Mean Plasma GH Levels Research Articles

"Micromegaly": an update on the prevalence of acromegaly with apparently normal GH secretion in the modern era.

Approximately 25% of cases of clinically active acromegaly cases treated in our academic center between 1996 and 2000, were diagnosed in patients who had elevated plasma IGF-1 levels, but apparently "normal" 24-h mean plasma GH levels. The current study served to update the data for patients with acromegaly referred to our facility, after increasing awareness of this "normal" GH subpopulation throughout the medical community. A retrospective chart review was conducted on 157 patients with acromegaly who underwent resection of a confirmed somatotroph pituitary adenoma at the University of Michigan Health System between the dates of 1 Jan 2001 to 23 Sept 2015. Overall prevalence of acromegalic patients with "normal" GH levels, defined as GH <4.7ng/mL, was 31%. Over time, the percentage of patients with "normal" GH at diagnosis did not decline: 26% from 2001 to 2005, 19% from 2006 to 2010, and 47% from 2011 to 2015. Mean pituitary tumor size was 1.8±0.1cm for the group with elevated GH, and 1.2±0.1cm for the group with "normal" GH (p<0.001). Percent microadenomas was higher in a group with "normal" GH as compared to those with elevated GH (48 vs. 12%, p<0.001), and tumors >2cm in the maximal diameter were encountered more frequently in the group with elevated GH (43 vs. 14%, p<0.001). Our data show that a substantial percentage of patients with clinical acromegaly have "normal" GH, and therefore strengthens the growing body of evidence which supports the leading role of IGF-1 levels in diagnostic evaluation. At the present time, questions about the natural course of "micromegaly" and treatment benefits compared to the subpopulation with elevated GH levels remain unanswered, but research continues to build on our understanding of the heterogeneous population of individuals.

Effect of recombinant human GH on circulating granulocyte colony-stimulating factor and neutrophils in patients with adult GH deficiency

We previously reported that short-term continuous subcutaneous infusion (CSI) of recombinant human growth hormone (rhGH) increased plasma erythropoietin levels and hemoglobin concentrations in patients with adult GH deficiency. In the present study, we investigated the effect of rhGH on plasma granulocyte colony-stimulating factor (G-CSF) levels and neutrophil counts in patients with adult GH deficiency. rhGH was administrated for 1 year in six patients with adult GH deficiency (age range, 24-69 years; mean +/- S.E.M., 51.7 +/- 5.8 years; two males and four females) by means of CSI at a rate of 0.25 U/kg per week. Blood samples were obtained in the morning after overnight fasting every month before and after the start of rhGH administration. Plasma GH, insulin-like growth factor I (IGF-I) and G-CSF levels, and neutrophil counts, were measured. Mean ( +/- S.E.M.) plasma GH levels increased from 0.26 +/- 0.14 to 2.28 +/- 0.20 microg/l 1 month after the start of rhGH administration. An increase of the plasma GH levels was accompanied by an increase in the plasma IGF-I levels from 64.7 +/- 8.5 to 293.3 +/- 80.6 microg/l. Plasma G-CSF levels increased at 2, 3, 8, 9 and 10 months after the start of rhGH administration compared with 28.6 +/- 11.0 ng/l at time 0. The neutrophil counts increased at 2, 3, 7, 8, 9, 11 and 12 months after the start of rhGH administration compared with 2822 +/- 377 neutrophils/microl at time 0. rhGH administration increased plasma G-CSF levels and neutrophil counts. GH and/or IGF-I might stimulate neutrophil production and/or release via G-CSF.

Clinically Silent Somatotropinomas May Be Biochemically Active

The diagnosis of acromegaly is suspected based on the typical clinical presentation and is subsequently confirmed biochemically by elevated GH and IGF-I concentrations. We report three female patients with pituitary tumors who presented without any signs or symptoms of acromegaly but with elevated IGF-I levels. Plasma GH was measured every 10 min for 24 h, and an oral glucose tolerance test was performed. All patients had abnormally elevated mean and trough plasma GH levels as well as post-glucose nadir GH concentrations. All patients had magnetic resonance imaging scans revealing pituitary tumors and underwent transsphenoidal surgery. Histologically, they had GH-producing pituitary tumors. Plasma IGF-I levels returned to normal in two patients after surgery. Some pituitary adenomas are true GH-secreting tumors despite not being accompanied by obvious clinical stigmata of acromegaly. Natural history of this disease is unknown because of the small number of reported patients and inconsistent results of biochemical testing. Based on the results of this and previous reports, we propose that all patients with known pituitary tumors, especially younger women with normal or mildly elevated prolactin level, be evaluated for GH excess.

