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PubMed2000

Actions of hypoxia on catecholamine synthetic enzyme mRNA expression before and after development of adrenal innervation in the sheep fetus.

We have investigated adrenal mRNA expression of the catecholamine synthetic enzymes tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) following acute hypoxia in fetal sheep before (< 105 days gestation, n = 20) and after (> 125 days gestation, n = 20) the development of adrenal innervation and following pretreatment with the nicotinic receptor anatgonist hexamethonium (n = 12). Total RNA was extracted from fetal adrenal glands collected at specific time points at 3-20 h after the onset of either hypoxia ( approximately 50% reduction in fetal arterial oxygen saturation (SO2) for 30 min), or normoxia. Before 105 days, there was a decrease in adrenal TH mRNA expression at 20 h after hypoxia and adrenal TH mRNA expression was directly related to the changes in arterial PO2 measured during normoxia and hypoxia. After 125 days, adrenal TH mRNA levels were suppressed for up to 12 h following hypoxia. In both age groups, adrenal PNMT mRNA expression increased at 3-5 h after hypoxia and was inversely related to the changes in fetal arterial PO2 during normoxia or hypoxia. After 125 days, the administration of hexamethonium (25 mg kg(-1), I.V.) reduced TH mRNA but not PNMT mRNA expression after normoxia. After hexamethonium pretreatment, there was no significant change in either adrenal TH or PNMT mRNA expression following hypoxia. We conclude that acute hypoxia differentially regulates adrenal TH and PNMT mRNA expression in the fetal sheep both before and after the development of adrenal innervation. After the development of adrenal innervation, however, the effect of acute hypoxia upon adrenal TH and PNMT mRNA expression is dependent upon neurogenic input acting via nicotinic receptors.

Adrenal Glands↗
PubMedDate not supplied

Magnetic resonance imaging of the presumed normal canine adrenal glands.

Forty-three dogs without evidence of endocrine disease that underwent spinal or abdominal magnetic resonance imaging (MRI) for clinical reasons were studied. Because the procedures were not optimized for inclusion of the adrenal glands, they were not always visible in all planes. Eighty-five of the 86 adrenal glands were seen and only the left gland in a 6-month-old Irish wolfhound could not be found. The right adrenal gland lay cranial to the left in all of the animals in which both glands were seen. The best landmarks for localization of the glands were vascular; both adrenal glands were always cranial to the ipsilateral renal vessels and in the region of the celiac and cranial mesenteric arteries. Various measurements were made on all the available scan planes. In some dogs the whole adrenal gland was difficult to visualize clearly, and this hindered the measuring process, especially when the right adrenal gland was in close contact with the caudal vena cava. The adrenal glands were mainly linear in shape but also had a variable degree of modification of their poles, especially the cranial pole of the right adrenal gland, which tended to be consistently wider and to present different shapes (rounded, arrowhead, inverted P, hook-shaped, triangular, or dome-shaped). Two main patterns of signal intensity were seen on fast spin echo (FSE) sequences (T2-weighted, T1-weighted, and T1-weighted after administration of a paramagnetic contrast medium): homogeneous and hypointense to surroundings or a corticomedullary type pattern with a hyperintense central area surrounded by a hypointense rim of tissue. The outline of the left adrenal gland was always very clear. The clarity of outline of the right adrenal gland was more variable, especially if it was in contact with the liver or the caudal vena cava. It was felt that the amount of retroperitoneal fat was not as important as stated in the human literature for visualization of the adrenal glands and that with an appropriate selection of scan planes and pulse sequences good assessment of the adrenal glands can be performed with MRI in canine patients.

Adrenal Glands↗
PubMed1982

Relationship between plasma corticosterone and adrenal epinephrine after diazepam treatment in rats.

Following recent observations that diazepam treatment increases adrenal epinephrine in rats, we were interested in studying the possible mechanisms of this action of diazepam on rat adrenal glands. All diazepam treatments studied (1-25 mg . kg-1.day-1 for 10 days) led to an increase in adrenal epinephrine following a linear dose-effect relationship. Since epinephrine synthesis is under neuronal and humoral controls, we investigated their respective importance in the effect of diazepam on the adrenal gland. The denervation of the adrenal gland did not prevent the increase in adrenal epinephrine by diazepam treatment. On the hand, diazepam treatment was shown to cause an increase in plasma corticosterone in parallel with an increase in adrenal epinephrine. Administration of dexamethasone (a synthetic corticoid) and hypophysectomy prevented the increase in adrenal epinephrine and plasma corticosterone resulting from diazepam treatment. We thus conclude that the increase in adrenal epinephrine seen after diazepam treatment is parallel to the increase in plasma corticosterone. Moreover, since the action of diazepam on adrenal epinephrine is prevented by dexamethasone or hypophysectomy, we hypothesize that diazepam is acting on the adrenal cortex via the release of adrenocorticotropic hormone (ACTH). ACTH and corticosterone would be responsible for the increased activity of epinephrine-synthesizing enzymes in adrenal medulla.

