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PubMed1995

Adrenal changes in murine pulmonary tuberculosis; a clue to pathogenesis?

When mice were infected with virulent Mycobacterium tuberculosis H37Rv by the intra-tracheal route, there was an early phase of adrenal hyperplasia, histologically resembling the adrenocorticotropic (ACTH)-driven changes seen in Cushing's disease. This was followed at 3 weeks by progressive atrophy until the weight of the adrenals was approximately 50% of that seen in control uninfected mice, in spite of the fact that the adrenals were not infected. All layers of the adrenal cortex were affected, but the medulla was normal. Electron microscope studies revealed apoptosis. The switch from adrenal hyperplasia to adrenal atrophy corresponded to onset of an IgG1 response recognising a wide range of mycobacterial components in Western blots. Delayed type hypersensitivity (DTH) responses were seen throughout, but differed in their sensitivity to TNF alpha. Thus if TNF alpha was injected at 24 h into DTH sites elicited during the phase of adrenal hyperplasia, there was no increment in swelling at 48 h. However similar injections of TNF alpha resulted in a doubling of the swelling in DTH sites elicited during the phase of adrenal atrophy. This may be relevant to the pathogenesis of cytokine-mediated tissue damage in the human disease. If 2 months before mice received the intratracheal infection, they were pre-immunised with 1 x 1097) autoclaved Mycobacterium vaccae, a stimulus previously shown to induce a Th1 pattern of response, the early increase in adrenal weight was attenuated and delayed, and the subsequent atrophy did not occur. In sharp contrast, pre-immunisation with 1 x 10(9) autoclaved M. vaccae, known to prime a mixed pattern of cytokine release (IFN gamma and IL-4), resulted in adrenal atrophy that began within 4 days of infection, and was complete by day 14. These results suggested that the pattern of cytokine release provoked by the infection, modulated the adrenal changes, perhaps in synergy with products derived from the organisms themselves. Since we have already shown that profound adrenal changes also occur in human tuberculosis, we now propose that a change somewhere in the cytokine-hypothalamo-pituitary-adrenal axis may underlie the T cell dysfunction and immunologically-mediated tissue damage in this disease.

Adrenal Glands↗
PubMed2000

Possible function of IL-6 and TNF as intraadrenal factors in the regulation of adrenal steroid secretion.

Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) and their mRNAs are present in the human, rat, and bovine adrenal cortex. The release of these cytokines from adrenal cells is regulated by factors that alter adrenal function (e.g., ACTH, angiotensin II, interleukin-1). IL-6 and TNF type 1 receptors are also present on adrenocortical cells. Exposure to IL-6 increases cortisol or corticosterone release from human, bovine, and rat adrenal cells. IL-6 increases basal and ACTH-stimulated aldosterone release, but inhibits angiotensin II-stimulated aldosterone secretion from bovine adrenal cells. IL-6 increases dehydroepiandrosterone (DHEA) release from human cells, but decreases DHEA secretion from bovine cells. TNF alpha inhibits corticosterone release from normal rat adrenal cells or fragments, but increases corticosterone release from cholestatic rat adrenal slices. TNF alpha decreases cortisol release from bovine and fetal human adrenal cells, but increases cortisol release from adult human adrenal cells. TNF alpha inhibits aldosterone secretion from rat and bovine adrenocortical cells. TNF alpha does not affect DHEA secretion from fetal human adrenocortical cells, but inhibits basal and ACTH-stimulated DHEA release from bovine adrenal cell. Because IL-6 and TNF alpha are produced in the adrenal gland and modify adrenal steroid secretion, these cytokines may function as intraadrenal factors in the regulation of adrenal steroid secretion.

Adrenal Cortex↗
PubMed1986

Peripheral venous catecholamines versus adrenal secretory rates after brain stem stimulation in cats.