Effect of long-term administration of recombinant human growth hormone (rhGH) on plasma erythropoietin (EPO) and haemoglobin levels in anaemic patients with adult GH deficiency.

We investigated the effect of recombinant human GH (rhGH) on erythropoietin (EPO) and haemoglobin (Hb) concentrations in anaemic patients with adult GH deficiency. rhGH was administrated in 8 patients with adult GH deficiency, three males and five females, aged from 24 to 69 years, mean (+/- SD) of 48.8 +/- 16.4 years, for 1 year by means of continuous subcutaneous infusion (CSI) at a flow rate of 0.036 U/kg/day using a portable syringe pump. Blood samples were obtained in the morning after an overnight fast every week for 1 month, followed by each month before and after the start of rhGH administration. Mean (+/- SE) plasma GH levels increased from 0.24 +/- 0.09 microg/l to 2.32 +/- 0.23 microg/l 1 week after the start of rhGH administration to maintain a steady state. Plasma IGF-I levels increased from 70.1 +/- 13.8 microg/l to 282.8 +/- 70.6 microg/l 1 week after the start of rhGH administration to maintain the steady state. Plasma EPO levels increased from 25.9 +/- 2.6 IU/l to 37.6 +/- 4.2 IU/l and 34.3 +/- 3.6 IU/l at 1 week and 2 weeks after the start of rhGH administration, respectively, and then decreased gradually to 14-9 +/- 2.1 IU/l at 10 months after the start of rhGH administration. Reticulocyte counts increased from 0.88 +/- 0.06% to 1.49 +/- 0.21% at 1 week. Hb concentrations increased from 103 +/- 5 g/l to 106 +/- 5 g/l at 2 weeks after the start of rhGH administration, and then increased gradually to reach the normal range. We conclude that EPO secretion was stimulated in the initial 2 weeks after the start of CSI of rhGH in anaemic patients with adult GH deficiency. Increased Hb concentrations after long-term administration of rhGH might be explained by direct stimulatory effects of rhGH and IGF-I on erythroid cells, which was accompanied by suppressed EPO secretion, in combination with a more generalized indirect impact of rhGH on physical activety. These findings suggest a beneficial effect of rhGH replacement in anaemic patients with adult GH deficiency.

Growth hormone gene polymorphisms and growth performance traits in duroc, Landrace and Tao-Yuan Pigs

This study investigated the restriction fragment length polymorphism (RFLP) of the porcine growth hormone (pGH) gene in Duroc, Landrace, and Tao-Yuan pigs and its effects on growth performance and levels of plasma growth hormone in peripheral circulation. Genomic DNA extracted from 81 Tao-Yuan, 60 Landrace and 48 Duroc pigs were subjected to Southern blot hybridization with a pGH cDNA probe. Polymorphism was detected with the restriction enzymes TaqI and DraI. A comparison of these three breeds showed significant differences in allelic frequencies. Blood samples for radioimmunoassay (RIA) of GH were collected biweekly during the experimental period from pigs 12 to 40 weeks of age. Tao-Yuan pigs showed a mean plasma GH level (2.51 ± 1.23 ng/mL) that was much lower than that of the Landrace (3.80 ± 1.52 ng/mL) and Duroc (4.20 ± 1.03 ng/mL) pigs (P< 0.05). Moreover, the Tao-Yuan pigs also showed poorer growth performance than the Landrace and the Duroc pigs both in the daily weight gain (0.37 ± 0.06 vs 0.67 ± 0.05 and 0.70 ± 0.05 kg/day, P< 0.01) and feed efficiency (3.12 ± 0.28 vs. 2.60 ± 0.14 and 2.52 ± 0.12, P< 0.05). These results suggest that the growth performance trait in these pigs is highly correlated with their growth hormone genotype.

Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly.

Pituitary irradiation suppresses GH hypersecretion in patients with acromegaly. Within 10 yr after radiotherapy, up to 80% of patients achieve plasma GH levels below 5 micrograms/L. Whether this is sufficient to normalize plasma insulin-like growth factor I (IGF-I) levels, is unknown. We examined the effect of radiotherapy on plasma IGF-I concentrations in patients with acromegaly. We reviewed hospital charts of 140 patients with acromegaly seen in our institution between 1975 and 1996. Data on plasma GH and IGF-I were extracted and tabulated longitudinally together with the information about the concomitant medical therapy. We included data from the patients who received radiotherapy as a part of their treatment and whose IGF-I was monitored for more than 1 yr afterward. To avoid the potential bias, the data for patients who were referred to us for medical therapy, having failed radiation elsewhere, were excluded. A total of 38 datasets were submitted for the final analysis. The average follow-up was 6.8 +/- 0.8 yr (range, 1-19). Only 2 patients achieved age- and sex-adjusted normal IGF-I levels while off medical therapy. Noncured patients had a mean plasma GH level of 4.6 +/- 1.1 micrograms/L but still elevated plasma IGF-I levels (219 +/- 26% of the upper normal limit) at the last follow-up visit. A random GH concentration below 1.5 micrograms/L was associated with a pathologically high plasma IGF-I concentration in 43% of instances. Radiotherapy appears to be ineffective in normalizing plasma IGF-I levels in acromegaly. A multicenter study to reevaluate the future use of this modality in patients with acromegaly is warranted.

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.

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.

Serum lipoproteins in acromegaly before and 6-15 months after transsphenoidal adenomectomy.

Acromegaly is a rare disorder characterized by over-secretion of GH, most often because of a pituitary adenoma. The disease is associated with disturbances in lipoprotein metabolism and an increased cardiovascular mortality. The aim of the present study was to investigate whether treatment of acromegaly results in changes in serum concentrations of lipids and apolipoproteins, including lipoprotein(a) (Lp(a)). Fourteen patients with clinical features of acromegaly and increased GH secretion were studied 1-10 months before and 6-15 months after transsphenoidal adenomectomy in an open study. Three patients had diabetes mellitus before surgery and two of these patients had normalized serum glucose levels post-operatively. Mean and baseline plasma GH levels were determined from 24-hour GH profiles. Serum samples were taken in the morning after an overnight fast. All patients were normocholesterolaemic, and four patients were hypertriglyceridaemic before treatment. Mean plasma GH levels decreased from 34.5 +/- 7.4 to 2.1 +/- 0.4 mU/l (mean +/- SEM). Serum IGF-I, insulin and free T3 levels decreased and serum SHBG concentrations increased post-operatively. There was no effect of treatment on serum cholesterol concentrations, but serum triglyceride concentrations decreased. Serum apolipoprotein (apo) B and apoE levels were unaffected by treatment. Serum apoA-I levels increased and Lp(a) levels decreased post-operatively. Successful treatment of acromegaly, resulting in normal mean GH values (< 5 mU/l) and/or normal responsiveness to TRH, have beneficial effects on serum lipoproteins with increased serum apoA-I levels and decreased serum levels of triglycerides and Lp(a). These effects seem to be independent of improvement in glucose tolerance, since patients with diabetes mellitus before surgery and normal fasting blood glucose levels post-operatively had similar lipoprotein responses to treatment as those with normal fasting blood glucose levels before surgery.

