[A hairy case].
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Adrenal Hyperplasia, Congenital↗
Biomedical subjects
B Allolio
Publications and source records attributed to B Allolio.
Evidence against a role of physiological concentrations of estrogen in post-myocardial infarction remodeling.
OBJECTIVES: The purpose of this study was to examine whether endogenous estrogen deficiency induced by ovariectomy affects chronic left ventricular dysfunction post-myocardial infarction (MI). BACKGROUND: Epidemiologic findings suggest that mortality of postmenopausal women is increased after MI, but the underlying mechanisms are unknown. METHODS: Rats were either not ovariectomized (non-OVX), ovariectomized (OVX) or ovariectomized and treated with subcutaneous 17-beta-estradiol (E2) pellets (OVX + E2). Two weeks later, animals were sham-operated (Sham) or left coronary artery ligated (MI). Eight weeks later, in vivo echocardiographic and hemodynamic measurements were performed. Thereafter, hearts were isolated and perfused isovolumically. RESULTS: Mean infarct size was similar among the three MI groups. Ovariectomy decreased serum E2 levels (11 +/- 4 vs. 49 +/- 11 pg/ml in non-OVX, p < 0.01) and increased body weight. These changes were reversed by E2 replacement. The degree of cardiac hypertrophy was similar for all groups post-MI. Left ventricular diameters were increased post-MI (8.9 +/- 0.4 in non-OVX + MI vs. 6.7 +/- 0.2 mm in non-OVX + Sham hearts, p < 0.0001), but OVX or OVX + E2 replacement did not alter left ventricular diameters in post-MI and Sham hearts. Left ventricular fractional shortening was severely impaired post-MI (19 +/- 2% vs. 50 +/- 3 in non-OVX + Sham hearts, p < 0.0001) with no influence of hormonal status. Left ventricular end-diastolic pressure, measured in vivo, was increased in all MI groups without significant differences between groups. Pressure-volume curves, obtained in perfused hearts, demonstrated a right and downward shift with reduced maximum left ventricular developed pressure post-MI (75 +/- 6 vs. 108 +/- 3 mm Hg in non-OVX + Sham hearts, p < 0.001) and were also unaffected by either OVX or E2 replacement. CONCLUSIONS: Chronic endogenous estrogen deficiency does not have major effects on the development of cardiac hypertrophy, dysfunction and dilation post-MI.
Animals↗
Dehydroepiandrosterone replacement in women with adrenal insufficiency.
BACKGROUND: The physiologic role of dehydroepiandrosterone in humans is still unclear. Adrenal insufficiency leads to a deficiency of dehydroepiandrosterone; we therefore, investigated the effects of dehydroepiandrosterone replacement, in patients with adrenal insufficiency. METHODS: In a double-blind study, 24 women with adrenal insufficiency received in random order 50 mg of dehydroepiandrosterone orally each morning for four months and placebo daily for four months, with a one-month washout period. We measured serum steroid hormones, insulin-like growth factor I, lipids, and sex hormone-binding globulin, and we evaluated well-being and sexuality with the use of validated psychological questionnaires and visual-analogue scales, respectively. The women were assessed before treatment, after one and four months of treatment with dehydroepiandrosterone, after one and four months of placebo, and one month after the end of the second treatment period. RESULTS: Treatment with dehydroepiandrosterone raised the initially low serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone into the normal range; serum concentrations of sex hormone-binding globulin, total cholesterol, and high-density lipoprotein cholesterol decreased significantly. Dehydroepiandrosterone significantly improved overall well-being as well as scores for depression and anxiety. For the global severity index, the mean (+/-SD) change from base line was -0.18+/-0.29 after four months of dehydroepiandrosterone therapy, as compared with 0.03+/-0.29 after four months of placebo (P=0.02). As compared with placebo, dehydroepiandrosterone significantly increased the frequency of sexual thoughts (P=0.006), sexual interest (P=0.002), and satisfaction with both mental and physical aspects of sexuality (P=0.009 and P=0.02, respectively). CONCLUSIONS: Dehydroepiandrosterone improves well-being and sexuality in women with adrenal insufficiency.
Adrenal Insufficiency↗
[Cushing syndrome: diagnosis and therapy].
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Cushing Syndrome↗
[Adrenal cortex insufficiency: diagnosis and therapy].
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Adrenal Cortex Function Tests↗
Risk factors for hip fracture not related to bone mass and their therapeutic implications.
