Growth Hormone Secretion In Rats Research Articles

Growth Hormone (GH) Secretion during Continuous Infusion of GH-Releasing Peptide: Partial Response Attenuation*

The synthetic hexapeptide GH-releasing peptide (GHRP; SK&F 110679) specifically stimulates GH release in man. To determine the effect of a continuous GHRP infusion and whether response attenuation occurs in man, we administered to six healthy subjects a 6-h infusion of saline and three doses of GHRP, each followed by a 1.0 micrograms/kg bolus injection. GH was measured every 10 min using an immunoradiometric assay. During the saline infusion, spontaneous GH peaks occurred at variable times in four of the six subjects. During the continuous GHRP infusion, a single burst of GH release occurred with the two lower doses (0.1 and 0.3 micrograms/kg.h). With the highest dose of 1.0 micrograms/kg.h, a primary burst of GH release was followed by sporadic secretory episodes of lesser magnitude during the infusion; the GH concentrations remained above baseline before administration of the iv GHRP bolus in all six subjects. The mass of GH secreted was indirectly determined using waveform-independent deconvolution analysis. Mean GH secretion rates (micrograms per L distribution volume/h) were calculated by dividing the GH mass by the time interval. The GH secretion rates during the infusion period (0900-1430 h) were 2.40 +/- 0.68, 2.47 +/- 0.61, 7.67 +/- 1.86, and 14.75 +/- 2.32 on the saline and GHRP (0.1, 0.3, and 1.0 micrograms/kg.h) infusion days, respectively (P less than 0.05, 1.0 micrograms/kg.h vs. saline). The GH secretion rates after the iv GHRP bolus were 18.28 +/- 3.81, 19.01 +/- 2.03, 11.70 +/- 2.55, and 7.86 +/- 0.80 on the saline and GHRP (0.1, 0.3, and 1.0 micrograms/kg.h) infusion days, respectively (P less than 0.05, 1.0 micrograms/kg.h vs. saline). Compared with the saline infusion, the GH response to GHRP infusions was dose dependent (r = 0.81; P less than 0.001). The GH response to the iv bolus was inversely related to the dose of the preceding 5.5-h continuous GHRP infusion (r = -0.58; P = 0.003), and the total amount of GH secreted (constant infusion plus the bolus infusion periods) was not different among the GHRP doses. Constant GHRP infusion stimulates GH release in man, and partial response attenuation occurs with a subsequent 1.0 micrograms/kg GHRP bolus. We hypothesize that GHRP is active at multiple sites and may act as a functional somatostatin antagonist. Further studies are needed to better determine the site(s) of GHRP action and its potential use as a diagnostic and therapeutic agent.

Cortisone effects on growth, food efficiency, and in vitro growth hormone release

These studies were designed to investigate the cause of growth retardation during glucocorticoid treatment in rats. In young animals, body weights and amounts of food consumed were measured at two-day intervals, beginning at 29 days of age. Average food intake and food efficiency were calculated. Animals were treated with cortisone (CORT, 5 mg/rat/day, s.c.) or saline (SAL) for eight days between 37 and 44 days. Growth hormone (GH) release by dispersed pituitary cells in response to nine concentrations of GH-releasing hormone (GHRH) were tested by in vitro perifusion at 45 and 73 days. As previously shown, CORT caused a cessation of growth during the treatment period, and body weight failed to catch up. Food efficiency was decreased during CORT treatment. All parameters of in vitro GH release including basal GH secretory rate, overall GH response to GHRH, and the GHRH concentration-response curves were significantly increased by CORT in the 45-day-old animals. An age-related increase in GH release was also observed between the 45 and 73 day saline-treated animals. These results support the hypothesis that glucocorticoids inhibit growth by induction of changes in food metabolism and GH secretion. The effect on the pituitary gland itself paradoxically involves an increase in GH secretory capacity in response to GHRH.

