Biomedical subjects

C A Jaffe

Publications and source records attributed to C A Jaffe.

10 recordsLinked to original sources

PubMed1996

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.

Adrenergic alpha-Agonists↗

PubMed1995

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.

Adult↗

PubMed1994

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.

Adolescent↗

PubMed1994

Persistence of rapid growth hormone (GH) pulsatility after successful removal of GH-producing pituitary tumors.

GH concentration profiles in patients with acromegaly are characterized by rapid GH pulsatility and high interpulse GH concentrations. Animal and human studies have shown that GH pulses are consequent upon periodic discharges of hypothalamic GHRH, whereas interpulse GH levels might reflect tonic secretion of hypothalamic SRIH. Thus, the pattern of GH secretion in acromegaly may conceivably be attributed to high GHRH pulse frequency and/or SRIH deficiency. If this assumption is correct, removal of a GH-producing tumor should be followed by a persistently high GH pulse frequency and a high recurrence rate. We have studied pulsatile GH secretion in 12 patients with acromegaly before and after apparently complete removal of their pituitary tumors. Despite normalization of GH secretion after surgery, the disease recurred in 3 patients within 3 yr. The other 9 patients had normal insulin-like growth factor-I and basal and dynamic GH concentrations for 24 +/- 4 months postsurgery. Parameters of GH secretion in this group (pre- and postsurgery) were compared to sex-, age-, and body mass index-matched controls. Plasma GH concentrations in the postoperative and control series were analyzed by a chemiluminescent assay with a sensitivity of 0.01 micrograms/L. Removal of the somatotroph tumor led to normalization of mean and interpulse (but not the nadir) GH levels, pulse amplitude, and responses to GHRH. However, GH pulse frequency (14.2 +/- 1.2 vs. 11.8 +/- 0.9 pulses/24 h) did not change and was significantly (P < 0.001) higher than the control value (8.7 +/- 0.9 pulses/24 h). Thus, SRIH secretion in acromegaly is not inherently deficient, and high interpulse GH levels reflect the mass of tumorous somatotrophs. The persistence of rapid GH pulsatility in apparently "cured" patients with acromegaly suggests that abnormally rapid GHRH pulsatility may be an inherent component of the disease process.

Acromegaly↗

PubMed1994

Acromegaly. Recognition and treatment.

Acromegaly is a chronic debilitating disease caused by growth hormone (GH) hypersecretion, usually from a pituitary adenoma. It is frequently diagnosed after many years of active GH hypersecretion, and causes significant morbidity and mortality due to cardiac, pulmonary and musculoskeletal changes. Local complications resulting from the pituitary tumour can also occur. The most important feature that will enable a physician to diagnosis the disease is clinical vigilance. Measurement of elevated plasma mecasermin (insulin-like growth factor I, IGF-I) is the single best test to make the diagnosis. Once the diagnosis is confirmed, a GH-secreting tumour should be sought, by performing a careful magnetic resonance imaging or computed tomography scan of the pituitary gland and hypothalamus. Therapy is directed at both preventing local complications of the tumour mass as well as normalising GH secretion. Surgical resection of the tumour is almost always the first step in treatment. If GH secretion is not normalised, which is best assessed by determining whether plasma IGF-I returns to the normal range, further treatment with radiation and/or medical therapy is required. Bromocriptine normalises GH in approximately 10% of patients and causes pituitary shrinkage in a similar fraction of patients. Octreotide is considerably more expensive than bromocriptine and is given subcutaneously, but is more effective in both normalising GH secretion and in shrinking tumours. Octreotide treatment of the pituitary tumours prior to surgical resection may be of value, but requires further investigation.

Acromegaly↗

PubMed1993

Suppression of growth hormone (GH) secretion by a selective GH-releasing hormone (GHRH) antagonist. Direct evidence for involvement of endogenous GHRH in the generation of GH pulses.

To study the potential involvement of growth hormone-releasing hormone (GHRH) in the generation of growth hormone (GH) pulses in humans we have used a competitive antagonist to the GHRH receptor, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2(GHRH-Ant). Six healthy young men were given a bolus injection of GHRH-Ant 400 micrograms/kg body wt or vehicle at 2200 h and nocturnal GH concentrations were assessed by every 10-min blood sampling until 0800 h. Integrated total and pulsatile GH secretion were suppressed during GHRH-Ant treatment by 40 +/- 6 (SE) % and 75 +/- 5%, respectively. GHRH-Ant suppressed maximum (7.6 +/- 2.2 vs 1.8 +/- 0.5 micrograms/liter; P < 0.001) and mean (3.3 +/- 1.0 vs 1.1 +/- 0.2 micrograms/liter; P = 0.02) GH pulse amplitudes. There was no change in integrated nonpulsatile GH levels, pulse frequency, or interpulse GH concentration. GHRH-Ant 400 micrograms/kg also suppressed the GH responses to intravenous boluses of GHRH 0.33 micrograms/kg given 1, 6, 12, and 24 h later by 95, 81, 59, and 4%, respectively. In five healthy men, the responses to 10-fold larger GHRH boluses (3.3 micrograms/kg) were suppressed by 82 and 0%, 1 and 6 h after GHRH-Ant 400 micrograms/kg, respectively. These studies provide the first direct evidence that endogenous GHRH participates in the generation of spontaneous GH pulses in humans.

Activity Cycles↗

PubMed1993

The growth hormone (GH) response to GH-releasing peptide (His-DTrp-Ala-Trp-DPhe-Lys-NH2), GH-releasing hormone, and thyrotropin-releasing hormone in acromegaly.