Modulatory role of estrogens and progestins on growth hormone episodic release in women with hypothalamic amenorrhea

To define the characteristics of spontaneous GH episodic secretion and the modulatory role of gonadal steroids in patients with hypothalamic amenorrhea associated with weight loss. Women were studied for 8 hours, sampling every 10 minutes, and plasma GH levels were measured by RIA. Fifteen patients with weight-loss-related amenorrhea were studied in baseline conditions. Five out of 15 patients underwent two cycles of hormonal replacement therapy with E2 patches (100 micrograms every 3 days for 24 days) and medroxyprogesterone acetate (MPA) (10 mg/d, from day 12 to day 24). On the second cycle of therapy, the pulsatility study was repeated twice: after only estrogen (day 11) and after E2 plus progestin (day 22). Four normally cycling women were studied as a reference group during midfollicular and midluteal phases. Amenorrheic patients showed mean plasma GH levels similar to healthy women during the follicular phase but significantly lower than those observed during the luteal phase. GH pulse frequency was higher in patients than in controls, whereas pulse amplitude was comparable with the follicular phase but lower during the luteal phase. During the hormonal replacement therapy, when only E2 was administered, GH pulse frequency decreased, whereas GH integrated plasma concentrations and GH pulse amplitude increased significantly. After MPA and E2 administration, GH pulse amplitude and GH plasma levels decreased, which was similar to pretreatment condition. The present study demonstrated that in amenorrhea associated with weight loss the frequency of GH episodic release is significantly higher than in normally cycling women. Moreover, a different modulatory role of estrogen (increased amplitude) and P (decreased amplitude) on the episodic release of GH in amenorrheic women undergoing a replacement treatment was shown by the present data.

GROWTH HORMONE (GH) RECEPTOR GENE EXPRESSION IN THE HYPOTHALAMUS IS INCREASED DURING PUBERTY

The development of a pulsatile pattern of GH secretion occurs at puberty. Although the mechanisms responsible for the generation of GH pulses are unknown, a direct feedback effect of GH on the hypothalamus (via GH receptors) appears to play an important role. We tested the hypothesis that GH receptor gene expression changes over puberty by comparing GH receptor mRNA levels in the periventricular nucleus (PeN) of prepubertal (25 days) and adult (70 days) male rats. We performed in situ hybridization on coronal brain slices using a 35S-UTP-labeled cRNA probe and measured autoradiographic silver grains above GH receptor mRNA-containing cells. We observed that cellular levels of GH receptor mRNA (reported as grains/cell±SE) were significantly higher in adult compared to prepubertal animals (116±6 vs 92±4, respectively; p<0.05). The factors responsible for this pubertal increase in GH receptor message are unclear; however, mean plasma levels of GH increase during puberty and GH has been shown to increase GH receptor mRNA levels in other tissues. Therefore, we tested the hypothesis that GH regulates GH receptor gene expression in the PeN by comparing cellular levels of GH receptor mRNA among groups of control and GH-deficient rats (both dwarfs and GHRH antibody-treated). GH deficiency did not significantly alter the GH receptor mRNA levels when compared with control levels. Conclusion: An increase in GH receptor gene expression may be involved in the pubertal development of pulsatile GH secretion. This increase in GH receptor mRNA most likely occurs independent of increased mean plasma GH levels.

Synergistic interaction between insulin-like growth factors-I and -II in central regulation of pulsatile growth hormone secretion.

Insulin-like growth factor (IGF)-I and -II peptides, receptors, mRNAs, and binding proteins are widely distributed in the central nervous system (CNS), yet their physiological role in the brain remains largely unknown. While earlier in vivo studies in the rat suggested that IGF-I may participate in feedback regulation of GH secretion at a CNS level, the preparations used were only partially pure. The recent availability of purified recombinant IGF-I and -II peptides prompted us to reexamine the involvement of the IGFs in vivo in central regulation of pulsatile GH secretion. Five groups of free-moving adult male rats bearing chronic intracerebroventricular (icv) and intracardiac venous cannulae were icv administered IGF-I (in doses of 0.5, 2, 3, and 10 micrograms) or the acid-saline vehicle; an additional group received 1 microgram of the potent IGF-I analog, long R3 IGF-I. Spontaneous 6-h plasma GH secretory profiles were obtained from all groups. Vehicle-injected control animals exhibited the typical pulsatile pattern of GH secretion, with most peak GH values above 150 ng/ml and trough levels below 1.2 ng/ml. Central administration of IGF-I alone or long R3 IGF-I at all doses tested failed to alter the pulsatile pattern of GH release; there were no significant differences in GH peak amplitude, GH trough level, GH interpeak interval, or mean 6-h plasma GH level compared to those in vehicle-injected controls. In a second study, designed to determine the effects of central administration of IGF-I and IGF-II, in combination, icv injection of 1 microgram IGF-I and 1 microgram IGF-II resulted in a marked suppression in the amplitude of spontaneous GH secretory bursts approximately 3 h after injection; both GH pulse amplitude (43.5 +/- 5.6 vs. 130.6 +/- 14.6 ng/ml; P less than 0.001) and mean plasma GH level (16.3 +/- 1.9 vs. 35.2 +/- 1.8 ng/ml; P less than 0.001) were severely reduced 3-6 h after injection compared to those in vehicle-injected controls. These results demonstrate that IGF-I alone does not play a physiologically important role in feedback regulation of GH secretion at the level of the CNS. Our findings suggest a synergistic interaction between IGF-I and -II in the brain for central control of pulsatile GH secretion.