The relationship between adrenal catecholamine secretion and peripheral venous catecholamine concentration was assessed in samples collected before and after brief (15-s) periods of brain stem electrical stimulation in cats anesthetized with alpha-chloralose-urethan. Adrenal blood flow from the left lumboadrenal vein averaged 0.75 +/- 0.05 ml/min (means +/- SE, n = 56). Peripheral norepinephrine (NE) concentration (1.19 +/- 0.07 ng/ml) was not well correlated with adrenal NE secretion (38.18 +/- 3.99 ng/min) before stimulation (r = 0.334, P less than 0.025). Although brain stem sites that evoked large increases in adrenal NE secretion often caused an increase in peripheral NE, sites that evoked significant decreases in adrenal NE secretion were not accompanied by decreases in peripheral NE. Peripheral epinephrine (E) concentration (0.11 +/- 0.01 ng/ml) was well correlated with adrenal E secretion (23.72 +/- 2.33 ng/min) before stimulation (r = 0.468, P less than 0.001). Brain stem stimulation-evoked changes in adrenal E secretion were generally reflected in changes of peripheral E concentration, although many exceptions were seen. Peripheral dopamine (DA) concentration (0.23 +/- 0.02 ng/ml) was well correlated with adrenal DA secretion (0.94 +/- 0.11 ng/min) before stimulation (r = 0.505, P less than 0.001). However, stimulus-evoked changes in adrenal DA secretion were not reflected in changes of peripheral DA concentration. The data indicate that, whereas brief periods of brain stem stimulation evoke a wide range of adrenal secretory responses, peripheral catecholamine responses best reflected adrenal secretion only when large increases in adrenal secretion were evoked and were poor indicators of decreased adrenal catecholamine secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1997

Developmental and functional biology of the primate fetal adrenal cortex.

The unique characteristics of the primate (particularly human) fetal adrenal were first realized in the early 1900s when its morphology was examined in detail and compared with that of other species. The unusual architecture of the human fetal adrenal cortex, with its unique and disproportionately enlarged fetal zone, its compact definitive zone, and its dramatic remodeling soon after birth captured the interest of developmental anatomists. Many detailed anatomical studies describing the morphology of the developing human fetal adrenal were reported between 1920 and 1960, and these morphological descriptions have not changed significantly. More recently, it has become clear that fetal adrenal cortical growth involves cellular hypertrophy, hyperplasia, apoptosis, and migration and is best described by the migration theory, i.e. cells proliferate in the periphery, migrate centripetally, differentiate during their migration to form the functional cortical zones, and then likely undergo apoptosis in the center of the cortex. Consistent with this model, cells of intermediate phenotype, arranged in columnar cords typical of migration, have been identified between the definitive and fetal zones. This cortical area has been referred to as the transitional zone and, based on the expression of steroidogenic enzymes, we consider it to be a functionally distinct cortical zone. Elegant experiments during the 1950s and 1960s demonstrated the central role of the primate fetal adrenal cortex in establishing the estrogenic milieu of pregnancy. Those findings were among the first indications of the function and physiological role of the human fetal adrenal cortex and led Diczfalusy and co-workers to propose the concept of the feto-placental unit, in which DHEA-S produced by the fetal adrenal cortex is used by the placenta for estrogen synthesis. Tissue and cell culture techniques, together with improved steroid assays, revealed that the fetal zone is the primary source of DHEA-S, and that its steroidogenic activity is regulated by ACTH. In recent years, function of the human and rhesus monkey fetal adrenal cortical zones has been reexamined by assessing the localization and ontogeny of steroidogenic enzyme expression. The primate fetal adrenal cortex is composed of three functionally distinct zones: 1) the fetal zone, which throughout gestation does not express 3 beta HSD but does express P450scc and P450c17 required for DHEA-S synthesis; 2) the transitional zone, which early in gestation is functionally identical to the fetal zone but late in gestation (after 25-30 weeks) expresses 3 beta HSD, P450scc, and P450c17, and therefore is the likely site of glucocorticoid synthesis, and 3) the definitive zone, which lacks P450c17 throughout gestation but late in gestation (after 22-24 weeks) expresses 3 beta HSD and P450scc, and therefore is the likely site of mineralocorticoid synthesis. Indirect evidence, based on effects of P450c21 deficiency and maternal estriol concentrations, indicate that the fetal adrenal cortex produces cortisol and DHEA-S early in gestation (6-12 weeks). However, controversy exists as to whether cortisol is produced de novo or derived from the metabolism of progesterone, as data regarding the expression of 3 beta HSD in the fetal adrenal cortex early in gestation are conflicting. During the 1960s, Liggins and colleagues demonstrated that in the sheep, cortisol secreted by the fetal adrenal cortex late in gestation regulates maturation of the fetus and initiates the cascade of events leading to parturition. Those pioneering discoveries provided insight into the mechanism underlying the timing of parturition and therefore were of particular interest to obstetricians and perinatologists confronted with the problems of preterm labor. However, although cortisol emanating from the fetal adrenal cortex promotes fetal maturation in primates as it does in sheep, its role in the regulation of primate parturition, unlike that in sheep

Adrenal Cortex↗
PubMed1996

Biphasic developmental expression of adrenocorticotropin receptor messenger ribonucleic acid levels in the baboon fetal adrenal gland.

