Medication use patterns among demented, cognitively impaired and cognitively intact community-dwelling elderly people

OBJECTIVE: The present study was conducted in order to describe human hypothalamo-pituitary adrenal (HPA) axis adaptation in a model of repeated physical stress (endurance training) that causes a moderate increase in cortisol levels. SUBJECTS: We performed the same stimulation tests (adrenal stimulation with ACTH or pituitary stimulation with combined CRH/LVP) in a population of 8 endurance-trained athletes in two distinct situations: resting (baseline cortisol values) and 2 h after the end of strenuous exercise (increased cortisol values) to evaluate the HPA axis sensitivity to endogenous sustained increases in cortisol concentrations. MEASUREMENTS: During these tests, saliva and plasma cortisol (Fs and Fp, respectively) were assessed and compared. RESULT: Cortisol values in both plasma and saliva at the end of 2 h of exercise were significantly higher than in rested controls: Fs 11.5 +/- 1.3 vs 6.5 +/- 0.8 nmol.l-1 and Fp 428 +/- 36 vs 279 +/- 27 nmol.l-1 (post exercise vs post rest sessions, respectively, P < 0.001 for both). After either hormone test (CRH/LVP or ACTH), cortisol levels in plasma and saliva increased similarly when rest was compared to post exercise. Saliva variations (delta %) under exogenous hormone stimulation were dramatically greater than plasma variations. For example, under ACTH stimulation, the relative increments in cortisol were on control day: delta Fs 980 +/- 139 vs delta Fp 218 +/- 43% (saliva vs plasma, respectively, P < 0.05) and on exercise day: delta Fs 605 +/- 89 vs delta Fp 102 +/- 14% (saliva vs plasma, respectively, P < 0.05). CONCLUSIONS: In endurance-trained athletes, displaying a moderate but sustained endogenous cortisol increase: (1) ACTH responses following pituitary stimulation are not blunted, (2) cortisol responses following maximal adrenal stimulation are not blunted. Our results favour the hypothesis of a decreased pituitary sensitivity to cortisol negative feedback whereas the hypothesis of a major decreased adrenal sensitivity to ACTH was discarded. The greater ability of saliva assays to detect a cortisol increase strongly supports its use in the study of HPA physiology, whether under basal or dynamic conditions.     

Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors

We studied a patient with food-induced, ACTH-independent, Cushing's syndrome and a unilateral adrenocortical adenoma. In vivo cortisol secretion was stimulated by mixed, glucidic, lipidic, or proteic meals. Plasma ACTH levels were undetectable, but iv injection of ACTH stimulated cortisol secretion. Unilateral adrenalectomy was followed by hypocortisolism with loss of steroidogenic responses to both food and ACTH. In vitro, cortisol secretion by isolated tumor cells was stimulated by the gut hormone gastric inhibitory polypeptide (GIP) and ACTH, but not by another gut hormone, glucagon-like peptide-1 (GLP-1). Both peptides stimulated the production of cAMP but not of inositol 1,4,5-trisphosphate. In quiescent cells, GIP and ACTH stimulated [3H]thymidine incorporation and p42-p44 mitogen-activated protein kinase activity. GIP receptor messenger ribonucleic acid (RNA), assessed by RT-PCR, was highly expressed in the tumor, whereas it was undetectable in the adjacent hypotrophic adrenal tissue, in two adrenal tumors responsible for food-independent Cushing's syndrome, and in two hyperplastic adrenals associated with ACTH hypersecretion. In situ hybridization demonstrated that expression of GIP receptor RNA was confined to the adrenocortical tumor cells. Low levels of ACTH receptor messenger RNA were also detectable in the tumor. We conclude that abnormal expression of the GIP receptor allows adrenocortical cells to respond to food intake with an increase in cAMP that may participate in the stimulation of both cortisol secretion and proliferation of the tumor cells.     

