Surgery of benign thyroid disease by ENT/head and neck surgeons and general surgeons: 233 cases of vocal fold paralysis in 3509 patients.

PURPOSE: Thyroid surgery is mainly performed by general surgeons (GS). The aim of this study is to evaluate the safety and efficiency of thyroid surgery by ENT/head and neck surgeons (ENT), especially regarding the incidence of vocal fold palsy (VFP). METHODS: We retrospectively analysed 3509 patients (69.0% female) who underwent surgery for benign thyroid diseases (56.8% nodular goitre, 18.6% inactive nodes, 14.0% thyroid autonomy, 7.0% Graves' disease). Operations were mainly performed with intraoperative neuromonitoring by GS (n = 1933) or physicians trained for head and neck surgery (n = 1576). 18.7% of the procedures were carried out by residents in training. RESULTS: VFP occurred in 233 subjects (6.6%); 6.2% in females and 7.6% in males. A lower rate (p < 0.001) was observed in operations performed by ENT (4.7%) than by GS (8.2%). No increased incidence of VFP was seen for surgeries performed by physicians in training (6.2%, n = 657). Prevalence of VFP was not different for minimally invasive (6.3%, n = 950) and conventional surgery (6.8%, n = 2559), but higher in total (7.2%, n = 1916) than in subtotal thyroidectomy (5.0%, n = 997). Postoperative haemorrhage (5.6 vs. 1.9%) and hypocalcaemia < 2.0 mmol/l (32.8 vs. 22.0%) were documented more frequently in patients with VFP, also substitution therapy with calcium (23.2 vs. 14.7%) and dihydrotachysterol (8.1 vs. 3.7%) had to be applied more frequently. CONCLUSION: Thyroid surgery performed by surgeons specifically trained for ENT/head and neck surgery is safe and has a significantly reduced rate of VFP. VFP is associated with other complications (postoperative haemorrhaging, hypocalcaemia).

Effects and pharmacokinetic properties of the rat/human corticotropin-releasing factor in rhesus monkeys.

The biological effects and pharmacokinetic properties of the recently sequenced rat/human corticotropin-releasing factor (r/hCRF) were evaluated in the rhesus monkey and compared to those of the previously studied ovine corticotropin-releasing factor (oCRF). An iv bolus of 0, 0.1, 1, 10, and 100 micrograms/kg r/hCRF and 1 microgram/kg oCRF were given to rhesus monkeys (four to five tests per dose). Serial blood samples were drawn before and up to 180 min after the injection for determination of plasma immunoreactive (IR) ACTH, cortisol, and IR-r/hCRF or IR-oCRF concentrations. Mean arterial blood pressure and heart rate were monitored. r/hCRF stimulated ACTH and cortisol secretion in a dose-dependent fashion. Its potency was similar to that of oCRF. r/hCRF, however, had a shorter half-life and a 3-fold higher MCR than oCRF. A dose-dependent decrease in the MCR of r/hCRF was observed, which may indicate a saturation of the clearance mechanisms. Significant decreases in mean arterial blood pressure, increases in heart rate, and a profound facial flush occurred at the dose of 100 micrograms/kg r/hCRF. We conclude that r/hCRF stimulates ACTH and cortisol secretion in a nonhuman primate with a potency similar to that of oCRF. The peptide has marked hypotensive effects at high doses and is cleared 3 times more rapidly than oCRF.

Determinants of serum leptin levels in Cushing's syndrome.