We have previously shown an estrogen-dependent developmental regulation of placental oxidation of cortisol to cortisone that results in enhanced fetal pituitary ACTH production and the induction of steroidogenic enzymes in and de novo cortisol production by the fetal adrenal in the second half of baboon pregnancy. However, it is not known whether the receptor for ACTH is simultaneously generated at this time in development to provide a mechanism for mediating the tropic action of ACTH on steroidogenesis in the primate fetal adrenal gland. Therefore, in the present study we determined the levels of ACTH receptor messenger RNA (mRNA) and correlated ACTH receptor expression with appearance of the mRNA for delta5-3beta-hydroxysteroid dehydrogenase/isomerase (3betaHSD), the enzyme protein that signals functional maturation of the definitive cortical zone in the baboon fetal adrenal. A baboon ACTH receptor complementary DNA was cloned and hybridized with polyadenylated RNA isolated from baboon (Papio anubis) fetal adrenals obtained in early (days 58-64; RNA from seven baboon fetuses pooled to yield three samples), mid-(days 99-103; RNA from five baboons pooled to yield four samples), and late (days 165-168; RNA of four individual baboon fetuses) gestation (term = 184 days). Expression of the primary 3.4-kilobase ACTH receptor mRNA transcript, determined by Northern blot and expressed as a ratio of beta-actin mRNA, was minimal early in gestation (mean +/- SE, 0.11 +/- 0.05 arbitrary densitometric units). However, fetal adrenal ACTH receptor mRNA levels increased (P < 0.001, by ANOVA) approximately 13-fold to 1.41 +/- 0.16 at midgestation, then declined by 70% (P < 0.001) to 0.41 +/- 0.10 in late gestation. To determine whether the decrease in ACTH receptor expression by the fetal adrenal in the second half of pregnancy reflected programmed cell death, the integrity of genomic DNA was assessed by 32P-labeled DNA gel electrophoresis and in situ DNA end labeling. Because DNA oligonucleosomes and apoptotic DNA strand breaks characteristic of apoptosis were absent in the adrenal glands of fetal baboons, the decline in ACTH receptor mRNA levels in the fetal adrenal did not seem to reflect programmed cell death. Expression of the single 2.0-kilobase mRNA transcript for 3betaHSD, an enzyme localized specifically in the definitive zone of the fetal adrenal, was minimal in early (0.01 +/- 0.00 arbitrary units) and mid- (0.10 +/- 0.01) gestation. However, 3betaHSD mRNA levels were markedly increased late in gestation to a value (1.38 =/- 0.34) approximately 13-fold greater (P < 0.001) than that in midgestation. These findings indicate that there was a biphasic monomodal developmental expression of the ACTH receptor in the baboon fetal adrenal, which contrasted with the progressive increase in adrenal weight, 3betaHSD expression, and de novo cortisol production previously determined. Because the fetal adrenal is comprised mainly of the fetal cortical zone throughout gestation, the decrease in ACTH receptor expression between mid- and late gestation seems to occur primarily in the latter zone and may signal a selective decline in tropic responsivity of and delta5-C19-steroid, e.g. dehydroepiandrosterone, biosynthesis within the baboon fetal adrenal gland.

3-Hydroxysteroid Dehydrogenases↗
PubMed1992

The relationship of clinical findings to CT scan evidence of adrenal gland metastases in the staging of bronchogenic carcinoma.

OBJECTIVE: To determine whether, during the staging of newly diagnosed bronchogenic carcinoma, clinical indicators predict the presence or absence of adrenal metastases detected by computerized tomographic (CT) scans. DESIGN: Retrospective review of charts and roentgenograms. SETTING: Academic medical center. PATIENTS: Two hundred five consecutive patients diagnosed with bronchogenic carcinoma, of whom 173 had sufficient data available for analysis. MEASUREMENTS: Charts were reviewed for abnormalities in three clinical categories (signs, symptoms, and routine laboratory tests) and the presence of extrapulmonary tumor spread. The CT scans were reviewed for evidence of adrenal involvement by radiologists blinded to clinical findings. MAIN RESULTS: Thirty patients had abnormal adrenal glands on CT scan. In 26 the abnormality was believed to represent adrenal metastasis, whereas in four the CT findings were consistent with adrenal adenomas. The frequency of adrenal metastases varied with the number of positive, clinical findings (chi 2 = 105.4; p < 0.001). All 26 patients with adrenal metastases had at least one clinical abnormality, and 21 (81 percent had abnormalities in either two or all three clinical categories. In 40 patients without any clinical indicators of widespread disease, none had CT evidence of adrenal metastases. The presence of adrenal metastases also varied with the extent of coexistent disease (chi 2 = 111.82; p < 0.001). Eighty-one percent (21) of the patients with and 18 percent of those without adrenal metastases had both intrathoracic and extrathoracic involvement. CONCLUSIONS: Our findings indicate that adrenal metastases are found in patients with a large tumor burden who have clinical indicators of widespread disease. We found no evidence of adrenal metastases by CT in any patient with a normal clinical evaluation. We conclude that CT scans through the adrenal glands are unnecessary when staging newly diagnosed bronchogenic carcinoma if the findings from the initial clinical evaluation are normal.

