Changes in serum sex hormone profiles after short-term low-dose administration of dehydroepiandrosterone (DHEA) to young and elderly persons.

In man, serum concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease with age after the twenties. For this reason, the decline in DHEA and DHEAS concentrations may be related to the development of some chronic diseases that are prevalent in the older age population. In this study, we evaluate the benefit and safety level of DHEA administration to men as a hormone replacement therapy. Twenty-two healthy Japanese males (age 26-63; mean +/- SD, 41.0 +/- 10.0 yrs.) received 25 mg DHEA once a day orally in the morning for two weeks. Serum concentrations of steroid hormones and cytokines were measured before and after the DHEA administration. Glucose tolerance and insulin resistance were also assessed before and after the DHEA administration using a 75 g oral glucose tolerance test and homeostasis model assessment (HOMA-R), respectively. Serum DHEA and DHEAS levels were significantly elevated after the DHEA administration for all ages of test subjects. In subjects who were older than 41 yrs. (older group) serum androstenedione and estradiol levels were elevated after the DHEA administration. Significant negative correlations were observed between the serum DHEA concentration and the serum concentration of fasting insulin, HOMA-R, leptin, and high-sensitivity C-reactive protein for all subjects. Daily administration of 25 mg DHEA increased the serum DHEA, DHEAS, androstenedione, and estradiol levels of the subjects of the older group to the same level as that of younger subjects.

Effects of the long-acting calcium channel blockers, amlodipine, manidipine and cilnidipine on steroid hormones and insulin resistance in hypertensive obese patients.

OBJECTIVE: To demonstrate that calcium channel blockers can improve insulin resistance clinically, we investigated the effects of the calcium channel blockers, amlodipine, manidipine and cilnidipine on serum levels of steroid hormones and insulin. SUBJECTS AND METHODS: Thirty hypertensive obese patients [15 men and 15 women; mean age 55.9 years, mean body mass index (BMI) 27.6] were divided into three groups and treated with either 5 mg of amlodipine, 20 mg of manidipine or 10 mg of cilnidipine. Blood pressure (BP), fasting plasma glucose (FPG), HbA1c, fasting serum immunoreactive insulin (F-IRI), insulin resistance index [as assessed by the homeostasis model assessment (HOMA-R)], serum DHEA, serum DHEA-S, plasma ACTH, serum cortisol, plasma renin activity (PRA), and serum aldosterone, were measured before and after 1, 2, 3 and 6 months of treatment. RESULTS: In all three groups, BP decreased significantly after 1 month and F-IRI and HOMA-R decreased significantly after 2-3 months. A concurrent rise in serum DHEA and DHEA-S levels was also observed, however, the differences were not significant. No changes in FPG, HbA1c, ACTH, cortisol, PRA or aldosterone levels were observed during treatment. CONCLUSIONS: We conclude that amlodipine, manidipine and cilnidipine all improve insulin resistance and consequently increase serum levels of DHEA and DHEA-S.

The clinically inapparent adrenal mass: update in diagnosis and management.

Clinically inapparent adrenal masses are incidentally detected after imaging studies conducted for reasons other than the evaluation of the adrenal glands. They have frequently been referred to as adrenal incidentalomas. In preparation for a National Institutes of Health State-of-the-Science Conference on this topic, extensive literature research, including Medline, BIOSIS, and Embase between 1966 and July 2002, as well as references of published metaanalyses and selected review articles identified more than 5400 citations. Based on 699 articles that were retrieved for further examination, we provide a comprehensive update of the diagnostic and therapeutic approaches focusing on endocrine and radiological features as well as surgical options. In addition, we present recent developments in the discovery of tumor markers, endocrine testing for subclinical disease including autonomous glucocorticoid hypersecretion and silent pheochromocytoma, novel imaging techniques, and minimally invasive surgery. Based on the statements of the conference, the available literature, and ongoing studies, our aim is to provide practical recommendations for the management of this common entity and to highlight areas for future studies and research.

A trial of intranasal ACTH(1-24) administration to a patient with isolated ACTH deficiency.