Corticosteroids and insulin increase leptin expression in vivo and in vitro. To investigate whether increased serum cortisol influences serum leptin concentrations in humans, we analyzed fasting serum leptin and insulin levels in 50 patients with Cushing's syndrome [34 female patients: 27 with the pituitary form and 7 with the adrenal form; age, 41.6 +/- 2.7 yr; body mass index (BMI), 29.6 +/- 1.2 kg/m2; 16 male patients all with the pituitary form; age, 39.2 +/- 3.1 yr; BMI, 26.3 +/- 2.3 kg/m2] and in controls matched for BMI, age, and gender. Serum leptin levels were higher in female than in male patients in both the Cushing (P < 0.01) and control (P < 0.001) groups. Disease-specific differences in serum leptin levels were only detected in male (106 vs. 67 pmol/L; Cushing's syndrome vs. control, P < 0.05), not female, patients. Multiple stepwise regression analysis of both patient groups revealed insulin as the best predictor of serum leptin concentrations, accounting for 37% of the variance in serum leptin levels, in contrast to BMI or mean serum cortisol (as measured by sampling in 10-min intervals over 24 h). In the subgroup of patients (n = 9) with pituitary adenoma, serum leptin levels were reduced after tumor resection, with concurrent decreases in serum cortisol, insulin, and BMI. In conclusion, chronic hypercortisolemia in Cushing's syndrome appears not to directly affect serum leptin concentrations, but to have an indirect effect via the associated hyperinsulinemia and/or impaired insulin sensitivity.

Time kinetics of the endocrine response to acute psychological stress.

A first-time parachute jump was chosen as a model to evaluate the endocrine response to acute psychological stress. In 43 inexperienced tandem parachutists, blood was drawn continuously from 2 h before to 1 h after the jump and analyzed at 10-min intervals for plasma concentrations of epinephrine (E), norepinephrine (NE), cortisol, GH, PRL, and TSH. In addition, heart rate was recorded throughout the experiment. There was a significant increase in heart rate and E concentrations during the jump itself. NE, cortisol, GH, PRL, and TSH peaked with a latency of 10-20 min. Apart from cortisol and TSH concentrations, which were still elevated 1 h after the stress event, plasma levels of the other endocrine variables normalized within 1 h following the jump. Statistically significant cross-correlations could be observed between E and NE (r = 0.60, no time lag) and between E and PRL (r = 0.58, 10-min time lag) only. Even in a very homogenous group of subjects and under well-controlled conditions, endocrine responses to acute psychological stress show considerable variations.

Pituitary-adrenal responsiveness to corticotropin-releasing hormone in patients receiving chronic, alternate day glucocorticoid therapy.

We examined the responsiveness of the pituitary-adrenal axis to ovine corticotropin-releasing hormone (oCRH) in 14 women with systemic lupus erythematosus receiving chronic, alternate day glucocorticoid therapy with prednisone. Testing was done twice and in a random order (at 2000 h) on the day when the steroid was taken (12 h after the last dose) and on the day when no glucocorticoid was administered (36 h after the last dose). Plasma ACTH and cortisol responses were markedly blunted on the day of treatment and mildly blunted on the day off treatment compared to those in normal subjects. Altered metabolic clearance of exogenous oCRF was not responsible for this difference, since the plasma disappearance curves of immunoreactive oCRH were similar on both days. The degree of suppression was dependent on the dose of prednisone, and the amount of cortisol secreted during the oCRH test was directly proportional to the logarithm of the concurrent plasma ACTH level. Thus, the cortisol response to ACTH was normal in all patients. These data suggest that the blunting of responsiveness to oCRH on both days of testing represents prednisolone suppression of the corticotroph cell. Despite this, the adrenal glands retain normal responsiveness to ACTH, suggesting that moderate decreases in daily ACTH secretion are compatible with sustaining normal adrenal function. Hence, the site of the mild suppression of the hypothalamic-pituitary-adrenal axis during chronic, alternate day treatment with glucocorticoids is central, whereas the adrenal glands appear to remain functionally unaffected.

Human corticotropin-releasing factor in man: pharmacokinetic properties and dose-response of plasma adrenocorticotropin and cortisol secretion.