Adrenal Glands↗
PubMed2004

Adrenal gland hematomas in trauma patients.

PURPOSE: To evaluate the frequency of detection of trauma-induced adrenal gland hematoma in current practice by using computed tomography (CT) and to correlate presence of adrenal hematoma with quantitative clinical indicators of injury severity. MATERIALS AND METHODS: The radiology information system and the trauma registry were searched for cases of adrenal hematoma detected at trauma CT during a 54-month period. CT images depicting adrenal masses with the published characteristics of adrenal hematoma were reviewed by readers who were unblinded to the initial interpretations. Injury severity score (ISS), associated injury, and patient outcome data were gleaned from the trauma registry. The control group comprised patients entered in the trauma registry during the study period who did not have a diagnosis of adrenal hematoma. RESULTS: Fifty-four adrenal hematomas were detected in 51 patients: 42 with right-gland, 12 with left-gland, and three with bilateral lesions. The hematomas were round or ovoid and had a mean maximum diameter of 2.8 cm +/- 0.7 (SD) and a mean attenuation of 52 HU +/- 12. Periadrenal stranding was seen with 48 (89%) hematomas. At follow-up CT, 32 of 35 hematomas had resolved or decreased in size and attenuation. One patient with adrenal hematoma had no other intraabdominal injuries. Compared with the 6,757 control patients, the 51 patients with adrenal hematoma had a higher mortality rate (10% vs 4%; P <.001, chi(2) test) and a higher mean ISS (25.2 vs 9.7; P <.01, t test). Adrenal hematoma was found in 24 (0.4%) of 5,665 trauma patients with an ISS of 0-19, as compared with six (5.0%) of 122 patients with an ISS of 40 or higher. CONCLUSION: Adrenal hematoma was detected in 51 (1.9%) of 2,692 trauma patients who underwent CT, or 0.8% of all patients (n = 6,808) entered in the trauma registry. Compared with the other trauma patients, the patients with adrenal hematomas had severe injuries associated with higher mortality.

Abdominal Injuries↗
PubMed2005

Adrenal vein sampling: how to make it quick, easy, and successful.

Adrenal vein sampling has a reputation as a difficult procedure. However, it is being performed more frequently at some institutions due to the realization that primary aldosteronism is more common than previously believed. At the author's institution, adrenal vein sampling with computed tomographic (CT) and laboratory correlation has been performed more than 800 times in the past 10 years. Adrenal vein sampling is used to determine whether autonomous hormone production is unilateral or bilateral; unilateral secretion can be treated with surgery. The venous drainage of each adrenal gland is predominantly via a central vein. Recognition of the right adrenal vein is the crux of adrenal vein sampling. CT is useful in planning adrenal vein sampling by demonstrating the anatomy and positions of the adrenal veins. A small amount of contrast material is injected gently and slowly into the adrenal vein; it is not necessary to perform formal venography to outline the entire gland. To confirm that the vein is draining the majority of adrenal cortical blood, the adrenal vein sample should have a significantly higher level of cortisol than a peripheral sample. Adrenal glands that are producing aldosterone demonstrate an aldosterone-cortisol ratio that is higher than the peripheral value.

Adrenal Glands↗
PubMed1997

Splanchnicotomy increases adrenal sensitivity to ACTH in nonstressed rats.