Adrenal Gland Neoplasms↗
PubMed2003

Inhibition of Src tyrosine kinase stimulates adrenal androgen production.

A unique characteristic of the primate adrenal is the ability to produce 19-carbon steroids, often called the adrenal androgens. Although it is clear that the major human adrenal androgens, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S), are produced almost solely in the adrenal reticularis, the mechanisms regulating production are poorly understood. Herein, we tested the hypothesis that the Src family of tyrosine kinases are involved in the regulation of adrenal androgen production. The NCI-H295R human adrenal cell line and primary human adrenal cells in culture were used to study adrenal androgen production and expression of enzymes involved in steroidogenesis. To examine the role of Src tyrosine kinase, cells were treated with PP2, a specific Src inhibitor. Alternatively, adrenal cells were transfected with an expression vector containing a dominant-negative form of Src. PP2 treatment inhibited basal cortisol production while significantly increasing the production of DHEA and DHEA-S (together referred to as DHEA(S)) in both adrenal cell models. The effect of PP2 on steroidogenesis occurred along with a rapid induction of steroidogenic acute regulatory (StAR) protein synthesis as revealed by Western analysis. Treatment with PP2 also increased mRNA levels for StAR, and cholesterol side-chain cleavage (CYP11A) and 17alpha-hydroxylase/17,20-lyase (CYP17) enzymes. Treatment of adrenal cells with the cAMP agonist dibutyryladenosine cyclic monophosphate (dbcAMP), stimulated the production of cortisol and DHEA(S). However, treatment of adrenal cells with a combination of PP2 and dbcAMP enhanced the production of DHEA(S) while inhibiting cortisol production. During dbcAMP treatment PP2 was able to augment the expression of CYP17 and to inhibit the induction of 3beta-hydroxysteroid dehydrogenase type 2 (HSD3B2) levels. Increasing the CYP17 to HSD3B2 ratio is likely to promote the use of steroid precursors for the production of DHEA(S) and not for cortisol. Taken together these data suggest that the inhibition of Src tyrosine kinases causes adrenal cells to adopt a reticularis phenotype both by the production of DHEA(S) and by the steroidogenic enzymes expressed.

Adrenal Glands↗
PubMed1997

[The vascular basis of pedicled adrenal transposition and its usage in the treatment of Cushing's disease].

To treat Cushing's disease, we studied the length and exterior diameter of the inferior phrenic and superior adrenal artery and vein, and the reflow of the adrenal vein. The length and exterior diameter of those blood vessels were divided and measured by veiner calipor. Six patients with Cushing's disease were treated by pedicled adrenal transposition to the musculus of the back. The right inferior phrenic artery was 75-110 mm from the exterior edge of the vena cava to the distant branch of the superior adrenal artery, while the left inferior phrenic artery was 70-90 mm from the left edge of the aorta to the distant branch of the superior adrenal artery, both of which have veins to accompany them. The superior adrenal artery came from the inferior phrenic artery relatively common and was divided into six branches. The exterior diameter of the distal superior adrenal artery was 1.5-2.5 mm and could be freed for 40-80 mm. Lateral veins could complete the adrenal blood drainage after the left central adrenal vein was ligated. The transpositioned blood vessel pedicle consisted of the distant inferior phrenic artery and vein, the distant branches of the superior adrenal artery and vein. The patient who had received the transposition treatment had neither hypocortisolism nor recurrence after 4 to 35 months. The length of the inferior phrenic, superior adrenal gland vessels could content the remained adrenal gland to reach their transposition bed when freed. The pedicled adrenal transposition to the musculi is an ideal method in the treatment of Cushing's disease.

Adrenal Glands↗
PubMed1983

Central and peripheral effects of clonidine on the adrenal medullary function in spontaneously hypertensive rats.

