Regulation of GH secretion in acromegaly: reproducibility of daily GH profiles and attenuated negative feedback by IGF-I.

GH hypersecretion is a hallmark of acromegaly. It is unknown whether the secretory activity of somatotroph adenoma is autonomous or is still governed by central or peripheral mechanisms. In this study we investigated whether GH secretion in acromegaly 1) has a reproducible circadian pattern and 2) is inhibited by exogenous IGF-I. Eleven patients with newly diagnosed acromegaly were studied in 2 protocols. In protocol 1, peripheral blood was sampled every 10 min for 48 h in 6 patients for the determination of concordance between 24-h GH profiles. There was no significant day to day variability in mean 24-h output. There was, however, a significant time effect, and the 24-h GH secretion pattern was maintained between days. In protocol 2, 5 patients were sampled for GH every 10 min twice, once during infusion of normal saline and once during iv infusion of recombinant human IGF-I (10 microg/kg x h). The recombinant human IGF-I infusion increased plasma IGF-I to approximately 230% of the baseline concentration. This resulted in GH suppression (4220 +/- 1950 vs. 3223 +/- 1472 microg/liter.min; P = 0.001), but did not alter GH secretion pattern. There were highly significant cross-correlations for 10 of the 11 of the subjects in the two protocols when the lag was 0 min. By harmonic analysis, nocturnal augmentation of GH was maintained, and maximum daily GH occurred at approximately 2300 h. These data demonstrate that the pattern of GH secretion in acromegaly is not random, but is highly preserved with 24-h periodicity. In addition, negative feedback regulation by IGF-I is preserved, although the degree of negative feedback is grossly attenuated. Thus, secretory activity of somatotroph adenomas is not autonomous or haphazard, but is still subject to both feedback and feedforward regulatory mechanisms.

Aging-related growth hormone (GH) decrease is a selective hypothalamic GH-releasing hormone pulse amplitude mediated phenomenon.

BACKGROUND: Aging is accompanied by declining growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels. The neuroendocrine mechanisms of this decline have been studied previously, but the interpretation of the data was confounded by the imprecision in GH measurements and by the intervening variables of altered body composition and decreased gonadal steroid milieu in the elderly subjects of both sexes. METHODS: To study the contribution of aging per se, we evaluated discrete parameters of GH pulsatility in young (n = 8 women, n = 8 men) and elderly (n = 11 women, in 10 men) subjects closely matched for body mass index. Blood samples for GH were obtained every 10 minutes for 24 hours. Plasma GH was measured by a sensitive chemiluminescent assay. GH pulsatility was assessed using cluster analysis. RESULTS: The elderly subjects had plasma IGF-I levels and integrated GH concentrations that were 32% to -56% of their sex-matched younger counterparts. The age-associated attenuation in GH was due to a decrease in GH pulse amplitude, whereas pulse frequency and nadir levels were unchanged. The majority of the young subjects (81%) reached their peak GH during the "lights off" period, whereas the majority of the elderly subjects (62%) peaked during the "lights on" period (p = .01). CONCLUSIONS: We conclude that aging in both sexes is accompanied by profound decreases in GH output and in plasma IGF-I concentrations. This effect is separate from the alterations in body mass index that accompany the normal aging process. Attenuation of GH output associated with aging is related solely to the lower GH and, by inference, GH-releasing hormone (GHRH) pulse amplitude.

Generation of growth hormone pulsatility in women: evidence against somatostatin withdrawal as pulse initiator.

