Plasma GH Levels Research Articles

Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide.

Somatostatin analogs are an alternative treatment to pituitary surgery and radiotherapy in acromegalic patients. Recently, a depot long-lasting formulation of slow release (SR) lanreotide has been shown to be effective in the short-term control of GH hypersecretion in acromegalic patients. We report the long-term follow-up of a cohort of 22 acromegalic patients treated with SR lanreotide during 1-3 yr. Thirteen females and 9 males, age 51 +/- 3 yr, presented with macroadenomas (n = 12), microadenomas (n = 8), or empty sella (n = 2). Seven patients previously had undergone a partial surgical removal of their adenomas, and 21 of them had mean plasma GH levels less than 5 micrograms/L during a previous octreotide treatment. According to GH values recorded after 3 months of twice monthly 30 mg SR lanreotide im injection, SR lanreotide was administered every 14 days (n = 13) or every 10 days (n = 9). At the 6-month visit, mean GH values were 5 micrograms/L or less in 68% and 2.5 micrograms/L or less in 27% of patients, and these results remained unchanged during the 1-3 yr follow-up period. During SR lanreotide treatment, the mean insulin-like growth factor I (IGF-I) concentrations remained in the normal range in 63% of patients. No escape from the treatment occurred in any of the cases. A significant decrease of the pituitary tumor volume was observed in 3 (13%) patients. The main side effect consisted of minor digestive problems during 48 h after each injection and was reported by 13 patients. Biannual gallbladder echographies revealed the occurrence of gallstones in 4 (18%) patients. In conclusion, these data confirm the efficacy and the tolerance of the long-term SR lanreotide administration (30 mg im every 10-14 days) in the control of acromegaly.

Profiles of the hormones somatostatin, gastrin, CCK, prolactin, growth hormone and cortisol. I. In dairy cows that are milked and fed separately or milked and fed simultaneously

The present study was performed to investigate how the profiles of the gastrointestinal hormones somatostatin, gastrin and CCK, the pituitary hormones prolactin and GH and the adrenocortical hormone cortisol was influenced in dairy cows exposed to two different management routines: (1) milking and feeding simultaneously, (2) milking and feeding separately. Four cows of the Swedish Red and White breed were used. Following separate feeding, the plasma levels of somatostatin, gastrin and prolactin increased, whereas the levels of GH and cortisol decreased. Prolactin was the only hormone that increased significantly in response to the milking stimuli. The level of CCK had decreased 20 min after milking. When the cows were milked and fed simultaneously the release of prolactin was larger than during separate milking or separate feeding, the release of gastrin was smaller compared with separate feeding and the plasma levels of GH were higher than during separate feeding. It is probable that the release of gastrin was inhibited by somatostatin in this treatment, since the release of somatostatin tended (p < 0.10) to be larger compared with separate feeding. These results show that the plasma levels of the studied hormones can be influenced by applying different milking and feeding routines. Since these hormones directly or indirectly may be of importance for milk production, the finding might have significance for a better management of dairy cows.

Growth hormone binding protein and free growth hormone in chronic renal failure.

Chronic renal failure in children is associated with growth failure. While the pathogenesis of uremic growth failure is multifactorial, an abnormal growth hormone/ insulin-like growth factor (GH-IGF) axis is an important contributory element. Patients with uremia exhibit insensitivity to the action of GH, as exemplified by high plasma GH levels, low IGF-I activity, and poor somatic growth. This insensitivity can be overcome by supraphysiological doses of exogenous GH. Plasma GH binding protein (GHBP, the circulating ectodomain of the GH receptor) levels are decreased in patients with renal failure, as are hepatic GH receptor levels in animal models. Since GHBP levels are thought to reflect GH receptor levels in tissues, it is likely that the uremic GH insensitivity in humans is mediated by a decreased number of GH receptors. Another implication of the low plasma GHBP is a disproportionate elevation of free plasma GH (the biologically active moiety) relative to total GH, lending additional support to the concept of GH insensitivity in uremia. GH kinetics are altered in renal failure because of: (1) inability to excrete GH and (2) changes in the bound fraction of GH in the circulation.

Perinatal ontogeny of porcine growth hormone receptor gene expression is modulated by thyroid status.