The sites of action of clonidine-induced adrenal suppressant effect were investigated in spontaneously hypertensive rats. For analysis of the adrenal medullary function, efferent adrenal nerve discharges and adrenal venous catecholamine secretion rates were determined. Five to 10 min after i.v. administration of clonidine (3-100 micrograms/kg), there was a decrease in both sympathetic adrenal nerve activity and adrenal catecholamine secretion rates along with the decrease in arterial blood pressure and heart rate. After acute splanchnicotomy, clonidine (50 micrograms/kg i.v.) produced a significant decrease in catecholamine secretion rates from the denervated adrenal medulla during electrical stimulation of the splanchnic nerve. Furthermore, i.c.v. administration of clonidine (1-10 micrograms) decreased adrenal nerve activity. These findings indicate that both the adrenal medulla and the spinal clonidine-induced adrenal suppressant effect. The fact that the clonidine-induced decrease in adrenal catecholamine secretion rates was approximately parallel to the decrease in preganglionic adrenal nerve discharges in nerve intact spontaneously hypertensive rats suggests that the central action of clonidine is important in the adrenal suppressant effect relative to its peripheral action.

Adrenal Medulla↗
PubMed1987

Impaired adrenal vascular response to hemorrhagic hypotension by an adreno-femoral venous shunt.

We studied the influence of an adreno-femoral venous shunt on the regional blood flow in the dog adrenal gland during hemorrhagic hypotension. An adreno-femoral venous shunt was placed transperitoneally in the left adrenal gland while the animal was under pentobarbital anesthesia. The right adrenal gland was left intact. Hemorrhagic hypotension was induced at 50 mm Hg mean arterial blood pressure for 1 hr in six dogs and the other six dogs served as normotensive controls. Nonradioactive microspheres (2 X 10(6), 15 +/- 2 micron) were injected into the ventricle. The adrenal cortical and medullary blood flows were estimated by microscopic counting of the microspheres in the serially sectioned adrenal gland. The total adrenal blood flow (sum of the cortical and medullary blood flows) of two methods was compared; the microsphere method vs timed venous sampling through the shunt. In the intact right adrenal gland, the cortical blood flow was significantly decreased, but the medullary blood flow remained unchanged during hemorrhagic hypotension. Subsequently the total adrenal blood flow was not significantly decreased. In the cannulated left adrenal gland, both the cortical and medullary blood flows were significantly decreased and adrenal vascular autoregulation was inhibited. The total adrenal blood flow calculated by the microsphere method showed a significant correlation with that by timed venous sampling through the shunt. These results indicate that the adrenal medullary vasculature autoregulates during hemorrhagic hypotension and that an adreno-femoral venous shunt abolishes this vascular response.

Adrenal Cortex↗
PubMed1995

Corticosteroids in human blood: IX. Evidence for adrenal secretion of sulfate-conjugated cortisol, 11 beta,17 alpha-dihydroxy-4-pregnene-3,20-dione-21-yl-sulfate.

A method was developed for the estimation of levels of cortisol-21-sulfate (F KS), cortisone-21-sulfate (ES), and 20(alpha + beta)-reduced cortisol-21-sulfates in blood plasma. Levels of these conjugates were determined in peripheral vein plasma of 42 normal subjects, 21 men, and 21 women (age range 20-64 years) and in adrenal vein plasma of patients with various adrenocortical disorders, six patients with primary hyperaldosteronism, five patients with Cushing's syndrome, and in two obese patients, suspected to have Cushing's syndrome, but with inconclusive laboratory findings. Adrenal vein blood was obtained by percutaneous, trans-femoral adrenal vein catheterization. Levels of non-conjugated (free) cortisol were determined in all plasma samples along with those of the sulfated steroids. F kappa S was found in all plasma samples, both in men and women. The variation in F kappa S levels paralleled that in the free cortisol levels, thus the ratio of F kappa/F kappa S was the same in the blood samples drawn at 8 AM as in those drawn at 4 PM or 5 PM (ranges: 17.5-36.3 in men, 23.6-45.8 in women). The levels of F kappa S were relatively lower in women than in men (women 610-880 ng/100 mL at AM, 300-510 ng/100 mL at PM; men: 760-1,220 ng/100 mL at AM, 380-760 ng/100 mL at PM). Plasma levels of total sulfate-conjugated delta 4-3-keto-C-21 steroids (F kappa S + E kappa S + 20(alpha+beta)-dihydrocortisol-21-sulfates) were 30-40% higher than those of the levels of cortisol-21-sulfate alone (separated by thin-layer chromatography). In the adrenal vein plasma, levels of delta 4-3-keto-C-21-steroid-21-yl sulfates were 20 to 40 times higher than levels of these steroids in the peripheral blood. The bulk of the steroid sulfate measured in the adrenal vein plasma consisted of cortisol-21-sulfate. The ratio of F kappa/F kappa S in the adrenal vein plasma was markedly smaller than in the peripheral vein plasma; it was 6.9-12.3 in males and 4.9-6.7 in females, whereas in the peripheral vein of the same subjects it was 19.2-43.7 in males and 21.4-48.3 in females. Cortisol-21-sulfate isolated from adrenal vein plasma was identified by mass spectrometry. The data presented provide evidence for the secretion of this conjugate by the adrenal cortex. Its secretion appears to be markedly elevated in patients with Cushing's syndrome, both due to hyperplasia and due to adrenal adenoma, as compared with normal subjects and patients with primary aldosteronism, both males and females. However, the F kappa/F kappa S ratio was markedly lower in Cushing's patients due to adrenal adenoma than due to adrenal hyperplasia, this suggesting that ACTH is stimulating intra-adrenal hydrolysis of cortisol sulfate.