To test whether endogenous hypothalamic somatostatin (SRIH) fluctuations are playing a role in the generation of growth hormone (GH) pulses, continuous subcutaneous octreotide infusion (16 microg/h) was used to create constant supraphysiological somatostatinergic tone. Six healthy postmenopausal women (age 67 +/- 3 yr, body mass index 24.7 +/- 1.2 kg/m(2)) were studied during normal saline and octreotide infusion providing stable plasma octreotide levels of 2,567 +/- 37 pg/ml. Blood samples were obtained every 10 min for 24 h, and plasma GH was measured with a sensitive chemiluminometric assay. Octreotide infusion suppressed 24-h mean GH by 84 +/- 3% (P = 0.00026), GH pulse amplitude by 90 +/- 3% (P = 0.00031), and trough GH by 54 +/- 5% (P = 0.0012), whereas GH pulse frequency remained unchanged. The response of GH to GH-releasing hormone (GHRH) was not suppressed, and the GH response to GH-releasing peptide-6 (GHRP-6) was unaffected. We conclude that, in women, periodic declines in hypothalamic SRIH secretion are not the driving force of endogenous GH pulses, which are most likely due to episodic release of GHRH and/or the endogenous GHRP-like ligand.

Leptin regulates pulsatile luteinizing hormone and growth hormone secretion in the sheep.

Administration of leptin during reduced nutrition improves reproductive activity in several monogastric species and reverses GH suppression in rodents. Whether leptin is a nutritional signal regulating neuroendocrine control of pituitary function in ruminant species is unclear. The present study examined the control of pulsatile LH and GH secretion in sheep. We determined whether exogenous leptin could prevent either the suppression of pulsatile LH secretion or the enhancement of GH secretion that occur during fasting. Recombinant human met-leptin (rhmet-leptin; 50 microg/kg BW; n = 8) or vehicle (n = 7) was administered s.c. every 8 h during a 78-h fast to estrogen-treated, castrated yearling males. LH and GH were measured in blood samples collected every 15 min for 6 h before fasting and during the last 6 h of fasting. Leptin was measured both by a universal leptin assay and by an assay specific for ovine leptin. During the fast, endogenous plasma leptin fell from 1.49 +/- 0.16 to 1.03 +/- 0.13 ng/ml. The average concentration of rhmet-leptin 8 h after leptin administration was 18.0 ng/ml. During fasting, plasma insulin, glucose, and insulin-like growth factor I levels declined, and nonesterified fatty acid concentrations increased similarly in vehicle-treated and leptin-treated animals. In vehicle-treated animals, LH pulse frequency declined markedly during fasting (5.6 +/- 0.5 vs. 1.1 +/- 0.5 pulses/6 h; fed vs. fasting; P < 0.0001). Leptin treatment prevented the fall in LH pulse frequency (5.0 +/- 0.4 vs. 4.9 +/- 0.4 pulses/6 h; P = 0.6). Neither fasting nor leptin administration altered GH pulse frequency. Fasting produced a modest increase in mean concentrations of circulating GH in control animals (2.4 +/- 0.5 vs. 3.4 +/- 0.6 ng/ml; P = 0.04), whereas there was a much greater increase in GH during leptin treatment (2.7 +/- 0.6 vs. 8.6 +/- 1.6 ng/ml; P = 0.0001). GH pulse amplitudes were also increased by fasting in control (P = 0.04) and leptin-treated sheep (P = 0.007). The finding that exogenous rhmet-leptin regulates LH and GH secretion in sheep indicates that this fat-derived hormone conveys information about nutrition to mechanisms controlling neuroendocrine function in ruminants.

Growth hormone secretory dynamics over the menstrual cycle.

Whether GH secretion in women varies over the menstrual cycle is uncertain. Previous investigations have led to conflicting conclusions; some studies suggested that there is an estrogen mediated rise in GH during the periovulatory (PO) and luteal (L) phases whereas others indicated no change in GH axis over the cycle. Differences in conclusions could relate to heterogeneity of the study populations, GH sampling paradigms or sensitivity of the GH assays used. In order to investigate whether GH secretion varied over the cycle, 24-h GH profiles using every 10-min sampling were obtained in 6 ovulatory women during the early follicular (EF), PO and L phases of the cycle. The TSH response to TRH, GH response to GRH and fasting plasma IGF-I were measured on each occasion. There was a trend toward higher integrated GH concentration (IGHC) during the PO phase, although this difference was not statistically significant (3284+/-721 vs 4542+/-872 vs 4071+/-699 microg/min/L; EF vs PO vs L; p=0.09). Similarly, deconvolution estimated GH secretion did not vary over the cycle (p=0.56). There were no differences in GH pulse amplitude or frequency. There were no correlations between IGHC and sex steroids. Serum IGF-I was constant over the cycle (272+/-38 vs 277+/-31 vs 265+/-38 microg/L; p=0.89). The TSH response to TRH and GH response to GRH did not vary over the cycle. We concluded that the effect of changes in the ovarian steroid milieu on the GH axis during spontaneous menstrual cycles is minimal.

