The adrenal cortex and the kidney.
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1. Human urine, its extracts, extracts of urine pretreated with enzyme preparations containing beta-glucuronidase and steroid sulphatase or beta-glucuronidase alone, and products derived from the specific solvolysis of urinary steroid sulphates, were submitted to the following sequence of operations: reduction with borohydride; oxidation with a glycol-cleaving agent (bismuthate or periodate); separation of the products into ketones and others; oxidation of each fraction with tert.-butyl chromate, resolution of the end products by means of paper chromatography or gas-liquid chromatography or both. 2. Qualitative experiments indicated the kind of information the method and some of its modifications can provide. Quantitative experiments were restricted to the direct treatment of urine by the basic procedure outlined. It was partly shown and partly argued that the quantitative results were probably as informative about the composition of the major neutral urinary steroids (and certainly about their presumptive secretory precursors) as those obtained by a number of established analytical procedures. 3. A possible extension of the scope of the reported method was indicated. 4. A simple technique was introduced for the quantitative deposition of a solid sample on to a gas-liquid-chromatographic column.
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1. The diurnal patterns of plasma aldosterone, plasma renin activity (PRA), cortisol and adrenocorticotrophic hormone (ACTH) in the supine and in the upright position have been studied in fourteen patients with primary aldosteronism, five with adenoma and nine with bilateral hyperplasia. Blood samples were drawn at intervals from 6 h to 30 min. 2. Supine patients with an adenoma showed marked diurnal variations of aldosterone, with maximal values at 08.00 hours and minimal values of 18.00 hours and secretory spurts beginning after 02.00 hours. Plasma cortisol paralleled aldosterone, and ACTH seemed to anticipate aldosterone and cortisol variations; PRA remained unchanged. In patients with hyperplasia, aldosterone was significantly lower than in the adenoma group at 08.00 hours, and its decline during the day was less marked; fluctuations rather than secretory episodes were seen. 3. After patients assumed the upright posture, aldosterone remained unchanged or decreased in patients with adenoma, whereas it significantly increased in hyperplasia; PRA remained low, although a slight increment was seen in the latter group. The different response of aldosterone in the two groups was not modified by the administration of propranolol, apparently excluding a renin-dependent mechanism. On the other hand, dexamethasone seemed to affect the response of aldosterone to the upright posture in both groups; in adenoma there was a slight but significant increase, and in hyperplasia the usual rise was partially suppressed. 4. It is concluded that ACTH has a predominant role in regulating aldosterone secretion in primary aldosteronism due to adenoma, whereas its action in bilateral hyperplasia is only permissive.
OBJECTIVE: Girls with precocious pubarche (PP) are at increased risk for ovarian dysfunction, hyperinsulinism and dyslipidaemia in adolescence, in particular when PP is preceded by reduced fetal growth. However, it is not known whether PP girls still have adrenal hyperandrogenism after puberty and if so, which fraction of PP girls develops so-called functional adrenal hyperandrogenism (FAH), an entity characterized by ACTH-dependent 17-ketosteroid excess. PATIENTS AND DESIGN: Data were longitudinally collected from 47 girls with PP: at birth (weight for gestational age), at diagnosis of PP (age 6.7+/- 1.1 years) and in adolescence (age 15.0+/-1.9 years). MEASUREMENTS: Serum dehydroepiandrosterone sulphate (DHEAS) and androstenedione were measured at PP diagnosis, as well as the 17-hydroxyprogesterone (17-OHP) response to ACTH; postpubertal evaluation included assessment of adrenal and ovarian function, and of insulin responses to a glucose load. PP girls were considered to have FAH in adolescence if both DHEA and androstenedione responses to ACTH were excessive (> 1500 ng/dl and > 350 ng/dl, respectively). RESULTS: At diagnosis of PP, girls had high DHEAS and androstenedione levels, as well as high 17-OHP responses to ACTH. In adolescence, PP girls had a normal BMI, presented with mild hirsutism and had high baseline and post-ACTH concentrations of most adrenal androgens, low SHBG levels and tended to have hyperinsulinemia and to present biological signs of ovarian hyperandrogenism. More than a third of the PP cohort developed FAH in adolescence. Neither baseline DHEAS, androstenedione, nor post-ACTH 17-OHP values at diagnosis of PP predicted the development of FAH in adolescence. In PP girls, only a low weight at birth was found to be significantly associated with subsequent FAH. CONCLUSIONS: These longitudinal findings in girls with PP point to the possibility of an endocrine sequence of prenatal onset: low weight at birth, PP in childhood and adrenal hyperandrogenism in adolescence. The pathophysiological mechanisms underpinning this newly recognized sequence remain to be identified.