Thirty-Second Sampling of Plasma Growth Hormone in Man: Correlation with Sleep Stages*

Both fasting and sleep increase the secretion of human GH and, therefore, might explain its predominantly nocturnal release. To study the precise temporal relationship between GH secretory episodes and cortical activity, GH measurements and electroencephalogram sleep stage recordings were performed every 30 s for 8 h in six young male volunteers fasted for 24 h. GH was measured in two drops of whole blood, which were directly sampled into the assay tube using a continuous blood withdrawal pump and a fraction collector. Concomitant serum sampling during a GH-releasing hormone test (n = 4) revealed a high correlation (r = 0.98) between GH measurements in serum and whole blood. GH pulses were objectively identified with Cluster analysis, and GH secretion rates were calculated with a waveform-independent deconvolution algorithm. When data were analyzed as replicates with 1-min intervals, the nocturnal pulse frequency was 1.2 pulses/h. Elimination of data points demonstrated 43% and 64% reductions in the number of GH pulses detected for 5- and 20-min sampling intervals, respectively. Mean GH concentrations and secretory rates were significantly higher during stage 3 and 4 sleep compared to stage 1, 2, and rapid eye movement sleep. GH secretory rates and peripheral GH concentrations were maximally correlated with sleep stage, with lags of 4.5 and 16 min, respectively, suggesting that maximal GH release occurs within minutes of the onset of stage 3 or 4 sleep. This temporal coincidence between pituitary GH secretion and delta sleep is consistent with cortical control over hypothalamic-pituitary function.

Temporal structure of in vivo growth hormone secretory events in humans

The time course of spontaneous growth hormone (GH) secretion was studied in 12 normal men by analyzing serum GH concentrations measured in blood collected at 5-min intervals over 24 h with a multiple-parameter deconvolution model to simultaneously resolve endogenous GH secretory and clearance rates. Twenty-four-hour profiles of serum GH concentrations were accounted for by an average of 12 +/- 1.2 (SE) discrete GH secretory bursts having a mean half-duration (duration at half-maximal amplitude) of 25 +/- 2.3 min, indicating that 95% of daily GH secretion occurred in 8.8 h. The majority (96%) of GH was secreted in volleys composed of multiple (4.0 +/- 0.4) discrete secretory bursts. Such volleys of GH secretion were separated by 171 +/- 19 min, whereas their constituent individual secretory events occurred every 36 +/- 1.7 min (P = 0.0001). Between secretory volleys, calculated GH secretory rates fell asymptotically to zero. Significant positive and negative autocorrelations were observed for the series consisting of successive GH secretory burst mass and interburst intervals, respectively. Linear regression analysis revealed significant negative correlations between the mass of GH secreted per burst and both the preceding and following interburst intervals. Estimates of the half-life of endogenous GH (17 +/- 1.7 min) and of the endogenous GH production rate (0.25 +/- 0.033 mg/m2 for an assumed distribution volume of 7.9% body wt) agreed well with earlier independent measurements. We conclude that the human pituitary gland secretes GH in volleys consisting of multiple secretory bursts, without measurable intervening tonic secretion. This pattern of in vivo GH release in normal humans is consistent with a model of high-frequency GH-releasing hormone secretory events superimposed on low-frequency episodes of somatostatin withdrawal.