The responses of plasma immunoreactive ACTH (IR-ACTH), cortisol, GH, PRL, and LH to a single iv injection of 0.01-5 micrograms/kg human corticotropin-releasing factor (hCRF) were investigated in healthy volunteers. The lowest effective dose of hCRF was 0.5 micrograms/kg. hCRF caused brief pulse-like elevations of plasma IR-ACTH and cortisol without any effect on the plasma concentrations of GH, PRL, and LH. By contrast, ovine CRF (oCRF), given for comparison, produced long-lasting stimulation of the human pituitary-adrenal axis. The difference in duration of effect between hCRF and oCRF may be attributed to an approximately 3-4 times higher MCR of hCRF [7.9 +/- 1.2 (+/- SE) ml/kg min; n = 14] than oCRF (1.9 +/- 0.1 ml/kg min; n = 9) in man. No serious side effects occurred at any of the doses of hCRF tested. The highest dose (5 micrograms/kg) caused a slight increase of heart rate that was not associated with significant changes in arterial blood pressure. All subjects receiving 5 micrograms/kg and one third of the subjects receiving 1 micrograms/kg hCRF experienced a transient facial flush. We conclude that hCRF causes brief plasma ACTH and cortisol secretory episodes in man, similar to the physiological plasma ACTH and cortisol secretory episodes. This is in contrast to oCRF, which causes prolonged ACTH and cortisol secretion. These differences between the two peptides may be explained by the higher MCR of hCRF than oCRF.

Pulsatile administration of human corticotropin-releasing hormone in patients with secondary adrenal insufficiency: restoration of the normal cortisol secretory pattern.

Human corticotropin-releasing hormone (hCRH) was administered in a pulsatile fashion to eight patients with secondary adrenal insufficiency. These patients were selected on the basis of a normal or exaggerated plasma ACTH response to exogenous ovine CRH, suggesting sparing of the corticotrophs. A continuous 48-h iv infusion of ACTH to restore the adrenal glands to an ACTH-responsive state preceded hCRH administration. Eight 1 microgram/kg bolus injections of hCRH were administered in a 24-h period. The time intervals between hCRH injections were selected to resemble the frequency of spontaneously occurring secretory episodes of plasma ACTH and cortisol. Four of the patients underwent a second study, of identical design, in which normal saline injections were administered instead of hCRH. Pulsatile hCRH treatment resulted in a secretory pattern of ACTH and cortisol similar to that in normal subjects. ACTH and cortisol levels during saline administration were low and had no circadian variation. These findings indicate that exogenous CRH is able to restore normal basal ACTH and cortisol secretory patterns when given in an appropriate manner. It is possible that the pulsatile administration of hCRH may prove to be a more physiological technique for restoring adrenal function of patients with corticotroph-sparing secondary adrenal insufficiency and may avoid some of the complications of glucocorticoid administration.

Testosterone and cognition in elderly men: a single testosterone injection blocks the practice effect in verbal fluency, but has no effect on spatial or verbal memory.

BACKGROUND: The relevance of the age-associated decline in testosterone for cognition in elderly men is still poorly understood. One hypothesis is that testosterone enhances spatial abilities, while it might impair verbal skills. METHODS: Thirty elderly men received a single testosterone (250 mg testosterone enanthate) or placebo injection. Cognitive performance was tested before and 5 days after treatment using spatial as well as verbal tests. RESULTS: Five days after injection, testosterone and estradiol levels were still in the supraphysiologic range. In the verbal fluency task, the placebo group, but not the testosterone group, showed a practice effect. Therefore, the testosterone group performed significantly worse than the placebo group after treatment. No effects of testosterone were observed in the other verbal and spatial tasks. CONCLUSIONS: The present finding, that testosterone blocks the practice effect in verbal fluency, partly supports the general idea that sex steroids modulate performance in tests with known gender differences. Moreover it demonstrates that these effects can occur rapidly. However, beneficial effects on spatial cognition or memory might need more time to develop and/or might only occur when a less pronounced testosterone increase is induced.

Transplantation of H-2Kb-transgenic adrenocortical cells in the mouse having undergone an adrenalectomy: functional and morphological aspects.