OBJECTIVE: Subclinical hypercortisolism (SH) is detected increasingly in a substantial proportion of patients with incidentally discovered adrenal adenomas. The clinical implications of SH are currently unclear. Osteoporosis is a well-known complication of glucocorticoid excess. So far, the impact of SH on bone mineral density (BMD) has been studied in a limited number of reports with discordant results. In the present study we evaluated the BMD in a large cohort of post-menopausal women with adrenal incidentalomas. : patients and measurements Forty-two post-menopausal women with incidentally discovered adrenal masses and radiological features highly suggestive of benign adrenal adenomas were investigated. All patients underwent a standard low-dose dexamethasone suppression test (LDDST; 0.5 mg 6-hourly for 2 days). The diagnosis of subclinical hypercortisolism (SH) was based on post-LDDST cortisol concentrations of > 70 nmol/l. According to this criterion patients were subdivided into two groups: with (n = 18; group A) or without (n = 24; group B) SH. There was no significant difference in age, years since menopause and body mass index between these groups. BMD was measured at L2-L4 vertebrae and three sites of the proximal femur by the dual energy X-ray absorptiometry (DEXA) method. RESULTS: Post-menopausal women with SH (group A) exhibited slightly but significantly lower absolute and age-adjusted BMD values compared to group B patients in the femoral neck (BMD g/cm2: 0.72 +/- 0.08 vs. 0.79 +/- 0.09; Z-score: -0.20 +/- 0.82 vs. +0.43 +/- 0.94, P < 0.05) and trochanter (BMD g/cm2: 0.60 +/- 0.09 vs. 0.69 +/- 0.10; Z-score: -0.32 +/- 1.0 vs. +0.30 +/- 1.05, P < 0.01). BMD measurements of the Ward's triangle were also lower in group A patients but the difference did not reach statistical significance (BMD g/cm2: 0.60 +/- 0.10 vs. 0.68 +/- 0.13, P = 0.06). There was no difference in the lumbar vertebrae between the two groups (BMD g/cm2: 0.888 +/- 0.13 vs. 0.90 +/- 0.16, P = 0.78; z-score: +0.50 +/- 1.16 vs. +0.11 +/- 1.5, P = 0.36). The number of patients in the osteoporotic range was minimal with no significant difference between the two groups. However, the frequency of osteopenia in group A was significantly greater than in group B patients in the trochanter and Ward's triangle areas. Serum osteocalcin (BGP) levels were significantly lower in group A compared to group B patients (18.6 +/- 8.6 vs. 26.2 +/- 8.1 ng/ml, P < 0.01); no difference existed regarding parathyroid hormone (PTH) concentrations (43 +/- 15.6 vs. 41.2 +/- 14.8 pg/ml, P = 0.72). CONCLUSIONS: In this series, post-menopausal women with subclinical hypercortisolism had lower absolute and age-adjusted BMD values and a higher rate of osteopaenia in the trabecular loaded and mixed cortical-trabecular bone of proximal femur. These data demonstrate that the subtle hypercortisolism of patients with adrenal incidentalomas may have an adverse effect on the bone mass of these patients.
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Corneal degeneration may occur with a deposition of lipids or calcium, or both. Calcareous and lipid degeneration may be either primary or secondary, associated with systemic diseases such as primary hyperlipidemia, hyperlipidemia associated with hyperadrenocorticism, and hypothyroidism. The authors report a case of bilateral corneal lipid and calcium degeneration in a 7-year-old female Poodle with hyperadrenocorticism. The condition worsened with Lysodren therapy but responded to surgical excision.
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OBJECTIVE: Evaluation of microsurgical transsphenoidal hypophysectomy for the treatment of pituitary-dependent hyperadrenocorticism (PDH) in cats. STUDY DESIGN: Prospective clinical study. ANIMALS OR SAMPLE POPULATION: Seven cats with PDH. METHODS: Urinary cortisol/creatinine ratios, pituitary-adrenocortical function tests, and computed tomography (CT) were performed on 7 cats that presented with a provisional diagnosis of hyperadrenocorticism. All cats underwent microsurgical transsphenoidal hypophysectomy with histologic examination of the excised specimen. Follow-up consisted of clinical evaluation, repeat adrenocortical function testing, and CT. RESULTS: Four cats had concurrent diabetes mellitus. In all cats, the urinary cortisol/creatinine (C/C) ratios were elevated. The dexamethasone screening test showed that 2 cats did not meet the criterion for hyperadrenocorticism. The response of the cats' plasma concentrations of cortisol and adrenocorticotrophic hormone to a high dose of dexamethasone varied from very sensitive to completely dexamethasone resistant. Basal plasma alpha-melanocyte-stimulating hormone concentrations were elevated in 2 cats with a pars intermedia adenoma and in 3 cats with an adenoma that originated from the anterior lobe. Preoperative CT enabled accurate assessment of pituitary size (5 nonenlarged pituitaries with a height <4 mm and 2 enlarged pituitaries with a height >5 mm) and localization relative to intraoperative anatomic landmarks. Two cats died within 4 weeks after surgery of a nonrelated disease. In the remaining 5 cats, the hyperadrenocorticism went into both clinical and biochemical remission. Hyperadrenocorticism recurred in 1 cat after 19 months, but no other therapy was given and the cat died at home 28 months after surgery. CT evaluation of this cat had identified pituitary remnants 6 weeks after surgery. The main postoperative complications were oronasal fistula (1 cat), complete dehiscence of the soft palate (1 cat), and transient reduction of tear production (1 cat). One cat died at 6 months (undefined anemia), and another cat at 8 months (recurrent nose and middle ear infection secondary to soft palate dehiscence) after surgery. In the surviving 2 cats, the remission periods at the time of writing were 46 and 15 months. In the 2 cats with sufficient follow-up time, the concurrent diabetes mellitus disappeared, ie, insulin treatment could be discontinued at 4 weeks and 5 months after hypophysectomy. In all 7 cats, the histologic diagnosis was pituitary adenoma. CONCLUSIONS: Microsurgical transsphenoidal hypophysectomy is an effective method of treatment for feline PDH in specialized veterinary institutions having access to advanced pituitary imaging techniques. Concurrent diabetes mellitus is usually reversible after hypophysectomy. Thorough presurgical screening for coexisting diseases is imperative. CLINICAL RELEVANCE: PDH in cats can be effectively treated by hypophysectomy. The neurosurgeon performing hypophysectomy must master a learning curve and must be familiar with the most frequent complications of the operation to treat them immediately and effectively. Urinary C/C ratios are sensitive indicators for the assessment of remission and recurrence of hyperadrenocorticism.