The ontogeny of growth hormone receptors (GHR) represents a critical stage in growth and metabolism. We have investigated the perinatal ontogeny of hepatic and skeletal muscle GHR gene expression in piglets, and its modulation by GH and thyroid hormones. Test piglets were rendered hypothyroid in late gestation by feeding the sow a high-glucosinolate rapeseed meal. Plasma and tissue samples were obtained from test and control piglets at various ages between 80 days of fetal life (80F) and 2 days postnatally. Plasma hormone levels were determined by radioimmunoassay and GHR mRNA by RNase protection assays. In controls, plasma thyroxine (T4) and 3,5,3'-triiodothyronine (T3) levels increased between 80F and birth and the early postnatal period was characterized by a marked surge in plasma T3. Test piglets were hypothyroid at 110F with total T4, total T3 and free T3 levels being reduced by 28, 53 and 33% respectively. By contrast, the postnatal increase in T3 was more marked in test than in control animals. Plasma GH levels decreased over the perinatal period and there was no effect of treatment. Hepatic GHR mRNA was at the lower limit of detection at 80F but by 110F was expressed in both groups of animals. However, fetal hypothyroidism at 110F resulted in a marked 70% decrease in hepatic GHR mRNA (p < 0.01). The higher postnatal rise in T3 in test piglets was accompanied by a recovery of hepatic GHR mRNA levels. By contrast with liver, skeletal muscle (longissimus dorsi) expressed high levels of GHR mRNA at 80F and hypothyroidism induced a 68% increase in GHR mRNA (p < 0.001). The present results suggest that thyroid hormones may modulate the perinatal ontogeny of GHR gene expression, in addition to other hormonal factors, and that this modulation is tissue-specific.

Changes in mediobasal hypothalamic dopamine and indoleamine metabolism after superior cervical ganglionectomy of rats.

Eight days after bilateral superior cervical ganglionectomy (Gx) of rats, norepinephrine content of medial basal hypothalamus (MBH) decreased significantly by 44-50%. To obtain information on other possible neurochemical sequela of Gx in MBH, we examined the metabolism of dopamine and serotonin in MBH of Gx rats by employing a high pressure liquid chromatography procedure. Eight days after Gx, MBH dopamine levels augmented significantly. Assessment of dopamine metabolism by measuring dihydroxyphenylacetic acid (DOPAC)/dopamine and homovanillic acid (HVA)/dopamine indexes indicated a significant decrease of MBH DOPAC/dopamine ratio after Gx. MBH serotonin levels increased, and 5-hydroxyindoleacetic acid (5-HIAA)/serotonin index decreased significantly in Gx rats. To examine the interaction Gx-induced changes on MBH dopamine and serotonin with the modified hormonal milieu produced by an ectopic pituitary transplant, adult male rats bearing an ectopic pituitary within the pectoral muscles from day 5 of life were submitted to Gx on day 60 of life and were studied 8 days later. MBH dopamine content increased significantly after pituitary grafting, an effect counteracted by a subsequent Gx, while Gx alone augmented MBH dopamine levels. DOPAC and HVA contents augmented in pituitary-grafted animals, an effect counteracted by Gx. Gx increased MBH serotonin content in control but not in pituitary-grafted rats. After pituitary grafting a decrease in MBH 5-HIAA levels was found, an effect reversed by Gx. Pituitary transplants brought about a significant increase of MBH DOPAC/dopamine index, and a significant decrease in 5-HIAA/serotonin index, both effects being counteracted by Gx. Gx of control rats resulted in a significant decrease of MBH 5-HIAA/serotonin index. Analyzed as a main effect in a factorial analysis of variance, Gx decreased MBH DOPAC/dopamine and HVA/dopamine indexes significantly. Plasma prolactin increased in pituitary-grafted rats, an effect further increased by a subsequent Gx. In pituitary-grafted, Gx rats plasma GH levels augmented significantly. The data suggest that superior cervical ganglion removal affects differentially dopamine and indoleamine metabolism in MBH of control and pituitary-grafted rats.

Studies on the analysis of endocrinologic and metabolic factors controlling the concentration of plasma insulin-like growth factor-I (IGF-I) in maternal rats

The effects of the difference of nutritional intake on the kinetics of IGF-I secretion were investigated by 48 hours refeeding with standard, low-protein, low-fat, or low-sugar diet after 72 hours fasting in nonpergnant rats. The effects of hormonal and nutritional changes on the plasma level of IGF-I were also examined in pregnant rats by administration of hGH (100μg/day) for 3 days from day 12 or day 17 of pregnancy and by fasting for 48 hours from day 18. Plasma levels of GH and IGF-I were measured by radioimmunoassay, and the nitrogen balance was determined by the Plegl-Damas method.When nonpregnant rats were fed diets containing different nutrients after 72 hours of fasting, feeding with a low-protein diet, decreased plasma levels of total protein and albumin, and a decreased nitrogen balance were found to be closely related to a fall in the plasma level of IGF-I. In the nonpregnant rats, it appeared that nutrient intake and protein metabolism were important factors in the control of IGF-I.When the pregnant rats were administered 100μg/day of GH from day 12 to day 14 or day 17 to day 20 of gestation, the plasma levels of IGF-I were not significantly higher than in the control group given physiological saline intramuscularly.The IGF-I level in pregnant rats was 87.6±17.5 ng/ml on day 18. When the rats fasted for 48 hours from day 18, the IGF-I level fell to 60.6±10.7 ng/ml on day 20, a value significantry lower than that in rats allowed free access to food (118.6±24.8 ng/ml). A significant decrease in the plasma levels of total protein, albumin, triglycerides, and total cholesterol was seen after 48 hours of fasting from day 18. The nitrogen balance was 48.6±38.5 mg/day on day 18, and became markedly negative (-279.4±94.1 mg/day) on day 20 after fasting for 48 hours. The plasma level of IGF-I decreased as the nutritional status of the rats worsened, and changes in the IGF-I concentration were in close agreement with changes of the simultaneously measured nitrogen balance.These findings suggest that plasma levels of IGF-I in pregnant rats are influenced by changes of nutrient metabolism, especially protein metabolism.

