action that involves release of GHRH, of relevance only in adult rats; and an action through the release of a still unknown hypothalamic "factor", which in infant and adult rats elicits GH release acting sinergistically with GHRH. Antonio Torsello, Department of Pharmacology, via Vanvitelli 32, 20129 Milano, Italy

scholarly journals Obestatin Partially Affects Ghrelin Stimulation of Food Intake and Growth Hormone Secretion in Rodents

Endocrinology ◽  
2007 ◽  
Vol 148 (4) ◽  
pp. 1648-1653 ◽  
Author(s):  
Philippe Zizzari ◽  
Romaine Longchamps ◽  
Jacques Epelbaum ◽  
Marie Thérèse Bluet-Pajot
Keyword(s):  
Food Intake ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Male Rats ◽  
Pituitary Cells ◽  
Gh Secretion ◽  
Freely Moving ◽  
Stimulation Of

Administration of ghrelin, an endogenous ligand for the GH secretagogue receptor 1a (GHSR 1a), induces potent stimulating effects on GH secretion and food intake. However, more than 7 yr after its discovery, the role of endogenous ghrelin remains elusive. Recently, a second peptide, obestatin, also generated from proteolytic cleavage of preproghrelin has been identified. This peptide inhibits food intake and gastrointestinal motility but does not modify in vitro GH release from pituitary cells. In this study, we have reinvestigated obestatin functions by measuring plasma ghrelin and obestatin levels in a period of spontaneous feeding in ad libitum-fed and 24-h fasted mice. Whereas fasting resulted in elevated ghrelin levels, obestatin levels were significantly reduced. Exogenous obestatin per se did not modify food intake in fasted and fed mice. However, it inhibited ghrelin orexigenic effect that were evident in fed mice only. The effects of obestatin on GH secretion were monitored in superfused pituitary explants and in freely moving rats. Obestatin was only effective in vivo to inhibit ghrelin stimulation of GH levels. Finally, the relationship between octanoylated ghrelin, obestatin, and GH secretions was evaluated by iterative blood sampling every 20 min during 6 h in freely moving adult male rats. The half-life of exogenous obestatin (10 μg iv) in plasma was about 22 min. Plasma obestatin levels exhibited an ultradian pulsatility with a frequency slightly lower than octanoylated ghrelin and GH. Ghrelin and obestatin levels were not strictly correlated. In conclusion, these results show that obestatin, like ghrelin, is secreted in a pulsatile manner and that in some conditions; obestatin can modulate exogenous ghrelin action. It remains to be determined whether obestatin modulates endogenous ghrelin actions.

In vitro pituitary GH secretion after GHRH, forskolin, dibutyryl cyclic-adenosine 3′,5′-monophosphate and phorbol 12-myristate 13-acetate stimulation in long-term orchidectomized rats

1996 ◽  
Vol 16 (1) ◽  
pp. 81-88 ◽  
Author(s):  
M Tena-Sempere ◽  
L Pinilla ◽  
E Aguilar
Keyword(s):  
Male Rats ◽  
Short Term ◽  
Compensatory Mechanisms ◽  
Gh Secretion ◽  
Camp Pathway ◽  
Kinase C ◽  
High Doses

ABSTRACT In the present work in vitro GH pituitary responsiveness to GHRH in short-term (STO) and long-term orchidectomized (LTO) male rats was compared. In agreement with previous data obtained in vivo, pituitaries from STO rats showed reduced GH release after GHRH stimulation while LTO male pituitaries presented responses similar to those from control animals after maximal GHRH (10-6 m) stimulation. This suggests that compensatory mechanisms have taken place, probably at the pituitary level, in order to restore GH pituitary responsiveness to high doses of GHRH. However, LTO male rats showed a reduced sensitivity to GHRH relative to intact males, as indicated by a higher EC50 vs controls (40·82 ± 12·03 nm vs 0·35 ± 0·09 nm in intact males). We aimed to investigate further the events involved in the compensatory mechanisms that take place in LTO rats. For this purpose, we compared in vitro GH secretion by pituitaries from intact and LTO male rats after stimulation with specific activators of the signal transduction pathways related to GH release. Forskolin and dibutyryl cyclic-adenosine 3′,5′-monophosphate were more effective in eliciting GH secretion (expressed in terms of percent increment over basal GH release) in LTO males, whereas phorbol 12-myristate 13-acetate was completely ineffective in stimulating GH release in this group. Thus, our results clearly showed that long-term orchidectomy enhances the effectiveness of the cAMP pathway in inducing GH release while it completely blunts that of the protein kinase C pathway. In conclusion, orchidectomy decreased the effectiveness of GHRH in eliciting GH release in vitro. However, long-term orchidectomy activated compensatory mechanisms that restored complete GH pituitary responsiveness to maximal GHRH stimulation. These mechanisms seem not to operate in STO rats. An increased effectiveness of the cAMP pathway in eliciting GH release in LTO rats is probably involved in the aforementioned compensatory mechanisms.