Adrenal Cortex Diseases↗
PubMed1999

[Differential diagnosis of space-occupying adrenal masses].

Computed tomography (CT) and magnetic resonance (MR) imaging are first line modalities in the evaluation of patients with adrenal gland masses, and have the potential to be very accurate for the localization of adrenal gland masses in patients with diseases associated with hyperfunctioning conditions of the adrenal gland. Both CT and MR imaging allow a specific diagnosis of acute adrenal hemorrhage, adrenal myelolipoma, and adrenal cysts. CT is also helpful in the assessment of patients with Addison's disease, particularly the subacute form secondary to granulomatous diseases. Quantitative evaluation of adrenal masses on unenhanced CT scans and/or qualitative analysis on chemical-shift MR imaging have been shown to be accurate in distinguishing adrenal adenomas from non-adenomas. Attenuation of 11 HE or less on unenhanced CT scans and/or signal loss on opposed phase MR images indicate adenoma with a high specificity and acceptable sensitivity. More recently, delayed-enhanced CT has yielded higher sensitivity and specificity values in distinguishing between adrenal adenomas and non-adenomas than both unenhanced CT and chemical-shift MR imaging do. On delayed-enhanced CT scans, adrenal adenomas exhibit a greater washout of contrast material than do adrenal non-adenomas. Therefore, adrenal non-adenomas have significantly higher attenuation than adenomas on delayed-enhanced CT scans obtained at several arbitrarily chosen time points (3-60 min) after the initiation of contrast material administration.

Adenoma↗
PubMed1997

Adrenal involvement in polycystic ovary syndrome.

The etiology of hyperandrogenic chronic anovulation is heterogeneous and relatively unknown in the majority of cases. Affected individuals in this latter segment are considered to have polycystic ovary syndrome (PCOS) of which 50 to 60% exhibit androgen excess of adrenal origin. An understanding of normal adrenal function provides insight into the factors that contribute to adrenal androgen excess in PCOS. Since pituitary ACTH secretion promotes developmental growth and overall steroidogenic efficiency within the adrenal cortex, it is probable that these actions of ACTH along with the adrenal's unique centripetal circulation play a major role in the induction of adrenarche. This latter phenomenon is characterized by alterations in adrenocortical morphology and steroidogenic enzyme activities culminating in increases in adrenal androgens to normal circulating adult levels. Thus, it is not surprising that adrenal dynamic testing has revealed increased 17,20 lyase activity or adrenal androgen hyper-responsiveness to ACTH as the two abnormalities leading to adrenal androgen excess in PCOS. Whereas 17,20 lyase hyperactivity diagnosed by defined criteria in response to pharmacological ACTH may be an intrinsic genetic defect, increases in 17,20 lyase activity and adrenal androgen hyper-responsiveness to ACTH in response to physiological ACTH may be promoted by the functional elevation of estrogen of ovarian origin in PCOS. The latest in vitro data suggest the estrogen may elicit its effect on the adrenal cortex through a receptor mediated mechanism. Therefore, the currently available data indicate that adrenal androgen excess in PCOS is also heterogeneous in etiology.

Adrenal Cortex↗
PubMed1995

Increased 17 alpha-hydroxyprogesterone response to ACTH in silent adrenal adenoma: cause or effect?