In vivo semiquantification of hypothalamic growth hormone-releasing hormone (GHRH) output in humans: evidence for relative GHRH deficiency in aging.

GH secretion declines with aging. The neuroendocrine mechanisms of somatopause are uncertain. To semiquantify endogenous hypothalamic GHRH output, we measured the suppressibility of spontaneous and GHRH-stimulated GH secretion by graded doses of a specific competitive GHRH receptor antagonist (N-Ac-Tyr1,D-Arg2)GHRH-(1-29) in healthy young and elderly men. Nocturnal GH was about 30% lower in the elderly than in the young. Graded boluses of GHRH elicited dose-dependent GH responses, with no difference between the two age groups. Graded infusions of GHRH antagonist suppressed GH responses to GHRH in a dose-dependent manner, but with similar potency in both groups. The degree of inhibition depended on the magnitude of GHRH bolus: the dose-inhibition curves for the low GHRH boluses were shifted to the left compared to those with the high GHRH bolus (P = 0.01). Similarly, the dose-inhibition curve for spontaneous GH secretion was shifted to the left for the elderly compared to the young men (P = 0.01). Thus, the model of graded infusions of GHRH antagonist differentiates between different amounts of GHRH presented to the pituitary, permitting semiquantification of the endogenous hypothalamic GHRH output in vivo. Our data suggest that there is an age-dependent decrease in the endogenous hypothalamic GHRH output contributing to the age-associated GH decline.

Androgen deprivation therapy for prostate cancer results in significant loss of bone density.

OBJECTIVES: Advanced prostate cancer is a frequently diagnosed condition in the aging male population, and many men will ultimately be treated with androgen deprivation therapy (ADT). Long-term consequences of ADT on bone mineral density (BMD) have not been systematically studied. We performed a pilot study to test the hypothesis that ADT in patients with prostate cancer results in the measurable loss of BMD. METHODS: A cross-sectional study of 32 men with prostate cancer who were about to begin ADT or who had been receiving ADT for more than 1 year was conducted. BMD was measured by single and dual energy x-ray absorptiometry in the lumbar spine, hip, and forearm. Linear regression analysis was used to estimate the time necessary to develop significant BMD loss in the spine, hip, and forearm regions. RESULTS: Five (63%) of 8 men who had not received ADT and 21 (88%) of 24 men who had received ADT for more than 1 year fulfilled the BMD criteria for osteopenia or osteoporosis at one or more sites. When BMD was compared at each site, men who received ADT for more than 1 year had significantly lower BMD in the lumbar spine than men who had not started treatment (P<0.05). On the basis of regression analysis, an estimated 48 months of ADT would be necessary to develop BMD criteria for osteopenia in the lumbar spine for a man with average BMD at the initiation of therapy. CONCLUSIONS: Pre-existing osteopenia and osteoporosis were common in men with prostate cancer before initiating ADT. Both ADT and the duration of ADT were significantly associated with the loss of BMD in men with prostate cancer.

Insulin hypoglycemia and growth hormone secretion in sheep: a paradox revisited.

