Recurrent severe hyperandrogenism during pregnancy: a case report.

This report describes the case of a 28 year old woman with virilisation occurring in two successive pregnancies. Recurrent maternal virilisation is rare (seven previous reports) and this case is unique in its severity. Differential diagnoses include ovarian disease and fetal aromatase deficiency. New techniques to exclude a fetal cause were used in this case. This patient presented during the third trimester of her first pregnancy with rapid onset of hirsuitism, increased musculature, and deepening voice. A blood hormone profile revealed significant hyperandrogenism (testosterone, 72.4 nmol/litre; normal range, 0.5-3.0). She delivered a normal boy and maternal androgen concentrations returned rapidly to normal (testosterone, 0.8 nmol/litre). She presented two years later, during her second pregnancy, with similar symptoms and biochemistry (testosterone, 47.5 nmol/litre). Again, she delivered a healthy normal boy and androgens returned immediately to normal (serum testosterone, 2.0 nmol/litre). Ultrasonography revealed no evidence of ovarian (or adrenal) masses in either pregnancy. Umbilical cord venous blood sampling and placental assays revealed no evidence of fetal aromatase deficiency. Recurrent hyperandrogenism during pregnancy is rare. Ovarian luteoma rarely recurs and hyperreactio luteinalis does not lead to such pronounced androgen concentrations. Therefore, this patient has a unique ovarian condition that could be harmful to offspring and mother.

Thyroid and sympathetic influences on plasma leptin in hypothyroidism and hyperthyroidism.

OBJECTIVES: To determine the dependence of plasma leptin concentrations upon circulating noradrenaline (NA) and thyroid hormones (TH) in humans. DESIGN: Cross-sectional study in 40 newly diagnosed untreated patients with primary thyroid disease, and 69 lean and obese euthyroid control subjects. MEASUREMENTS: Plasma leptin, NA, free T3 (fT3) and TSH in the fasting state. Anthropometry and % body fat (electrical bioimpedance). RESULTS: Leptin levels were highest in 37 obese euthyroid and 22 hypothyroid (median [interquartiles]31.5 [19.0- 48.0], 19.2 [11.5-31.5] ng ml(-1)), and lowest in 32 lean euthyroid and 18 hyperthyroid subjects (6.6 [3.9-14.4], 8.9 [5.5-11.1]; ANOVA, P< 0.0001). Plasma NA was similar in all groups (P= n.s.). In obese controls, TSH correlated with % body fat and leptin (r= 0.67, r= 0.61; P< 0.001). Treatment of hypothyroidism (n= 10) with T4 reduced leptin from 20.8 [11.8-31.6] to 12.9[4.6-21.2] (P= 0.005) with no change in BMI. CONCLUSIONS: Thyroid status modifies leptin secretion independently of adiposity and NA. The data suggest leptin-thyroid interactions at hypothalamic and adipocyte level.

ACTH and cortisol release following intravenous desmopressin: a dose-response study.

OBJECTIVE: Desmopressin (DDAVP) is a synthetic analogue of AVP, the companion regulator of corticotrophin-releasing hormone (CRH) in the control of ACTH synthesis and release from the pituitary corticotrophs. The body of evidence from human studies suggests that DDAVP alone, unlike AVP, does not bring about ACTH release, although recent evidence suggests idiosyncracies of response in healthy subjects. We examined whether DDAVP exerted any consistent effect on ACTH and cortisol release, and also if this occurred in a dose-dependant manner. DESIGN AND SUBJECTS: A total of 18 subjects participated in the study. Saline, 5 microg, 10 microg and 15 microg DDAVP were administered as an intravenous bolus at 1300 h; 5, 7, 18 and 8 subjects, respectively, participated in each arm of the study. Plasma ACTH and cortisol responses were measured over a 120-minutes period. RESULTS: Significant between group comparisons were demonstrated for both ACTH (P < 0.05) and cortisol responses (P < 0. 005) measured as maximum increment from baseline. The ACTH response to 5, 10 and 15 microg DDAVP was significantly greater than saline at all three doses, whilst maximal responses were seen at 10 microg. The cortisol responses to 10 and 15 microg DDAVP doses, but not 5 microg, were significantly greater than following saline. 11/18 subjects were deemed 'responders' following 10microg DDAVP on the basis of both ACTH and cortisol output. CONCLUSIONS: This data suggests that DDAVP is capable of stimulating ACTH and cortisol release when administered alone as a bolus in over 50% of healthy subjects. This is in contrast to much of the extant literature. The mode of administration may be pertinent to this effect. This finding has implications for the recent focus on DDAVP as a diagnostic tool in disorders such as Cushing's Disease.