Nature of Altered Growth Hormone Secretion in Hyperthyroidism*

Hyperthyroidism is accompanied by various neuroendocrine regulatory disturbances that affect not only the thyrotropic, but also the gonadotropic, corticotropic, and somatotropic axes. To examine the nature of alterations in neuroendocrine control mechanisms that direct the somatotropic axis in hyperthyroidism, we have applied a novel deconvolution technique designed to estimate the number, amplitude, and mass of significant underlying GH secretory events after the influence of GH metabolic clearance has been removed mathematically. To this end, blood was sampled at 10-min intervals for 24 h in seven hyperthyroid and seven age-matched euthyroid men. The subsequent GH time series were assayed by immunoradiometric assay (sensitivity, 0.08 ng/mL) and submitted to quantitative deconvolution analysis. We found that hyperthyroid compared to euthyroid men 1) had significantly more GH secretory bursts per 24 h (viz. 15 +/- 1.0 vs. 10 +/- 1.1; P = 0.017); 2) secreted 3 times as much GH per burst (3.7 +/- 0.80 vs. 1.3 +/- 0.42 ng/mL distribution vol; P = 0.013); 3) achieved a maximal rate of GH secretion in each burst 2.3-fold higher than that in control men (0.14 +/- 0.028 vs. 0.060 +/- 0.015 ng/mL.min; P = 0.017); and 4) had 3.7-fold higher 24-h endogenous GH production rates (P less than 0.01). Neither hyperthyroid nor euthyroid men had significant interburst (tonic) GH secretion. We conclude that the somatotropic axis in hyperthyroid men is marked by a higher frequency of spontaneous GH secretory bursts, a higher rate of maximal GH secretion attained per burst, and a larger mass of GH released per burst. These neuroregulatory disturbances result in a nearly 4-fold increase in the 24-h production rate of GH in thyrotoxicosis.

Dual Defects in Pulsatile Growth Hormone Secretion and Clearance Subserve the Hyposomatotropism of Obesity in Man*

We have examined the mechanisms underlying reduced circulating GH concentrations in the obese human. Computer-assisted (deconvolution) analysis was used to determine endogenous GH secretory and clearance rates quantitatively from entire 24-h plasma GH concentration profiles. These analyses revealed that the half-life (t 1/2) of endogenous GH was significantly shorter in obese (11.7 +/- 1.6 min) than in normal weight subjects (15.5 +/- 0.81 min; P less than 0.01). The accelerated blood disposal rate of GH was not due to decreased circulating concentrations of GH-binding protein, since the latter were similar in obese (25 +/- 1.0%) and normal weight (24 +/- 2.3%) men. However, obese men had significantly fewer GH secretory bursts (3.2 +/- 0.53 vs. 9.7 +/- 0.67/day; P less than 0.01). Among the rare GH secretory bursts that occurred in obese subjects, there were significantly prolonged mean intersecretory burst intervals (282 +/- 65 vs. 131 +/- 11 min; P less than 0.05). The resultant daily GH production rate in obese men was reduced to one fourth that in normal weight individuals. Both GH secretion rate and burst frequency were negatively correlated with the degree of obesity (ponderal index). The decreases in GH burst frequency and half-life were specific, since GH secretory pulse amplitude (maximal rate of GH release), the mass of GH released per burst, and the duration of computer-resolved GH secretory bursts were not different in obese and normal weight men. We conclude that obese men harbor a double defect in GH dynamics involving both GH secretion and clearance, and that the severity of the GH secretory deficiency is proportionate to the degree of obesity.

Growth Progression and 24-Hour Hormone Profile in an Infant Treated Chronically with a Long-Acting Somatostatin Derivative

The diagnosis of nesidioblastosis was established in a 9-month-old male child with a history of recurrent convulsive seizures and hypoglycemia. After unsuccessful subtotal pancreatectomy, treatment was started with the long-acting somatostatin derivative Sandostatin (Octreotide, Sandoz) at a dosage of 25 micrograms t.i.d. spaced between carbohydrate-enriched meals. With this regime, blood glucose was maintained at the low normal range and seizures ceased. During a 30-month observation period, growth velocity and weight progression were well within the predicted limits. A 24-hour hormone profile recorded at the end of the observation period revealed the following: (1) failure to improve blood glucose with carbohydrate-enriched food due to reactive hyperinsulinemia; (2) hyperglycemic reaction after administration of Sandostatin caused by a reduction of plasma insulin; this effect was particularly marked during sleep; (3) low mean GH, decreased spiking frequency and reduced area covered by the nocturnal peaks by recognized standards, and (4) normal somatomedin C levels for age. Interpretation of growth hormone (GH) data is hindered by the lack of pertinent information from the patient's age group. Recording of normal growth progression in the case illustrated here can only be explained by the capability of a reduced GH secretory rate to maintain full biological activity as shown by the normal plasma level of somatomedin C. Indeed, recent evidence has been provided elsewhere for normal growth progression in the presence of low GH secretion, although other factors unrelated to this hormone may also be operative at this early age. Further reports concerning the treatment of non-GH-dependent conditions with somatostatin derivatives will certainly contribute to the better understanding of the mechanisms governing growth in the postnatal period.