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Accidental Falls↗
[Paraneoplastic hypertrichosis lanuginosa et terminalis in a 27-year old woman with parotid carcinoma].
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Adult↗
Suramin treatment in hormone- and chemotherapy-refractory prostate cancer.
OBJECTIVES: Suramin, a polysulfonated naphtylurea with anti-growth factor activity, was used in the treatment of metastatic, hormone- and chemotherapy-refractory prostate cancer. Recent studies have proved the effect of suramin on prostate cancer. METHODS: Between March 1990 and January 1994, 27 patients with metastatic prostate cancer were enrolled in this study. Treatment regimen consisted of a loading phase, allowing patients to reach suramin serum levels between 180 and 250 microg/mL using a suramin dose of 1.4 g/m2 at 3-day intervals. Constant suramin serum levels were maintained by a 0.5 to 1-g/m2 dose every 7 to 10 days. Because previous studies showed suramin to have serious toxicity, compromised organ status was excluded by repeated examinations. RESULTS: Six patients did not complete the suramin loading phase because of side effects and were removed from the study. With an average cumulative suramin dose of 14.2 g, 33% of the assessable patients (7 of 21) experienced a more than 50% reduction of prostate-specific antigen (PSA) and/or alkaline phosphatase (AP) serum levels. Mean survival in these suramin-responsive patients was 495 days. Two of these patients experienced a remarkable reduction of metastases in bone scan examinations. Another 48% of the patients (10 of 21) had essentially unchanged AP and PSA serum levels during suramin treatment, indicating stable disease. Mean survival of these patients was 341 days. In 4 patients undergoing suramin treatment, continuous clinical progression of the disease was observed (mean survival 79 days). Toxicity was less or comparable to prior reported studies; the most common side effects were polyneuropathy, allergic skin rash, and vortex keratopathy. CONCLUSIONS: Suramin has limited, but significant, efficacy even in chemotherapy- and hormone-refractory prostate cancer, without serious toxicity.
Aged↗
5-HT1A receptor function in normal subjects on clinical doses of fluoxetine: blunted temperature and hormone responses to ipsapirone challenge.
Serotonergic receptors of the 5-HT1A subtype have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, including specific serotonin reuptake inhibitors (SSRIs). We examined the effect of clinical doses of the SSRI, fluoxetine, on 5-HT1A receptor function in 15 normal volunteers. Hypothermic and hormone responses to the 5-HT1A receptor agonist, ipsapirone (0.3 mg per kg, per os) were examined after two weeks of placebo and again, after the subjects had been receiving fluoxetine for four weeks. On fluoxetine, the hypothermic response to ipsapirone was significantly blunted, as were ACTH, cortisol and growth hormone release. Ipsapirone plasma levels were significantly increased by fluoxetine but a pharmacokinetic effect could not have accounted for the observed blunting of 5-HT1A receptor mediated effects. These findings confirm and extend previous observations in rodents and humans and indicate that both post-synaptic 5-HT1A receptors in the hypothalamus, which mediate hormone responses to 5-HT1A agonists, and pre-synaptic 5-HT1A receptors which (putatively) mediate the hypothermic response, are rendered subsensitive by chronic SSRI administration. Since fluoxetine did not have significant effects on mood and other psychological variables in these subjects, alterations in 5-HT1A receptor function induced by SSRIs may have psychotropic relevance only in the context of existing perturbations of serotonergic function which underlie the psychopathological states in which these drugs are therapeutically effective.
Adrenocorticotropic Hormone↗
Age at menarche and cortical bone geometry in premenopausal women.
Previous studies have suggested that the timing of puberty might have an impact on the adult skeleton. What composite of bone structure could be affected by the timing of puberty is unknown at present. In this study, we evaluated the relationship between age at menarche and bone cortex geometry at the distal radius. Using peripheral quantitative computed tomography, we determined total area of the radial cross section, cortical bone area, periosteal cortical perimeter, endosteal cortical perimeter, and cortical width in 169 healthy premenopausal women aged 40-45 years. When stratified according to age at menarche (early, <12 years In = 22]; intermediate, 12-14 years [n = 118]; late, >14 years [n = 29]), only endosteal cortical perimeter varied significantly between the groups (p = 0.02, by analysis of variance), the mean value being 10% higher in the late compared to the early menarche group. However, weight and body mass index also exhibited significant variations between groups. After adjustment for weight the differences in endosteal cortical perimeter remained significant (p = 0.03). In multiple regression analysis, endosteal cortical perimeter was the only parameter of cortex geometry, which was independently associated with age at menarche. In a model including height and weight, age at menarche explained about 2% of the variability in endosteal cortical perimeter (p = 0.04). These data suggest that the bone marrow cavity of the distal radius may be slightly larger when puberty occurs later. Whether this marginal effect influences fracture risk in later life appears questionable.