OBJECTIVE: Recent studies suggest a possible connection between silent adrenal nodules and mild forms of 21-hydroxylase deficiency. It remains unclear whether the enzymatic deficiency is generalized or intrinsic to the adrenal mass. To help to clarify this, we have studied 17 alpha-OH-progesterone (17OH-P) response to ACTH stimulation in a group of patients with adrenal 'incidentaloma' in comparison with normal subjects. In patients who underwent surgical treatment, the test was repeated to evaluate possible modifications in 17OH-P behaviour after resection of the adrenal mass. SUBJECTS AND METHODS: Fifteen subjects with incidentally discovered asymptomatic adrenal masses were studied. Basal hormone evaluations were normal, with normal cortisol suppression after low-dose dexamethasone. Iodocholesterol scanning, performed in 12 patients, showed normal bilateral adrenal uptake in 2 subjects and an increased uptake on the side of the lesion in 10 subjects. In every patient, ACTH stimulation was performed to evaluate the secretory response of cortisol, 17OH-P, progesterone and dehydroepiandrosterone sulphate. An identical test was performed in 10 control subjects with normal adrenal glands, matched for age and sex. In six patients with an adrenal lesion > 3.5 cm, the ACTH stimulation test was repeated one month after surgery. RESULTS: The 17OH-P response to ACTH stimulation was significantly higher in subjects with adrenal 'incidentaloma' than in controls (P < 0.01). In particular, 10 subjects out of 15 (66%) evidenced a 17OH-P peak > 18 nmol/l at 60 minutes. No differences were seen in baseline 17OH-P or cortisol levels or in cortisol response to ACTH between the two groups. Dehydroepiandrosterone sulphate concentrations were significantly lower in patients with adrenal 'incidentaloma' than in normals. In six patients who had an increased 17OH-P response to ACTH on initial evaluation, the ACTH test was repeated one month after surgery. In five of these patients, 17OH-P response to ACTH was clearly reduced, suggesting that in these cases the enzymatic defect was restricted to the adenoma. In the other patient, however, stimulated 17OH-P levels remained unchanged. In this case, therefore, all of the adrenal tissue seems to be involved, suggesting a late-onset 21-hydroxylase deficiency. No significant modifications in cortisol response to ACTH were observed. CONCLUSION: It seems therefore that in some cases of incidentaloma the steroidogenic enzymatic defect may be secondary to the adenomatous proliferation, while in others such defects may induce the development of silent adrenal nodules.

17-alpha-Hydroxyprogesterone↗
PubMed1984

Dopamine may be a neurohormone in rat adrenal cortex.

In the periphery, dopamine (DA) is a precursor for norepinephrine (NE) and epinephrine (EPI) biosynthesis and is itself a neurotransmitter in sympathetic ganglia. In addition, DA may function as a neurohormone in providing maximum tonic inhibition of aldosterone secretion from the adrenal cortex. We have quantified the catecholamine content of the adrenal gland and have examined factors that regulate DA content of the adrenal cortex. Adult male Sprague-Dawley rats were assigned to one of four groups: adrenal demedullated (ADM); adrenal denervated via splanchnic nerve section (ADN); adrenal demedullated-denervated (DMN); and sham-operated controls (Sham). Ten days after surgery, rats were killed by decapitation, and the adrenals were removed and later assayed for catecholamine content. Compared with Sham, ADM and DMN decreased NE and EPI levels by 92-99% but DA levels by only 57-58%. ADN decreased levels of each catecholamine by 18-26%. These findings indicate that the adrenal cortex contains approximately 40% of the total gland content of DA and less than 8% of the total gland content of NE and EPI. Furthermore, DA in the adrenal cortex does not appear to require an intact splanchnic nerve supply to the adrenal. In a second experiment, we examined the effects of inhibition of catecholamine biosynthesis with alpha-methyl-p-tyrosine (alpha-MPT) on DA content in Sham and ADM rats. In Sham rats, alpha-MPT decreased adrenal DA by 44% and heart NE by 37%. In contrast, treatment of ADM rats with alpha-MPT increased adrenal DA by 49% but decreased heart NE by 36%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1997

Adrenal vasoactive intestinal peptide participates in neonatal corticosteroid production in the rat.