Awake rats demonstrate an ultradian rhythm in adrenal secretion of corticosterone. Splanchnic denervation in unstressed rats increases the frequency of corticosterone pulses, revealing an inhibitory function of adrenal innervation. In contrast, one day after surgical stress, adrenal denervation reduces adrenal pulsatility, suggesting a stimulatory function of adrenal innervation. To test whether neural modulation of pulsatile secretion was due to a direct effect of the splanchnic nerve on adrenal sensitivity to adrenocorticotropic hormone (ACTH), rats treated with dexamethasone were administered repetitive pulses of ACTH, and the amplitude of corticosterone responses was determined. Intact or control (C) and splanchnicotomized (SPLNX) rats were tested at 2 or 5 days after surgery. Five days after surgery, adrenal responsiveness in C animals was reduced compared with SPLNX animals. However, no differences were seen 2 days after surgery. To determine whether the reduction in adrenal responsiveness involved a cellular or organ level mechanism, dispersed adrenal cortical cells isolated from intact or denervated adrenal glands were stimulated with ACTH, and corticosterone secretion was determined. Consistent with in vivo results, denervation increased the responsiveness of adrenal cells obtained 5, but not 1 or 2, days after surgery. These findings support a neurally mediated inhibition of adrenal sensitivity to ACTH in unstressed rats.

Activity Cycles↗
PubMed1976

Compensatory adrenal growth: a neurally mediated reflex.

The responses of young rats to left adrenalectomy or left adrenal manipulation were compared to surgical sham adrenalectomy in which adrenals were observed but not touched. At 12 h right adrenal wet weight, dry weight, DNA, RNA, and protein content were increased (P less than 0.05) after the first two operations. Left adrenal manipulation resulted in increased right adrenal weight at 12 h but no change in left adrenal weight. Sequential manipulation of the left adrenal at time 0 and the right adreanl at 12 h resulted in an enlarged right adrenal at 12h (P less than 0.01), and an enlarged left adrenal at 24 h (P less than 0.05), showing that the manipulated gland was capable of response. Bilateral adrenal manipulation of the adrenal glands resulted in bilateral enlargement at 12 h (P less than 0.01). Taken together with previous results, these findings strongly suggest that compensatory adrenal growth is a neurally mediated reflex.

Adrenal Glands↗
PubMed1980

Adrenal regeneration. Time course, effect of hypothalamic hemi-islands and response to unilateral adrenalectomy.

Regeneration of rat adrenals was studied after bilateral enucleation to determine whether there is a neural component mediating this process as there is in compensatory adrenal growth after unilateral adrenalectomy. Regeneration was approximately 50% complete (based on criteria of wet weight and DNA content) by 10 days after enucleation; at this time circulating ACTH levels were twice as high in enucleates as in sham-operated controls, but corticosterone levels were normal. Regeneration was apparently complete at sometime between 3 and 6 weeks and circulating ACTH and corticosterone levels were normal at these times compared to controls. Unilateral adrenal enucleation resulted in compensatory growth of the opposite gland, not regeneration of the enucleated gland. Unilateral hypothalamic hemi-islands made with a Halász knife resulted in bilateral augmentation of adrenal regeneration at 10 days and 6 weeks. From these results we conclude that adrenal regeneration after bilateral enucleation occurs by different afferent and efferent mechanisms than compensatory adrenal growth after unilateral adrenalectomy. Additional studies were performed in rats 3 and 6 weeks after adrenal enucleation to test whether the adrenal medulla participates either in compensatory adrenal growth or in the augmented ACTH response to ether vapors observed in unilaterally adrenalectomized rats. Normal compensatory adrenal growth occurred 3 days after unilateral adrenalectomy in rats bilaterally enucleated 6 weeks earlier. Prior enucleation did not inhibit the increased ACTH response of unilaterally adrenalectomized rats to ether. Therefore, the adrenal medulla does not mediate compensatory adrenal growth or the augmented ACTH response of unilaterally adrenalectomized rats to ACTH-releasing stimuli.

Adrenal Glands↗
PubMed1990

Adrenal androgen excretion during adrenarche. Relation to race and blood pressure.

We have previously shown that black children have higher blood pressures than white children. In the present study, we examined whether a possible racial difference in adrenal androgen production during adrenarche might contribute to the racial disparity in blood pressure. Adrenal androgen production was estimated from urinary excretion of adrenal androgen metabolites that showed cross-reactivity with antisera to dehydroepiandrosterone sulfate (DHEA-S). Urine samples were collected overnight in 798 children, one third of whom were black. Analyses were performed for two different age groups, less than 10 years and 10 years or more of age. In children less than 10 years of age, adrenal androgen excretion rates were 17% higher in blacks than in whites (p = 0.0099); adrenal androgen excretion rates tended to be higher in older black children as well, but differences here were not statistically significant. Adrenal androgen excretion rates were positively correlated with diastolic blood pressure in the older age group only (p = 0.014). However, when the relation of race to blood pressure was examined along with adrenal androgen excretion adjusted for age, sex, and weight, race remained an independent contributor to the level of blood pressure, suggesting that a difference in adrenal androgens could not explain the racial differences in blood pressure. In summary, black children produced more adrenal androgen, but this did not explain their higher blood pressures. In older children, where adrenal androgen excretion rates were higher, diastolic blood pressure and adrenal androgen excretion were positively related, suggesting that adrenal androgens participate in establishing the level of blood pressure in young people.