Food-dependent Cushing's syndrome: characterization and functional role of gastric inhibitory polypeptide receptor in the adrenals of three patients

In the present work, the presence of gastric inhibitory polypeptide (GIP) receptors and their functional role in the adrenal cells of three patients with food-dependent Cushing's syndrome were studied. RT-PCR and in situ hybridization studies demonstrated the presence of GIP receptor in the adrenals of the three patients. The presence of this receptor was also demonstrated in two human fetal adrenals, but not in two normal adult human adrenals or in the adrenals of one patient with nonfood-dependent Cushing's syndrome. Freshly isolated cells from patient adrenals responded in a dose-dependent manner to the steroidogenic action of both ACTH and GIP, whereas cells from normal adrenals responded only to ACTH. Treatment of cultured normal adrenal cells with ACTH, but not with GIP, increased the messenger ribonucleic acid (mRNA) levels of cholesterol side-chain cleavage cytochrome P-450, P450c17, and 3beta-hydroxysteroid dehydrogenase, whereas both hormones enhanced these mRNAs in patients' adrenal cells, although the effects of ACTH were greater than those of GIP. Moreover, pretreatment with ACTH enhanced the steroidogenic responsiveness of both normal and patient adrenal cells, whereas GIP caused homologous desensitization, and this was associated with a marked reduction of GIP receptor mRNA levels, as demonstrated by RT-PCR and in situ hybridization. Finally, both ACTH and GIP inhibited DNA synthesis in one patient's adrenal cells, whereas in normal adrenal cells only ACTH had this effect. In conclusion, the present data demonstrate that ectopic expression of functional GIP receptors is the main cause of food-dependent Cushing's syndrome.     

The combined corticotropin-releasing hormone/lysine vasopressin test discloses a corticotroph phenotype

The combined administration of CRH and vasopressin to man now offers a powerful means to directly assess the pituitary corticotroph reserve. A double blind, randomized, placebo-controlled, cross-over trial offered the opportunity to perform the combined CRH/lysine vasopressin (LVP) test (100 micrograms ovine CRH, followed by 1 IU LVP over 15 min) on 3 different occasions without treatment in 10 normal male subjects. We showed that peak ACTH plasma levels after stimulation had wide intersubject variation, whereas they were remarkably stable in a given individual, with a mean intraclass correlation coefficient of 0.90 (95% confidence limits, 0.74-0.96). Peak ACTH plasma levels after CRH/LVP administration were not significantly correlated with basal plasma cortisol levels (r = -0.14; P > 0.45), but were strongly and inversely correlated with peak cortisol plasma levels after Cortrosyn stimulation (0.25 mg, im; r = -0.78; P < 0.0001). These data provide the first evidence that the overall hypothalamic-pituitary-adrenocortical axis has an intrinsic activity that is constitutively fixed for a given individual. The power of the combined CRH/LVP test offers a unique means to measure a genuine corticotroph phenotype in each individual.     

Chlormadinone acetate as a possible effective agent for congenital adrenal hyperplasia to suppress elevated ACTH and antagonize masculinization

We report two cases of congenital adrenal hyperplasia (CAH) in which administration of chlormadinone acetate (CMA), a substituted progestational agent for prostatic disease, suppressed ACTH hypersecretion and lowered plasma testosterone levels. Case 1 was 83-year-old male with advanced prostatic carcinoma and CAH due to 21-hydroxylase deficiency. His plasma testosterone did not decrease in spite of a bilateral orchiectomy. Case 2 was 40-year-old female with CAH due to 21-hydroxylase deficiency suffering from virilization after the cessation of cortisol supplement therapy because of her breast carcinoma. In these two cases, oral administration of CMA at a daily dose of 75-100 mg suppressed ACTH and cortisol to subnormal levels and reduced testosterone levels. With the suppressive effect on ACTH excess and antiandrogenic action, CMA may be suitable for patients with CAH suffering from symptoms due to overproduced ACTH or adrenal androgen.     