The relationship between GH, IGF-I, IGF-II, IGF-BP-3 and 17β-estradiol plasma levels in patients undergoing controlled ovarian hyperstimulation -possible implication on implantation

(1996). The relationship between GH, IGF-I, IGF-II, IGF-BP-3 and 17β-estradiol plasma levels in patients undergoing controlled ovarian hyperstimulation -possible implication on implantation. Gynecological Endocrinology: Vol. 10, No. sup4, pp. 90-91.

Effect of intravenous or intracerebroventricular injections of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 on GH release in conscious, freely moving male rats.

The present study was designed to examine the effects of intracerebroventricular injection of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP) on GH secretion in freely moving conscious male rats and to determine whether the central action of GHRP is mediated by increased GHRH and/or somatostatin (SRIF) release. A significant and dose-related suppression of natural fluctuations in plasma GH occurred immediately after intracerebroventricular injection of GHRP at the doses of 1, 3 and 10 mu g/rat and was sustained for more than 1 h. An intracerebroventricular injection of GHRP also suppressed plasma GH rises after an intravenous injection of [D-Ala2, Nle27] human GHRH (1-28)agmatine (hGHRH analog), but the GH suppression by intracerebroventricular GHRP was significantly blunted in rats treated with antirat SRIF gamma-globulin (SRIF-ab). In addition, the suppression by intracerebroventricular GHRP of hGHRH-analog-induced GH release was observed even in rats treated with anti-rat GHRH goat gamma-globulin (GHRH-ab) which does not cross-react with hGHRH analog, and again its suppression was significantly attenuated by simultaneous treatment with SRIF-ab and GHRH-ab. Furthermore, intracerebroventricularly injected GHRP was effective enough to inhibit the central-nervous-system (endogenous GHRH)-driven natural GH-secretory surges in SRIF-ab-treated rats. When 10 mu g/kg GHRP was injected intravenously every 1 h during a 7-hour observation period in control rats without antibody treatment, plasma GH levels were increased with the peak 10 min after each injection during the surge period of the GH-secretory rhythm, but the plasma GH response to GHRP was frequently absent during its trough period. In addition, in SRIF-ab-treated rats, basal GH levels as well as plasma GH peaks after GHRP injections were markedly elevated and the obvious plasma GH rises after GHRP could be observed even during the trough period. In GHRH-ab-treated rats, basal GH levels were lower, and the plasma GH response to GHRP was significantly attenuated as compared with those in control rats. Plasma GH peaks after GHRP injections in rats simultaneously treated with SRIF-ab and GHRH-ab were higher than those in rats given GHRH-ab alone, but its difference in GH response was obviously smaller than that observed between SRIF-ab-treated and control rats, suggesting a crucial role of endogenous GHRH in GHRP-induced GH release. To further clarify the interaction of GHRH and GHRP in GH release, hGHRH analog was injected intravenously alone or simultaneously with GHRP in rats treated with SRIF-ab and GHRH-ab. The peak GH values after simultaneous injection of hGHRH analog and GHRP were significantly higher than the sum of GH peaks after each injection of hGHRH analog and GHRP. In conclusion, an intracerebroventricular injection of GHRP suppresses GH secretion by a central mechanism which is likely to include increased SRIF release, reduced GHRH release or both. We have confirmed that intravenous injection of GHRP can stimulate GH release by itself in an immunologically nullified condition of circulating endogenous GHRH and SRIF in rats, and that endogenous SRIF modestly suppresses the GH-stimulating effect of intravenously injected GHRP while both endogenous and exogenous GHRH markedly enhance GH release by intravenously injected GHRP in a synergistic manner.

