Subsequent Growth Hormone Research Articles

Differential locomotor interactions between dopamine D1/D2 receptor agonists and NMDA antagonists

A group of 14 healthy subjects received 50 mg/kg body weight of 2 deoxy-D-glucose (2DG) IV in a 20-minute infusion to induce glucoprivation and stimulate the release of growth hormone (GH), prolactin (PRL), pancreatic polypeptide (hPP), and catecholamines. Six subjects having spontaneously high GH baseline levels (> 8 ng/mL) failed to mount a GH response to 2DG-induced glucoprivation while eight subjects having low GH baseline levels (< 8 ng/mL) all had increases (> 10 ng/mL) of GH levels after 2DG (P < 0.05). Baseline level of GH was a reliable predictor of subsequent GH response to 2DG. Administration of the alpha2-adrenoreceptor agonist clonidine (0.5 mg po) reliably increased GH levels (P < 0.05). Elevated GH levels following clonidine administration abolished GH responses to subsequently infused 2DG (P < 0.05). While these data do not exclude the possibility of a short loop feedback control of GH secretion, they strongly suggest that the direction of the GH response to a provocative stimulus is determined by the antecedent GH level and that an alpha-adrenoreceptor mechanism is involved in such a biphasic modulation of GH levels. Clonidine administration significantly reduced total catecholamine, pancreatic polypeptide, and prolactin response to 2DG while opiate receptor blockade with naloxone (10 mg IV bolus followed by 2 mg/hr) did not affect catecholamine and pancreatic polypeptide response but did slightly attenuate the GH and PRL response to glucoprivation. We conclude that alpha adrenoreceptor mechanisms are of major importance while opiate receptor mechanisms are of relatively minor importance in modulating the effects of glucoprivation on sympathetic outflow and hPP, GH, and PRL levels.

Tumor necrosis factor-alpha affects growth hormone secretion by a direct pituitary interaction.

Administration of 50, 250, and 1,250 ng/kg iv of recombinant bovine tumor necrosis factor-alpha (RBTNF) did not affect basal plasma concentrations of growth hormone (GH) or thyroid-stimulating hormone in male calves. However, when administered 30 min before challenge with 1 microgram/kg iv of thyrotropin-releasing hormone (TRH), 250 ng/kg of RBTNF increased the subsequent incremental GH response. At 1,250 ng/kg of RBTNF, GH response to TRH was significantly blunted. For each dose of RBTNF administered, the incremental change in plasma thyroid-stimulating hormone following TRH was not significantly different from control. To examine direct effects of RBTNF on pituitary function, fresh bovine pituitaries were sliced into 1-mm cubes and incubated with 0 or 10(-8), 10(-9), or 10(-10) M RBTNF. Additional cultures were treated with 10(-8) or 10(-9) M GH-releasing factor or 10(-8) M TRH and 0 or 10(-8) M RBTNF. Media GH increased in cultures with 10(-10) M RBTNF and declined linearly as RBTNF concentration increased. RBTNF blocked GH release from GH-releasing factor- and TRH-challenged pituitary slices. Membranes prepared from homogenized bovine pituitaries had specific saturable binding characteristics for monomeric 125I-RBTNF. Membranes treated with 4 M MgCl2 for 10 min and washed free of Mg2+ produced Scatchard plots fit to a two-site model (high affinity site Kd = 6.6 nM), while Scatchards of non-Mg(2+)-treated membranes fit a single site (Kd = 8.9 nM). Polyacrylamide gel electrophoresis separation of 125I-RBTNF cross-linked pituitary membranes showed specific binding of monomeric 125I-RBTNF to protein components ranging in molecular weight from 19,000 to 77,000. The data suggest that RBTNF has modulatory effects on the regulation of GH secretion acting directly at the pituitary through specific receptors.