In patients with acromegaly, GH-producing pituitary tumors release GH in response to specific stimuli such as GH-releasing hormone (GHRH) and are also responsive to a variety of nonspecific stimuli, such as TRH or GnRH, and may exhibit paradoxical responses to glucose and dopamine. In healthy humans, the synthetic peptide GH-releasing peptide (GHRP) (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) releases GH by a putative mechanism of action that is independent of GHRH. How these tumors respond to GHRP is not well characterized. We studied the GH responses to GHRH, GHRP, and TRH stimulation in 11 patients with active acromegaly. The peak GH responses to GHRP and GHRH were not correlated (r = 0.57; P = 0.066). In contrast, the peak GH responses to GHRP and TRH were highly correlated (r = 0.95; P < 0.001). In conclusion, in patients with acromegaly, the GH response to GHRP is qualitatively normal and does not appear to depend on GHRH.

Acromegaly↗

PubMed1993

Effects of a prolonged growth hormone (GH)-releasing peptide infusion on pulsatile GH secretion in normal men.

Bolus injection of the synthetic hexapeptide GH-releasing peptide-6 (GHRP-6) reliably promotes GH secretion. However, desensitization to the GH-releasing effects of GHRP has been shown to occur during short term iv infusion. To determine whether humans would remain responsive to prolonged exposure to GHRP and to study the mechanism of action of GHRP, we compared the effects of a 34-h iv infusion of either GHRP or normal saline on parameters of pulsatile GH concentration in nine healthy young men. Each infusion was administered from 0800 h on day 1 to 1800 h on day 2. GHRP was given as a 1 microgram/kg loading bolus, then at the rate of 1 microgram/kg.h. A 50-microgram iv bolus of TRH was given at 0800 h on day 2, followed by iv boluses of GH-releasing hormone (GHRH; 1 microgram/kg, iv, at 1000, 1200, and 1400 h) and then a bolus of GHRP (1 microgram/kg at 1600 h). The integrated GH concentration (IGHC) and parameters of pulsatile GH concentration were calculated for the period between 1400 h on day 1 to 0800 h on day 2, and IGHC was calculated for 2 h after each bolus of GHRP or GHRH. During GHRP infusion, there was a significant increase in IGHC (2908 +/- 450 vs. 1374 +/- 160 micrograms x min/L), maximum pulse amplitude (15.2 +/- 2.8 vs. 8.4 +/- 1.7 micrograms/L), and mean pulse amplitude (7.0 +/- 1.1 vs. 3.8 +/- 1.5 micrograms/L). Plasma insulin-like growth factor-I increased from 252 +/- 23 to 312 +/- 23 micrograms/L. There was no change in either GH pulse frequency or interpulse GH concentration. During GHRP infusion, the GH responses to the GHRH boluses were augmented; however, baseline TSH was lower, and the GH and TSH/PRL responses to GHRP and TRH, respectively, were smaller. We conclude that the pituitary remains sensitive to GHRP during a prolonged GHRP infusion. The mechanisms of the GHRP effect on GH secretion are uncertain, and the possibility that GHRP acts as a functional somatostatin antagonist is discussed. The contrasting effects of GHRP on GH and TSH/PRL secretion could be due to differential effects of GHRP on the pituitary and hypothalamus.

Adult↗

PubMed1993

Amiodarone-induced thyroid dysfunction.

Cases of hypothyroidism and hyperthyroidism associated with amiodarone therapy are described, and the mechanisms, clinical appearance, and management of amiodarone-induced thyroid dysfunction are discussed. A 72-year-old man with a history of recurrent ventricular tachycardia unresponsive to conventional antiarrhythmic drugs was started on amiodarone therapy. Initially he responded well, but after three months he began to have fatigue, dry skin, and intolerance of cold. His serum thyroid-stimulating hormone (TSH) concentration had risen from 4.4 microU/mL before amiodarone therapy began to 20 microU/mL, consistent with hypothyroidism. He was started on sodium levothyroxine for thyroid hormone replacement; the dosage was adjusted in accordance with subsequent TSH measurements. His hospital course was complicated by congestive heart failure. The second patient was a 43-year-old man with a history of atrial fibrillation who developed hyperthyroidism when placed on amiodarone therapy. He had persistent sweating, intolerance of heat, restlessness, and tachycardia. Thyroid function tests confirmed the presence of hyperthyroidism. The patient was treated with propylthiouracil and propranolol, and amiodarone was discontinued. He remained unresponsive to the propylthiouracil, which was discontinued, and was scheduled for radioactive iodine treatment. The mechanism of amiodarone-induced thyroid dysfunction may involve the large iodine content of the drug. Amiodarone-induced hypothyroidism may range in severity from mild symptoms to severe myxedema; the skin, hair, and nails are particularly affected. Persons with clinical hyperthyroidism secondary to amiodarone treatment show the signs and symptoms of a hypermetabolic state resulting from thyroid hormone excess. Amiodarone-induced hypothyroidism is treated with levothyroxine and hyperthyroidism with antithyroid drugs. Amiodarone can cause thyroid dysfunction, which can have serious consequences.

Adult↗

PubMed1992

Treatment of acromegaly with dopamine agonists.

This article reviews the current understanding of how dopamine agonists stimulate growth hormone secretion in normal individuals, yet suppress growth hormone secretion in acromegaly patients. Although bromocriptine normalizes growth hormone or somatomedin C hypersecretion in a minority of patients, a significant number of subjects have a clinical response. Side effects of bromocriptine treatment and newer dopamine agonists are discussed. These drugs can be useful medical therapy, either used alone in selected patients or in combination with other therapeutic modalities.

Acromegaly↗