Reducing post-partum anoestrous interval in first-calf Bos indicus crossbred beef heifers. III. Effect of nutrition on responses to weaning and associated variation in metabolic hormone levels

Interactions between effects of undernutrition and weaning on the duration of post-partum anoestrus and associated variation in milk yield, suckling behaviour, and metabolic hormone levels in Droughtmaster [Bos indicus x Bos taurus (518, 3/8)] first-calf cows were studied in 2 successive years. Low body condition score at calving (3.5f 0.1, scale 1-9) was associated with prolonged post-partum anoestrous intervals in suckled cows, but provided cows were maintaining liveweight, ovarian cyclicity resumed within 50 days if calves were weaned 70 days post-partum. This response to weaning was totally inhibited in cows that calved in low body condition that lost liveweight post-partum (Year 1). In contrast, marked levels of post-partum liveweight loss (23%) did not affect resumption of ovarian cyclicity in response to weaning (at 50 days post-parturn), or time to conception, among cows that calved with high body condition scores (5.8 � 0.2, Year 2). Reduced milk yields and calf weight gains among underfed cows were associated with higher suckling frequencies and durations ( P &lt; 0.05). Acyclic interval after weaning was negatively related to body condition score at weaning (P &lt; 0.01), and positively related to preweaning suckling intensity (P &lt; 0.01). The time taken to resume ovarian cyclicity after weaning increased by a factor of 1.2 for every half unit decrease in body condition score at weaning, and by a factor of 1.3 for every 30-min increase in time suckled per day prior to weaning. Within level of nutrition, higher frequencies and durations of suckling were associated with higher plasma prolactin levels. Plasma IGF-1 levels were consistently depressed in underfed cows, whereas plasma insulin and GH levels were less affected by nutritional treatments. Effects of undernutrition in suckled cows appear to operate at least partly through interactions with milk yield and suckling intensity. Management of post-partum anoestrus in Bos indicus cows should focus on the conservation of cow body condition and on the strategic use of early weaning.

In obesity the somatotrope response to either growth hormone-releasing hormone or arginine is inhibited by somatostatin or pirenzepine but not by glucose.

It is known that spontaneous and stimulated GH secretion is reduced in obesity. On the other hand, it has been recently reported that, in obese subjects, plasma GH levels did not change during a hyperglycemic clamp. To further study the sensitivity of somatotrope cells to inhibitory influences in obesity, we studied the effect of somatostatin, pirenzepine, or glucose on the GH response to GHRH or arginine in 32 obese patients and 30 controls. Basal GH levels were lower in obese than in normal subjects (1.0 +/- 0.6 vs. 4.8 +/- 0.7 micrograms/L, P < 0.05), while insulin-like growth factor-I levels were similar in both groups (137.3 +/- 13.2 vs. 138.8 +/- 12.2 micrograms/L). In obese as well as in control subjects pirenzepine abolished the GH response to either GHRH (AUC0-120: 43.7 +/- 9.6 vs. 258.3 +/- 59.9 micrograms/L/h, P < 0.04 and 113.0 +/- 75.0 vs. 870.5 +/- 255 micrograms/L.h, P < 0.01, respectively) or arginine (6.5 +/- 2.5 vs. 118.7 +/- 55.9 micrograms/L.h, P < 0.05 and 47.7 +/- 7.3 vs. 334.0 +/- 157.5 micrograms/L.h, P < 0.01, respectively). Differently from pirenzepine, glucose blunted the GH response to either GHRH or arginine in control subjects (260.8 +/- 38.3 vs. 479.5 +/- 83.9 micrograms/L.h, P < 0.03 and 294.8 +/- 46.3 vs. 625.1 +/- 139.1 micrograms/L.h, P < 0.05, respectively), but failed to modify it in obese patients (193.7 +/- 39.4 vs. 172.4 +/- 33.6 micrograms/L.h and 121.1 +/- 43.4 vs. 155.1 +/- 39.7 micrograms/L.h, respectively). On the other hand, somatostatin deeply blunted the GHRH-induced GH release in obese patients (58.5 +/- 25.4 vs. 548.7 +/- 196.6 micrograms/L.h, P < 0.05) as well as in controls (181.4 +/- 44.4 vs. 759.7 +/- 46.6 micrograms/L.h, P < 0.04). In conclusion, our results show that, in obesity, the stimulated GH release is refractory to the inhibitory effect of glucose but not of pirenzepine, in spite of their likely common mechanism of action, i.e. increase of hypothalamic somatostatin release. Exogenous somatostatin is able to abolish GH secretion both in normal and obese subjects. These data suggest the existence of a peculiar inhability of hyperglycemia to trigger somatostatinergic release in obesity.

The role of neuropeptide Y (NPY) in the control of LH secretion in the ewe with respect to season, NPY receptor subtype and the site of action in the hypothalamus