Direct effects of medroxyprogesterone acetate (MPA) and megestrol acetate (MGA) on rat testicular steroidogenesis

1980 ◽  
Vol 94 (3) ◽  
pp. 419-425 ◽  
Author(s):  
Robert L. Barbieri ◽  
Kenneth J. Ryan
Keyword(s):  
Serum Testosterone ◽  
Difference Spectrum ◽  
Male Rats ◽  
Type I ◽  
Testicular Steroidogenesis ◽  
Rat Interstitial Cells ◽  
Cytochrome P 450 ◽  
Cells Cultured

Abstract. The effects of MPA and MGA on rat testicular steroidogenesis were examined by studying: 1) serum testosterone in hCG primed animals treated with MPA or MGA, 2) testosterone synthesis in rat Leydig cells cultured with MPA or MGA, 3) MPA and MGA binding to rat testis microsomal cytochrome P-450 and 4) MPA and MGA inhibition of enzymes of rat testicular steroidogenesis. In immature rats receiving 1.0 IU of hCG per day 20 mg/kg of MPA or MGA reduced serum testosterone by 57 and 56%, respectively. In mature male rats receiving 50.0 IU of hCG per day 20 mg/kg of MPA or MGA reduced serum testosterone by 40 and 29%, respectively. In rat interstitial cells cultured with 10 ng of rat LH, 1 μm MPA or MGA inhibited testosterone production by 32 and 23%, respectively. Addition of MPA or MGA to microsomal preparations resulted in a type I cytochrome P-450 difference spectrum. MPA and MGA inhibited rat testicular 17α-hydroxylase, 17,20-lyase, and the 3β- and 17β-hydroxysteroid dehydrogenases. These findings suggest that MPA and MGA inhibit rat testicular steroidogenesis in vivo and in vitro.

Oestrogenic regulation of testicular androgen production during development in the rat

1985 ◽  
Vol 105 (2) ◽  
pp. 211-218 ◽  
Author(s):  
B. A. Keel ◽  
T. O. Abney
Keyword(s):  
Serum Testosterone ◽  
Male Rats ◽  
Serum Prolactin ◽  
Testicular Function ◽  
Intact Male ◽  
Oestrogen Treatment ◽  
Testosterone Production ◽  
Age Related ◽  
Serum Lh

ABSTRACT The influence of age on the sensitivity of the testis to oestrogens was investigated. Intact male rats at 10, 25, 40 and 53 days of age were injected s.c. with vehicle, 5 or 50 μg oestradiol or diethylstilboestrol (DES)/100 g body wt twice daily for 2 days; the animals were killed 12 h after the last injection. Subsequently, the concentrations of testicular androgens and serum LH, prolactin, testosterone and androstanediol (5α-androstane-3α, 17β-diol) were measured. Testicular androgen production was determined in vitro in the presence or absence of human chorionic gonadotrophin (hCG) or dibutyryl cyclic AMP (dbcAMP). Androgens in the serum and testes displayed an age-related alternating pattern with androstanediol being the major androgen produced at 27 days of age. As a result of oestrogen treatment, serum LH concentrations were decreased while serum prolactin was increased. Serum testosterone was decreased by 36–55% in the 12-day-old group and further reduced by 95% of control values by day 55; serum androstanediol was less sensitive to oestrogen suppression. Testicular concentrations of both testosterone and androstanediol exhibited a marked reduction in 12-day-old animals as a result of oestrogen administration. These values were reduced by 85–95% at day 27 and remained suppressed even at 55 days. Basal production of testosterone was unaffected by oestrogen treatment in 12- and 27-day-old animals but was markedly decreased by day 42. Significant suppression of basal production of androstanediol was observed as early as day 12. Oestradiol treatment caused a significant reduction in hCG responsiveness of both androgens at days 12, 42 and 55. Oestrogen administration resulted in a significant (32–59%) decline in dbcAMP-responsive testosterone production in the 42-day group and a further suppression in the 55-day group. A marked inhibition of dbcAMP-stimulated androstanediol production was also observed in the 42- and 55-day groups. Testosterone production in response to dbcAMP was not significantly altered in the 12- and 27-day groups. With few exceptions the effects of oestradiol and DES on testicular function were similar. The data presented here suggest that the inhibitory effects of oestrogens become more pronounced as the animal approaches adulthood, that oestradiol and DES are similarly effective in regulating testicular function at all ages studied and that the production of both testosterone and androstanediol are suppressed by oestrogen administration. J. Endocr. (1985) 105, 211–218

EFFECT OF PREPUBERTAL HEMIORCHIDECTOMY ON THE RESPONSE OF THE TESTIS TO LUTEINIZING HORMONE

1979 ◽  
Vol 82 (1) ◽  
pp. 95-104 ◽  
Author(s):  
LIISA SELIN ◽  
W. H. MOGER
Keyword(s):  
Luteinizing Hormone ◽  
Incubation Medium ◽  
Serum Testosterone ◽  
Male Rats ◽  
Intact Rats