Adolescent↗
Cushing's syndrome due to an ectopic ACTH-secreting pituitary tumour mimicking occult paraneoplastic ectopic ACTH production.
A 32-year-old man presenting with typical features of Cushing's syndrome showed baseline cortisol and ACTH values indicating ACTH-dependent disease. Dynamic function tests (dexamethasone, corticotropin releasing hormone (CRH), desmopressin), were suggestive of paraneoplastic ectopic ACTH production. However, inferior petrosal sinus (IPS) ACTH sampling demonstrated a maximum baseline central (363 pmol/l)-peripheral (19 pmol/l) ACTH gradient of 19.1 for the right IPS, conventionally suggestive of Cushing's disease. However, again, IPS ACTH level did not increase after CRH stimulation. Magnetic resonance imaging, while showing no evidence of an intrasellar tumour, revealed an 1.5 x 1.0 cm mass in the left sphenoid sinus which was initially interpreted as most probably being a mucosal polyp. After neurosurgical removal of the tumour, transient secondary adrenal insufficiency was present. The structure and immunostaining characteristics of the tumour demonstrated an ACTH cell adenoma of the pituitary. Ectopic ACTH-secreting pituitary adenomas may cause significant difficulties in differential diagnosis, localisation and appropriate therapy. Thus, although these tumours are rare, they should be included in the list of possible causes of ACTH-dependent Cushing's syndrome.
ACTH Syndrome, Ectopic↗
Drinking water fluoridation and bone.
Drinking water fluoridation has an established role in the prevention of dental caries, but may also positively or negatively affect bone. In bone fluoride is incorporated into hydroxylapatite to form the less soluble fluoroapatite. In higher concentrations fluoride stimulates osteoblast activity leading to an increase in cancellous bone mass. As optimal drinking water fluoridation (1 mg/l) is widely used, it is of great interest, whether long-term exposition to artificial water fluoridation has any impact on bone strength, bone mass, and -- most importantly -- fracture rate. Animal studies suggest a biphasic pattern of the effect of drinking water fluoridation on bone strength with a peak strength at a bone fluoride content of 1200 ppm followed by a decline at higher concentrations eventually leading to impaired bone quality. These changes are not paralleled by changes in bone mass suggesting that fluoride concentrations remain below the threshold level required for activation of osteoblast activity. Accordingly, in most epidemiological studies in humans bone mass was not altered by optimal drinking water fluoridation. In contrast, studies on the effect on hip fracture rate gave conflicting results ranging from an increased fracture incidence to no effect, and to a decreased fracture rate. As only ecological studies have been performed, they may be biased by unknown confounding factors -- the so-called ecological fallacy. However, the combined results of these studies indicate that any increase or decrease in fracture rate is likely to be small. It has been calculated that appropriately designed cohort studies to solve the problem require a sample size of >400,000 subjects. Such studies will not be performed in the foreseeable future. Future investigations in humans should, therefore, concentrate on the effect of long-term drinking water fluoridation on bone fluoride content and bone strength.
Biomechanical Phenomena↗
Telomerase activity in benign and malignant adrenal tumors.
Histological analysis of surgically removed adrenal masses often fails to differentiate between benign and malignant tumors. In normal cells, the telomeric ends of the chromosomes are shortened with each cell division, leading to chromosome destabilization and cellular senescence after a critical number of cell cycles. In tumor cells, telomere shortening is prevented by a specific DNA polymerase, called telomerase. In an effort to clarify the role of telomerase in the pathogenesis of adrenal tumors, and to test whether its activity could serve as marker of malignancy, we measured telomerase activity in 41 human adrenal tissue samples that were classified both by the clinical course and by histological examination. Telomerase activity was determined by TRAP ELISA and expressed as high (>50% of positive control telomerase activity), medium (31-50%), low (11-30%), very low (< or = 10%), or absent (0%). The 8 normal adrenal tissue samples showed very low levels of telomerase activity. Mean telomerase activity also very low in 3/3 incidentalomas, 6/6 Cushing adenomas, 6/6 Conn adenomas, 7/7 adrenocortical carcinomas, 8/8 benign pheochromocytomas, and 2/3 malignant pheochromocytomas. In contrast, one malignant pheochromocytoma showed high telomerase activity. These data indicate that telomerase activity may not be a suitable marker for malignancy in the adrenal gland. Our results also challenge the current dogma of close correlation between cell dedifferentiation and telomerase activity.