Testosterone and Oxandrolone, a Nonaromatizable Androgen, Specifically Amplify the Mass and Rate of Growth Hormone (GH) Secreted per Burst without Altering GH Secretory Burst Duration or Frequency or the GH Half-Life*

We investigated the mechanisms by which androgens increase mean circulating GH concentrations in boys. We tested two hypotheses: 1) testosterone increases serum GH concentrations at least in part via an androgen receptor-mediated mechanism, rather than exclusively by way of aromatization to estrogen; 2) androgen augments one or more specific features to GH secretion (secretory burst number, amplitude, and/or duration) and/or prolongs the half-life of GH removal. To examine these hypotheses, prepubertal boys with constitutionally delayed development and/or growth were given injections of testosterone (100 mg monthly; n = 7) or treated with oral oxandrolone, a nonaromatizable androgen (1.25 mg twice daily; n = 5). Pulsatile GH release was studied before and during androgen administration by sampling blood at 20-min intervals for 24 h. The immunoreactive GH time series were subjected to a novel deconvolution technique, which revealed that 1) testosterone and oxandrolone each increased mean (24-h) serum GH concentrations significantly; 2) both androgens augmented the daily endogenous GH secretory rate significantly; 3) increased GH production resulted from a higher mass of GH secreted per burst and a higher maximal rate of GH secretion within each burst; and 4) androgens amplified the magnitude of the nyctohemeral rhythm in the mass (but not frequency) of GH secretory pulses. The observed effects of androgen were specific, since the number and duration of GH secretory bursts and the subject-specific GH half-life were unaltered by androgen treatment. We conclude that androgen acting apart from conversion to estrogen is capable of specifically activating the somatotropic axis via distinct neuroendocrine secretory mechanisms.

Effects of Somatostatin on the Growth Hormone‐Releasing Factor‐Induced Growth Hormone Secretion in Rats with Electrical and Chemical Inhibitions of Endogenous Growth Hormone‐Releasing Factor and Somatostatin

Abstract The episodic pattern of growth hormone (GH) secretion of the male rat was simulated in rats exhibiting impaired GH-releasing factor (GRF) and Somatostatin (SRIF) secretion, by administering various combinations of human GRF-(1-44)NH(2) (hGRF) and SRIF. Electrical lesions of the arcuate nucleus resulted in a marked decrease in the amplitude of GH secretory bursts, while the administration of cysteamine (200 mg/kg) did not change the GH secretory profile in rats with arcuate nucleus lesions. Immunohistochemical examinations revealed a marked decrease of GRF and SRIF immunoreactivity in the median eminence of the cysteamine-treated rats with arcuate nucleus lesions. The intravenous injection of 5 mug of hGRF every 3 h caused equivalent surges of GH in the cysteamine-treated rats with arcuate nucleus lesions. The additional infusion of 4 mug/h of SRIF during the trough periods of GH secretion did not affect the amplitude of the GH surges. Hourly injection of 5 mug of hGRF caused transient desensitization to hGRF. Interestingly, the additional infusion of 4 mug/h of SRIF every 3 h enhanced the amplitude of the GH bursts induced by the fourth and the seventh hGRF injections. However, the more frequent injection of 5 mug of hGRF every 30 min caused constant desensitization to hGRF with time, and the additional infusion of 4 mug/h of SRIF every 3 h did not change the attenuated responses to hGRF. These results indicated that the simultaneous administration of hourly GRF and continuous SRIF with brief pauses was most effective for producing high GH peaks. This simulation model suggests that SRIF may play an important role not only in the production of GH troughs, but also in the maintenance of GH surges with distinct peaks in the male rat.