Although insulin-induced hypoglycemia is a potent stimulus for growth hormone (GH) secretion in humans, hypoglycemia was reported to suppress GH in sheep. We investigated whether GH suppression in sheep during insulin hypoglycemia resulted from the dose of insulin administered or the fed state of the animal. Saline or insulin (0.05, 0.2, 1.0, or 5.0 U/kg) intravenous boluses were administered to eight fasted ewes in a crossover experiment. In another experiment, four sheep were fed 2 h before intravenous administrations of either 0.2 or 5 U/kg of insulin. All doses of insulin resulted in comparable hypoglycemia, although the duration of hypoglycemia increased directly with insulin dose. Hypoglycemia in fasted animals stimulated GH secretion. The GH rise above baseline was inversely related to the insulin dose, and the insulin doses of 1 and 5 U/kg resulted in late suppression of GH below baseline concentrations. Insulin administration to fed animals caused an identical degree of hypoglycemia but no increase in GH. Insulin-hypoglycemia stimulates GH secretion in sheep in a manner similar to humans, and the response is dependent on both fed state and insulin dose.

Reevaluation of conventional pituitary irradiation in the therapy of acromegaly.

External beam pituitary irradiation has been frequently used in the treatment of growth hormone (GH) secreting pituitary adenomas. Many studies have demonstrated that serum GH declines rapidly and reliably following treatment and early "cure" rates, based on a basal serum GH below 10 micrograms/L were as high as 80%. The definition of "cure" has become more stringent over time and retrospective studies have indicated that GH must be below 2.5 micrograms/L for acromegalics to achieve mortality rates comparable to a normal population. Only 20% of irradiated patients will achieve this goal by 10 yr. Even fewer will achieve a normal serum insulin-like growth factor I (IGF-I) levels. Although pituitary irradiation still has a role in the control of tumor size, its importance as a treatment for normalizing serum GH is being reevaluated.

Peak bone mass in young healthy men is correlated with the magnitude of endogenous growth hormone secretion.

GH plays a key role during adolescence in longitudinal bone growth and the attainment of peak bone mass. We explored the hypothesis that in early adulthood, bone mineral accretion and/or maintenance in men with normal GH and bone mineral status are related to the magnitude of endogenous GH secretion. Overnight plasma GH concentrations (sampled every 10 min from 2100-0500 h) were measured in 15 healthy, lean, Caucasian men (age, 24+/-1 yr; body mass index, 22.6+/-0.6 kg/m2; mean +/- SE). Total body, femur, and lumbar spine bone mineral mass/density were measured by dual energy x-ray absorptiometry. Total body and femoral bone mineral mass correlated with both total nocturnal GH and maximal GH concentrations even when bone mineral mass was adjusted by height (P = 0.005-0.02; r = 0.58-0.74). Neither spinal nor total body bone mineral density (BMD) correlated with GH. Maximum GH correlated with the BMD of all four femoral sites (P = 0.01-0.04; r = 0.55-0.66), whereas total nocturnal GH correlated with only one (trochanter; P = 0.01; r = 0.64) femoral site. Our data support the hypothesis that GH continues to play a role in the accretion and/or maintenance of bone mass in young men. This relationship is more evident in the bone mineral mass achieved than in the BMD.

Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test.

We retrospectively reviewed dynamic ACTH and cortisol responses to insulin hypoglycemia in 193 subjects with suspected ACTH deficiency to ascertain the predictive values of various diagnostic criteria. Based on the achievement of a peak cortisol level of 18 micrograms/dL or above, 133 subjects were classified as having an intact hypothalamic-pituitary-adrenal (HPA) axis, and 60 subjects were determined to have ACTH deficiency. Baseline and peak cortisol concentrations were strongly correlated (r = 0.63; P < 0.0001). Peak cortisol increased in parallel to ACTH increments, but plateaued at approximately 22 micrograms/dL at peak ACTH levels above approximately 75 pg/mL (r = 0.61; P < 0.0001). Basal cortisol values above 17 micrograms/dL or below 4 micrograms/dL were highly predictive of an intact or impaired HPA axis, respectively, but intermediate values had only limited sensitivity and specificity. The criteria of HPA axis integrity, defined as an increment in plasma cortisol of more than 7 micrograms/dL above the baseline or as a doubling of the baseline cortisol value, were associated with high false positive and false negative rates. We conclude that 1) the baseline morning serum cortisol concentration has very limited predictive power in differentiating between normal and impaired HPA function; 2) the use of criteria based on incremental changes in serum cortisol from baseline leads to unacceptably high false positive and false negative rates; and 3) insulin hypoglycemia is still the best indicator of the integrity of the response of the HPA axis to stress.