Polygraphic sleep patterns and growth hormone secretion in children after cranial irradiation

The effects of radiotherapy on subsequent growth hormone (GH) secretion and sleep organization was studied by simultaneous evaluation of spontaneous sleep-related GH secretion (SSRGHS), arginine-insulin tolerance test (AITT) and polygraphic sleep recording in a follow up of 19 children who underwent surgical removal of an intracranial tumour and cranial radiotherapy 1-7 years previously. Electrophysiological patterns of sleep phases, the amount and distribution of sleep stages were normal, suggesting that the procedure utilized should not entail modifications of SSRGHS per se. Long-term after radiotherapy SSRGHS and AITT GH responses were lower than those of the medium-term group. The lack of correlation between SSRGHS and AITT GH secretion suggests that SSRGHS and AITT measure different aspects of GH secretion. The highest value of GH plasma level (peak) corresponded to slow wave sleep, mainly during the first non-rapid eye movement-rapid eye movement (NREM-REM) cycle, in practically all the patients. Although the SSRGHS synchronization with SWS of the first NREM-REM cycle was preserved, no sleep measure was correlated with the SSRGHS. The usefulness of polygraphic monitoring of sleep patterns was confirmed.

Pre-exposure of rat anterior pituitary cells to somatostatin enhances subsequent growth hormone secretion.

The precise roles of GH-releasing factor (GRF) and somatostatin (SRIF) in the orchestration of pulsatile GH secretion have not yet been fully determined. We examined the interactions of rat GRF and SRIF in the concentration ranges present in rat hypophysial-portal blood, on the secretion of GH from dispersed male rat anterior pituitary cells in monolayer culture. The effects of exposing cells to GRF and/or SRIF (0.01-1.nmol/l) for 1 h were compared with the effects of preincubation of cells with SRIF before experimental incubations. As anticipated, the stimulatory effects of 0.1-1 nmol GRF/1 were abolished by concurrent incubation with SRIF at an equimolar concentration, although SRIF, at these concentrations, did not significantly inhibit basal GH secretion. Conversely, pre-exposure to 0.1 nmol SRIF/1 for 30 or 60 min, resulted in an increase in GH secretion during a subsequent 60-min incubation period, both in the absence or in the presence of GRF (0.01-1 nmol/l). Pretreatment with GRF caused increased responsivity to GRF rather than significant sensitization of the GH response to GRF. These observations demonstrate actions of SRIF, at low and probably physiological concentrations, which are more complex than those of a pure inhibitor of GH secretion. Pre-exposure of the pituitary to SRIF enhances subsequent GH secretion, suggesting that SRIF may play an additional physiological role in amplifying the GRF signal.

Feedback-inhibition of growth hormone (GH) secretion in fowl: GH-induced down-regulation of thyrotrophin-releasing hormone binding to pituitary membranes

Administration of ovine GH to immature domestic fowl blunted their subsequent GH response to thyrotrophin-releasing hormone (TRH), a GH secretagogue in birds. The in-vivo administration of GH also reduced the ability of radiolabelled TRH to bind to plasma membranes of the pituitary caudal lobe, in which GH cells predominate. These inhibitory effects of GH were mediated by extrapituitary actions, since GH had no direct inhibitory effects on TRH-induced GH release or on pituitary TRH binding in vitro. GH inhibition of GH secretion and TRH binding would not appear to be mediated by hypothalamic somatostatin (SRIF) or peripheral somatomedin (IGF-I), since SRIF and IGF-I had no direct effects in vitro.

Growth hormone (GH) secretion in the conscious rat: negative feedback of GH on its own release.

The negative-feedback effects of GH on its own secretion were studied in conscious male and female rats bearing indwelling double-bore venous cannulae. Intravenous infusions of human GH (hGH; 20-60 micrograms/h) or somatostatin (SS; 10 micrograms/h) were given while frequent serial microsamples of blood were withdrawn using an automatic blood-sampling system. In both sexes, i.v. infusions of hGH for 6 h inhibited endogenous GH secretory pulses, with a slow onset of the inhibition. There was no rebound GH secretion immediately following the removal of the hGH infusion, but spontaneous GH secretion gradually returned to normal. Infusions of hGH did not inhibit the pituitary GH response to repeated GH-releasing factor (GRF) injections (1 microgram) given i.v. every 40 min to female rats. By contrast, infusions of SS, which also blocked spontaneous GH release, dramatically reduced the GH responses to serial GRF injections. When SS Infusions were stopped, the subsequent GRF-induced GH secretory responses were enhanced. These results show that GH can inhibit its own release when given by i.v. infusion to conscious male and female rats. Since GH responses to GRF are maintained during a GH infusion, the feedback effect of GH is unlikely to be exerted directly on the pituitary or by increasing SS release. Our results are consistent with the idea that GH feedback in the conscious rat involves an inhibition of GRF release.