Homicide in the United States, 1951-1990: synchronous age-specific rate changes in adult men

We report a man with pre-Cushing's syndrome due to ACTH-independent bilateral macronodular adrenocortical hyperplasia. Plasma ACTH was low and urinary 17-OHCS was not suppressed by a high dose of dexamethasone (8 mg), but plasma cortisol was responsive to exogenous ACTH. The adrenal glands were enlarged and contained multiple nodules composed of large clear cells and small compact cells. The steroid levels in the adrenal glands were lower than those in overt Cushing's syndrome due to the adrenocortical adenoma. This suggests that the tumor produces insufficient amounts of active hormones to have a clinical effect.     

The influence of dose and dose rate on the incidence of neoplastic disease in RFM mice after neutron irradiation

The effect of circadian rhythm and alterations in posture on plasma aldosterone concentration was studied in 13 patients with primary aldosteronism (six adenoma, five idiopathic hyperplasia, two carcinoma) to define the regulatory mechanism in each of these pathologic subtypes. Blood samples for aldosterone, cortisol, renin, and potassium concentrations were obtained every 4 h during prolonged recumbency (32 h) and upright posture (16 h). During recumbency, aldosterone and cortisol followed a normal circadian pattern in patients with adenoma and hyperplasia, with peak values at 0400-0800 h and the nadir at 1600-2400 h. Normalized aldosterone and cortisol values correlated significantly in both groups (adenoma r=+0.66, P less than 0.001; hyperplasia r=+0.42, P less than 0.01). With upright posture, aldosterone levels declined parallel to the normal circadian fall in cortisol in patients with adenoma (r=+0.68, P less than 0.001); whereas aldosterone levels increased in patients with hyperplasia parallel to small increments in renin (r=+0.65, P less than 0.001) and potassium (r=+0.64, P less than 0.001). During the administration of dexamethasone, aldosterone no longer correlated with cortisol in patients with adenoma but continued to correlate with renin during upright studies in patients with hyperplasia (r=+0.77, P less than 0.01). Aldosterone circadian rhythm was abnormal in patients with carcinoma and no effect of posture was noted. Unilateral adrenalectomy restored the normal postural relationship in four patients with adenoma. These studies suggest that aldosterone secretion is under continuous ACTH control regardless of posture in patients with adenoma, whereas persistent adrenal responsiveness to small increments in renin and/or potassium mediate the postural increase in plasma aldosterone in patients with hyperplasia. True adrenal autonomy occurs only in patients with adrenal carcinoma and when ACTH is suppressed in those with adenoma.     

Failure to control the airway in a patient with Hunter''s syndrome

We report a 36-year-old man with proximal dominant muscle weakness, thymic tumor, diabetes mellitus, hypokalemia, and increased levels of plasma ACTH and cortisol. The diagnosis of carcinoid tumor was made on the basis of pathological findings in the biopsied specimen of the thymic tumor. The proximal muscle weakness was considered to be due to steroid myopathy resulting from the overproduction of cortisol from the adrenal glands induced by the ectopic ACTH secreted by the thymic carcinoid tumor. Although thymoma in frequently associated with myasthenia gravis, we should also consider carcinoid tumors in patients with a thymic tumor presenting with a proximal muscle weakness.     

Adrenocortical function in patients with active pulmonary tuberculosis

STUDY OBJECTIVE: To assess adrenal function in patients with acute pleuropulmonary tuberculosis (APT) and compare it with that function in patients with community-acquired pneumonia (CAP). PATIENTS: Over a period of 6 months all consecutive patients 18 years of age or older with newly diagnosed APT and CAP were entered into the study. MEASUREMENTS: The whole patients had the following investigations: 1) Serum Na+, K+ and glucose concentrations 2) Systolic and diastolic blood pressures. 3) An ultrasonographic study of the adrenal glands. 4) A standard ACTH stimulation test. RESULTS: There was no significative difference in the serum cortisol level between the two groups at any time of the ACTH stimulation test (basal, 30 and 60 minutes), neither when taking into account the increments between basal and 60 minutes after stimulation serum cortisol levels. All patients in both groups had normal ACTH stimulation test with a peak stimulated cortisol level at 60 minutes > 504 nmol/L. CONCLUSIONS: We did not find evidence of adrenal cortical dysfunction in patients with acute pleuropulmonary tuberculosis or with community-acquired pneumonia in our hospital.     