BACKGROUND: A new model of cellular adrenocortical transplantation after bilateral adrenalectomy in the mouse was established. This model was used to study the effects of the expression of the transgenic MHC class I molecule H-2K(b) (Kb) on graft survival and morphologic features, corticosterone secretion, and the possibility of tolerance induction in the recipient. METHOD: A single cell suspension of purified adrenocortical cells was grafted under the kidney capsule of B10.Br (H-2k) mice having adrenalectomies. Syngeneic, fully MHC-mismatched, and MHC class I-incompatible Kb-transgenic mice served as donor strains. To analyze graft function, urinary excretion and serum levels of corticosterone were monitored over 100 days. Tolerance induction in the graft recipients of Kb-transgenic and third party skin grafts was tested on day 50 after adrenocortical transplantation. Histological sections of the adrenocortical grafts were obtained on day 100. RESULTS: Recipients of syngeneic and Kb-transgenic grafts displayed pretransplant corticosterone levels on days 20, 50, and 100 and ACTH-stimulated serum corticosterone levels similar to those of controls on day 100 after adrenocortical transplantation. In contrast, in recipients of fully MHC-mismatched grafts, corticosterone excretion was significantly reduced. In this group, 4 of 7 mice did not survive. Syngeneic skin grafts survived indefinitely in recipients of syngeneic and Kb-transgenic adrenocortical grafts, whereas Kb-transgenic and fully MHC-mismatched skin grafts were acutely rejected. Tissue sections of the adrenocortical grafts revealed vascularized cell conglomerates in syngeneic and Kb-transgenic grafts without infiltrations of mononuclear cells. Furthermore, a differentiation similar to adrenocortical organization was partly found. CONCLUSION: In conclusion, a model of cellular adrenocortical transplantation was established. The results show that syngeneic transplantation resulted in physiological corticosterone levels early after transplantation, whereas fully MHC-incompatible grafts were rejected. Recipients of Kb-transgenic grafts showed unimpaired adrenocortical function, but did not tolerize toward Kb-transgenic skin grafts. Possible mechanisms include a local immunomodulatory effect of glucocorticoids secreted by the graft and a low immunogenicity of the relatively small numbers of transplanted cells.

Effect of liver damage on the pharmacokinetics of dexamethasone.

By measuring the pharmacokinetics of dexamethasone in 48 patients with various degrees of disturbances in liver function, we could demonstrate a decrease in the metabolic clearance of this steroid by 53% if the activity of the plasma cholinesterase was lowered to less than 2 kU/l. Results suggest that the dosage of dexamethasone given for diagnostic or therapeutic purpose needs to be adjusted in such patients.

The cortisol response to awakening in relation to different challenge tests and a 12-hour cortisol rhythm.

Recent studies have shown that cortisol levels rapidly increase within the first 30 minutes after awakening. This response is rather robust over weeks or months and is altered by chronic stress and burnout. The present study investigated to what extent the cortisol response to awakening relates to responses following hCRH, ACTH(1-24), or psychosocial stress challenges in 22 healthy subjects. Furthermore, a 12-hour circadian cortisol profile was obtained to compare the morning response with cortisol levels obtained throughout the day. Results show that the morning cortisol response was of similar magnitude to that following injection of 1 microg/kg h-CRH or exposure to a brief psychosocial stressor (TSST). All of these were significantly smaller compared to maximal stimulation of the adrenal cortex by ACTH(1-24). Correlation analyses revealed that the morning cortisol response was closely related only to the cortisol response following 0.25 mg ACTH(1-24) (r=0.63, p=0.002). We conclude that the morning cortisol response to awakening can provide important information on the (re)activity of the HPA axis in addition to more 'traditional' methods like hCRH or Synacthen challenge tests. The sensitivity/capacity of the adrenal cortex appears to play a crucial role for the magnitude of cortisol responses observed after awakening.

Thyroid and adrenal function in HIV-infected outpatients.