Participation of tri-iodothyronine and metabolic clearance rate in the inhibition of growth hormone secretion in thyroxine-treated domestic fowl

Surgical thyroidectomy increases basal and TRH-induced GH concentrations in the peripheral plasma of immature domestic fowl. Replacement therapy with thyroxine (T4; 100 micrograms/kg per day for 7 days, i.m.) suppressed the GH responses to thyroidectomy. Bolus administration of T4 (10 micrograms/kg, i.m.) to thyroidectomized birds promptly lowered the circulating GH concentrations, which remained suppressed for at least 4 h. Chronic (daily injections for 7 days) or acute (one injection) pretreatment of thyroidectomized birds with iopanoic acid (IOP; 40 mg/bird, i.m.) before the bolus administration of T4 attenuated, but did not prevent, inhibition of circulating GH levels by T4. Administration of IOP (40 mg/bird i.m.) 24 h and immediately before the administration of tri-iodothyronine (T3; 3 micrograms/kg, i.m.) or T4 (10 micrograms/kg, i.m.) also failed to suppress thyroidal inhibition of circulating GH concentrations in thyroidectomized birds. Administration of IOP alone had no effect on GH concentrations. Circulating T3 concentrations were not enhanced following the administration of T4 to IOP-treated birds, indicating its inhibition of hepatic monodeiodinase activity. The metabolic clearance rate (MCR) of 125I-labelled chicken GH in the plasma of thyroidectomized fowl was less than that in sham-thyroidectomized birds. Following pretreatment with T4 (100 micrograms/kg per day for 7 days) sham-thyroidectomized and thyroidectomized birds did not differ significantly in their MCR. The GH secretion rate in thyroidectomized birds was similar to that in sham-thyroidectomized birds and in both groups was markedly reduced following pretreatment with T4. These results demonstrate thyroidal inhibition of circulating GH concentrations in fowl.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in insulin, glucagon and growth hormone secretion rates in sheep fed supplemental energy

ZusammenfassungVeränderungen in den Insulin‐, Glukagon‐ und Wachstumshormon‐Sekretionsraten beim Schaf bei unterschiedlicher EnergiezufuhrDer Effekt von Energiezulagen in der Diät auf basale Plasmakonzentrationen, Sekretionsraten, Halbwertszeiten und Verteilungsvolumen von Wachstumshormon (GH), Insulin und Glukagon wurde an 6 erwachsenen Hammeln nach einer nächtlichen Hungerperiode bestimmt. Es wurden zwei Energiestufen (5,27 MJ ME/kg TS und Tier und 9,54 MJ ME/kg TS und Tier) bei gleichem Proteingehalt der Ration untersucht. Die aufgeführten Parameter wurden mit Hilfe der Verschwindensrate des immunoreaktiven Hormons nach intravenöser Injektion der Hormone bestimmt. Die Plasmakonzentrationen von GH und Glukagon lagen signifikant höher bei niedriger Energieversorgung, die Konzentration von Insulin signifikant niedriger. Der Anstieg von Plasma‐GH bei niedriger Energieversorgung wurde wahrscheinlich durch einen Anstieg der GH‐Sekretion verursacht. Der Anstieg der Glukagonkonzentration im Plasma bei energiearm gefütterten Schafen war begleitet von einer steigenden Glukagon‐Sekretion. Durch eine energiereiche Diät wurde die Plasma‐Insulinkonzentration um etwa 16% gesteigert (P < 0,06). Steigende Plasma‐Insulinwerte waren begleitet von einem erhöhten Insulinabbau und einem Trend zu gesteigerter Sekretion.Aus den Ergebnissen kann gefolgert werden, daß Veränderungen in der Plasma‐Glukagonkonzentration und von GH bei unterschiedlicher Energiezufuhr durch unterschiedliche Sekretionsraten verursacht werden, wobei dem Insulin eine wichtige Rolle zukommt.