Adrenal Glands↗
PubMed1972

Metabolism of adrenal cholesterol in man. I. In vivo studies.

The kinetics of plasma and adrenal cholesteral equilibration were analyzed in patients undergoing bilateral adrenalectomy for generalized mammary carcinoma. A biological model is proposed to help in the understanding of adrenal cholesterol physiology. It comprises two intracellular compartments: (1) A compartment of free adrenal cholesterol which is small (of the order of 17 mg) but turns over very fast; it is renewed approximately 8 times per day: 3 times by the inflow of free plasma cholesterol, and 5 times by the hydrolysis of esterified adrenal cholesterol, the contribution of adrenal cholesterol synthesis appearing to be relatively small. (2) A compartment of esterified adrenal cholesterol which is 20 times larger; it is constantly renewed by in situ esterification and hydrolysis with a daily fractional turnover rate of the order of 0.25. The direct and selective accumulation of plasma cholesteryl esters is practically absent. Only free adrenal cholesterol returns to plasma, mostly after conversion into steroid "hormones."However small the synthesis of adrenal cholesterol may be, it seems more important in the zona "reticularis." On the other hand, the inflow of plasma cholesterol and the turnover of the free adrenal compartment tend to be faster in the zona "fasciculata." The equilibration of plasma and adrenal cholesterol can proceed unmodified under conditions of ACTH suppression. In one patient with Cushing's disease the size of the two adrenal compartments was clearly increased but their equilibration with plasma cholesterol proceeded normally. In another patient the kinetics of hydrocortisone corresponded to those of free adrenal cholesterol in the control studies.

Adrenal Glands↗
PubMed1990

Modulation of adrenocorticotropin-stimulated baboon fetal adrenal dehydroepiandrosterone formation in vitro by estrogen at mid- and late gestation.

We have reported that ACTH stimulation of dehydroepiandrosterone (DHA) formation by the baboon fetal adrenal at midgestation was suppressed by estrogen. Because fetal adrenal regulation changes with advancing gestation, the action of estrogen on fetal adrenal steroidogenesis may also be dependent on the degree of fetal adrenal maturation. We examined this possibility in the present study by determining the effects of ACTH and estrogen on DHA formation by adrenal cells of fetuses obtained from baboons at mid- and late gestation and from animals administered the antiestrogen MER-25 throughout late gestation. Because low density lipoprotein (LDL) provides substrate for the fetal adrenal, we also determined whether the effect of estrogen was mediated by LDL uptake. Adrenals were removed from baboon fetuses on day 100 (midgestation; n = 7) and day 170 (late gestation; n = 6; term, day 184) of gestation from untreated animals and on day 170 from fetuses whose mothers were treated with MER-25 on days 140-170 (25 mg/kg BW.day; n = 7). Cells were dispersed with 0.2% collagenase and incubated at 37 C for 3 h in 4 ml medium 199 with 10 nM ACTH, 10(-6) M estradiol and/or 500 micrograms LDL. The secretion of DHA into medium was determined by RIA. At midgestation, mean (+/- SE) basal DHA formation (nanograms per 10(5) cells/3 h) was 5.8 +/- 2.1, and DHA was increased (P less than 0.01) by ACTH to 20.0 +/- 5.9. Although estradiol alone had no effect, estradiol prevented the increase in DHA obtained with ACTH. Basal DHA production by adrenals of late gestation (0.7 +/- 0.3 ng/10(5) cells) was lower (P less than 0.01) than at midgestation. ACTH increased (P less than 0.01) DHA in a comparable manner near term in the presence (2.0 +/- 0.4) or absence (1.7 +/- 0.4) of estradiol. Thus, in contrast to day 100, estrogen did not attenuate the action of ACTH on adrenal cells on day 170. In fetal adrenal cells obtained on day 170 from MER-25-treated baboons, DHA formation (1.4 +/- 0.6 ng/10(5) cells) was comparably increased (P less than 0.05) to 2.4 +/- 0.2 and 3.0 +/- 0.5 ng/10(5) cells by ACTH in the absence or presence of estradiol. Thus, ACTH remained effective in enhancing DHA by adrenal cells of fetuses exposed in utero to antiestrogen. DHA formation by adrenals of midgestation was increased (P less than 0.05) to 15.4 +/- 4.8 and 27.4 +/- 7.5 ng/10(5) cells, respectively, by LDL and ACTH plus LDL.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Glands↗
PubMed1992