Time course of the corticosteroid-dopaminergic interaction during metyrapone and dexamethasone administration

Recent studies performed with depressed patients and normal subjects suggest that corticosteroids may alter dopaminergic activity. We measured the time course of the interaction between corticosteroid and plasma homovanillic acid (HVA) levels in 10 young healthy subjects after the administration of 2 mg of dexamethasone in session 1 and after the administration of 4.5 g of metyrapone in session 2. Plasma levels of adrenocorticotropic hormone (ACTH), 11-desoxycortisol, cortisol, HVA, and prolactin (PRL) were measured at 08:00, 09:00, 12:00, 15:00, and 16:00 h on a baseline day and during both drug-administration sessions. Dexamethasone administration resulted in a significant decrease in plasma levels of ACTH, 11-desoxycortisol, and cortisol at all time points and to a significant decrease in PRL secretion in the early morning. Plasma HVA levels were unchanged after dexamethasone administration. Metyrapone administration resulted in a significant decrease in cortisol levels and a significant increase in ACTH and 11-desoxycortisol levels. Plasma HVA levels were significantly increased in the early morning, while PRL levels were unaltered. These results are discussed in relation to the neurochemical and behavioral changes associated with steroid administration and interpreted with regard to a possible association between HVA and PRL in the effects of corticosteroids on dopaminergic activity.     

Functioning of the porcine pituitary-adrenocortical axis during neonatal development

A study was conducted with neonatal boars to measure age-related changes in functioning of the pituitary-adrenocortical axis. Pigs were randomly assigned to control (n = 7-10/age) or treated (1-min restraint, n = 9-11/age) groups to be sampled at either 12, 19, or 26 days of age. Blood samples were taken via catheter 10 min before and 3, 10, and 20 min after restraint or at similar time intervals in controls. One day later, pigs were killed and adrenal glands obtained for ACTH receptor measurements. Basal plasma ACTH concentrations were greatest (p = 0.035) on day 12 when compared with later ages, but basal plasma cortisol concentrations were comparable at the three ages. Compared with controls, restraint elevated incremental plasma ACTH and cortisol responses at each age (p < 0.004). On day 12, maximal plasma ACTH (p = 0.0006) and incremental cortisol (p < 0.006) responses to restraint were greater than at later ages. Binding to adrenal ACTH receptors was greatest (p < 0.05) at day 13, which may help explain the apparently increased in vivo response of the adrenal gland to ACTH at this time. Restrained pigs had increased growth rates with increasing age (p = 0.016) whereas growth rates for control pigs did not differ with age. At day 27, 24 h after the 1-min restraint, body weights of restrained pigs exceeded those of control pigs (p = 0.045). At day 20, adrenal DNA and protein in pigs restrained 24 h previously were greater than in control pigs (p < 0.05). These data suggest age-related changes in functioning of the pituitary-adrenal axis in neonatal boars, and an absence of period during neonatal life when the porcine pituitary adrenocortical axis cannot respond to a stressor. The data also indicate both rapid and long-term responses of the adrenal to a very modest stressor and suggest an extreme sensitivity of neonatal pigs to environmental perturbations.     