We investigated parameters of thyroid and endocrine functions in 100 HIV-infected men who were grouped according to the CDC criteria. Progression of the disease was associated with a 44% increase in plasma TBG and a 15% increase in plasma CBG, while the T4/TBG ratio was decreased by 20%, plasma DHEAS was lowered by 30% and urinary aldosterone excretion fell by 70%. Plasma T4, T3 and TSH and urinary excretion of cortisol and catecholamines was not influenced by the disease. A weak, but significant negative correlation was found between plasma CBG and the body mass index of the patients. Significant positive correlations were observed between CD-4 cell count and the T4/TBG-ratio or plasma DHEAS levels. TBG was inversely correlated with CD-4 cell count and DHEAS. Thus, an increase in plasma TBG and a shift from adrenal androgen and mineralocorticoid steroid secretion towards cortisol secretion may be endocrine markers for progression of the disease in patients with HIV-infection.

Endocrine testicular function in HIV-infected outpatients.

We investigated endocrine testicular function in 100 HIV-infected men who were grouped according to the CDC criteria. Progression of the disease was associated with a 27% decrease in plasma oestradiol, which was the only parameter that was weakly correlated with CD4 cell count (r = 0.312, p <0.05). Individual data showed a decreased plasma concentration of total and free testosterone in 35% and 26% of the subjects, respectively, but we could not demonstrate an increased frequency of hypogonadism going along with a progression of the stage of disease. There was no significant correlation between androgen, SHBG or FSH levels and duration of HIV-infection, BMI or CD4 cell count. Hypergonadotropic hypogonadism was associated with an euthyroid sick state in a 15% subgroup of patients reporting a decrease in libido. Plasma T3 was significantly correlated with testosterone (r = 0.419, p <0.01) and mean plasma T3 was significantly decreased in 8 subjects suffering from erectile impotence. Thus, hypogonadism occurs frequently in HIV-infected outpatients. Like euthyroid sickness it does not seem to be a predictor for progression of the disease but an indicator of actual state of health.

Follow-up in 103 patients with catecholamine-secreting tumours.

103 patients from a group of 115 patients with catecholamine secreting tumours were reinvestigated 7.0 +/- 4.9 years following surgery. Throughout the follow-up period 15 patients had died. In four of them death was definitively, in seven subjects possibly associated to the primary endocrine disorder. Following surgery improvement of general well-being was documented in 85% of the patients. Hypertension was corrected in 61 %, but 26% of the patients remained hypertensive and symptoms of hypotension like orthostasis developed in 24%. A significant increase in weight (> 5 kg) was observed in 26% of the subjects throughout the follow-up period, but did not result in a higher prevalence of diabetes mellitus which had to be treated in 16% of the patients before and only 14% following surgery. However, palpitations, increased sweating and headache persisted in 16%, 17% and 12% of the patients, respectively. Symptoms of cardiac insufficiency developed in 32%. Persistent discomfort related to the scar was reported by 55% of the patients following lumbar surgery and by 30% of the subjects that were operated on via a transabdominal approach. Hence we conclude that surgery of catecholamine-secreting tumours results in an improvement of health and well-being in most subjects according to objective criteria as well as to the judgement of the patients themselves.

[Exogenous effects on ACTH and cortisol secretion]. / Exogene Einflüsse auf die ACTH- und Kortisolsekretion.

The availability of human corticotropic hormone, together with sensitive methods of measuring ACTH and cortisol have recently made possible studies on the mode of secretion of these hormones, secreted episodically and parallel in man, and exogenous factors modulating their liberation. Time of day, meals, physical activity and stress, lack of sleep and REM sleep all have an influence on the daily rhythm of their secretion. Phenytoin, ketoconazole, and cyproterone acetat modify the secretion of cortisol; opiates and diazepam inhibit that of ACTH. The liberation of CRH and ACTH is stimulated by the appetite suppressant, serotonin, and inhibited by the appetite-stimulating antagonist cyproheptadine and by glucocorticoids.

[Swollen parotid gland and lower leg erythema. Presentation of differential diagnosis and therapy based on a case report]. / Parotisschwellung und Unterschenkel-Erythem. Darstellung von Differentialdiagnose und Therapie anhand einer Fallbeschreibung.