Regulatory mechanisms of growth hormone secretion are sexually dimorphic.

Sexually dimorphic growth hormone (GH) secretory pattern is important in the determination of gender-specific patterns of growth and metabolism in rats. Whether GH secretion in humans is also sexually dimorphic and the neuroendocrine mechanisms governing this potential difference are not fully established. We have compared pulsatile GH secretion profiles in young men and women in the baseline state and during a continuous intravenous infusion of recombinant human insulin-like growth factor I (rhIGF-I). During the baseline study, men had large nocturnal GH pulses and relatively small pulses during the rest of the day. In contrast, women had more continuous GH secretion and more frequent GH pulses that were of more uniform size. The infusion of rhIGF-I (10 microg/kg/h) potently suppressed both spontaneous and growth hormone-releasing hormone (GHRH)-induced GH secretion in men. In women, however, rhIGF-I had less effect on pulsatile GH secretion and did not suppress the GH response to GHRH. These data demonstrate the existence of sexual dimorphism in the regulatory mechanisms involved in GH secretion in humans. The persistence of GH responses to GHRH in women suggests that negative feedback by IGF-I might be expressed, in part, through suppression of hypothalamic GHRH.

Growth hormone (GH)-releasing peptide-6 requires endogenous hypothalamic GH-releasing hormone for maximal GH stimulation.

GH-releasing peptide-6 (GHRP-6) is a potent GH secretagogue that releases GH by uncertain mechanisms. To assess whether GHRH is required for GH release by GHRP-6 in humans, we used the specific antagonist to GHRH (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2 (GHRH Ant). We have previously shown that GHRH-Ant (400 microg/kg) blocked the GH response to 0.33 and 3.3 microg/kg boluses of GHRH by 95% and 81%, respectively. Nine healthy men between the ages of 20 and 30 yr were studied on two occasions. They received either saline or GHRH-Ant (400 microg/kg, i.v.) at 0840 h, followed by GHRP-6 (1 microg/kg, i.v. bolus) at 0900 h. Blood was sampled every 10 min from 0800-1100 h. GH responses were measured as the maximal increase over the baseline GH concentration and as the area under the curve. GHRH-Ant eliminated most of the GH response to GHRP-6 [maximal increase over the baseline GH concentration, 33.8 +/- 4.8 vs. 6.2 +/- 1.8 microg/L (mean +/- SEM; P < 0.0001); area under the curve, 1701 +/- 278 vs. 376 +/- 113 microg/min x L (P < 0.001)]. These data show that endogenous GHRH is necessary for most of the GH response to GHRP-6 in humans.

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.

In vivo Investigation of Hypothalamic Secretory Activity.

The finding that all pituitary hormones are released in a discrete pulsatile fashion and that the pulsatile properties of the pituitary hormone secretion are altered in some physiologic and pathologic conditions prompted the development of techniques designed to study the pattern of release and the regulation of secretion of the hypothalamic neuropeptides. This review describes the currently used techniques to assess hypothalamic hormone secretion. (Trends Endocrinol Metab 1997;8:105-111). (c) 1997, Elsevier Science Inc.

Suppression of growth hormone (GH) hypersecretion due to ectopic GH-releasing hormone (GHRH) by a selective GHRH antagonist.