Growth hormone releasing factor stimulates and somatostatin inhibits prolactin release from human mixed somatotroph-lactotroph adenomas in perifusion.

The effects of human growth hormone-releasing factor (hGRF) and somatostatin on growth hormone (GH) and prolactin (PRL) secretion in perifusion of dispersed cells of human GH-secreting adenomas, obtained from seven acromegalic patients with hyperprolactinaemia, were examined. Six adenomas stained for both GH and PRL on immunohistochemical examination, and one contained only GH. GH release was consistently stimulated in a dose-dependent manner by hGRF (0.01, 0.1 and 1.0 nM) in all seven adenomas studied. PRL release was undetectable in two adenomas. In the other five, hGRF stimulated PRL release and the response was dose related. Furthermore, the PRL response was significantly correlated with the GH response to hGRF. When cells were perfused with somatostatin (1 nM), GH and PRL secretion induced by hGRF was completely antagonized. We also evaluated the effect of hGRF pretreatment on the subsequent GH response to hGRF in two adenomas. hGRF pretreatment (1 nM) for 210 min reduced the GH response to a subsequent hGRF challenge (100 nM) in one tumour but not in the other. In conclusion, the PRL response is similar to the GH response in mixed GH and PRL-secreting adenomas after exposure to GH release-stimulating and inhibiting hormones. After prolonged exposure to hGRF, some adenomas remain responsive to further stimulation with hGRF, whereas others do not.

Free fatty acids block growth hormone (GH) releasing hormone-stimulated GH secretion in man directly at the pituitary.

Increases in plasma FFA levels inhibit GH responses to a variety of pharmacological and physiological stimuli. To gain further insight into the mechanism by which FFA exert their effect, we studied the plasma GH responses to GHRH-(1-44) (1 microgram/kg, iv) in normal subjects in whom plasma FFA levels were raised by a lipid-heparin infusion (250 mL 10% Intralipid plus 2500 U heparin). Paired tests were performed in 10 normal subjects, with and without lipid-heparin pretreatment. Lipid-heparin infusion from -30 to 120 min increased mean FFA levels from 0.41 +/- 0.03 (+/- SEM) to 3.12 +/- 0.40 mmol/L at 120 min. The mean plasma GH levels after GHRH administration were lower at all times; however, the values were significantly different (P less than 0.05) only at the later times (45, 60, and 90 min). When considered individually, an all or none pattern was observed; 5 subjects had no plasma GH response to GHRH, and 5 had no reduction. To investigate the time relationships between the FFA peak and subsequent GH blockade, a different protocol of paired tests was performed with GHRH with or without a different lipid-heparin infusion protocol. Lipid-heparin was infused from -90 to 0 min, with an additional heparin pulse at -15 min, to obtain a higher and earlier (0 min) FFA increase. FFA increased from 1.06 +/- 0.19 to 11.61 +/- 0.83 mmol/L at zero time. The GHRH-induced GH secretory peak (15.8 +/- 3.5 ng/ml) at 15 min was completely blocked (0.9 +/- 0.2 ng/ml), and the mean plasma GH levels were also lower at 30, 45, and 60 min. To determine whether the FFA-induced blockade of GH secretion was exerted in the pituitary, a series of in vitro studies was conducted using monolayer cultures of rat anterior pituitary glands, with GHRH concentrations of both 10(-10) and 10(-8) M and 10(-5) M forskolin to stimulate GH release. Both caprylic and oleic acid inhibited basal GH release and GHRH- or forskolin-induced GH release. PRL release was not altered, nor were toxic actions noted on the cells. In conclusion, FFA are able to block GH secretion directly at the pituitary level.

Growth hormone secretion from chicken adenohypophyseal cells in primary culture: Effects of human pancreatic growth hormone-releasing factor, thyrotropin-releasing hormone, and somatostatin on growth hormone release