The plasma pattern of growth hormone in conscious rats during late pregnancy

The plasma GH levels of female rats during late pregnancy were determined using an automatic method for repetitive blood sampling from conscious animals. The plasma GH patterns were analysed by a pulse analysis computer program (PULSAR). The mean plasma GH levels were about twofold higher in pregnant females on days 15, 18 and 22 of gestation than in age-matched non-pregnant females. The basal plasma GH levels were also increased, while there was no change in GH pulse amplitude or frequency. The augmentation of GH release was even more pronounced on day 20 of gestation, with a fourfold increase in mean plasma GH levels compared with those in non-pregnant females. This increase reflected an increase in both basal plasma GH levels and GH pulse amplitude, but there was no increase in pulse frequency. In female rats that delivered on day 22 of gestation, the basal and mean plasma GH levels increased during parturition. Pregnant females consistently responded to multiple i.v. infusions of 1 microgram human GH-releasing factor analogue (hGRF(1-29)-NH2) given at 45-min intervals on day 18 of gestation. Both basal and GRF analogue-stimulated plasma GH levels were undetectable after hypophysectomy of pregnant rats. The present study demonstrates an increase in basal plasma GH levels during late pregnancy and a marked increase in both basal plasma GH levels and GH pulse amplitude on day 20 of gestation. Furthermore, hypophysectomy of pregnant rats results in undetectable GH levels, indicating that the high levels of GH during pregnancy are derived from the pituitary.

EFFECT OF OCTAPEPTIDE SOMATOSTATIN ANALOGUE (SMS 201‐995) ON PLASMA 7B2 (A NEUROENDOCRINE POLYPEPTIDE) LEVELS IN PATIENTS WITH ACROMEGALY

We studied the sequential changes of plasma levels of immunoreactive '7B2' (IR-7B2), a neuroendocrine polypeptide, after a subcutaneous injection of 50 micrograms of synthetic octapeptide somatostatin analogue (SMS 201-995) in seven patients with acromegaly due to GH-producing pituitary adenoma. Compared to the basal levels, mean plasma IR-7B2 and GH levels significantly decreased, until 5 and 10 h respectively after the administration of SMS 201-995. The mean (+/- SEM) nadir levels of plasma IR-7B2 and GH were 68.1 +/- 10.1 and 13.1 +/- 6.9%, respectively, compared to mean plasma levels before treatment (100%). Plasma IR-7B2 as well as GH levels did not change significantly when saline was administered subcutaneously to three acromegalic patients. In addition, plasma IR-7B2 levels did not change significantly after the administration of SMS 201-995 in normal subjects or in patients with primary hypothyroidism in whom SMS 201-995 induced a decrease of plasma TSH levels. These results strongly suggest that SMS 201-995 has an unequivocal suppressive effect on the synthesis and/or the secretion of 7B2 in human somatotroph adenoma cells.

Does SMS 201-995 normalize growth hormone secretion in acromegaly? GH day profiles and GH concentrations after oral glucose loading.