We have recently demonstrated that a competitive antagonist of GHRH, (N-Ac-Tyr1,D-Arg2)GHRH-(1-29)NH2 (GHRH-Ant), eliminates nearly all nocturnal GH pulsatility in normal subjects, supporting the hypothesis that GH pulsatility is driven by GHRH. In this study, we compared the effects of every 12 h i.v. boluses of either GHRH-Ant or saline on 24-h GH profiles in a patient with acromegaly due to a metastatic GHRH-secreting carcinoid tumor. Bolus doses of GHRH-Ant (400 micrograms/kg, i.v.) acutely suppressed GH concentration to 30-40% of the pretreatment baseline, and this effect lasted 3-4 h. Administration of GHRH (0.33 microgram/kg, i.v.) bolus resulted in a small rise in GH, and this effect was blocked by GHRH-Ant (400 micrograms/kg). During saline treatment, the secretory patterns of both GH and ectopic GHRH were pulsatile; however, there was no correlation between changes in plasma GHRH and GH concentrations. This lack of correlation was probably due to the majority of circulating GHRH immunoreactivity consisting of nonbiologically active GHRH fragments. These data support the hypothesis that GH hypersecretion in the ectopic GHRH syndrome requires GHRH receptor occupancy and validates the use of GHRH-Ant to probe the potential involvement of endogenous GHRH in patients with acromegaly due to pituitary somatotropinoma.

Nocturnal growth hormone (GH) secretion is eliminated by infusion of GH-releasing hormone antagonist.

The neuroendocrine mechanisms underlying the generation of pulsatile GH secretion in humans are poorly understood. GH secretory pulses are likely to result from acute GHRH secretory episodes, acute decreases in hypothalamic somatostatin secretion, or a combination of these mechanisms. In earlier studies we demonstrated that a single i.v. bolus of a competitive GHRH antagonist [N-Ac-Tyr1,D-Arg2)GHRH-(1-29); GHRH-Ant] blocked 40% of the nocturnal GH release. Failure to more completely eliminate nocturnal GH secretion could be due to either incomplete antagonism of endogenous GHRH action by GHRH-Ant or a non-GHRH component of GH release. We subsequently investigated whether a continuous infusion of GHRH-Ant would more completely eliminate nocturnal GH secretion. Eight men were given a 400 micrograms/kg i.v. bolus of GHRH-Ant at 2300 h, followed by a 50 micrograms/kg.h i.v. infusion of GHRH-Ant between 2300-0700 h or a saline bolus followed by a saline infusion. An i.v. bolus of GHRH (1 microgram/kg) was given at 0500 h on both occasions. Blood was sampled every 10 min between 2300-0700 h. As measured by the area under the curve (AUC) from 2400-0500 h, GHRH-Ant suppressed GH secretion by an average of 89% (1795 +/- 412 vs. 164 +/- 46 micrograms/min.L; P = 0.004). The response to GHRH was suppressed by 79% (484 +/- 140 vs. 64 +/- 19 micrograms/min.L; P = 0.02). These data demonstrate that the previously observed nonsuppressible GH secretion was probably due to incomplete blockade of pituitary GHRH receptors and that all or nearly all of nocturnal GH pulsatility can be attributed to the effect of hypothalamic GHRH.

Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli.

The roles of hypothalamic growth hormone-releasing hormone (GHRH) and of somatostatin (SRIF) in pharmacologically stimulated growth hormone (GH) secretion in humans are unclear. GH responses could result either from GHRH release or from acute decline in SRIF secretion. To assess directly the role of endogenous GHRH in human GH secretion, we have used a competitive GHRH antagonist, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2 (GHRH-Ant), which we have previously shown is able to block the GH response to GHRH. We first tested whether an acute decline in SRIF, independent of GHRH action, would release GH. Pretreatment with GHRH-Ant abolished the GH response to exogenous GHRH (0.33 microgram/kg i.v.) but did not modify the GH rise after termination of an SRIF infusion. We then investigated the role of endogenous GHRH in the GH responses to pharmacologic stimuli of GH release. The GH responses to arginine (30 g i.v. over 30 min), L-dopa (0.5 g orally), insulin hypoglycemia (0.1 U/Kg i.v.), clonidine (0.25 mg orally), or pyridostigmine (60 mg orally) were measured in healthy young men after pretreatment with either saline of GHRH-Ant 400 microgram/kg i.v. In every case, GH release was significantly suppressed by GHRH-Ant. We conclude that endogenous GHRH is required for the GH response to each of these pharmacologic stimuli. Acute release of hypothalamic GHRH may be a common mechanism by which these compounds mediate GH secretion.