Neuropeptide Y1-36 (NPY1-36) acts through Y1 and Y2 receptors while the C-terminal NPY fragments NPY18-36 and N-acetyl[Leu28,31]pNPY24-36 act only through the Y2 receptor. We have investigated the effects of intracerebroventricular (i.c.v.) administration of NPY1-36, NPY18-36 and N-acetyl[Leu28,31]pNPY24-36 on LH secretion in the ovariectomised (OVX) ewe. These peptides were administered into a lateral ventricle (LV) or the third ventricle (3V) of OVX ewes during the non-breeding and breeding seasons. Microinjections of NPY were also made into the preoptic area (POA) during both seasons to investigate the effects of NPY at the level of the GnRH cell bodies. Tamed sheep were fitted with 19 gauge guide tubes into the LV, 3V or the septo-preoptic area (POA). Jugular venous blood samples were taken every 10 min for 3 h. Sheep were then given NPY1-36 (10 micrograms), NPY18-36 (100 micrograms) or saline vehicle into the LV; N-acetyl[Leu28,31]pNPY24-36 (100 micrograms), NPY1-36 (10 micrograms or 100 micrograms), NPY18-36 (10 micrograms or 100 micrograms) or saline vehicle into the 3V, or NPY1-36 (1 microgram, 5 micrograms, 10 micrograms) into the POA. Blood sampling continued for a further 3 h. LH was measured in plasma by radioimmunoassay. LV or 3V injection of 10 micrograms NPY1-36 caused a small but significant (P < 0.025) increase in the interval from the last pre-injection pulse of LH to the first post-injection LH pulse during the breeding season. Other LH pulse parameters were not significantly affected. NPY18-36 did not produce any significant change in LH pulsatility when injected into the LV, and neither peptide had any effect on plasma prolactin or GH levels. There was a significant (P < 0.01) reduction in LH pulse frequency after 3V injection of 10 micrograms and 100 micrograms NPY and 100 micrograms NPY18-36. Pulse amplitude was reduced by 3V administration of the Y2 agonist, N-acetyl[Leu28-31]pNPY24-36 and 100 micrograms NPY18-36. When the amplitude of the first post-injection LH pulse was analysed, 10 micrograms NPY also had a significant (P < 0.05) suppressive effect. During the non-breeding season, 100 micrograms NPY1-36 (but not 10 micrograms) decreased (P < 0.01) LH pulse frequency. LH pulse amplitude was significantly (P < 0.01) decreased by 100 micrograms NPY18-36. Doses of 10 micrograms NPY1-36 and 100 micrograms NPY18-36 had greater inhibitory effects on pulse frequency during the breeding season but the suppressive effect of 100 micrograms NPY was similar between seasons. Microinjections of NPY into the POA decreased (P < 0.01) average plasma LH levels during the non-breeding season at a dose of 10 micrograms but did not significantly affect pulse frequency or amplitude. We conclude that a substantial component of the inhibitory action of NPY on LH secretion in the absence of steroids is mediated by the Y2 receptor. This inhibition is probably exerted by way of a presynaptic action on GnRH terminals in the median eminence as NPY does not modulate the frequency or amplitude of LH pulses at the level of the GnRH cell bodies in the POA.

Disturbed anabolic hormonal patterns in burned patients: the relation to glucagon.

Complex changes in the anabolic regulators of metabolism occur after major injury. We have studied the time course for IGF-I and IGFBP-1 after burn injury and their relations to circulating levels of other anabolic and catabolic hormones. The hormonal patterns during the onset of sepsis were also investigated. Eight patients (age 36 (6) years, mean (SEM)) with major burn injury (burn area 42 (6) %) were studied. The first 2 days since the burn were used for rehydration therapy (rehydration period), after which a complete total parenteral nutrition (TPN) period was initiated. Seven positive blood cultures, during the study period. Six of the eight survived. The hormonal changes determined in the morning during the first 7 days after the burn and from day 22 to 24 were investigated. The superimposed effects of sepsis were studied by normalizing all data to the day of positive blood cultures and clinical onset of sepsis. On admission, plasma levels of glucagon, IGFBP-1 and GH were elevated while levels of IGF-I were low. During the first week after the burn, morning levels of glucagon and insulin increased while levels of GH and IGF-I decreased. GH levels were still elevated compared to healthy subjects. Despite the increase in insulin levels, IGFBP-1 remained elevated. Three weeks after the burn injury, IGF-I levels were increased but still markedly below normal, while IGFBP-1 levels remained unchanged. Persistent elevations of insulin levels were combined with reductions in glucagon levels. Admission levels of IGFBP-1 correlated to nitrogen loss (negative nitrogen balance) during the first 24 hours after the burn (r = 0.84, P < 0.05). A correlation between negative nitrogen balance and glucagon levels was found during early catabolic period in the rehydration period (i.e. days 2-3, r = 0.84, P < 0.01). The relative change in IGFBP-1 levels in the rehydration period correlated to changes in glucagon levels (days 2-3 vs admission, r = 0.85, P < 0.05). The insulin/glucagon molar ratio correlated to the IGF-I/IGFBP-1 ratio during both the rehydration period (days 2-3, r = 0.77, P < 0.05) and the third week after the burn (r = 0.77, P < 0.05). During the most catabolic phase in the first week after the burn (TPN period) there was an inverse relation between IGF-I and IGFBP-I and glucagon (r = 0.83, P < 0.05). During the less catabolic third week after the burn, an inverse correlation was found between IGF-I and glucagon (r = -0.83, P < 0.05). Sepsis, superimposed upon the burn trauma, was associated with transient elevations in IGFBP-1 and reductions in insulin despite elevated levels of glucose and a further 50% increase in nitrogen losses. The present findings show that marked changes is important anabolic regulating factors occur after major burn injury. Uncoupling of the GH-IGF-I axis, and the attenuation of the inhibitory effects of insulin on IGFBP-1, both contribute to the reduction in IGF-I levels and bioavailability, factors which may play an important role in post injury metabolism. Furthermore, these data suggest that the catabolic hormones (catecholamines, cortisol and glucagon), primarily glucagon seem to be involved in the modulation of IGF-I and IGFBP-1 levels following burn injury.