The influence of plasma on basal and ACTH-stimulated in vitro adrenocortical steroidogenesis.

Early descriptions of in vitro ACTH bioassays all emphasised the need to use extracted plasma samples due to interference by an unidentified component. The aim of these studies was to elucidate the effects of whole plasma on ACTH steroidogenic activity in vitro and to identify the responsible factor. A sensitive in vitro dispersed bovine adrenocortical cell bioassay was established. The addition of 10% ACTH-depleted human pooled plasma to the incubation media resulted in basal steroidogenesis equivalent to that achieved with 10(-9) M ACTH1-24 and potentiated the steroidogenic activity of 10(-9) M ACTH1-24 by 7.8-fold. This potentiation was dependent on the concentration of both ACTH and plasma in the media, but did not result from the mitogenic effect of plasma. A pituitary source was excluded and the potentiating activity was not extractable by Vycor glass. Column chromatography demonstrated two peaks of activity corresponding to molecular weights of 650 and 220x10(3) Da. These peaks did not correspond to the plasma binding of 125I-ACTH which resulted from non-specific binding to albumin. Lipoprotein-deficient serum had no effect on either basal or ACTH-stimulated steroidogenesis, but both were restored by the addition of purified lipoproteins. However, novel findings demonstrated a differential effect of low (LDL) and high (HDL) density lipoproteins on basal and ACTH-stimulated steroid production; thus, LDL exerted a greater effect on the former, whilst HDL potentiated the steroidogenic activity of added ACTH more than LDL. The addition of the lipoproteins to lipoprotein-deficient serum restored its basal and ACTH potentiating effects, the cholesterol concentrations of the chromatographic fractions exactly paralleling their ACTH potentiating effect. These findings suggest that not only are lipoproteins the plasma factor(s) which potentiates ACTH steroidogenic activity in in vitro bioassays, but also that they exert differential effects on basal and ACTH-stimulated steroid production.

The effect of naloxone on adrenocorticotropin and cortisol release: evidence for a reduced response in depression.

BACKGROUND: Endogenous opioid peptides inhibit the hypothalamic-pituitary-adrenal (HPA) axis by influencing the release of hypothalamic corticotropin releasing factors. This study examines whether increased activity of the HPA axis in major depression is associated with reduced opioid tone. METHODS: We measured the adrenocorticotropin (ACTH) and cortisol responses to an intravenous bolus of naloxone 0.125 microg/kg in 13 depressed outpatients and 13 healthy volunteers. RESULTS: The mean cortisol response was significantly reduced (P<0.05), and the ACTH response was also non-significantly reduced in the depressed subjects. CONCLUSIONS: These findings imply that the degree of inhibitory endogenous opioid tone is reduced in depression. Various mechanisms for the finding are discussed, including possible alteration in the function of alpha-adrenergic pathways. CLINICAL IMPLICATIONS: Reduced endogenous opioid tone may explain why some depressed individuals self-medicate with opiates, and depression is associated with opiate withdrawal. Opioid pathways may have a role in the mechanism of action of antidepressant drugs, and may be of relevance in the development of novel antidepressants. LIMITATIONS OF THE STUDY: The sample size was small, leading to a failure of the difference of the basal cortisol levels and also the delta ACTH between the groups to reach statistical significance.

Desmopressin augments pituitary-adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers.