Zonal distribution and regulation of adrenal renin in a transgenic model of hypertension in the rat.

The hypertensive transgenic rat [TGR (mRen-2)27] is a genetic model of hypertension in which transfection of the Ren-2 mouse renin gene into rats results in severe hypertension. These transgenic rats express a high level of renin in the adrenal gland, and the hypertension is ameliorated by treatment with angiotensin-converting enzyme inhibitors. In this study we investigated the distribution of adrenal renin in the TGR rat and examined the regulation of adrenal renin in a monolayer culture of adrenal cells. High concentrations of active renin and prorenin were found in the adrenal capsular (glomerulosa) and decapsular (fasciculata-medullary) portions of the TGR adrenal. This is in contrast with the Sprague-Dawley (S-D) rat, in which adrenal renin is found mostly in the active form and located primarily in the glomerulosa cells. The zonal distribution of aldosterone was also different in the TGR, with substantial amounts of aldosterone in the zona fasciculata as well as in the glomerulosa, while in the S-D rat, aldosterone is limited to the zona glomerulosa. In the primary monolayer culture of glomerulosa cells, TGR cells had significantly higher levels of active renin and prorenin and showed an increased response to ACTH and high potassium in the medium. Renin activity in the medium was predominantly in the form of prorenin and significantly higher than that in the S-D rat. Cultured fasciculata cells from TGR also produce renin that is stimulated by ACTH, but not by a high potassium concentration. Renin activity in the adrenal homogenate, medium, and plasma from TGR rats was completely inhibited by the renin inhibitor (CP 71362; 1 microM), but only slightly inhibited (12.3 +/- 3%) by a monoclonal antibody that inhibits renin activity from S-D rat tissues by 79.2 +/- 2.5%, suggesting that renin in the plasma and adrenal glands from TGR appears to derive primarily from mouse renin. In conclusion, the TGR (mRen-2)27 rats have higher than normal levels of adrenal renin, and the cultured cells show an exaggerated renin response to ACTH and potassium. The distribution of the renin enzyme in the adrenal zones of the TGR is similar to the distribution of mouse adrenal renin.

Adrenal Glands↗
PubMed1997

Influence of dietary sodium restriction on angiotensin II receptors in rat adrenals.

