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Objective: To determine the association between preoperative thyroid hormone replacement and complications following major abdominal surgery., Methods: A retrospective case series was performed of patients enrolled in the Michigan Surgical Quality Collaborative (MSQC) who underwent major abdominal surgery at an academic institution over a 10-year period. The principal explanatory variable was preoperative thyroid hormone replacement. Primary outcomes were morbidity, mortality and length of stay., Results: 2700 patients were identified. On multivariate analysis correcting for established predictors of operative morbidity, patients on preoperative thyroid replacement had a 1.5- fold increased risk of serious morbidity(p ​= ​0.01), and a 1.7- fold greater risk for serious sepsis(p ​= ​0.04). Thyroid replacement was associated with longer length of stay(p ​< ​0.001). While there was a high degree of missing data for surgical approach (31.1 ​% missing data), results suggest that patients on thyroid hormone replacement were more likely to undergo an open rather than minimally invasive surgery(p ​< ​0.01). Open surgery was associated with greater risk of serious morbidity(p ​= ​0.003) and longer length of stay(p ​< ​0.001)., Conclusions: Preoperative thyroid hormone replacement independently predicts operative morbidity and length of stay following major abdominal surgery., Competing Interests: Declaration of competing interest We have no conflicts of interest to disclose. This manuscript has not been published elsewhere and is not under consideration by another journal., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ghrelin, a 28-amino acid hormone that is acylated post-translation, is the endogenous ligand for the growth hormone (GH) secretagogue (GHS) receptor (GHS-R). The highest concentrations of ghrelin are found in the stomach; however ghrelin peptide is also present in hypothalamic nuclei known to be important in the control of GH and feeding behavior. Exogenous ghrelin potently stimulates pituitary GH release through a mechanism that is dependent, in part, on endogenous GH-releasing hormone. Whether endogenous ghrelin plays a role in the control of GH secretion and growth is not clear and ghrelin deficient animals appear to grow normally. In contrast, experimental animal and clinical data suggest that abnormalities in GHS-R signaling could impact growth. Ghrelin or other GHS are clinically useful for GH-testing and limited data suggest that they might be useful in the treatment of some patients with GH deficiency. Substantial data have implicated ghrelin as an important regulator of feeding behavior and energy equilibrium. Ghrelin has a potent orexigenic effect in both animals and humans and this effect is mediated through hypothalamic neuropeptide Y (NPY) and Agouti-related peptide (AgRP). Appetite simulation coupled with other metabolic effects promotes weight gain during chronic treatment with ghrelin. These metabolic effects are in part mediated through an increase in respiratory quotient (VQ). Presence of ghrelin appears to be necessary for the development of obesity in some animal models. Whether abnormalities in ghrelin signaling are involved in human obesity is not yet known.

Pheochromocytomas offer the opportunity to explore multiple pathophysiological mechanisms through functional imaging. MIBG scintigraphy and PET scanning with tracers of the sympathetic nervous system are based on uptake of catecholamines and catecholamine-like compounds by hNET, the human norepinephrine transporter. In-111 pentetreotide scanning involves the imaging of somatostatin receptors on the cellular surface of tissues. FDG PET scanning examines the transport and incorporation of FDG into cells. We present a patient with malignant pheochromocytoma who underwent multitracer imaging to characterize the tumor and probe its pathophysiology to direct a therapeutic approach. This case underscores the inherent difficulties in the diagnosis and localization of malignant pheochromocytomas. Multiple approaches to functional and anatomic imaging may be required to fully delineate the extent of disease and similarly to direct radionuclide-based therapy.

Context: Some indirect evidence suggests hypothalamic control of GH secretion in acromegaly., Objective: The objective of the study is to examine whether GH secretion in acromegaly is dependent on endogenous GHRH., Patients and Study Design: We studied eight patients with untreated acromegaly due to a GH-producing pituitary tumor. All patients received an iv infusion of normal saline for 24 h and GHRH-antagonist (GHRH-ant) at 50 microg/kg x h for 7 d. GH was measured every 10 min for 24 h during the normal saline infusion and on the last day of the GHRH-ant infusion. A group of nine different patients with untreated acromegaly served as the control group and underwent blood sampling for GH every 10 min for two 24-h periods to assess the day-to-day variability of GH secretion., Setting: The study was set in a university referral center., Main Outcome Measure: Twenty-four-hour mean GH was the main outcome measured., Results: In six of eight subjects treated with GHRH-ant, 24-h mean GH decreased by 5.8-30.0% during iv GHRH-ant and, in three subjects, the change in the 24-h mean GH was greater than the upper limit of the 95% confidence interval of the spontaneous day-to-day variability of the mean GH in patients with acromegaly. Based on the binomial distribution, the probability of this magnitude of change to occur in three of eight subjects by chance alone is 0.0008., Conclusion: In some patients with acromegaly due to a pituitary adenoma, GH secretion is under partial control by endogenous GHRH.