SUMMARY Administration of FSH to hypophysectomized male rats has been shown to increase the capacity of the testes to secrete testosterone in response to LH. Studies were done to assess the effect of increased endogenous FSH on the response of the testis to LH. At 17 and 24 days of age, animals hemiorchidectomized at 10 days of age had significantly higher serum FSH levels and testicular weights than sham-operated rats. To study the testicular response to LH in vivo, hemiorchidectomized animals were sham-operated and the sham-operated animals were hemiorchidectomized at 17 or 24 days of age. Luteinizing hormone (30 μg/100 g body wt) or saline was administered immediately after the operation and the animals were autopsied 90 min later. Chronic hemiorchidectomy significantly increased the serum testosterone response to LH at 17 but not at 24 days of age. The testicular response to LH in vitro was also investigated. Testes from rats hemiorchidectomized or sham-operated at 10 days of age and killed at 17 and 24 days of age were incubated for 3 h in the presence or absence of 100 ng LH/ml incubation medium. Significantly more 5α-androstane-3α,17β-diol and androsterone were produced by the testes from hemiorchidectomized than from sham-operated animals at 17 days of age but not at 24 days of age. The production of testosterone in vitro was not influenced by hemiorchidectomy at either age. These results suggest that serum FSH concentration is the factor limiting LH responsiveness before but not after the prepubertal increase in FSH levels. However, treatment of intact rats from 10 to 16 days of age with 20 μg rat FSH/day did not increase the serum testosterone response to LH.

scholarly journals Insulin and IGF-I Inhibit GH Synthesis and Release in Vitro and in Vivo by Separate Mechanisms

Endocrinology ◽  
2013 ◽  
Vol 154 (7) ◽  
pp. 2410-2420 ◽  
Author(s):  
Manuel D. Gahete ◽  
José Córdoba-Chacón ◽  
Qing Lin ◽  
Jens C. Brüning ◽  
C. Ronald Kahn ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Inhibitory Effect ◽  
Pituitary Cell ◽  
Primary Role ◽  
Gh Secretion ◽  
Relative Contribution ◽  
Primary Mouse ◽  
Igf I

Abstract IGF-I is considered a primary inhibitor of GH secretion. Insulin may also play an important role in regulating GH levels because insulin, like IGF-I, can suppress GH synthesis and release in primary pituitary cell cultures and insulin is negatively correlated with GH levels in vivo. However, understanding the relative contribution insulin and IGF-I exert on controlling GH secretion has been hampered by the fact that circulating insulin and IGF-I are regulated in parallel and insulin (INSR) and IGF-I (IGFIR) receptors are structurally/functionally related and ubiquitously expressed. To evaluate the separate roles of insulin and IGF-I in directly regulating GH secretion, we used the Cre/loxP system to knock down the INSR and IGFIR in primary mouse pituitary cell cultures and found insulin-mediated suppression of GH is independent of the IGFIR. In addition, pharmacological blockade of intracellular signals in both mouse and baboon cultures revealed insulin requires different pathways from IGF-I to exert a maximal inhibitory effect on GH expression/release. In vivo, somatotrope-specific knockout of INSR (SIRKO) or IGFIR (SIGFRKO) increased GH levels. However, comparison of the pattern of GH release, GH expression, somatotrope morphometry, and pituitary explant sensitivity to acute GHRH challenge in lean SIRKO and SIGFRKO mice strongly suggests the primary role of insulin in vivo is to suppress GH release, whereas IGF-I serves to regulate GH synthesis. Finally, SIRKO and/or SIGFRKO could not prevent high-fat, diet-induced suppression of pituitary GH expression, indicating other factors/tissues are involved in the decline of GH observed with weight gain.

The interrelationships of thyroid and growth hormones: effect of growth hormone releasing hormone in hypo- and hyperthyroid male rats

1986 ◽  
Vol 113 (4_Suppl) ◽  
pp. S367-S375 ◽  
Author(s):  
Allen W. ROOT ◽  
Dorothy SHULMAN ◽  
Jennifer ROOT ◽  
Frank DIAMOND
Keyword(s):  
Growth Hormone ◽  
Thyroid Hormones ◽  
Secretory Response ◽  
Metabolic Effects ◽  
Male Rats ◽  
Male Rat ◽  
Peripheral Tissues ◽  
Releasing Hormone

ABSTRACT Growth hormone (GH) and the thyroid hormones interact in the hypothalamus, pituitary and peripheral tissues. Thyroid hormone exerts a permissive effect upon the anabolic and metabolic effects of GH, and increases pituitary synthesis of this protein hormone. GH depresses the secretion of thyrotropin and the thyroid hormones and increases the peripheral conversion of thyroxine to triiodothyronine. In the adult male rat experimental hypothyroidism produced by ingestion of propylthiouracil depresses the GH secretory response to GH-releasing hormone in vivo and in vitro, reflecting the lowered pituitary stores of GH in the hypothyroid state. Short term administration of large amounts of thyroxine with induction of the hyperthyroid state does not affect the in vivo GH secretory response to GH-releasing hormone in this animal.

Interaction of clonidine and GHRH on GH-secretion in vivo and in vitro

1987 ◽  
Vol 116 (3_Suppl) ◽  
pp. S154
Author(s):  
J. ALBA-LOPEZ ◽  
M. LOSA ◽  
Y. SPIESS ◽  
A. KÖNIG ◽  
K. VON WERDER
Keyword(s):  
Gh Secretion

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

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