A primary culture of chicken adenohypophyseal cells has been developed to study the regulation of growth hormone (GH) secretion. Following collagenase dispersion, cells were exposed for 2 hr to vehicle (control) or test agents. Human pancreatic (tumor) growth hormone-releasing factor (hpGRF) and rat hypothalamic growth hormone-releasing factor stimulated GH release to similar levels. GH release was increased by the presence of dibutyryl cyclic AMP. Thyrotropin-releasing hormone (TRH) alone did not influence GH release; however, TRH plus hpGRF together exerted a synergistic (greater than additive) effect, increasing GH release by 100 to 300% over the sum of the values for each secretagogue acting alone. These relationships between TRH and hpGRF were further examined in cultured cells exposed to secretagogues for two consecutive 2-hr incubations. TRH pretreatment enhanced subsequent hpGRF-stimulated GH release by about 80% over that obtained if no secretagogue was present during the first incubation. In other experiments, somatostatin (SRIF) alone did not alter GH secretion. However, SRIF reduced hpGRF-stimulated GH release to levels found in controls. Furthermore, GH release stimulated by the presence of both TRH and hpGRF was lowered to control values by SRIF. The results of these studies demonstrate that a primary culture of chicken adenohypophyseal cells is a useful model for the study of GH secretion. Indeed, these results suggest that TRH and hpGRF regulate GH secretion by mechanisms which are not identical.

Effect of continuous somatostatin and growth hormone-releasing hormone (GHRH) infusions on the subsequent growth hormone (GH) response to GHRH. Evidence for somatotroph desensitization independent of GH pool depletion.

Continuous infusions of growth hormone-releasing hormone (GHRH) attenuate the subsequent growth hormone (GH) response to GHRH. To test whether this phenomenon can occur in the absence of GH pool depletion, we examined the effects of continuous infusions of 10 nM GHRH and of 10 nM somatostatin (SRIH), separately or in combination, on dispersed, perifused rat anterior pituitary cells. Columns of these cells were given either GHRH alone for 5 h, GHRH and SRIH together for 3 h followed by GHRH alone, or SRIH alone for 3 h followed by GHRH or medium. SRIH blunted both basal GH release and the GH response to GHRH, without affecting the subsequent GH responses to GHRH. The GHRH infusions attenuated the subsequent GH response to GHRH, even when GH release was initially prevented by the concurrent infusion of SRIH. Furthermore, the degree of attenuation was similar in the presence or absence of SRIH, suggesting that pool depletion plays little role in the desensitization process under these experimental conditions. The results are consistent with the hypothesis that a short-term infusion of GHRH leads to attenuation of the GH response in rat anterior pituitary cells primarily through receptor effects rather than through GH pool depletion.

Release of Growth Hormone (GH) from Purified Somatotrophs: Interaction of GH-Releasing Factor and Somatostatin and Role of Adenosine 3′,5′ -Monophosphate*

An acutely dispersed and purified preparation of somatotrophs obtained from rat adenohypophyses was used to study the mechanism of action of GH-releasing factor (GRF). Synthetic GRF [human pancreatic, hpGRF-(1-40)-OH] stimulated the immediate (within 4 min) release of GH in a dose-related manner, with a preceding or concurrent increase in cAMP in the somatotrophs. Somatostatin, at concentrations as low as 1.0 ng/ml, completely blocked the GRF-induced increase in GH release, with only a partial reduction in the GRF-induced accumulation of cAMP in the somatotrophs. 3-Isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, potentiated the action of GRF in increasing cAMP in the somatotrophs, with subsequent GH release. These results along with those of previous studies suggest that cAMP is an intracellular mediator in the action of GRF and that somatostatin has a major effect on blocking GH release at a step subsequent to cAMP accumulation.

Effect of dopamine, bombesin and cysteamine hydrochloride on plasma growth hormone response to synthetic growth hormone-releasing factor in rats

In urethane anesthetized rats, an intracerebroventricular (icv) injection of 2 μg bombesin 5 min prior to the administration of synthetic human growth hormone-releasing factor (GRF) (1 μg/kg, iv) inhibited plasma growth hormone (GH) response, while cysteamine hydrochloride (90 mg/kg, sc) administered 150 min beforehand depleted immunoreactive somatostatin content in the pituitary-stalk median eminence and consequently potentiated the response to GRF. Under the same experimental conditions, central injection of 1.89 μg (10 −8M) dopamine hydrochloride or iv administration of L-DOPA (10 mg/kg) did not influence the subsequent plasma GH response to GRF. Results suggest indirectly that bombesin and cysteamine, but not dopamine, predominantly modulate somatostatin release from the hypothalamus.