Nocturnal augmentation of growth hormone (GH) secretion is preserved during repetitive bolus administration of GH-releasing hormone: potential involvement of endogenous somatostatin--a clinical research center study.

Pulsatile GH secretion in humans is under the dual and opposing regulation of hypothalamic GHRH and SRIH. GH pulses result from acute GHRH secretory discharges, and their occurrence and amplitude are augmented at night. We hypothesized that normal adults have predictable circadian or ultradian patterns of SRIH secretion and that this rhythm modulates both spontaneous GH secretion and the GH response to GHRH in a similar manner. To test this hypothesis, we compared baseline GH concentration patterns with GH profiles during submaximal iv boluses of GHRH. Every 20 min blood sampling for plasma GH determination over a 24-h period was performed in seven middle-aged men on days 1 and 7. Each subject received a GHRH (0.33 microgram/kg) iv bolus every 2 h on days 2-7, during which the GH responses to the first two boluses were measured. Plasma insulin-like growth factor I (IGF-I) was measured at 0800 h on each day. [The subjects had GH response to every GHRH bolus] and the integrated GH concentration on day 7 was increased 4.3 +/- 0.6-fold over that in the baseline study on day 1. There was no acute or chronic desensitization to GHRH, and the pituitary remained equally responsive to the GHRH boluses despite a 2.6-fold increase in IGF-I by day 7. During this same time period, there was a 1.4-fold increase in IGF-binding protein 3. The subjects showed similar circadian patterns of GH secretion at baseline and during repetitive GHRH boluses, with a maxima on each day occurring during the early night-time hours. These data demonstrate that healthy men remain sensitive to the GH-releasing effects of submaximal bolus doses of GHRH despite significant increases in GH and IGF-I. The similarities between the GH concentration profiles during days 1 and 7 are consistent with the hypothesis that the ultradian pattern of GH secretion in humans is in part a product of hypothalamic GHRH discharges superimposed on more slowly changing SRIH secretion.

Negative feedback regulation of pulsatile growth hormone secretion by insulin-like growth factor I. Involvement of hypothalamic somatostatin.

To investigate the mechanisms of the negative feedback inhibition of growth hormone (GH) secretion by IGF-I, we studied parameters of GH pulsatility in six normal, fed men before and during a 48-h infusion of recombinant human IGF-I (rhIGF-I) (10-15 micrograms/kg per h). Plasma levels of IGF-I increased from the baseline value of 163.5 +/- 9.3 micrograms/liter (mean +/- SE) to a new steady state of 452.0 +/- 20.9 micrograms/liter during the infusion. Plasma GH concentrations were measured every 10 min for 24 h during both saline and rhIGF-I infusions using a sensitive chemiluminescent assay. Overall, GH concentrations were suppressed during the rhIGF-I infusion by 85 +/- 3%, mainly by attenuating spontaneous GH pulse amplitude (77 +/- 4% suppression). The apparent GH pulse frequency was attenuated from 7.8 +/- 0.9 to 4.7 +/- 0.6 pulses/24 h (P = 0.006). Administration of rhIGF suppressed GH responses to exogenous GH-releasing hormone by 82 +/- 3%, and thyroid-stimulating hormone responses to thyrotropin-releasing hormone were also suppressed by 44 +/- 9%. This constellation of hormonal effects is most compatible with the rhIGF-I-induced stimulation of hypothalamic somatostatin secretion.