BACKGROUND: Corticotropin-releasing hormone (CRH) and vasopressin (VP) are the two principal neuropeptide regulators of the hypothalamic-pituitary-adrenal axis in man, with VP serving to augment CRH-induced adrenocorticotropic hormone (ACTH) release. Unlike VP, desmopressin (DDAVP), which is a synthetic analogue of VP, when administered alone, has not been shown in healthy subjects to have consistent ACTH-releasing properties. It has been suggested that chronic fatigue syndrome (CFS), characterized by profound fatigue and a constellation of other symptoms, may be caused by a central deficiency of CRH. METHODS: We administered 100 micrograms ovine CRH (oCRH) and 10 micrograms DDAVP, both alone and in combination, to a group of subjects with CFS, and to a group of healthy volunteers. Our aim was to establish the effect of DDAVP on CRH-induced ACTH release in these two groups. RESULTS: The delta-ACTH responses to oCRH were attenuated in the CFS (21.0 +/- 4.5 ng/L) compared to the control subjects (57.8 +/- 11.0 ng/L; t = 3.2, df = 21, p < .005). The delta-cortisol responses were also reduced in the CFS (157.6 +/- 40.7 nmol/L) compared to the healthy subjects (303.5 +/- 20.9 nmol/L; t = 3.1, df = 21, p < .01). The delta-ACTH and delta-cortisol responses to DDAVP alone did not differ between the two groups. On administration of both CRH and DDAVP no response differences between the two groups for either ACTH (p = .3) or cortisol output (p = .87) were established. Comparing the ACTH and cortisol responses to CRH and CRH/DDAVP in only those individuals from each group who had both tests, the cortisol output to the combination was significantly greater in the CFS compared to the healthy group. The ACTH output was also increased in the former group, though this was not significant. CONCLUSIONS: DDAVP augments CRH-mediated pituitary-adrenal responsivity in healthy subjects and in patients with CFS. That DDAVP was capable of normalizing the pituitary-adrenal response to oCRH in the CFS group suggests there may be increased vasopressinergic responsivity of the anterior pituitary in CFS and/or that DDAVP may be exerting an effect at an adrenal level.

Desmopressin normalizes the blunted adrenocorticotropin response to corticotropin-releasing hormone in melancholic depression: evidence of enhanced vasopressinergic responsivity.

Major depression is associated with significant disturbance in hypothalamic-pituitary-adrenal axis functioning, including blunted release of ACTH in response to CRH infusion. Eight melancholic depressives and eight matched healthy comparison subjects underwent, in random order, the following challenges: placebo, CRH, CRH + DDAVP. Blood for ACTH and cortisol estimation was drawn at -15, 0, 15, 30, 45, 60, 90, and 120 min. A blunted release of ACTH, in response to CRH challenge, was observed in depression (P < 0.01), whereas maximal cortisol responses in both groups were similar, despite elevated baseline levels in depression (P < 0.05). The combined CRH/DDAVP infusion produced similar ACTH and cortisol release in both groups. These results suggest that melancholic depression is associated with enhanced pituitary vasopressinergic responsivity.

Dissociation of pituitary-adrenal and catecholamine activation after induced cardiac arrest and defibrillation.

To avoid factors which confound attempts to characterize the neuroendocrine response to cardiac arrest, we studied the pituitary-adrenocortical and catecholamine responses to induced ventricular fibrillation (VF) and direct current cardioversion in 10 patients undergoing testing of 'implanted cardioverter defibrillator' devices under sedation. Plasma concentrations of epinephrine were increased 5 min after VF (from a mean basal of 0.39 (S.E.M. 0.09) to a peak of 0.632 (0.212) nmol litre-1; P < 0.05) but were unchanged at other times. Plasma concentrations of norepinephrine did not change at any time. Plasma concentrations of cortisol increased significantly at 10 min (from a mean of 367 (SEM 62) to 539 (64) nmol litre-1; P < 0.001) and remained increased 30 min after VF (470 (74) nmol litre-1; P < 0.05) but had returned towards baseline at 60 min, whereas plasma prolactin concentrations were increased at 5 min (from a mean of 224 (SEM 54) to 320 (63) mu. litre-1; P < 0.01) and remained increased until the end of the sampling period at 60 min (288 (65) mu. litre-1; P < 0.05). Concentrations of adrenocorticotrophic hormone (ACTH) (n = 5) tended to increase but this was not statistically significant. We conclude that a short period of cardiac arrest in lightly sedated humans activated the pituitary-adrenocortical axis but did not appear to stimulate catecholamine secretion. These findings raise questions about the nature and mechanisms of the neuroendocrine response to cardiac arrest.