Pharmacological evidence for opioid and adrenergic mechanisms controlling growth hormone, prolactin, pancreatic polypeptide, and catecholamine levels in humans

A group of 14 healthy subjects received 50 mg/kg body weight of 2 deoxy-D-glucose (2DG) IV in a 20-minute infusion to induce glucoprivation and stimulate the release of growth hormone (GH), prolactin (PRL), pancreatic polypeptide (hPP), and catecholamines. Six subjects having spontaneously high GH baseline levels (> 8 ng/mL) failed to mount a GH response to 2DG-induced glucoprivation while eight subjects having low GH baseline levels (< 8 ng/mL) all had increases (> 10 ng/mL) of GH levels after 2DG ( P < 0.05). Baseline level of GH was a reliable predictor of subsequent GH response to 2DG. Administration of the alpha 2-adrenoreceptor agonist clonidine (0.5 mg po) reliably increased GH levels ( P < 0.05). Elevated GH levels following clonidine administration abolished GH responses to subsequently infused 2DG ( P < 0.05). While these data do not exclude the possibility of a short loop feedback control of GH secretion, they strongly suggest that the direction of the GH response to a provocative stimulus is determined by the antecedent GH level and that an alpha-adrenoreceptor mechanism is involved in such a biphasic modulation of GH levels. Clonidine administration significantly reduced total catecholamine, pancreatic polypeptide, and prolactin response to 2DG while opiate receptor blockade with naloxone (10 mg IV bolus followed by 2 mg/hr) did not affect catecholamine and pancreatic polypeptide response but did slightly attenuate the GH and PRL response to glucoprivation. We conclude that alpha adrenoreceptor mechanisms are of major importance while opiate receptor mechanisms are of relatively minor importance in modulating the effects of glucoprivation on sympathetic outflow and hPP, GH, and PRL levels.

Somatostatin release from the median eminence of unanesthetized rats: lack of correlation with pharmacologically suppressed growth hormone secretion.

We describe a push-pull perfusion technique to investigate the role of somatostatin in the pharmacological suppression of growth hormone (GH) secretion. Immunoreactive somatostatin (IRS) released from the median eminence (ME) was studied in chronically cannulated, unanesthetized male rats. In control rats which received vehicle injection, plasma GH levels showed a normal ultradian rhythm and relatively stable levels of IRS (around 30 pg/15 min) appeared in the perfusate during the 6-h perfusion. Intracerebroventricular (i.c.v) administration of human growth hormone (40 micrograms), neurotensin (2 micrograms), glucagon (25 micrograms) or intravenous (i.v.) injection of oxymetazoline (50 micrograms/kg b.w.), an alpha-adrenergic agonist, or endotoxin (150 micrograms/kg b.w.) suppressed subsequent GH surges. In these rats, however, IRS levels in the ME perfusate failed to change significantly compared to control rats. These results suggest that changes in somatostatin release may play a minor role in the suppression of plasma GH levels caused by these substances, and that major regulatory effects may be achieved via the suppression of growth hormone-releasing factor release.

Negative feedback suppression of sleep-related growth hormone secretion.

Previous studies have demonstrated that injections of growth hormone (GH) can blunt subsequent GH secretory responses to daytime pharmacological stimulation. The current study was undertaken to determine whether GH administration to normal subjects would suppress sleep-related secretion. GH (2 U im) was given nine times over 5 days to each of six subjects, and sleep studies with blood sampling were performed 6 h after the last injection. Secretion during the first 2 h of sleep was decreased by 62.4%, indicating that sleep-related GH secretion may be responsive to a negative-feedback mechanism.

Growth hormone and rat liver mitochondria effects on urea cycle enzymes

Effects of hypophysectomy and subsequent growth hormone administration on mitochondrial enzymes of the urea cycle were investigated in rat liver. Hypophysectomy increased the activities of the two mitochondrial enzymes, carbamyl phosphate synthetase and ornithine transcarbamylase but not of the cytosolic enzyme, argininosuccinate synthetase. The activity of mitochondrial phosphate dependent glutaminase was not affected. Administration of bovine growth hormone (100 μg/100 g body weight) for two weeks decreased the activities of carbamyl phosphate synthetase and ornithine transcarbamylase almost to the normal level. These results suggest a specific effect of growth hormone on mitochondrial enzymes of the urea cycle and serve to explain the increased urea formation in hypopituitarism.

Growth-hormone dependence of non-suppressible insulin-like activity (NSILA) and of NSILA-carrier protein in rats.