GH secretion in acromegaly was studied in 8 patients before and during treatment with SMS 201-995, a somatostatin analogue, 100 micrograms twice daily, by evaluating GH day profiles and GH suppressibility after oral glucose tolerance tests (OGTT). Normalization of GH secretion, estimated by OGTT, was only observed in the three patients who had a decrease in plasma GH to less than 2 micrograms/l after SMS 201-995 injection, and who had the lowest mean plasma GH levels during the day and the largest percent decline of mean plasma GH levels. We conclude that real normalization of GH secretion during SMS 201-995 therapy only occurs in a subset of patients. The data illustrate that the applicability of the generally held cut-off value of 5 micrograms/l, between normal and abnormal plasma GH, has to be reconsidered in the case of chronic intermittent subcutaneous therapy with SMS 201-995.

Episodic Growth Hormone Secretory Pattern in Male Rats: Relationship to Gonadal Steroid Hormones

In the present study sequential blood samples were obtained from freely-behaving male rats bearing chronic intracardial venous cannulae. Blood samples were obtained at 20 min intervals for 6 h from intact rats, castrated rats, castrated rats treated with either testosterone propionate (TP) or estradiol benzoate (EB) and intact rats treated with either TP or EB. Intact rats demonstrated normal episodic GH secretion. The mean baseline GH concentration was similar in intact and castrated rats, while the overall mean plasma GH levels and the magnitude of the mean plasma GH secretory spikes were significantly higher in intact rats. Injection of castrated rats with TP completely counteracted the effect of castration on GH secretory pattern. Injection of TP to intact male rats did not induce any significant changes in the GH secretory pattern. Treatment of intact males with EB significantly elevated mean baseline GH concentration, while the magnitude of the mean GH secretory spikes was significantly reduced. When EB was injected to castrated males, the overall mean GH levels and the magnitude of the mean GH secretory spikes were significantly reduced, while the mean baseline GH was significantly elevated. The data of the present work suggest that gonadal steroids are responsible, at least in part, for the differences in GH secretory pattern between males and females; and that the increase in the magnitude of GH secretory spikes in males could account for the greater increase in growth rate at puberty in males than in females.

Urinary growth hormone (GH) measurements are useful for evaluating endogenous GH secretion.

Daily (24-h) urinary GH excretion was measured using a highly sensitive sandwich enzyme immunoassay in 10 normal adults, 6 patients with hypopituitarism, 25 normal but short children who had normal plasma GH responses (peak plasma GH level, greater than 10 micrograms/L) to provocative tests, and 8 patients with acromegaly. The mean urinary GH values in the normal adults, patients with acromegaly, and patients with hypopituitarism were 13.8 +/- 4.0 (+/- SE) and 431.1 +/- 149.1 ng/g creatinine (Cr) (1.56 +/- 0.45 and 48.77 +/- 16.87 ng/mmol Cr) and undetectable, respectively; these mean values were significantly different from each other. In the normal but short children the urinary values ranged from undetectable to 55.8 ng/g Cr (6.31 ng/mmol Cr). All of the normal but short children and 4 patients with hypopituitarism participated in a 24-h endogenous GH secretion study. The urinary GH values correlated significantly with the mean 24-h plasma GH concentrations as an index of endogenous GH secretion (r = 0.81; P less than 0.001) and plasma somatomedin-C levels (r = 0.67; P less than 0.001), respectively. In 6 patients with acromegaly whose plasma GH levels were constant throughout a 4-h period, the urinary GH values also significantly correlated with the mean plasma GH levels (r = 0.95; P less than 0.01). These data indicate that urinary GH measurements reflect endogenous GH secretion and that measurement of urinary GH excretion is a useful, simple, and practical method for evaluating endogenous GH secretion.

Chronic sex steroid exposure increases mean plasma growth hormone concentration and pulse amplitude in men with isolated hypogonadotropic hypogonadism.