Bilateral massive macronodular adrenal gland hyperplasia. A rare cause of Cushing's syndrome

A 46-year-old man with known arterial hypertension for 10 years had, over the last two years, developed increasing obesity, particularly of the trunk, with other symptoms typical of Cushing's syndrome. Hormone analysis demonstrated hypercortisolism and decreased plasma ACTH concentration. The dexamethasone inhibition test failed to show any significant suppression of serum cortisol. Plasma ACTH was not increased in the corticotrophin-releasing hormone and the metyrapone tests. In the short ACTH test there was an excessive cortisol increase. Abdominal computed tomography revealed both adrenals to be enlarged (6 x 4 cm) and coarsely nodular. Adrenolytic treatment with ketoconazole (400 mg daily) caused symptoms of adrenal insufficiency, but a reduced dosage of 200 mg daily lowered the cortisol level to between 5 and 11 micrograms/dl and normalized the blood pressure and clinical signs of Cushing's syndrome disappeared. Subsequent bilateral adrenalectomy confirmed the diagnosis of massive macronodular adrenal hyperplasia. Substitution treatment with twice daily 25 mg cortisone acetate and 0.05 mg fludrocortisone was started postoperatively.     

Effect of losartan, an angiotensin II receptor antagonist, on response of cortisol and aldosterone to adrenocorticotrophic hormone

Many imidazole derivatives are shown to inhibit adrenal steroid biosynthesis. The present study was undertaken to examine an effect of another imidazole derivative, losartan (an angiotensin II receptor antagonist), on responses of cortisol and aldosterone to adrenocorticotrophic hormone (ACTH). Nine patients with essential hypertension were given placebo orally for 7 days and 50 mg of losartan for the next 9 days. Response of serum cortisol and plasma aldosterone to intramuscular ACTH injection were determined before and at the end of the treatment with losartan. Serum cortisol and plasma aldosterone significantly increased after ACTH injection in both periods of treatment (placebo and losartan). The increments in these parameters during treatment with losartan were not significantly different from those during treatment with placebo. These results suggest that the inhibitory effect of losartan on adrenal steroid biosynthesis is negligible.     

Time course of changes in free thyroid indices, rT3, TSH, cortisol and ACTH following exposure to sulfur mustard

In order to evaluate the time course of changes in serum concentration of thyroid hormones, cortisol and ACTH in patients exposed to chemical weapons containing sulfur mustard, we measured serum concentrations of hormones on the first, third and fifth week following injury in 13 soldiers and compared them to the results obtained from 34 control men. Free T4 and T3 indices were decreased and rT3, cortisol and ACTH were increased in the first week following exposure. There was a subnormal TSH response to TRH in 2 of 3 men tested. Except for an increase in FT4I and a decrease in TSH by the third week, and a steady decline in serum cortisol, serum hormone concentrations were unchanged until the fifth week after injury. The decline in serum cortisol occurred despite a constant increase in serum ACTH. By the fifth week only 1 of 13 men had serum cortisol levels > 10 micrograms/dl. We conclude that exposure to chemical weapons containing sulfur mustard results in alterations in serum concentrations of thyroid and adrenal hormones and ACTH, resembling changes seen in burn trauma. Some evidence of direct effects of mustard on endocrine glands exist.     

Hypofunction of the stress axis in Sj?gren's syndrome

OBJECTIVE: To examine the functional integrity of the hypothalamic-pituitary-adrenal (HPA) and thyroid axes in Sj?gren's syndrome (SS) via the assessment of basal and stimulated adrenocorticotropin (ACTH), cortisol, thyroid stimulating hormone (TSH), and prolactin levels. METHODS: Pituitary function of the HPA axis was assessed by determining the basal plasma levels of ACTH in the late afternoon, as well as the ACTH released to ovine corticotropin releasing hormone (oCRH) stimulation; adrenal function was assessed by measuring plasma cortisol levels in the late afternoon at baseline and after release of the endogenous ACTH during oCRH stimulation. Basal and thyrotropin releasing hormone (TRH) stimulated levels of TSH and prolactin were also assessed. Healthy volunteers were used as controls. RESULTS: Patients with SS, compared to controls, were characterized by significantly lower ACTH levels (pg/ml), (5.1 +/- 0.5 vs 11.4 +/- 1.5, respectively; p < 0.05) and cortisol levels (microg/ml), (2.4 +/- 0.6 vs 5.9 +/- 1.2, respectively; p < 0.05). Furthermore, a blunted pituitary and adrenal response to oCRH compared to controls was observed: peak plasma ACTH and cortisol levels for patients with SS were 46.2 +/- 5.4 pg/ml and 15.7 +/- 1.6 microg/ml, respectively, and for controls 61.5 +/- 3.8 and 19.6 +/- 0.7, respectively (p < 0.05). Basal TSH levels were significantly elevated in patients (1.3 +/- 0.3 microIU/ml vs 0.9 +/- 0.05 microIU/ml; p < 0.05). CONCLUSION: The above findings indicate hypoactivity of the HPA axis in patients with SS. Further studies are needed to definitively identify the locus of the defects and assess the significance of the pattern of the perturbations to the pathogenesis and expression of SS.     

Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis

Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin (IL)-6, and this cytokine is also a potent stimulus of the hypothalamic-pituitary-adrenal axis. To evaluate the 24-h circadian secretory dynamics of ACTH, cortisol, and IL-6 and their interactions in patients with early untreated RA, we recruited and studied five newly diagnosed, untreated RA patients early in the course of their disease and five age-, gender-, and race-matched control subjects. We collected serial blood samples over 24 h and measured plasma ACTH and cortisol every 30 min and IL-6 every hour. The 24-h collection was followed by administration of ovine CRH (oCRH) and post-oCRH serial blood samples over 2 h. We analyzed the 24-h overall levels of these hormones and their circadian variations and performed time-lagged cross-correlation analyses among them. The untreated RA patients had 24 h time-integrated plasma ACTH, plasma cortisol levels, and urinary free cortisol excretion that were not significantly different from control subjects, in spite of their disease activity. However, an earlier morning surge of plasma ACTH and cortisol in the patients was suggested. Plasma ACTH and cortisol responses to oCRH were similar in RA patients and controls. IL-6 levels were significantly increased in the RA patients compared with control subjects during the early morning hours (P < 0.05). There was pronounced circadian variation of plasma Il-6 levels. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with elevated levels of IL-6 before the elevations of ACTH and cortisol by 1 and 2 h, respectively. In the same patients, we detected a negative effect of cortisol upon IL-6 exerted with a delay of 5 h. The data presented here suggest that although endogenous IL-6 may stimulate secretion of ACTH and cortisol, overall activity of the hypothalamic-pituitary-adrenal axis remains normal and apparently is insufficient to inhibit ongoing inflammation in early untreated RA patients.     

Overnight dexamethasone pre-treatment improves the performance of the lysine-vasopressin test in the diagnosis of Cushing's syndrome

OBJECTIVE: There is no endocrine test which is completely reliable for the confirmation of Cushing's syndrome and in separation of the various aetiologies. We have tested the hypothesis that overnight dexamethasone pre-treatment should result in a better performance of the lysine-vasopressin (LVP) test in the diagnosis of Cushing's syndrome. STUDY DESIGN AND PATIENTS: We studied 61 subjects, including 25 pituitary-dependent and 9 pituitary independent Cushing's (7 adrenal tumour and 2 ectopic ACTH syndromes), 18 euadrenal controls, 4 depressed subjects, and 5 cushingoid patients. The subjects received 1 mg of dexamethasone orally at 2300 h and the following morning they were given 10 IU of lysine-vasopressin im. MEASUREMENTS: Plasma cortisol (RIA) was measured at times -15, 0, 15, 30, 45, 60, 75, 90 and 120 minutes. RESULTS: The dexamethasone-modified LVP (Dx/LVP) test resulted in four patterns of cortisol response. The dexa sensitive pattern (positive suppression and negative response to LVP) was found in euadrenal subjects; the dexa insensitive pattern (negative suppression and positive response to LVP) was seen in Cushing's disease; a non-responsive pattern (negative suppression and negative response to LVP) was observed only in pituitary independent Cushing's; and an indeterminate pattern (positive suppression and positive response to LVP) was equivocal, being observed in 2 control subjects, 1 patient with Cushing's disease and 1 depressed patient. In separating control subjects from Cushing's syndromes the Dx/LVP test had 88.9% sensitivity, 100% specificity and 96.2% diagnostic accuracy; when the test was used to segregate Cushing's disease from control subjects we found 96.0% sensitivity, 100% specificity and 97.7% diagnostic accuracy. The performance variables for the Dx/LVP test in separating pituitary dependent from pituitary independent Cushing's were uniformly 100%. Depressed and cushingoid subjects did not differ from control subjects in their cortisol patterns during the test. Successful removal of the pituitary microadenoma in Cushing's disease was invariably followed by a reversal of the abnormal cortisol pattern (dexa insensitive) during the test to a dexa sensitive pattern indistinguishable from that of control subjects. CONCLUSION: These results confirm our hypothesis and suggest that an improved performance of any corticotroph stimulus (oCRH, LVP, AVP or desmopressin) in the diagnosis of Cushing's syndrome should result from pre-treatment with dexamethasone.     