Non-functioning pituitary tumors are relatively common. A large number of these tumors are incidentally found pituitary microadenomas (<1 cm) and are usually of no clinical importance. Those tumors that require treatment are generally macroadenomas and come to medical attention because of mass effect and/or hypopituitarism. Visual field defects are present in roughly 70% of patients with non-functioning macroadenoma at the time of diagnosis and the majority of these patients have at least growth deficiency and hypogonadism. By immunocytochemistry, the large majority of these tumors are glycoprotein producing and less commonly they are non-functioning somatotroph, lactotroph or corticotoph adenomas. In contrast to the immunocytochemistry results, only a minority of these tumors actively secrete intact gonadotrophs or glycoprotein subunits. Therapy is directed at eliminating mass effect and correcting hypopituitarism. There are anecdotal reports of tumor shrinkage during therapy with either dopamine agonists or somatostatin agonists; however tumor response to medical treatment is not reliable. For most patients, transphenoidal resection of the tumor is the preferable primary treatment. Surgery improves visual defects in the majority of patients and a lesser number will recover pituitary function. In the past, pituitary radiation was commonly administered following pituitary surgery; however the need for routine radiation has recently been reevaluated. Although tumor recurrence at 10 years post surgery may be as high as 50%, few patients with recurrence will have clinical symptoms. Close follow-up with surveillance pituitary scans should be performed after surgery and radiation therapy reserved for patients having significant tumor recurrence.

GH secretory profiles in humans are pulsatile and exhibit nocturnal elevation during the early hours of sleep. Fasting augments GH output and rhythmicity. Ghrelin was suggested to exhibit nocturnal increases and to rise in response to nutritional deprivation. We examined whether ghrelin may be an underlying mechanism of GH rhythmicity and response to fasting. We studied nine young healthy subjects during normal feeding and after 2 d of complete fasting. Plasma GH was measured every 10 min, and plasma total and active ghrelins were measured every 20 min. Fasting augmented mean daily plasma GH (1.47 +/- 0.25 vs. 3.30 +/- 0.6 microg/liter; P = 0.012). Neither mean daily total ghrelin (4.19 +/- 0.64 vs. 4.35 +/- 0.74 microg/liter; P = 0.75) nor mean daily active ghrelin (0.13 +/- 0.02 vs. 0.13 +/- 0.02 microg/liter; P = 0.34) changed as a result of fasting. All subjects exhibited nocturnal augmentation of GH secretion; there were no corresponding nocturnal increases in either total or active ghrelin concentrations. Similarly, cross-correlation analysis failed to find any relation between GH and ghrelin pulses. We conclude that ghrelin is unlikely to be of importance in the generation of rhythmic or nutritionally mediated GH secretion.

We report a case of cryptococcal thyroiditis presenting with hyperthyroidism that evolved through a transient euthyroid phase to hypothyroidism and finally recovered to normal function. This four-phase clinical presentation is similar to that of subacute thyroiditis, and it is unusual in the setting of infectious nonviral thyroiditis. Cryptococcal thyroiditis is rare; only three cases have been reported. Our patient is the first who survived the disseminated cryptococcal infection with thyroid involvement, thus enabling longitudinal clinical and endocrinologic follow-up.