Adenoma↗
Multiple mechanisms are involved in the acute vasodilatory effect of 17beta-estradiol in the isolated perfused rat heart.
The purpose of this study was to define the dose-dependent effects of 17beta-estradiol on coronary flow and cardiac function in isolated rat hearts and to identify the mechanisms involved in its vasodilator action. Hearts from female and male Wistar rats were perfused at constant pressure (100 mm Hg). Stereoisomer specificity and the mechanism of vasodilation by 17beta-estradiol were examined in female rat hearts. Function was measured by a left ventricular (LV) balloon and coronary flow (CF) with an ultrasonic flowmeter. 17Beta-estradiol at 10(-6), 5 x 10(-6), and 10(-5) M increased CF in female hearts by 5 +/- 2, 27 +/- 4 (p < 0.05 vs. baseline), and 40 +/- 4% (p < 0.05 vs. baseline), respectively. The effect of 17beta-estradiol in hearts from male rats was similar but less pronounced compared with females [deltaCF 8 +/- 3, 19 +/- 3 (p < 0.05 vs. baseline)] and 25 +/- 7% (p < 0.05 vs. baseline; p < 0.05 vs. female 17beta-estradiol). Maximum vasodilation by the stereoisomer 17alpha-estradiol was significantly smaller [deltaCF 5 +/- 3, 4 +/- 3 (p < 0.05 vs. female 17beta-estradiol) and 14 +/- 1% (p < 0.05 vs. baseline; p < 0.05 vs. female 17beta-estradiol)] for 10(-6), 5 x 10(-6), and 10(-5) M. Pretreatment with the NO-synthesis inhibitor Nomega-methyl-L-arginine (10(-4) M) had no effect on the maximal vasodilator response to 17beta-estradiol (10(-5) M) [deltaCF 36 +/- 6% (p < 0.05 vs. baseline)]. When hearts were pretreated with the prostaglandin-synthesis inhibitor diclofenac (10(-6) M), the maximal vasodilator effect of 17beta-estradiol was partially attenuated [deltaCF 12 +/- 7% (p < 0.05 vs. female 17beta-estradiol)]. Similarly, pretreatment with the K+ATP-blocker glibenclamide (10(-6) M) partially inhibited the maximal vasodilator effect of 17beta-estradiol [deltaCF 22 +/- 6% (p < 0.05 vs. baseline; p < 0.05 vs. female 17beta-estradiol)]. Pretreatment with the Ca2+ channel antagonist nifedipine (7.2 x 10(-8) M) completely blocked the vasodilator effect. In isolated perfused rat hearts, 17beta-estradiol induced marked acute coronary vasodilation; this effect is in part gender specific, and in female hearts, largely stereoisomer specific. The dilator effect is mediated predominantly by calcium channel blockade, but prostaglandin release and K+ATP channel activation also are involved. In the isolated perfused rat heart, NO production does not contribute to the acute vasodilator effect of 17beta-estradiol.
Animals↗
MEN1 gene analysis in sporadic adrenocortical neoplasms.
Adrenocortical tumors occur as sporadic tumors, as part of the multiple endocrine neoplasia type 1 (MEN1) syndrome or as part of other hereditary disorders. We recently cloned the MEN1 gene, a tumor-suppressor gene located on chromosome 11q13. Subsequently, we showed that sequential somatic inactivation of both alleles of the MEN1 gene contributes to the development of some sporadic endocrine neoplasms (parathyroid, enteropancreatic neuroendocrine, bronchial carcinoid, and pituitary tumors). We now studied whether somatic inactivation of the MEN1 gene contributes to the pathogenesis of sporadic adrenocortical neoplasms. Seven adrenocortical carcinomas, 2 adrenocortical carcinoma cell lines, and 11 aldosterone-secreting, 8 cortisol-secreting, and 5 nonsecreting benign adrenocortical tumors were studied. Seven tumors (5 of 5 carcinomas, 2 of 21 nonsecreting benign adenomas; P < 0.001) exhibited loss of heterozygosity on 11q13. All 33 tumors and cell lines were screened for mutation throughout the MEN1 open-reading frame and adjacent splice junctions. None exhibited a mutation within the MEN1-coding region. We conclude that somatic MEN1 mutation within the MEN1-coding region does not occur commonly in sporadic adrenocortical tumors, although the majority of adrenocortical carcinomas exhibit 11q13 loss of heterozygosity.