Immunolocalisation of P450(C17) in the fetal sheep adrenal gland during gestation and in response to ACTH and glucocorticoid administration

In sheep, increased output of cortisol from the fetal adrenal gland is critical to organ maturation and parturition. Cortisol synthesis is determined in part by the activity of P450(C17) enzyme. We have used immunohistochemistry and Western immunoblotting to examine the distribution of P450(C17) in the ovine fetal adrenal during gestation, and after ACTH or dexamethasone administration to fetuses between Days 125 and 130. The patterns were compared with changes in 3beta-hydroxysteroid dehydrogenase (3beta-HSD) localisation and levels. Adrenal tissue was obtained from four fetuses at each of Days 63-65, 100, 125-130 and term (>140 days). Further animals were chronically catheterised and infused with ACTH, dexamethasone or saline for 96 h beginning on Day 125. Immunohistochemistry for P450(C17), 3beta-HSD, and phenylethanolamine-N-methyl transferase (PNMT) was conducted using standard techniques. At Day 63-65 of pregnancy immunoreactive (ir-)P450(C17) was present in cords of cells throughout the adrenal gland. Ir-P450(C17) was reduced or was undetectable at Day 100, but had increased by Day 125-130, and was present throughout the zona fasciculata of the adrenal cortex of term animals. An increase in P450(C17) protein was also seen between Day 100 and 125 by Western blotting, and after ACTH treatment. Dexamethasone administration led to a marked reduction in ir-P450(C17) levels. In contrast, ir-3beta-HSD was present in the fetal adrenal cortex between Day 100 and term, and was less affected by ACTH or dexamethasone treatment. We conclude that P450(C17) in the fetal sheep adrenal is responsive to regulation by ACTH, and that changes in its levels correlate with previously reported alterations in patterns of cortisol output by the fetal adrenal gland.     

Chemoreflex contribution to adrenocortical function during acute hypoxemia in the llama fetus at 0.6 to 0.7 of gestation

This study tested the hypothesis that the fetal llama, a species adapted to the chronic hypoxia of life at high altitude, demonstrates a potent carotid chemoreflex influence on adrenocortical responses during acute hypoxemia. Plasma ACTH and cortisol concentrations, and mesencephalic and adrenal blood flows were measured during a 1-h period of acute hypoxemia in six intact and four carotid sinus-denervated llama fetuses at 0.6-0.7 of gestation. Fetal PaO2 was reduced from approximately 23 to about 14 mm Hg in both intact and carotid-denervated groups during acute hypoxemia. During hypoxemia, fetal plasma ACTH, adrenal blood flow, and, therefore, delivery of ACTH to the adrenals increased to similar extents in both intact and carotid-denervated fetal llamas. Despite this, the increase in plasma cortisol in hypoxemia in intact fetuses was absent in carotid-denervated fetuses. In addition, the increase in delivery of cortisol to the mesencephalon calculated in intact fetuses during hypoxemia did not occur in the carotid-denervated group. These data suggest that the integrity of the carotid chemoreceptors is indispensable to cortisol release during acute hypoxemia in the llama fetus, even at 0.6-0.7 of gestation.