Using a continuous subcutaneous octreotide infusion to create constant supraphysiological somatostatinergic tone, we have previously shown that growth hormone (GH) pulse generation in women is independent of endogenous somatostatin (SRIH) declines. Generalization of these results to men is problematic, because GH regulation is sexually dimorphic. We have therefore studied nine healthy young men (age 26 +/- 6 yr, body mass index 23.3 +/- 1.2 kg/m2) during normal saline and octreotide infusion (8.4 microg/h) that provided stable plasma octreotide levels (764.5 +/- 11.6 pg/ml). GH was measured in blood samples obtained every 10 min for 24 h. Octreotide suppressed 24-h mean GH by 52 +/- 13% (P = 0.016), GH pulse amplitude by 47 +/- 12% (P = 0.012), and trough GH by 39 +/- 12% (P = 0.030), whereas GH pulse frequency and the diurnal rhythm of GH secretion remained essentially unchanged. The response of GH to GH-releasing hormone (GHRH) was suppressed by 38 +/- 15% (P = 0.012), but the GH response to GH-releasing peptide-2 was unaffected. We conclude that, in men as in women, declines in hypothalamic SRIH secretion are not required for pulse generation and are not the cause of the nocturnal augmentation of GH secretion. We propose that GH pulses are driven primarily by GHRH, whereas ghrelin might be responsible for the diurnal rhythm of GH.

After evaluating a patient who appeared to have a falsely abnormal response to the dexamethasone suppression test while taking troglitazone, we examined the effects of troglitazone on the activity of hepatic CYP3A4 and the screening tests for Cushing's syndrome. We studied five healthy women and three healthy men, aged 25 +/- 2 yr, before and after treatment with troglitazone (600 mg daily) for 28 d. Baseline 0800 h cortisol and corticosterone were similar before and after troglitazone treatment. Before troglitazone treatment, all subjects suppressed 0800 h cortisol below 1.8 micro g/dl (mean, 0.66 +/- 0.08 micro g/dl) during the 1-mg overnight dexamethasone suppression test (DST), whereas during troglitazone treatment none of the subjects suppressed 0800 h cortisol below 1.8 micro g/dl (mean, 9.0 +/- 1.8 micro g/dl). Serum dexamethasone levels decreased by 66 +/- 4%, and the erythromycin breath test measurements increased by 27 +/- 8%, indicating increased CYP3A4 activity during troglitazone treatment. The hydrocortisone suppression test (HST) was performed by administering 50 mg hydrocortisone at 2300 h. Using the criterion of suppression of 0800 h plasma corticosterone by more than 50%, the specificity of the HST was 100% both before and after troglitazone treatment. In conclusion, troglitazone induced the activity of CYP3A4 leading to falsely abnormal DST. HST is a useful alternative to the DST in patients taking medications that increase the activity of CYP3A4.

We studied plasma ghrelin and GH concentrations over a 24-h period in young healthy men and women and in patients with acromegaly. Healthy subjects were restudied after administration of GH-lowering agents, octreotide or GHRH antagonist. Ghrelin concentrations in women studied during the late follicular stage of the cycle were about 3-fold higher than in men. Suppression of GH secretion by GHRH antagonist did not alter ghrelin concentration profiles. In the presence of high GH levels (acromegaly), ghrelin levels were similar to those found in healthy men. Administration of somatostatin analog octreotide suppressed both GH and ghrelin concentration profiles. We conclude that: 1) ghrelin secretion is sexually dimorphic in humans, with women in the late follicular stage having higher levels than men; 2) ghrelin secretion is suppressed by somatostatin; and 3) GH has no influence over ghrelin secretion.

Background: Previous epidemiologic investigations of the associations of sex-steroid hormones and benign prostatic hyperplasia (BPH) have focused on predominately white populations. The objective of this study was to evaluate potential associations of body mass index (BMI), cigarette smoking, use of alcohol, and endogenous sex-steroid hormones with prostate volume in a population-based sample of African American (AA) men, ages 40-79 yr., Methods: A total of 369 AA men without clinical evidence of prostate cancer were identified in the Flint Men's Health Study by using a population-based sampling procedure. All subjects underwent a complete urologic evaluation that included prostate volume determination by transrectal ultrasonography and serum assays for androgens and estrogens., Results: After age adjustment, BMI (weight (kg)/height (m)2) was positively correlated with increasing levels of androstanediol glucuronide (AG), estradiol (E2), estrone sulfate (E1S), and the ratios of E2:total testosterone (TT) and E2:free testosterone (FT); however, increasing BMI was negatively correlated with androstenedione (AD), FT, TT, and sex hormone-binding globulin (SHBG). Multivariable regression models demonstrated that prostate volume increased with age (P < 0.001) and BMI (P = 0.02) and decreased with increasing levels of SHBG (P = 0.01). Larger prostatic volumes were also marginally associated with increasing levels of TT (P = 0.058)., Conclusion: Circulating serum levels of SHBG and endogenous sex-steroid hormones are correlated with prostate volume and potentially impact the natural history of BPH. However, longitudinal studies are needed to demonstrate the temporal relationships of hormones and growth factors in the pathogenesis of BPH in AA men., (Copyright 2002 Wiley-Liss, Inc.)