The low dose ACTH test in chronic fatigue syndrome and in health.

OBJECTIVE: A number of dynamic tests of the hypothalamic-pituitary-adrenal axis provide evidence for a mild central adrenal insufficiency in chronic fatigue syndrome (CFS). The 1 microgram adrenocorticotropin (ACTH) test has been proposed to be more sensitive than the standard 250 micrograms ACTH test in the detection of subtle pituitary-adrenal hypofunctioning. We aimed to establish whether the 1 microgram ACTH test would support such a dysregulation in CFS, and also, given the relative novelty of this test in clinical practice and the uncertainty with regard to appropriate cut-off values for normality, to compare our healthy volunteer data with those of previous studies. PATIENTS AND DESIGN: Twenty subjects with CFS, diagnosed according to Centres for Disease Control and Prevention criteria, were compared with 20 healthy volunteer subjects. All participants underwent a 1 microgram ACTH test beginning at 1400 h. Plasma samples for cortisol estimation were drawn at 0, +30 and +40 min. RESULTS: Baseline cortisol values did not differ between CFS patients and healthy subjects. The delta cortisol (maximum increment from baseline) value was significantly lower in the CFS than the volunteer group (P < 0.05). Comparison of the +30 min cortisol values revealed no significant differences. Using an incremental cortisol of > 250 nmol/l as an arbitrary cutoff point, two (10%) of the healthy subjects and nine (45%) of the CFS subjects failed the test on this basis (chi 2 = 4.3, df = 38, P < 0.05). CONCLUSIONS: This study provides further evidence for a subtle pituitary-adrenal insufficiency in subjects with chronic fatigue syndrome compared to healthy volunteers. Disparities between our healthy volunteer data and those of other groups using the 1 microgram ACTH test suggest that the test may not be as reliable as previously indicated.

Blunted adrenocorticotropin and cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome.

Hypofunctioning of the pituitary-adrenal axis has been suggested as the pathophysiological basis for chronic fatigue syndrome (CFS). Blunted adrenocorticotropin (ACTH) responses but normal cortisol responses to exogenous corticotropin-releasing hormone (CRH), the main regulator of this axis, have been previously demonstrated in CFS patients, some of whom had a comorbid psychiatric disorder. We wished to re-examine CRH activation of this axis in CFS patients free from concurrent psychiatric illness. A sample of 14 patients with CDC-diagnosed CFS were compared with 14 healthy volunteers. ACTH and cortisol responses were measured following the administration of 100 microg ovine CRH. Basal ACTH and cortisol values did not differ between the two groups. The release of ACTH was significantly attenuated in the CFS group (P < 0.005), as was the release of cortisol (P < 0.05). The blunted response of ACTH to exogenous CRH stimulation may be due to an abnormality in CRH levels with a resultant alteration in pituitary CRH receptor sensitivity, or it may reflect a dysregulation of vasopressin or other factors involved in HPA regulation. A diminished output of neurotrophic ACTH, causing a reduced adrenocortical secretory reserve, inadequately compensated for by adrenoceptor upregulation, may explain the reduced cortisol production demonstrated in this study.

Naloxone-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome.

BACKGROUND: Opioidergic pathways have an inhibitory regulatory influence on the hypothalamic-pituitary-adrenal axis (HPA) in man. Previous studies have suggested impairment of pituitary-adrenal activation in chronic fatigue syndrome (CFS). We, therefore, decided to investigate the extent of opioid inhibition of HPA activity in CFS as a possible explanation for the reputed HPA hypofunctioning in patients with CFS. METHOD: Thirteen patients with CFS, diagnosed according to CDC criteria, were compared with thirteen healthy subjects. Adrenocorticotropin (ACTH) and cortisol (CORT) responses were measured following the administration of the opiate antagonist naloxone. RESULTS: Baseline ACTH and cortisol levels did not differ between the two groups. The release of ACTH (but not cortisol) was significantly blunted in the CFS subjects compared with controls. CONCLUSIONS: Naloxone mediated activation of the HPA is attenuated in CFS. Excessive opioid inhibition of the HPA is thus an unlikely explanation for the HPA dysregulation in this disorder.

