Association of preoperative thyroid hormone replacement with perioperative complications after major abdominal surgery.

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 â€‹= â€‹0.01), and a 1.7- fold greater risk for serious sepsis(p â€‹= â€‹0.04). Thyroid replacement was associated with longer length of stay(p â€‹< â€‹0.001). While there was a high degree of missing data for surgical approach (31.1 â€‹% missing data), results suggest that patients on thyroid hormone replacement were more likely to undergo an open rather than minimally invasive surgery(p â€‹< â€‹0.01). Open surgery was associated with greater risk of serious morbidity(p â€‹= â€‹0.003) and longer length of stay(p â€‹< â€‹0.001). CONCLUSIONS: Preoperative thyroid hormone replacement independently predicts operative morbidity and length of stay following major abdominal surgery.

Multimodality imaging of malignant pheochromocytoma.

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.

Clinically non-functioning pituitary adenoma.

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.

The role of endogenous growth hormone-releasing hormone in acromegaly.

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.

Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism.

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.

Endogenous circulating ghrelin does not mediate growth hormone rhythmicity or response to fasting.

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.

Cryptococcal thyroiditis and hyperthyroidism.

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.

Troglitazone induces CYP3A4 activity leading to falsely abnormal dexamethasone suppression test.

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.

Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels.

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.

Pulsatile and nocturnal growth hormone secretions in men do not require periodic declines of somatostatin.

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.

Relationship of serum sex-steroid hormones and prostate volume in African American men.

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.

Growth hormone secretion pattern is an independent regulator of growth hormone actions in humans.

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.

Acromegaly with apparently normal GH secretion: implications for diagnosis and follow-up.

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.

Insulin-like growth factor-1, insulin-like growth factor binding protein-3, and body mass index: clinical correlates of prostate volume among Black men.

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.