The importance of gender-specific growth hormone (GH) secretion pattern in the regulation of growth and metabolism has been demonstrated clearly in rodents. We recently showed that GH secretion in humans is also sexually dimorphic. Whether GH secretion pattern regulates the metabolic effects of GH in humans is largely unknown. To address this question, we administered the same daily intravenous dose of GH (0.5 mg. m(-2). day(-1)) for 8 days in different patterns to nine GH-deficient adults. Each subject was studied on four occasions: protocol 1 (no treatment), protocol 2 (80% daily dose at 0100 and 10% daily dose at 0900 and 1700), protocol 3 (8 equal boluses every 3 h), and protocol 4 (continuous GH infusion). The effects of GH pattern on serum IGF-I, IGF-binding protein (IGFBP)-3, osteocalcin, and urine deoxypyridinoline were measured. Hepatic CYP1A2 and CYP3A4 activities were assessed by the caffeine and erythromycin breath tests, respectively. Protocols 3 and 4 were the most effective in increasing serum IGF-I and IGFBP-3, whereas protocols administering pulsatile GH had the greatest effects on markers of bone formation and resorption. All GH treatments decreased CYP1A2 activity, and the effect was greatest for pulsatile GH. Pulsatile GH decreased, whereas continuous GH infusion increased, CYP3A4 activity. These data demonstrate that GH pulse pattern is an independent parameter of GH action in humans. Gender differences in drug metabolism and, potentially, gender differences in growth rate may be explained by sex-specific GH secretion patterns.

The biochemical diagnosis of acromegaly is conventionally based on elevated plasma GH levels that fail to suppress after an oral glucose load. We studied 16 newly diagnosed patients with acromegaly with normal mean plasma GH but elevated age and gender-adjusted plasma IGF-I concentrations (476 +/- 29 microg/liter, mean +/- SE). Plasma GH was sampled every 10 min for 24 h, and an oral glucose tolerance test was performed. The control group included 46 healthy subjects. All patients had 24-h mean GH values that overlapped with those of the healthy controls. Mean plasma GH was less than 2.5 microg/liter in 12 patients. Patients had higher 24-h nadir GH values than healthy controls (P < 0.001). During the oral glucose tolerance test, nadir plasma GH was less than 1 micro g/liter in eight patients. Plasma IGF-I normalized in 11 of 14 patients after transsphenoidal surgery. Four patients with normal IGF-I after transsphenoidal surgery were restudied. Mean and nadir GH decreased in all of them. In our experience in many patients with acromegaly, the diagnosis could be missed if only the existing GH-based criteria are used. Revised GH criteria in combination with plasma IGF-I should be used for the diagnosis and follow-up of acromegaly.

Objectives: To examine the relationship between insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), and body mass index and prostate volume, as a surrogate marker for benign prostatic hyperplasia, in a community-based sample of black men. Epidemiologic studies examining the role of IGF-1 and IGFBP-3 suggest that increased levels of serum IGF-1 and decreased levels of serum IGFBP-3 are associated with an increased risk of prostate cancer. Few studies have examined these factors with respect to benign prostatic hyperplasia, and these have been limited to white men., Methods: The study population consisted of a sample of 364 black men, 40 to 79 years of age, residing in Genesee County, Michigan. Men with prostate cancer or prior prostate surgery were excluded. All subjects completed a clinical examination, which included a complete urologic examination with transrectal ultrasonography, anthropometric measurements, and serum assays for IGF-1 and IGFBP-3., Results: Multivariable regression models demonstrated that prostate volume increased with increasing age (P <0.0001) and body mass index (P = 0.03). IGFBP-3 rather than IGF-1 was positively associated with increasing prostate volume (P = 0.003)., Conclusions: This is the largest study describing the relationships between IGF-1, IGFBP-3, and body mass index and prostate volume, and the only study in black men. Although earlier studies demonstrated an association between IGF-1 and prostate cancer risk, our findings indicate that IGFBP-3 is more relevant for prostate enlargement, suggesting that IGF-1 and IGFBP-3 may play different pathophysiologic roles in benign and malignant prostatic conditions.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.