Administration of human recombinant insulin-like growth factor-I in critically ill patients.

OBJECTIVES: To study the pharmacokinetics of a single subcutaneous dose of recombinant human insulin-like growth factor-I (IGF-I) in patients with systemic inflammatory response syndrome in the intensive care unit (ICU). To evaluate the effects of exogenous recombinant human IGF-I on circulating concentrations of IGF-I binding protein-1 (IGFBP-1), IGF-I binding protein-3 (IGFBP-3), and growth hormone in the critically ill patient; to assess the safety of the subcutaneous administration of 40 microg/kg of recombinant human IGF-I in these patients; and to investigate any effect this dose might have on nitrogen balance, creatinine clearance, and serum electrolyte and lipid concentrations. DESIGN: Open-labeled, noncontrolled, prospective, single-dose study of eight fully evaluable ICU patients with systemic inflammatory response syndrome. SETTING: ICUs in a teaching hospital and a linked district general hospital in England. PATIENTS: Nine patients were examined, eight of whom were fully evaluable. INTERVENTIONS: Subcutaneous administration of 40 microg/kg of recombinant human IGF-I. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken 24 hrs before the subcutaneous injection of 40 microg/kg of recombinant human IGF-I, and for 48 hrs thereafter. Urine was collected throughout this period. Serum concentrations of IGF-I, IGFBP-1, IGFBP-3, growth hormone, and insulin were measured by radioimmunoassay. IGF-I concentrations (median and range) increased significantly above baseline values (35 ng/mL [20 to 144]) from 15 mins (p < .02) until 10 hrs (p < .02) after injection of recombinant human IGF-I. Peak IGF-I concentrations were sustained from 2 hrs (90.5 ng/mL [23 to 228]) to 5 hrs (88.5 ng/mL [29 to 300]). By 24 hrs, circulating IGF-I concentrations had returned to baseline values. Baseline IGF-I concentrations were extremely low, and although peak values were three times greater, these values only approached the fifth percentile of defined reference ranges for normal values. Compared with values in less seriously ill patients, maximum IGF-I concentrations were reached earlier, the elimination half-life was shorter, clearance was more rapid, and the apparent volume of distribution was similar. IGFBP-3 concentrations also increased after recombinant human IGF-I injection, and at 3 to 4 hrs were significantly elevated, from 30 mins (p = .04) to 8 hrs (p = .04). There was marked between-patient variability in changes in circulating IGF-I, and IGFBP-1, and IGFBP-3 concentrations. More severely ill patients had the lowest circulating IGF-I concentrations and the least response to exogenous recombinant human IGF-I. Elevated baseline circulating growth hormone concentrations (2.3 ng/mL, range 0.8 to 4 [5.1 mU/L, 1.5 to 8]) were significantly depressed from 4 hrs (0.5 ng/mL, 0.5 to 1.5 [1 mU/L, 1 to 3], p = .01) to 6 hrs (0.8 ng/mL, 0.5 to 4 [1.5 mU/L, 1 to 8], p = .02) after recombinant human IGF-I administration. CONCLUSION: We observed no adverse effects (e.g., hypoglycemia) that could be attributed to recombinant human IGF-I therapy.

A combined test using desmopressin and corticotropin-releasing hormone in the differential diagnosis of Cushing's syndrome.