The accumulation of IGF-I in kidneys of streptozotocin-diabetic adult rats is not associated with elevated plasma GH or IGF-I levels

Nephropathy is a major complication of diabetes mellitus and is associated with expansion of the mesangium and an increase in kidney size in both humans and rats. Interestingly, early kidney enlargement occurs only in postpubertal animals, and is preceded by a significant increase in the levels of extractable renal IGF-I. This study examined the possibility that this difference is GH dependent, and that very early changes in plasma GH and/or IGF-I in the adult animal are associated with an early accumulation of renal IGF-I. Silastic jugular catheters were placed in adult (13-14 week) male Sprague-Dawley (S-D) rats for blood collection and drug injection. Serial blood samples were taken every 30 min in groups of saline control and streptozotocin (STZ) (50 μg/kg, IV) rats from 1-6 h, 9-15 h, and 24-30 h post-injection, and plasma GH profiles were determined by RIA. Renal IGF-I content was assessed following acid extraction. Following STZ, there was an immediate, step-wise reduction in peak GH levels (saline controls, 54±7 ng/mlvs 30±5 (1-6 h); 23±10 (9-15 h); and 13±3 ng/ml (24-30 h post-STZ);P<0.05 for all STZ groupsvs control). The same significant step-wise reduction was observed in the integrated area under the curve for GH. A separate group of rats were treated with a GH-releasing factor antagonist (GRF-AN) for 5 days prior to STZ, to suppress pulsatile GH release, and reduce plasma IGF-I. Chronic GRF-AN administration reduced plasma IGF-I levels significantly to 63% of control values (P<0.01). However, despite the reduction in plasma IGF-I, renal IGF-I remained significantly elevated 24 h post-STZ compared with controls and not significantly different from animals treated with STZ alone (467±49 ng IGF-I/g KW in control salinevs 778±100 in saline/STZ and 705±87 ng IGF-I/g KW in chronic GRF-AN/STZ rats (P<0.05)). In conclusion, following STZ administration in the adult rat, there is an immediate reduction in GH levels, indicating the renal IGF-I accumulation occurs without initial increases in plasma GH levels. Furthermore, when plasma IGF-I levels in the adult are significantly reduced renal IGF-I content remains elevated. These data suggest that early diabetic renal growth is not associated with elevated circulating GH levels, and that high basal plasma IGF-I levels are not necessary for IGF-I accumulation.

Effects of chronic octreotide treatment on GH secretory dynamics and tumor growth in rats bearing an ectopic somatotroph (GC) tumor.

The effects of octreotide, a long-acting somatostatin agonist selective of the sstr2/sstr3/sstr5 receptor subtypes, on ectopic GH secretion and tumor growth were investigated in Wistar-Furth female rats implanted with GH secreting (GC) cells which express mostly somatostatin receptors of the sstr1 and sstr2 subtypes. Octreotide dose dependently inhibited thymidine incorporation (-57%) and GH secretion (-41%) from GC cells in culture. In vivo, 6 weeks after GC cell implantation, plasma GH, IGF-1 and insulin levels were highly elevated. Cluster analysis of GH secretory dynamics revealed that GH secretion was less pulsatile in GC-implanted than in control animals. Furthermore, in GC-implanted animals, passive immunization either with SRIH or GHRH antisera, did not affect GH plasma levels. Three weeks after GC cell implantation, when tumors became palpable, octreotide (1 micrograms/h/kg BW) or saline was infused constantly for three weeks by osmotic minipumps. In octreotide treated rats, GH, IGF-1 and insulin levels were not different from sham-implanted animals and tumors weight were reduced by 80%. High affinity somatostatin binding sites were found in equivalent amounts on tumors from octreotide-treated or saline-treated animals. These findings indicate that GH secretion in GC-rats is mainly derived from the tumors and independent of hypothalamic control and that octreotide reduces both GH secretion and tumor growth. We conclude that the GC-implanted rat represents a good animal model to test the antisecretory and antitrophic properties of somatostatin analogs in vivo.

Glycosylated and non-glycosylated prolactin forms are increased after opioid administration as part of surgical anaesthesia.