The aim of this study was to investigate whether hypercortisolism in dogs with congenital portosystemic shunts disappeared after surgical closure of the shunts concomitantly with recovery from hepatic encephalopathy. We examined 22 dogs before and four weeks after partial surgical closure of a single, large congenital portosystemic shunt (PSS). Parameters measured to characterise the basal activity of the pituitary-adrenal axis were the cortisol:creatinine (c/c) ratio in home-sampled urine and total and free cortisol in plasma. The binding characteristics of cortisol binding globulin (CBG) in pooled pre- and postoperative plasma were also determined. Ammonia and bile acid concentrations were measured in plasma to characterise the liver perfusion and function. Clinical symptoms relevant to liver function, cortisol excess, and hepatic encephalopathy were recorded semiquantitatively using a standardized questionnaire. The dogs had hypercortisolism before surgery, which had normalized four weeks later. The pre- and postoperative concentrations (means +/- SEM) were, respectively, 238+/-45 nM and 126+/-19 nM for total cortisol, 15.5+/-2.6 nM and 8.4+/-1.3 nM for free cortisol in plasma, 13.4+/-4.3 x 10(-6) and 3.9+/-0.4 x 10(-6) for c/c in urine. The pre- and postoperative Bmax values of CBG were 41 and 79, and Kd values were 3.8 and 5.5. The concentrations of ammonia were 217+/-23 microM and 32+/-3.1 microM, and of bile acids 1 10+/-33 and 11.1+/-2.0 microM, respectively. We conclude that there is a close relation between portosystemic encephalopathy and hypercortisolism in dogs with PSS and that both deviations resolve completely within four weeks of closure of the shunt.
The effects of adrenalectomy (Adx) and hypercorticism on the ACTH content in the anterior (AH) and the neurointermediate lobe (NIL) of the pituitary in Long Evans (+/+), heterozygous (+/DI) and homozygous (DI/DI) Brattleboro rats were determined using dispersed adrenal cells bioassay. Adx decreased the NIL-ACTH content in +/DI and DI/DI rats and left it unchanged in the +/+ rats. Adx increased the AH-ACTH content in the three groups. Hypercorticism had a delayed decreasing effect both in the AH and in the NIL in all rats, with one exception for the NIL in DI/DI rats. Conversely to what appeared in Wistar rats, in Long Evans and Brattleboro rats the corticosterone administered in drinking water was unable to reduce the increase in AH-ACTH activity. These data suggest that Brattleboro, and, to a lesser extent, Long Evans rats from which the former are derived present some particularities in the regulation of their corticotropic function at the AH and the NIL level. We also observed that NaCl (0.9%) added to drinking water and hypercorticism are two factors able to increase diabetes insipidus in homozygous rats without modifying the water intake in Long Evans and heterozygous rats.
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Radio-immunological estimation of free cortisol in urine in a group of normal persons showed a median daily excretion of 42,5 +/- 22,8 mug (n = 31) using radio-loss-labelling, extraction, and thin layer chromatography. After simple extraction the median value was 54.1 +/- 15.3 mug/d (n = 10). Radioimmunological estimation in simple urine extract seems to be sufficient for routine clinical purposes. The estimation of free cortisol in urine permits a better differentiation between normal adrenal function and adrenal hyperactivity than the determination of 17-hydroxycorticosteroids (17-OHCS). This is shown by comparison of 1) the frequency distribution of the basal values of 17-OHCS and free cortisol in normal persons and in Cushing's disease, 2) the suppression effect of dexamethasone on 17-OHCS and free cortisol in Cushing patients, and 3) the stimulatory effect of ACTH on 17-OHCS and free cortisol in normal persons.
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