Adrenal Cortex Neoplasms↗
Biotransformation of oral dehydroepiandrosterone in elderly men: significant increase in circulating estrogens.
The most abundant human steroids, dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, may have a multitude of beneficial effects, but decline with age. DHEA possibly prevents immunosenescence, and as a neuroactive steroid it may influence processes of cognition and memory. Epidemiological studies revealed an inverse correlation between DHEAS levels and the incidence of cardiovascular disease in men, but not in women. To define a suitable dose for DHEA substitution in elderly men we studied pharmacokinetics and biotransformation of orally administered DHEA in 14 healthy male volunteers (mean age, 58.8 +/- 5.1 yr; mean body mass index, 25.5 +/- 1.5 kg/m2) with serum DHEAS concentrations below 4.1 micromol/L (1500 ng/mL). Diurnal blood sampling was performed on 3 occasions in a single dose, randomized, cross-over design (oral administration of placebo, 50 mg DHEA, or 100 mg DHEA). The intake of 50 mg DHEA led to an increase in serum DHEAS to mean levels of young adult men, whereas 100 mg DHEA induced supraphysiological concentrations [placebo vs. 50 mg DHEA vs. 100 mg DHEA; area under the curve (AUC) 0-12 h (mean +/- SD) for DHEA, 108 +/- 22 vs. 252 +/- 45 vs. 349 +/- 72 nmol/L x h; AUC 0-12 h for DHEAS, 33 +/- 9 vs. 114 +/- 19 vs. 164 +/- 36 micromol/L x h]. Serum testosterone and dihydrotestosterone remained unchanged after DHEA administration. In contrast, 17beta-estradiol and estrone significantly increased in a dose-dependent manner to concentrations still within the upper normal range for men [placebo vs. 50 mg DHEA vs. 100 mg DHEA; AUC 0-12 h for 17beta-estradiol, 510 +/- 198 vs. 635 +/- 156 vs. 700 +/- 209 pmol/L x h (P < 0.0001); AUC 0-12 h for estrone, 1443 +/- 269 vs. 2537 +/- 434 vs. 3254 +/- 671 pmol/L x h (P < 0.0001)]. In conclusion, 50 mg DHEA seems to be a suitable substitution dose in elderly men, as it leads to serum DHEAS concentrations usually measured in young healthy adults. The DHEA-induced increase in circulating estrogens may contribute to beneficial effects of DHEA in men.
Aged↗
Comment on primary localization of an ectopic ACTH-producing bronchial carcinoid tumor by indium111 pentetreotide scintigraphy.
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ACTH Syndrome, Ectopic↗
Alendronate increases bone density and bone strength at the distal radius in postmenopausal women.
In addition to the alendronate Osteoporosis Intervention Trial (FOSIT) core protocol 901-0A of 1908 enrolled patients, the use of peripheral quantitative computed tomography (pQCT) was explored for the assessment of response to therapy. Bone mineral and strength related parameters at two different sites at the distal radius were explored in a subset of the multicenter core study. One hundred and three patients were entered into the substudy and given either a daily dose of 10 mg of alendronate or placebo for 1 year. Measurements were done at months 0, 3, 6, and 12. Inclusion criteria were bone mineral density (BMD) measurements at the lumbar spine of -2 SD. The response to therapy was assessed by dual-energy X-ray absorptiometry in the lumbar spine and the hip, and by pQCT in the ultradistal and the shaft sites of the radius. In line with the FOSIT core study, alendronate increased BMD at the lumbar spine and the hip, and it decreased the serum biochemical markers of bone turnover. The substudy showed differences between the therapy and placebo group in trabecular bone density (8.4%, p = 0.095), in total density (6.8%, p = 0.009), and in the bone strength index (BSI) (15. 6 mm3, p = 0.037) at the ultradistal site due to treatment and no changes at the radius shaft. A significant correlation was observed between percentage changes from baseline in BMD of the lumbar spine, and in total density and bone strength at the ultradistal radius site in the treatment group, but not in the placebo group. Thus, the ultradistal radius site did respond to alendronate therapy. The increased bone density accompanied a significant gain in the BSI at the ultradistal site, a finding that might help explain the reduced wrist fractures in the alendronate Fracture Intervention Trial.
Aged↗