Differential Actions of Dopamine Receptor Subtypes on Gonadotropin and Growth Hormone Release in vitro in Goldfish

Incubation of cultured goldfish pituitary cells with 10 nM to 1 microM apomorphine (APO), a non-selective dopamine agonist, increased growth hormone (GH) release in a dose-dependent manner. GH release was also stimulated in a dose-dependent manner by 0.1 nM to 1 microM salmon gonadotropin (GTH)-releasing hormone (sGnRH), sGnRH analog, and chicken GnRH-II (cGnRH-II). The magnitude of GH responses to 1 microM GnRHs were less than that to 1 microM APO. GH responses to 10 nM to 1 microM APO were not significantly increased by the addition of GnRHs. Static incubations with 0.1 nM to 1 microM of the dopamine D1 agonist SKF38393 did not alter basal GTH release, or the GTH responses to 10 nM sGnRH and cGnRH-II. In contrast, the D1 agonist SKF38393 significantly increased basal GH secretion with maximal stimulation achieved at 100 nM concentration, and GH responses to 10 nM sGnRH and 10 nM cGnRH-II were enhanced by simultaneous applications of SKF38393. Incubation with 1 microM of the D2 agonist LY171555 decreased basal GTH release. Additions of 0.1 nM to 1 microM LY171555 caused dose-dependent decreases in the GTH secretion induced by 10 nM sGnRH and cGnRH-II. In contrast, basal and GnRH-stimulated GH release were not affected by coincubations with LY171555. The D1 antagonist SKF83566 and the D2 antagonist domperidone, at 1 microM concentrations, specifically blocked the D1 agonist SKF38393-stimulated increase in GH release and the D2 agonist LY171555-induced depression of GTH secretion, respectively. In cell column perifusion studies, the D1 agonist SKF38393 at 0.1 nM to 1 microM had no effects on GTH release, but significantly elevated GH secretion rates when applied at 0.1-1 microM concentrations. The GH release induced by 1 microM SKF38393 was significantly reduced by simultaneous perifusion with 1 microM of the D1 antagonist SKF83566. Treatments with SKF38393 and/or SKF83566 did not affect net GTH and GH responses to sGnRH challenges. In contrast, perifusion with 0.1 and 1 microM of the D2 agonist LY171555 depressed basal as well as sGnRH-induced GTH responses. These effects of 1 microM LY171555 were completely blocked by simultaneous applications of 1 microM domperidone, a D2 antagonist. Treatments with these D2 selective drugs did not affect basal and sGnRH-stimulated GH release. These results indicate that in cultured goldfish pituitary cells, activation of dopamine D1- and D2-like receptors specifically stimulates GH release and inhibits both basal and stimulated GTH secretion, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth hormone secretory rates in children as estimated by deconvolution analysis of 24-h plasma concentration profiles.

The kinetics of growth-hormone (GH) distribution and elimination was estimated in five GH-deficient children who received 11 intravenous single injections of GH. The plasma disappearance data were analyzed in terms of a two-compartment model. The kinetic parameters obtained were then used in calculating the GH-secretory rate by a numerical deconvolution technique. A simple formula was derived for calculation of the cumulated secretion from the area under the concentration curve of 145 healthy children of various ages, heights, and stages of puberty. The estimated 24-h GH secretion increased with age, corresponding to a two- to fourfold increase during the adolescence period. The highest secretions were found in pubertal stages 3-4. In prepubertal children the heights correlated markedly with the secretion of GH (r = 0.83). Thus an indication of the range of the GH secretion in normal growing children is found, which is important to estimate substitution doses for treatment of GH-deficient children.