To assess the ability of desmopressin to differentiate between pituitary and ectopic ACTH-dependent Cushing's syndrome and to determine whether diagnostic accuracy could be improved by administering it together with human sequence CRH, we examined its effects on cortisol and ACTH secretion when given alone or in combination with CRH in patients with Cushing's syndrome of varied etiology and compared these data to the results of a standard CRH test in the same individuals. Each patient was studied on three occasions, in random order, separated by at least 48 h. At 0900 h, via an indwelling forearm cannula, 10 micrograms desmopressin, 100 micrograms CRH, or a combination of the two were given as an iv bolus; thereafter, blood was drawn every 15 min for 2 h. The responses to the individual agents were determined according to the timing and calculation criteria suggested by Nieman et al. (1993). A total of 25 patients with Cushing's syndrome were studied: 17 patients with pituitary-dependent Cushing's syndrome, Cushing's disease (CD); 5 patients with occult ectopic ACTH secretion (EC); and 3 patients with primary adrenal (ACTH-independent) Cushing's syndrome. In this series, the best discrimination among ACTH-dependent patient groups was achieved using the combined test. Using the responses of plasma cortisol, all 17 patients with CD showed a rise greater than any of the 5 patients with EC, whereas 1 patient with CD showed a plasma ACTH response within the range seen in the patients with EC. Plasma cortisol responses to desmopressin alone were seen in 14 of 17 patients with CD and 1 of 5 patients with EC and, after CRH alone, in 15 of 17 patients with CD but in no patient with EC. In contrast, plasma ACTH responses after CRH alone were seen in 14 of 17 patients with CD and 2 of 5 patients with EC and, after desmopressin alone, in 12 of 17 with CD and 3 of 5 with EC, thus indicating overlapping responses between the groups and poorer discrimination. No responses were seen in the ACTH-independent group. These data indicate that desmopressin causes the secretion of ACTH and cortisol in patients with ACTH-dependent Cushing's syndrome, and that in combination with CRH, it may provide an improvement over the standard CRH test in the differential diagnosis of ACTH-dependent Cushing's syndrome. Furthermore, these data suggest that there may be abnormalities in vasopressin receptor function or number in ACTH-secreting tumors.

Effects of antidepressant treatment on corticotropin-induced cortisol responses in patients with melancholic depression.

To date, there appears to be no consensus of opinion as to whether the adrenal glands are hyperresponsive during depression and, if so, whether this a state-dependent phenomenon. We aimed to determine the effects of antidepressant treatment on ACTH-induced cortisol responses in patients with melancholic depression. Seven female patients with DSM-III-R major depressive disorder, non-psychotic, melancholic subtype, were evaluated using the following rating scales: the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale and the Newcastle Endogenicity Scale. All subjects were then given an intravenous bolus dose (250 micrograms) of tetracosactrin, a potent stimulus of adrenocortical hormone secretion. Plasma levels of cortisol were measured at times 0, + 30, + 60, + 90, + 120 and + 180 min. Patients were then randomised to receive either 50 mg of sertraline or 20 mg of paroxetine (both of which are selective serotonin re-uptake inhibitors) and were re-tested while medication-free. Treatment resulted in a significant decrease in delta (the difference between the baseline values and the maximum increase post-ACTH administration) cortisol values of 1633.3 +/- 378.5 nmol/l vs. 595.1 +/- 207.7 nmol/l. Successful pharmacological treatment of major depressive disorder appears to be associated with a reduction in ACTH-induced cortisol release in drug-free patients.

Outcome of transsphenoidal surgery for acromegaly using strict criteria for surgical cure.

OBJECTIVE: Previous studies of surgical treatment for acromegaly have used varied criteria for 'cure', but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer-term outcome for patients not offered further treatment when post-operative levels of GH < 5 mU/l were achieved. DESIGN: We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew's Hospital between 1985 and 1993. PATIENTS: One hundred consecutive patients (53 male, mean age 46 years, range 18-68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5-8 years) after operation. MEASUREMENTS: GH levels are represented as a mean value from a four-point day curve taken at 0830, 1300, 1700 and 1900 h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured. RESULTS: Post-operatively, 42% of patients achieved a mean GH level of < 5 mU/l. The success of surgery was related to the preoperative GH level; 65% of the patients with preoperative GH levels < 20 mU/l but only 18% of the patients with GH levels > 100 mU/l achieved post-operative GH values < 5 mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post-operative GH levels of < 5 mU/l. Of the 42 patients considered in remission post-operatively (mean GH < 5 mU/l), 32 were available for long-term follow-up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow-up of 3.8 years (range 0.5-8). There were no peri-operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post-operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted. CONCLUSIONS: The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post-operative GH < 5 mU/l are achieved.