BACKGROUND: Isolated adrenocorticotropic hormone (ACTH) deficiency is a rare cause of secondary adrenocortical insufficiency. Normally it could be used therapeutically as an alternative to glucocorticoid treatment in these patients. We investigated the possibility of therapeutic approach as intranasal ACTH replacement therapy in patients with ACTH deficiency. CASE REPORT: A 32-year-old woman with general fatigue, weakness of legs and loss of consciousness due to severe hyponatremia was admitted to our hospital. Endocrinological studies showed low levels of plasma ACTH and serum cortisol with the loss of circadian rhythm. Plasma ACTH and serum cortisol levels failed to respond after intravenous injection of human corticotropin releasing hormone (hCRH), however, serum cortisol showed a blunted response to ACTH(1-24) stimulation test. She was diagnosed isolated ACTH deficiency. We performed continuous intranasal administration of ACTH(1-24) to the patient. There were no cortisol, aldosterone and dehydroepiandrosterone (DHEA) responses to a single intranasal ACTH(1-24) administration while these levels increased 6 days after intranasal treatment of ACTH(1-24). CONCLUSIONS: These data demonstrate that adrenocortical steroids production are stimulated by intranasal administration of ACTH(1-24) in this patient with isolated ACTH deficiency. We suggest that intranasal administration of ACTH offers a therapeutic approach as ACTH replacement therapy in patients with ACTH deficiency. The latter may be more physiologic than glucocorticoid replacement.

[Phase III additional clinical study of 111In-pentetreotide (MP-1727): diagnosis of gastrointestinal hormone producing tumors based on the presence of somatostatin receptors].

Additional phase III multicenter clinical study was performed to investigate the efficacy, safety, and usefulness of somatostatin receptor scintigraphy using 111In-pentetreotide (MP-1727), which binds to somatostatin receptors. Forty patients were included in the study; Group A: 18 patients, gastrointestinal hormone producing tumors had been detected with conventional imaging modalities, Group B: 22 patients, no tumors had been detected with conventional imaging modalities in spite of high serum hormone levels. By comparing the results of the octreotide suppression test, 12/16 cases (75.0%) of Group A and 11/19 cases (57.9%) of Group B were assessed as "effective." By comparing the results of immunohistological examination, 5/9 cases (55.6%) of Group A and 2/4 cases (50.0%) of Group B were assessed as "effective." Severe adverse events were not observed in any of the evaluable 35 cases. MP-1727 was judged as clinically useful in 11/16 cases (68.8%) of Group A and 5/19 cases (26.3%) of group B. These results suggest that MP-1727 scintigraphy is very useful for the diagnosis and decision of the therapeutic strategy of gastrointestinal hormone producing tumors.

Comment: the corticotropin-releasing hormone stimulation test in white coat hypertension.

This study was undertaken to clarify the status of the ACTH and cortisol responses to CRH in patients with white coat hypertension. White coat hypertension was defined as a difference between clinic blood pressure and ambulatory blood pressure of at least 20 mm Hg for systolic blood pressure and/or 10 mm Hg for diastolic blood pressure. CRH stimulation tests were performed between 1400 and 1700 h in 11 patients with white coat hypertension (4 males and 7 females) and 11 normal subjects (4 males and 7 females). Blood pressure and heart rate were measured 15 min before, at time zero, and 15, 30, 60, and 120 min after initiation of the CRH stimulation tests. In white coat hypertension, both the mean systolic blood pressure (162 +/- 15 mm Hg) and diastolic blood pressure (97 +/- 10 mm Hg) were higher than in controls (P < 0.01) on 3 occasions. The mean ambulatory blood pressure for the 24-h period of the test did not differ between patients with white coat hypertension and normal subjects. Basal levels of ACTH and cortisol did not differ between patients with white coat hypertension and control subjects. However, challenge with CRH elevated ACTH (30 min) and cortisol (30, 60, and 120 min) to levels higher than those in controls, with the net increase in both ACTH and cortisol being higher than that in controls over the study period (P < 0.01). These significant responses suggest that white coat hypertension is associated with hypothalamic-pituitary-adrenal hypersensitivity to stressors.