Sex steroid administration can increase the GH response to provocative stimuli, but the relationship of sex steroids to spontaneous GH secretion is still controversial. We sought to characterize the effect of sex steroids on the plasma GH concentration by examining the 24-h pattern of episodic GH secretion in nine previously untreated adult men with isolated hypogonadotropic hypogonadism before and during long term testosterone, gonadotropin, or pulsatile GnRH treatment. After chronic sex steroid exposure, the mean 24-h plasma GH level, mean GH pulse amplitude, and mean area under the curve of pulses were significantly increased compared to pretreatment values [3.2 +/- 1.8 ( +/- SD) vs. 1.8 +/- 1.2 ng/mL (P less than 0.01); 11.4 +/- 7.2 vs. 5.5 +/- 4.4 ng/mL (P less than 0.05); and 720 +/- 547 vs. 316 +/- 371 ng/mL X 20 min (P less than 0.05), respectively], while mean 24-h pre- and posttreatment GH pulse frequencies were indistinguishable (5.7 +/- 2.1 posttreatment vs. 5.0 +/- 3.2 pretreatment; P = NS). The mean posttreatment plasma somatomedin-C level also rose significantly during treatment (1.89 +/- 0.65 vs. 1.28 +/- 0.48 U/mL; P less than 0.01). We conclude that the increase in the mean plasma GH level during chronic sex steroid exposure is due mainly to augmentation of GH pulse amplitude, and that sex steroids probably increase spontaneous GH secretion.

Growth hormone inhibitory and stimulatory actions of L-dopa in patients with acromegaly.

It is not clear whether dopamine (DA) has a central stimulating activity on GH secretion in patients with acromegaly, as it does in normal subjects. To clarify this, we compared the GH inhibitory potencies of DA, which does not cross the blood-brain barrier (BBB), and L-dopa or bromocriptine, which do cross the BBB, in 23 patients with acromegaly. Further, we examined the central effects of L-dopa after selectively blocking peripheral (median eminence and pituitary) DA receptors with domperidone (a DA D2 receptor blocker which does not cross the BBB). After the administration of DA (5 micrograms/kg X min, iv, for 90 min), L-dopa (500 mg, orally), or bromocriptine (2.5 mg, orally), the mean plasma GH decrease was greatest after DA [maximum decrement, 71.9 +/- 3.8% (+/- SEM); n = 21] compared to L-dopa (44.1 +/- 5.6%; n = 23; p less than 0.001) or bromocriptine (58.9 +/- 5.0%; n = 20; p less than 0.02). Eleven of these patients received a single infusion of domperidone (0.22 mg/min, iv, for 180 min) or a combination of domperidone and L-dopa. Mean plasma GH levels did not change during domperidone alone. However, plasma GH levels in these patients increased significantly when L-dopa was administered 30 min after the start of domperidone infusion (vs. control study: at 90 min, 137.3 +/- 10.8% vs. 100.2 +/- 3.9%, p less than 0.01; at 120 min, 138.8 +/- 19.7% vs. 106.5 +/- 3.1%, p less than 0.05). In contrast, one patient who had a distinct plasma GH increase in response to the domperidone-L-dopa test had no increase in plasma GH when given L-dopa 30 min after the start of a sulpiride infusion (DA D2 receptor blocker which crosses the BBB; 1.1 mg/min, iv, for 180 min). Unlike GH, plasma PRL responses to domperidone infusion were not modified by the additional administration of L-dopa. These results suggest that in acromegaly, DA has not only direct suppressive effects on the pituitary tumor somatotrophs, but also indirect stimulatory effects via the hypothalamus; therefore, the hypothalamic GH-releasing system is not entirely suppressed by excessive tumor GH secretion.

Growth hormone secretion in genetic large (LL) and small (SS) rats.

We investigated whether genetic selection for growth influences pituitary GH secretion in two strains of rats, LL (large) and SS (small). Animals were bled every 15 min for 6 h via an indwelling atrial Silastic catheter, and GH levels were determined by RIA. LL and SS males displayed a low frequency, high amplitude episodic pattern of GH secretion, with surges of GH occurring at 3- to 4-h intervals, separated by trough periods of approximately 60-120 min. In contrast, LL females showed a high frequency, low amplitude pattern of GH secretion, with GH pulses occurring every 1-2 h. The number of GH pulses in SS females was lower than that in LL females. SS males and SS females displayed lower peak amplitudes and lower baseline levels and, therefore, lower mean plasma GH levels compared to LL animals. The anterior pituitary GH content was not significantly different in LL and SS animals of either sex. Thus, the reduction of GH levels in SS animals is most likely the result of reduced release of GH-releasing factor from the hypothalamus or an attenuated pituitary sensitivity to GH-releasing factor.