Met-enkephalin and catecholamine release during feline intestinal ischemia-reperfusion.

Release of met-enkephalin-like immunoreactivity (MLI) into the circulation was investigated during feline intestinal ischemia-reperfusion in relation to the mass of ischemic tissue and in correlation to the sympathoadrenergic, response as gauged by plasma norepinephrine (NE) and epinephrine (E) levels. Chloralose anesthetized cats were randomized to a control group (C, n = 7), 20 cm segmental (S, n = 7), or complete intestinal ischemia (l, n = 7) for 90 min followed by reperfusion for 180 min. MLI and NE/E concentrations were assayed by radioimmunoassay and chromatography, respectively. Severe mucosal lesions and cardiovascular decompensation were observed in l animals in association with increased MLI and NE levels in femoral venous and portal venous plasma, whereas no such responses were observed in the S or C groups. MLI and NE concentrations were consistently higher in portal venous than in femoral venous plasma in 1 animals and correlations between MLI and NE levels were found during reperfusion in the portal, but not the systemic, circulation. Concentrations of E remained unchanged in all groups and did not correlate to MLI release. We conclude that: 1) intestinal MLI release and sympathetic activation occur only when the ischemic insult is sufficient to cause circulatory collapse, characteristic of an "on-off" rather than a "dose-response" pattern; and 2) intestinal MLI and NE release at reperfusion are correlated whereas MLI and E release do not appear to be related events.

Haemodynamic and metabolic responses of the lower limb after high intensity exercise in humans.

This study assessed blood flow in the common femoral, superficial femoral and profunda femoris arteries, the effects of vasodilator metabolites and changes in blood pressure and pulse during recovery after high intensity exercise (Wingate test). Mean common femoral artery flow increased sevenfold in response to the exercise. The subsequent decline in mean common femoral artery flow was mono-exponential with a mean time constant of 19 min. The post-exercise increase in profunda femoris artery flow (ninefold) was significantly greater than the superficial femoral artery flow (fourfold, P < 0.05). Systolic blood pressure and heart rate decreased monotonically throughout recovery. In contrast, diastolic blood pressure showed a significant fall below baseline at 3 min (P < 0.05) with a return to baseline at 60 min. The greatest drop below baseline (approximately 20 mmHg) occurred around 7 min. Lactate reached a maximum of 13.6 +/- 2.3 mmol -1 at 8 min (P < 0.05) and was still significantly above baseline at 60 min. pH remained below 7.2 until 20 min of recovery. The results demonstrate that following high intensity exercise, blood flow to the limbs appears to be controlled by complex interactions of various vaso-active metabolites, each contributing proportionally more at different times during recovery.

Central 5-hydroxytryptaminergic function in irritable bowel syndrome.

BACKGROUND: Psychological factors may contribute to the aetiology and exacerbation of symptoms in irritable bowel syndrome (IBS), suggesting that the central nervous system may be an important site of dysfunction in IBS. Hormonal responses after a serotonergic challenge assess the functional integrity of central 5-hydroxytryptaminergic pathways and are diminished in depression. The aim of this study was to determine whether hormonal responses in IBS after a serotonergic challenge would be decreased, as in depression, or exaggerated, as have been reported in another functional gastrointestinal disorder, nonulcer dyspepsia. METHODS: Fourteen IBS patients, 16 healthy volunteers, and 9 patients with inflammatory bowel disease were given 30 mg d-fenfluramine, a selective stimulus to central 5-hydroxytryptaminergic pathways. RESULTS: Plasma prolactin and cortisol concentrations during the following 5 h increased to a similar extent in all three subject groups, despite increased levels of anxiety and depression (as scored on the Hospital Anxiety and Depression Scale and Beck Depression Inventory) in the IBS and inflammatory bowel disease patients compared with the healthy controls. Base-line cortisol concentration correlated with the magnitude of affective disorder. CONCLUSION: In contrast to the alterations of central 5-hydroxytryptamine receptor sensitivity seen in depression and non-ulcer dyspepsia, central 5-hydroxytryptaminergic pathways function normally in IBS.