Previous studies have shown that non-glycosylated prolactin (NG-PRL) increased more markedly than glycosylated hormone (G-PRL) after TRH or metoclopramide stimulation. The aim of the present study was to determine whether such results could be extended to opioid-induced PRL stimulation. Open and prospective study. Using a newly developed IRMA specific for NG-PRL, we determined G-PRL and NG-PRL immunoreactivities after administration of 0.8-1.2 mg of the opioid drug phenoperidine as part of an anaesthesia. Ten male patients anaesthetized for surgical treatment of a prolapsed lumbar intervertebral disc. Samples were obtained hourly pre and post-operatively, and every 15 minutes during operation for determination of plasma PRL, NG-PRL and G-PRL. Plasma cortisol, ACTH and GH levels were measured in an attempt to differentiate the respective roles of stress and opiate agonists in the variations of PRL levels during surgery. A dramatic increase in PRL levels was observed in all patients from an average of 300 +/- 90 to 1200 +/- 330 mU/l (mean + SEM) 30 minutes after drug administration. The proportion of G-PRL immunoreactivity was not significantly different when basal (25.2%) and stimulated (27%) values were compared (P > 0.05), and when mean increments of NG-PRL and G-PRL were compared (345 and 348%, respectively). The opioid drug induced a significant decrease in cortisol levels after injection and during operation (from 585 +/- 63 to 99 +/- 51 nmol/l) with a concomitant decrease in ACTH levels. GH levels were not significantly altered during anaesthesia but were significantly greater (P < 0.05) after than before surgery (5.0 +/- 1.3 vs 0.98 +/- 0.54 mU/l, respectively). We conclude from the present and from previous data that opioid induced anaesthesia is accompanied by an increase in both glycosylated and non-glycosylated PRL and that different PRL secretagogues may induce distinct responses in terms of PRL molecular forms.

DNA synthesis by pituitary tumours, with reference to plasma hormone levels and to effects of bromocriptine

In parathyroid adenomas and experimentally in the normal rat pituitary gland, cell replication and secretory activity were previously shown to be correlated. A similar relationship has now been investigated in human pituitary tumours, since this could have relevance to their growth and aetiology. The effect of bromocriptine on the two variables was examined. Data were derived from 50 patients undergoing operation for pituitary tumour, including 15 with acromegaly and 11 with prolactinoma. Preoperative plasma levels of GH, PRL and gonadotrophins were measured by radioimmunoassay. DNA synthesis, an index of cell replication, was measured in vitro in freshly removed tumour tissue. Nuclear diameter of tumour cells was measured in histological sections and immunostaining for relevant hormones was carried out on tumour tissue. DNA synthesis was correlated (P < 0.05) with plasma hormone levels in cases of prolactinoma, both treated and not treated with bromocriptine, and in a group of putative FSH secreting tumours from male patients. The correlation was not significant in cases of acromegaly. Comparisons of mean values between groups treated and not treated with bromocriptine showed significantly lower DNA synthesis and mean nuclear diameter in prolactinomas under treatment but not in GH secreting tumours. The findings in prolactinomas suggest a close relationship between secretion and tumour cell replication dependent on still undefined agents, but including dopamine, affecting both variables, and isoforms of PRL, which may stimulate or inhibit replication of PRL secreting cells. The basis of the relationship in FSH secreting tumours is unknown. The relationship was absent in the non-homogeneous group of GH secreting tumours. When secretion and growth are correlated, the secretory process may be the site of the primary abnormality in the tumour cell. Evidence that bromocriptine inhibits tumour cell replication was obtained for prolactinomas but not for GH secreting tumours.

Metabolic clearance of recombinant human growth hormone in health and chronic renal failure

Despite the increasing therapeutic use of recombinant human growth hormone (rhGH), its metabolic clearance has not been investigated in detail. To evaluate the kinetics of rhGH as a possible function of GH plasma concentration and glomerular filtration rate (GFR), we investigated the steady state metabolic clearance rate (MCR), disappearance half-life, and apparent volume of distribution of rhGH at low and high physiological as well as supraphysiological plasma GH levels during pharmacological suppression of endogenous GH secretion in human subjects with normal and reduced renal function. GH in plasma and urine was determined by an immunoradiometric assay, and GFR by inulin clearance. In all subjects MCR decreased and plasma half-life increased with increasing plasma GH concentrations (P < 0.001). MCR of rhGH was approximately half in patients with chronic renal failure at each GH level and plasma half-life was increased by 25-50%. Allowing for the linear dependence of MCR on GFR and assuming single-compartment distribution, the estimated renal fraction of total MCR was 25-53 and 4-15% in controls and patients, respectively. Saturation of extrarenal disposal of GH was suggested by an inverse hyperbolic relationship between extrarenal MCR and plasma GH concentrations in all subjects. Fractional GH excretion was up to 1,000-fold higher in patients than in controls. We conclude that MCR of hGH is a function of plasma GH concentrations and GFR. Extrarenal elimination is saturable in the upper physiological range of GH concentrations, whereas renal MCR is independent of plasma GH levels. The kidney handles GH like a microprotein involving glomerular filtration, tubular reabsorption, and urinary excretion.