Intranasal administration of adrenocorticotropin-(1-24) stimulates adrenocortical hormone secretion.

To determine the efficiency of transmucosal absorption of ACTH, we measured serum cortisol, aldosterone, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S) levels after intranasal (in) vs. iv administration of ACTH-(1-24) (250 microg) in 12 healthy adult men (mean age, 24.3 +/- 3.2 yr; range, 21-31 yr), who had received no prior medication and had no symptoms of rhinitis. Blood was collected at 0, 30, 60, 120, and 180 min after administration of ACTH-(1-24), and the levels of adrenocortical steroids were measured by specific RIAs. There were no side-effects associated with in or iv ACTH administration. After in administration, serum cortisol and aldosterone increased rapidly by 224.7 +/- 39.2% and 147.2 +/- 50.5%, respectively, peaking 30 min after ACTH-(1-24) administration, and decreasing to basal levels within 120 min. These increases in serum cortisol and aldosterone were lower than those obtained after iv administration. Thirty minutes after in or iv administration of ACTH-(1-24), DHEA increased by 49.1 +/- 27.2% and 81.6 +/- 17.1%, respectively, and remained elevated for 180 min. Serum DHEA-S levels did not change after in administration of ACTH-(1-24) and increased only slightly after iv injection. Adrenocortical steroid levels did not increase after in administration of saline. These data demonstrate that adrenocortical steroids are stimulated by in administration of ACTH-(1-24). We suggest that intranasal administration of ACTH offers both a diagnostic approach as an adrenal function test and a therapeutic approach as ACTH replacement therapy in patients with ACTH deficiency. The latter may be more physiological than glucocorticoid replacement.

Decreased steroidogenic enzyme 17,20-lyase and increased 17-hydroxylase activities in type 2 diabetes mellitus.

OBJECTIVE: To analyze activities of adrenal steroidogenic enzymes in type 2 diabetes mellitus, serum levels of 11 steroid hormones were measured simultaneously. SUBJECTS: We studied 130 patients with type 2 diabetes mellitus (74 men and 56 women between the ages of 40 and 69 years), whose blood glucose control had been poor (more than 10% in HbA(1c)). Age-matched normal subjects served as the control group. METHODS: Serum levels of steroid hormones (pregnenolone (Preg), progesterone (Prog), deoxycorticosterone (DOC), corticosterone (B), 17-hydroxypregnenolone (17-OH-Preg), 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), cortisol (F), dehydroepiandrosterone (DHEA) and Delta4-androstenedione (Delta4A)) were measured by HPLC/RIA methods. Fasting plasma glucose (FPG), HbA(1c), ACTH, serum immunoreactive insulin (IRI) and DHEA sulfate (DHEA-S) were also measured. We analyzed product/precursor ratios to assess relative activities of adrenal steroidogenic enzymes. RESULTS: Serum levels of ACTH and F were high and DHEA and DHEA-S were low in both male and female patients under poor blood glucose control. Following 6-months treatment with diet only or with sulfonylurea, FPG and HbA(1c) improved, and blood concentrations of ACTH and F decreased while DHEA and DHEA-S levels increased to within the normal range. DHEA/17-OH-Preg and Delta4A/17-OHP ratios, reflecting 17,20-lyase activity, were low before treatment and recovered to the normal range after treatment, and 17-OH-Preg/Preg and 17-OHP/Prog ratios, reflecting 17-hydroxylase activity, were high before treatment, and fell within the normal range after treatment. 3beta-Hydroxysteroid dehydrogenase, 21-hydroxylase and 11beta-hydroxylase activities remained within the normal range both before and after treatment. CONCLUSIONS: These data suggest that the decrease in DHEA and DHEA-S concentrations together with the high F levels that occur in patients with type 2 diabetes mellitus is associated with low 17,20-lyase and high 17-hydroxylase activity in the adrenal steroidogenic enzymes. High insulin concentrations may further lower DHEA and DHEA-S levels.