Autocrine-paracrine inhibition of growth hormone and prolactin production by GH3 cell-conditioned medium.

In previous work we have shown that perifused GH3 cells exhibit spontaneously accelerating growth hormone (GH) and prolactin (PRL) secretory rates. This behavior contrasts with GH and PRL secretion rates that are decreasing or stable over the same 3-d period in static cell culture. We now report that GH3 cells maintained in serum-supplemented medium produce an autocrine-paracrine factor(s) which inhibits GH secretion in plate culture; PRL release is frequently reduced as well. The inhibitory effect of conditioned medium on GH secretion was concentration dependent, whereas PRL release was stimulated at low and inhibited at high concentrations over the same range. Extensive dialysis of conditioned medium using membranes with a molecular weight cut-off of 12,000-14,000 did not remove GH inhibition but produced a retentate that stimulated PRL secretion. Heat-inactivation of conditioned medium did not abolish inhibition of GH release but did remove the PRL-stimulatory effect. IGF-I added to fresh culture medium did not reproduce the GH-inhibitory effects of conditioned medium. We conclude that GH3 cell secretory behavior in perifusion and plate culture systems may be partially explained by the production of an autocrine-paracrine factor: its accumulation in plate culture inhibits GH and PRL secretion whereas its removal, by perifusing medium, allows GH and PRL secretion to accelerate.

The half-life of exogenous growth hormone after suppression of endogenous growth hormone secretion with somatostatin.

We have estimated the half-life of serum growth hormone (GH) in six subjects on 14 occasions following an intravenous bolus injection of either 50 or 500 mU of biosynthetic human growth hormone (B-hGH) while endogenous GH secretion was suppressed by a continuous infusion of somatostatin. The disappearance curve of serum GH was mono-exponential and the mean half-life was 8.9 min (SD 1.5). This is less than previously reported and has important implications for the performance of GH profiles, which should be performed with 10-15 min sampling intervals, and the calculation of pituitary GH secretion rates.

Effect of exertion on the stimulation of ornithine decarboxylase activity by growth hormone in rats

To investigate the effect of stressful stimulation on tissue responsiveness to growth hormone (GH), we examined ODC activity as a measure of hepatic sensitivity to the hormone during forced exertion in rats. GH caused a 15-fold increase in ODC activity in the livers of resting rats at 3 hours after the injection of hormone. Forced walking in a rotating cylinder enhanced the effect of GH on ODC activity by up to 66% above the effect in resting rats, and this enhancement was positively related to the speed of rotation of the cylinder. These results suggest that tissue hypersensitivity to GH stimulation is a consequence of forced exertion. This hypersensitivity to GH would tend to compensate for the inhibitory effects of forced exertion on GH secretion in rats.

Metabolic clearance rates of synthetic human growth hormone in lean and obese male rhesus monkeys.

The MCR of synthetic human GH was studied in eight adult male rhesus monkeys (Macaca mulatta). Four monkeys were lean (less than 20% body fat), and four were obese (greater than 35% body fat). The monkeys were given a single bolus injection of GH (2.5 micrograms/kg BW), followed by a constant infusion of GH (250 micrograms/h) for 2.5 h. Venous blood samples were collected before the infusion and every 10 min during the infusion. In both groups a plateau of the plasma GH concentrations, indicating a steady state, was reached 70 min after the start of the infusion. The MCR of GH was calculated from the ratio of the constant GH infusion rate and the plateau plasma GH concentration in each monkey. The MCR of synthetic GH was 12.7 +/- 1.7 (+/- SD) L/24 h in the lean group and 19.5 +/- 2.9 L/24 h in the obese group (P less than 0.007). However, the MCR/kg ratio in the lean monkeys was the same as that in the obese animals. We conclude that 1) MCR of GH is directly proportional to body weight; and 2) the lower plasma GH levels in obesity may be due to an increase in its MCR not compensated for by an appropriate increase in the rate of GH secretion.