The potential of immuno-neutralization of somatostatin for improving pig performance

Abstract Immuno-neutralization of somatostatin (SRIF) has shown some promise as a technique for the enhancement of growth and lactation performance in sheep and cattle. In pigs, active immunization against SRIF has failed to promote growth. While a more consistent GH response to GRF injections in SRIF-immunized pigs has been described, the effects of this approach on mean plasma GH, IGF-I and thyroxine levels are equivocal. Since reproductive functions in the pig are affected by GH as well and since the existence of SRIF-like immunoreactivity has been proven in porcine ovaries, the influence of immuno-neutralization of SRIF on reproductive performance has also been investigated. In one report ovulation rates and first litter size tended to be higher, while own work only describes adverse effects on ovarian activity. Although passive transfer of immunity against SRIF through colostrum to litters has been shown, preweaning survival and mean pig weaning weight were not improved. In conclusion, so far there is no indication to suggest that in the near future immuno-neutralization of SRIF might become a practical tool to improve pig performance, possibly because of the poor antibody response in pigs. In addition evidence exists in vivo and in vitro, that SRIF besides its well known negative effect, may also stimulate GH release providing another possible explanation why all attempts to improve pig performance through immuno-neutralization of SRIF have failed so far.

The reduction of circulating growth hormone and prolactin in streptozocin-induced diabetic male rats is possibly caused by hypothalamic rather than pituitary changes.

To gain further information on diabetes-related disorders in the somatotrophic and lactotrophic axes, we undertook a functional, morphometrical and densitometrical study of the arcuate nucleus (AN), median eminence (ME) and anterior pituitary gland of adult male rats one month after streptozocin-induced diabetes (STZ-D). The basal secretory activity of somatotrophs and lactotrophs was tested by the reverse haemolytic plaque assay (RHPA) and plasma GH and prolactin (PRL) levels were determined by RIA. The number of GH-releasing factor (GRF)-labelled axons and the amount of axonal tyrosine hydroxylase (TH)-immunoreactivity increased in STZ-D. There were no significant differences in any of the other densitometrical measurements performed on GRF-, somatostatin-, thyrotropin-releasing hormone- and TH-labelled ME axon cross-sections as well as those on tuberoinfundibular-dopaminergic neurones of the AN in STZ-D compared with control rats. Plasma GH and PRL levels and measurements on anterior pituitary GH- and PRL-labelled structures were decreased in STZ-D. However, the GH and PRL plaque areas were increased after RHPA implying that the secretory capacity of somatotrophs and lactotrophs was not impaired. Taken together, these results suggest that the accumulated GRF in the ME is due to reduced GRF release. This could account for the reduced amplitude and/or frequency of GH secretory pulses. The increased axonal TH-immunoreactivity may indicate an increased dopamine synthesis. If coupled to increased release this could, in turn, be partly responsible for the reduced plasma and anterior pituitary PRL concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pituitary surgery in elderly patients with acromegaly.

Because of the common belief that there is an increase in surgical risk and morbidity involved in the surgical therapy of elderly patients with acromegaly, physicians tend to either neglect therapy altogether or choose radiation therapy combined with medical treatment. In consideration of the expected increasing number of elderly patients resulting from social structure change in the coming years, we decided to investigate the outcome in 15 patients with acromegaly (13 women and 2 men) older than 64 years (mean, 68.3 yr) at the time of surgery in the form of a retrospective study. Medical treatment using either dopamine agonists (9 patients) and/or octreotide (4 patients) were attempted in 11 patients. For various reasons, however, medical therapy could not be permanently continued in any of these patients. The mean preoperative growth hormone (GH)-plasma level without medical treatment was 47.4 +/- 64.2 (mean +/- standard deviation) micrograms/L. At the time of operation, 13 of 15 patients had additional diseases, which led to an increased anesthesiological risk. Transnasal tumor removal was performed without anesthesiological or surgical complications in all patients. The radicality of tumor removal was controlled intraoperatively by GH measurements in eight patients. There was no postoperative mortality or serious morbidity. Postoperative basal GH-plasma levels were normal (< 4.5 micrograms/L) in all patients. None of the 13 patients who participated in long-term follow-up examinations (mean, 4.2 yr) revealed signs of definite tumor recurrence. The mean GH-plasma level at follow-up was 1.6 +/- 0.9 (mean +/- standard deviation) micrograms/L. One patient died 2 years after the operation of causes unrelated to pituitary surgery.(ABSTRACT TRUNCATED AT 250 WORDS)