ABSTRACT The effects of hypophysectomy and subsequent growth hormone (GH) treatment on the serum levels of NSILA and of its binding protein were studied in rats. After hypophysectomy NSILA levels fall to 6 % of the normal. Under GH treatment they rise slowly to 65 % of normal after 12 d. In parallel with the changes of serum NSILA, [35S] sulphate incorporation into costal cartilage in vitro is markedly decreased in hypox animals and restored towards the normal by GH treatment. The relative binding activity of [125I] NSILA-S of serum "stripped" from endogenous NSILA is also reduced after hypophysectomy to approx. 30 % of normal, i. e. to a lesser extent than serum NSILA levels. This concentration of binding protein is sufficient to bind trace amounts of labelled NSILA-S. The half-life of an intravenously injected tracer of [125I]NSILA-S is not significantly decreased in hypox animals. Substitution with GH results in a rise of the relative binding activity to normal after 12 d. Chromatography of serum, equilibrated with [125I]NSILA-S tracer, on Sephadex G-200 at neutral pH reveals different radiochromatographic patterns for serum from hypox and normal rats: In hypox rats the main peak of radioactivity appears at 60 % bed volume, in normal rats between 45 and 50 %. During GH treatment this main peak shifts from 60 back to 45–50 %. The distribution of binding activity is similar for normal and hypox rat serum after chromatography on Sephadex G-200 at acidic pH. Furthermore, the binding characteristics of "stripped" hypox and normal serum are identical. This suggests that the same binding protein is present in the normal and hypox rat serum in different molecular forms. It is concluded that GH is a major factor regulating the level of NSILA and of its binding protein in the rat.

Effect of thyroidectomy on the secretory profiles of growth hormone, thyrotropin and corticosterone in the rat.

Changes in pituitary hormone secretions following thyroidectomy were examined in sequentially collected blood samples every 15 min day and night for 7 hr from male rats via cannulae into the right atria. Pulsatile growth hormone secretions were observed every 2.5 or 3.5 hr in normal rats, while thyroidectomy 3 weeks prior to experiments abolished the growth hormone burst. Corticosterone profiles from normal rats showed also episodic patterns which were more often observed in the night experiment. The eisodic secretion of corticosterone seemed to inhibit the subsequent growth hormone burst but not vice versa. The interrelation between integrated concentrations of growth hormone and corticosterone showed a negative correlation although the coefficient was not statistically significant. After thyroidectomy, the basal level of corticosterone decreased and the episodic secretion was blunted. There was no nyctohemeral variation in the plasma thyrotropin level in normal rats but small and slow fluctuations. Thyroidectomy caused about ten-fold elevation in the basal thyrotropin level and, in addition to this, a decrease at 1500 hr and an increase during the night, followed thereafter by a decreasing tendency to 0400 hr. Power spectral analysis revealed smaller components in growth hormone secretion of normal rats, which had periods of 60, 40 and 36 min, besides the hormone burst. The spectral analysis also made it clear that there were small and frequent components (40 or 36 min period) in corticosterone secretion.

Growth hormone and liver mitochondria: Effects on cytochromes and some enzymes

The effects of hypophysectomy and subsequent growth hormone treatment on liver mitochondrial levels of cytochromes, flavoprotein, cytochrome oxidase and NADH oxidase were studied in rats. Hypophysectomy lowered cytochrome a, a 3, b, c, and c 1, concentrations and cytochrome oxidase activity. On the other hand, flavoprotein concentration and NADH oxidase activity were increased. Administration of either human or bovine growth hormone restored the cytochrome levels. Cytochrome oxidase activity was also increased but did not reach its original level. Only the bovine hormone exerted a lowering effect on flavoprotein and NADH oxidase activities. These and other results suggest that growth hormone influences mitochondrial electron transport.

The effect of hypophysectomy in retarding the ageing process of the loose connective tissue of the rat.

Hypophysectomy and subsequent growth hormone administration have been reported to have an effect on mucopolysaccharide metabolism. A technique is described by which comparative measurements are made of the ability of subcutaneous connective tissue to retain saline injected into it. This technique has been used in the examination of a group of hypophysectomized rats. Their tissue was found in this regard to have the character of that expected of normal rats about 100 days younger than those examined. This was the interval between the hypophysectomy and the examination of the tissues, and it is therefore suggested that hypophysectomy has an effect, specific or non-specific, that retards the ageing process of common connective tissue.