A 20-year-old woman developed erythema of the lower legs and swelling of both parotid glands. Her lung function parameters were initially unremarkable, and only discrete pulmonary-hilar changes were visible on the chest X-ray, and acute sarcoidosis was considered as one of the possible differential diagnoses. The paper describes in detail the diagnostic approach and the establishment of the differential diagnosis. The first attempts at therapy with the non-steroidal antiinflammatory drug diclofenac were unsuccessful, but treatment with glucocorticoids that was thereupon tried proved effective.

Suppression of basal plasma cortisol and adrenal androgen concentrations, but not of ACTH and cortisol responses to hCRH by low-dose dexamethasone in rhesus monkeys.

Glucocorticoid treatment at replacement doses does not result in a suppression of ACTH and cortisol responses to corticotropin-releasing hormone (CRH), while basal plasma concentrations of cortisol and adrenal androgens are efficiently suppressed 34 h after starting treatment. This finding could be demonstrated in rhesus monkeys receiving a continuous infusion of dexamethasone (1 microgram/kg per h) for 48 h and confirms our observations in patients on alternate-day prednisone therapy and in patients with congenital adrenal hyperplasia on glucocorticoid replacement therapy. We conclude that the decrease of basal adrenal steroid secretion resulting from glucocorticoid replacement therapy represents an effect on hypothalamic rather than on pituitary function.

[Adrenal cortex insufficiency and hypothyroidism in advanced age]. / Nebennierenrindeninsuffizienz und Hypothyreose im höheren Lebensalter.

In geriatric patients symptoms of endocrine disorders easily can be regarded to be due to the patient's old age. This is demonstrated in a case of an 80-year-old woman suffering from the combination of adrenal insufficiency and hypothyroidism. Early recognition of typical clinical signs and adequate, simply performed replacement therapy results in a significant improvement of the patient's quality of life.

[A rare cause of gynecomastia in a more than 70-year-old man. Case report and differential diagnostic considerations]. / Seltene Ursache einer Gynäkomastie eines über 70jährigen Mannes. Kasuistik und differentialdiagnostische Uberlegungen.

Gynecomastia in elderly men is relatively common and may be caused by age-related endocrinal and metabolic disorders, the use of certain drugs, or specific medical conditions. We report here on the rare case of a 77-year-old man in whom gynecomastia was one of the major symptoms of a bronchial carcinoma which had metastasized to the mediastinum. The differential diagnosis of the condition is described in detail.

Effect of fenfluramine on episodic ACTH and cortisol secretion.

OBJECTIVE: The central serotoninergic system is known to modulate the activity of the hypothalamic-pituitary-adrenal axis, but the effect of fenfluramine, a serotonin reuptake inhibitor, on ACTH and cortisol secretion is not well understood. We have therefore evaluated its effects on the hypothalamic-pituitary-adrenal axis in healthy controls. DESIGN: Episodic secretion of ACTH and cortisol was investigated in 6 healthy volunteers under basal conditions and again during treatment with 20 and 60 mg fenfluramine given orally every 8 hours. On all occasions blood samples were obtained at 10-minute intervals for 24 hours and the mode of hormone secretion was analysed by three different methods (PULSAR, CLUSTER, DESADE). In addition ACTH and cortisol responses to CRH were tested at the end of the sampling period. RESULTS: At the lower dose fenfluramine had no effect on ACTH and cortisol secretion. At the higher dose a significant increase of mean plasma ACTH (+85%) and cortisol (+129%) levels as well as of urinary free cortisol secretion (+44%) was observed. Fenfluramine did not modulate the frequency, but increased the amplitudes of ACTH and cortisol secretory episodes. ACTH and cortisol responses to CRH injection remained unchanged. Maximum plasma levels of d-fenfluramine and d-norfenfluramine were documented 2-4 hours after the ingestion of the drug. CONCLUSION: Fenfluramine stimulates the activity of the hypothalamic-pituitary-adrenal axis at a suprapituitary level by modulating the amplitude of ACTH and cortisol secretory bursts.