Cholecystokinin is a satiety hormone in humans at physiological post-prandial plasma concentrations.

1. Intravenous infusions of the brain/gut hormone, cholecystokinin, have been shown to reduce food intake in a subsequent test meal. However, in previous studies the doses administered were large and likely to have produced plasma concentrations far in excess of the normal post-prandial range. 2. In this study cholecystokinin-8 was infused intravenously to six healthy subjects in doses that reproduced physiological post-prandial concentrations. Plasma concentrations of cholecystokinin were measured using a novel sensitive and specific radioimmunoassay. The effect of cholecystokinin-8 infusion on subsequent food intake in a standard test meal was compared with the effect of saline infusion in the same subjects. 3. Food intake (mean +/- SEM) was significantly less during cholecystokinin (5092 +/- 665 kJ) than during saline infusion (6418 +/- 723 kJ, P = 0.03). During cholecystokinin infusion, plasma concentrations increased from 0.45 +/- 0.06 pmol/l to 7.28 +/- 2.43 pmol/l immediately before the meal. With saline infusion there was no premeal increase in plasma cholecystokinin concentration. 4. This paper describes a novel radioimmunoassay for measurement of plasma concentrations of cholecystokinin. Using this assay we have demonstrated that cholecystokinin is important in control of satiety in humans.

Investigation, management and therapeutic outcome in 12 cases of childhood and adolescent Cushing's syndrome.

OBJECTIVE: Cushing's syndrome in childhood and adolescence is rare. We analysed the clinical presentation, investigation, management and therapeutic outcome in 12 paediatric patients with Cushing's syndrome. DESIGN: Retrospective review of case notes. PATIENTS: Twelve patients, 7 males and 5 females, aged 7.6-17.8 years with Cushing's syndrome who were admitted to St Bartholomew's Hospital between 1978 and 1993, were studied. Aetiologies of the Cushing's syndrome patients were: Cushing's disease (9), adrenal adenoma (1), nodular adrenocortical dysplasia (1) and ectopic ACTH syndrome (1). One further male patient, aged 17.8 years who presented with Nelson's syndrome after bilateral adrenalectomy for Cushing's disease in 1978, is described. MEASUREMENTS: Presenting symptoms, endocrine tests for hypercortisolism, imaging studies, simultaneous bilateral inferior petrosal sinus sampling and therapeutic strategies are discussed. RESULTS: The dominant clinical features were obesity, short stature, virilization, headaches, fatigue and emotional lability. Investigations confirmed Cushing's syndrome by demonstrating absent cortisol circadian rhythm and impaired suppression on low dose dexamethasone test and differentiated Cushing's disease from other aetiologies by high dose dexamethasone and hCRH tests. In Cushing's disease, pituitary CT scan identified a microadenoma in 4 out of 9 subjects. In 5 of the 9 patients (3 with a normal pituitary CT, 2 with a suggested microadenoma), a pituitary MRI scan was performed and confirmed the CT findings. Inferior petrosal sinus catheterization for ACTH in 4 patients confirmed excess pituitary ACTH secretion, correctly lateralizing the tumour in all cases. Cushing's disease was treated by transsphenoidal surgery alone in 6 patients and combined with pituitary irradiation in 3 patients. Of these 9 patients, 7 are cured and 2 are in remission. The patient with Nelson's syndrome is cured after total hypophysectomy. CONCLUSIONS: This series describes the clinical features, aetiologies and management of juvenile Cushing's syndrome. Investigation with low and high-dose dexamethasone suppression tests and hCRH test identified the aetiology in each case. Collaboration between paediatric and adult endocrine units together with an experienced neurosurgeon and a radiotherapist contributed to the successful therapeutic outcome of these patients.