46 CALCULATION OF PITUITARY GROWTH HORMONE (GH) SECRETION RATE IN CHILDREN

We have assessed the half-life of endogenous GH in 8 normal adults by measuring the decline of GH concentrations in venous blood taken at 10 minute intervals following stimulation by bolus intravenous injection of GHRH followed by an infusion of somatostatin-14 (3μg/kg/min) over 120 minutes. The half-life of GH (18.24 min) was calculated from natural log transformed data, the decline being described by a simple exponential consistent with a single pool model. GH delivery rate from the pituitary gland was calculated by deconvolution using the estimate of the endogenous half-life and 24 hr GH profiles in 16 prepubertal and 12 pubertal children. GH production was negligible at the end of each secretory cycle, an ‘on-off’ phenomenon. GH secretion rate was relatively constant for size during childhood but a 3-4 fold increase was demonstrated during puberty. Knowledge of GH delivery rate from the pituitary gland should be taken into account in calculating the therapeutic regimen of GH and/or GHRH, especially during puberty.

Long-term maintenance of growth hormone secretion in perifused rat anterior pituitary cells

We studied the effect of rat growth hormone-releasing factor-(1–43) acid, rGRF(1–43)OH, on the long-term secretion of rat growth hormone (rGH) in dispersed primary cultured cells of rat anterior pituitaries over a period of 7 days or longer. Results of the perifusion assay show that freshly dispersed cells secrete more rGH than 4-day-old redispersed cells ( P < 0.05), that a stabilization period ranging from 4 to 24 h allows a greater production of rGH per day than longer periods ( P < 0.05) and that the working concentrations of rGRF-(1–43)OH and prostaglandin E 2 (PGE 2) that insured the best responsiveness and longer viability are 50 pM and 10–1000 nM, respectively. Under these conditions, the cells continued secreting rGH after 42 days of perifusion, and 315 milligrams of rGH was produced over that period.

Phorbol ester and phospholipase C-induced growth hormone secretion from pituitary somatotroph adenoma cells in culture: effects of somatostatin, bromocriptine, and pertussis toxin.

To clarify the role of the breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2) in GH secretion in human somatotrophs and the effects of inhibitors of GH secretion on this mechanism, we studied the effects of 12-tetradecanoylphorbol-13-acetate (TPA) and phospholipase C (Plase C) on GH secretion and the interactions of somatostatin (SRIH), bromocriptine, and pertussis toxin (IAP) with TPA or Plase C, using human GH-secreting pituitary adenoma cells in culture. SRIH (10(-9)-10(-7) M) inhibited and TPA (10(-10)-10(-8) M) and Plase C (0.125-1.0 U/mL) stimulated GH secretion. SRIH (10(-9)-10(-7) M) inhibited GH release induced by TPA (10(-8) M) or Plase C (1.0 U/mL). Bromocriptine (10(-8) M) also inhibited 10(-8) M TPA-induced GH secretion. When adenoma cells were treated with 100 ng/mL IAP for 24 h, basal and TPA-induced GH secretion rates did not change. However, the inhibitory effects of SRIH (10(-8) M) or bromocriptine (10(-8) M) on basal and 10(-8) M TPA-stimulated GH secretion were attenuated. In addition, IAP reduced GH secretion induced by 0.5 U/mL Plase C, while SRIH inhibition of Plase C-evoked GH release was diminished by IAP. We conclude that the hydrolysis of PIP2 by Plase C, which causes activation of protein kinase C by 1,2-diacylglycerol and Ca2+ mobilization by inositol 1,4,5-triphosphate, is a physiological intracellular mechanism leading to GH secretion in human somatotrophs; SRIH inhibits GH secretion mediated by this mechanism, and bromocriptine blocks at least protein kinase C-mediated GH release; the inhibitory guanine nucleotide-binding protein (Ni) is involved in these inhibitory effects of SRIH and bromocriptine; and Ni modulates the breakdown of PIP2 by Plase C.