Neonatal rats (3-14 days old) exhibit a period of adrenal hyporesponsiveness characterized by blunted corticosterone (B) responses to stress and reduced adrenal sensitivity to adrenocorticotropic hormone (ACTH). Several adrenomedullary peptidergic systems like vasoactive intestinal peptide (VIP) are postulated to influence cortical function. VIP is known to stimulate corticosterone secretion in vitro and to be released from the adrenal medulla following splanchnic nerve stimulation. Here, we tested whether 1) accelerated sympathetic innervation of the adrenal gland by daily L-thyroxine (T4) treatment modified the ontogeny of adrenal VIP and 2) an increase in VIP synthesis could prematurely increase adrenal sensitivity and corticosteroid output during neonatal life. Immunohistochemical VIP staining revealed a different ontogenetic pattern between adrenal regions from days 2-18 and different sensitivities to T4 treatment. Capsular staining was most abundant at all ages and increased with T4 treatment, whereas medullary staining was seen by day 18 and was not affected by T4. Throughout development, VIP receptors were detected mostly in the capsular region, but not in the adrenal cortex. Although receptor levels were not modified by T4 injections, T4 significantly enhanced VIP mRNA levels in the whole adrenal at all ages. In vivo administration of VIP (0.1-2.0 mg/kg body wt ip) to 9- to 12-day-old neonates increased pituitary ACTH, adrenal B, and aldosterone secretion significantly. Corticotropin-releasing factor immunoneutralization before VIP injection diminished VIP-induced ACTH release but still produced small but significant B and aldosterone secretion. Our results show that 1) VIP innervation of the adrenal capsule is present soon after birth and is increased by sympathetic activity whereas VIP appears only much later in the medulla and does not coincide with the onset of splanchnic innervation and 2) exogenous VIP stimulates ACTH, B, and aldosterone release during development and the effect of VIP on steroidogenic secretion is occurring through ACTH secretion, but also, at least in part, directly at the level of the adrenal gland.

Adrenal Cortex↗
PubMed1991

Prospective evaluation of unilateral adrenal masses in patients with operable non-small-cell lung cancer.

Although adrenal metastases are frequently noted with non-small-cell lung cancer (NSCLC) at autopsy, their incidence in patients with operable NSCLC is unclear. We prospectively assessed consecutive patients with otherwise operable NSCLC for the incidence and histology of unilateral adrenal masses. Assessment included blood chemistries, lung function tests, bronchoscopy, chest x-ray, bone scan, and computed tomography (CT) of the head, chest, and upper abdomen. Of 246 patients with otherwise operable NSCLC, 10 (4.1%) had a unilateral adrenal mass. Unilateral adrenal masses were needle-aspirated under CT control. If cytology was nondiagnostic, adrenalectomy was performed. Four (40%) of 10 patients had adrenal metastases proven by needle aspiration. Of the six (60%) patients with benign unilateral adrenal masses, one was demonstrated by needle aspiration. In the other five patients, a nondiagnostic needle aspiration led to adrenalectomy, which yielded two adenomas, two hyperplastic nodules, and one hemorrhagic cyst. There was no significant difference between the patients with benign and metastatic unilateral adrenal masses with respect to patient age or stage and size of adrenal mass. Patients with benign unilateral adrenal masses underwent curative resection of their NSCLC and had significantly prolonged survival compared with patients with metastatic unilateral adrenal masses treated with chemotherapy (P = .037). Median survival of patients with benign and metastatic unilateral adrenal masses was greater than 30 months and 9 months, respectively. In conclusion, the presence of unilateral adrenal masses in patients with otherwise operable NSCLC should not preclude thoracotomy without pathologic proof of metastatic disease.

Adenoma↗
PubMed2005

Molecular basis of adrenal insufficiency.

Defective production of adrenal steroids due to either primary adrenal failure or hypothalamic-pituitary impairment of the corticotrophic axis causes adrenal insufficiency. Depending on the etiologies of adrenal insufficiency, clinical manifestations may be severe or mild, have gradual or sudden onset, begin in infancy or childhood/adolescence. Adrenal crisis represents an endocrine emergency, and thus the rapid recognition and prompt therapy for adrenal crisis are critical for survival even before the diagnosis is made. The recognition of various disorders that cause adrenal insufficiency, either at a clinical or molecular level, often has implications for the management of the patient. Recent molecular-genetic analysis for the disorder that causes adrenal insufficiency gives valuable insights into the adrenal organogenesis, the regulation of steroid hormone biosynthesis, and the developmental and reproductive endocrinology. In this review we present the latest information on the molecular basis of adrenal insufficiency, with special emphasis on congenital lipoid adrenal hyperplasia, P450-oxidoreductase deficiency, and adrenal hypoplasia congenita.

Adrenal Cortex↗