We studied the distribution of angiotensin II (AII) receptors type 1 (AT1) and type 2 (AT2) and the effects of a low sodium intake on these two subtypes of receptors in male rat adrenals. Binding studies on adrenal slices, on cell membranes and on cell suspensions were performed using [125I]AII and specific analogs for AT1 (Losartan) and AT2 (PD 123319) receptors. The distribution of AT1 was also studied by immunofluorescence. Complementary approaches were necessary to reach our goal. Indeed, by autoradiography on adrenal slices, [125I]AII was shown to bind to the zona glomerulosa (ZG) and to the medulla (M). When coincubated with [125I]AII, PD 123319 displaced [125I]AII from the medulla and from the ZG, indicating the presence of AT2 receptors in both zones. Losartan partially displaced [125I]AII from the ZG, indicating the presence of AT1 receptors in that zone. Furthermore, the labeling intensity of the medulla (AT2 receptors) was much stronger in adrenal sections from rats kept on a low sodium regimen than from controls. Immunofluorescence microscopy revealed that AT1 receptors were located mainly in the ZG of control rats. After sodium restriction, AT1 receptors appeared to be uniformly distributed within an enlarged ZG; furthermore AT1 receptor-positive cells were found to a limited degree in the zona fasciculata and possibly in the zona reticularis, and a greater number of these positive cells appeared in these zones under sodium restriction. Cell suspensions from rats fed a low sodium diet showed a 2.7- and 2.1-fold increase in total AII receptors in adrenal ZG and ZFR + M cells when compared with controls. Based on Losartan displacement, we calculated that [125I]AII bound to AT1 and to AT2 receptors was increased in both ZG and ZFR + M cell preparations under sodium restriction. Results of binding studies on cell membranes were also indicative of an increasing effect of sodium restriction on AT1 and AT2 receptors binding capacity. Furthermore, Northern blotting analysis revealed 3.0- and 2.5-fold increases in the level of AT1 receptor mRNA in the ZG and the ZFR + M of rats fed a low sodium diet as compared with those fed a normal diet. The low sodium intake resulted in a weaker increase (1.5-fold) in the level of AT2 receptor messenger RNA in the ZG, with no changes in the ZFR + M preparations. In conclusion, in this study complementary approaches were needed to determine the localization of AT1 and AT2 receptors in the rat adrenal, and to show the increasing effects of a low sodium regimen on the adrenal level of these receptors. Immunofluorescence studies revealed AT1 receptors mainly in the ZG and also in some cells of the inner adrenal cortex zones; in adrenals of rats kept on a low sodium diet the ZG was markedly enlarged, and an increased number of immunoreactive cells with AT1 receptors were observed throughout that zone; also more immunoreactive cells were present in the inner zones of the adrenal cortex. Furthermore in the adrenals of rats kept on a low sodium diet, we observed: 1) an increased number of AT1 and AT2 receptors in cell suspensions from the ZG, and in cell suspensions of the ZFR + M; 2) an increased level of AT1 and AT2 receptor mRNAs in the ZG; 3) an increased level of AT1 receptor mRNA, with no changes in the AT2 mRNA level in the ZFR + M. These results suggest a role for AT1 as well as for AT2 receptors in controlling adrenal function and differentiation under normal as well as under physiological stimulation of AII production following sodium restriction.

Adrenal Glands↗
PubMed2006

Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years' experience.

CONTEXT: Primary adrenal failure is a life-threatening condition that can be caused by a range of etiologies, including autoimmune, metabolic, and developmental disorders. The nuclear receptors DAX1 (NR0B1) and steroidogenic factor-1 (SF1/Ad4BP, NR5A1) play an important role in adrenal development and function, and mutations in these transcription factors have been found in patients with adrenal hypoplasia. OBJECTIVE: Our objective was to investigate the prevalence of DAX1 and SF1 mutations in children and adults with primary adrenal failure of unknown etiology (i.e. not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease). PATIENTS: One hundred seventeen patients were included. Eighty-eight individuals presented in infancy or childhood with adrenal hypoplasia or primary adrenal failure of unknown etiology (n = 64 46,XY phenotypic males; n = 17 46,XY gonadal dysgenesis/impaired androgenization; n = 7 46,XX females). Twenty-nine individuals presented in adulthood with Addison's disease of unknown etiology. METHODS: Mutational analysis of DAX1 (NR0B1) (including exon 2alpha/1A) and SF1 (NR5A1) was done by direct sequencing. RESULTS: DAX1 mutations were found in 58% (37 of 64) of 46,XY phenotypic boys referred with adrenal hypoplasia and in all boys (eight of eight) with hypogonadotropic hypogonadism and a family history suggestive of adrenal failure in males. SF1 mutations causing adrenal failure were found in only two patients with 46,XY gonadal dysgenesis. No DAX1 or SF1 mutations were identified in the adult-onset group. CONCLUSIONS: DAX1 mutations are a relatively frequent cause of adrenal failure in this group of boys. SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals.

Adolescent↗
PubMed1998

Corticotropin regulates vascular endothelial growth factor expression in human fetal adrenal cortical cells.

The human adrenal cortex has a complex vasculature that is essential for growth, organ maintenance, and access of secreted hormones to the circulation. Growth and function of the adrenal cortex are regulated by corticotropin (ACTH), the actions of which are in part mediated by locally produced growth factors. As cortical growth and vascularization must increase in a coordinated manner, we hypothesized that ACTH also influences adrenal cortical angiogenesis by stimulating the local expression of specific angiogenic factors. Vascular endothelial growth factor (VEGF) is a potent endothelial cell-specific angiogenic peptide, the expression of which has been detected in adrenal cortical cells. Therefore, we examined the localization of VEGF expression in the midgestation (16-20 weeks) human fetal adrenal cortex and determined whether VEGF expression and secretion by isolated human fetal adrenal cortical cells are regulated by ACTH. By immunohistochemical analysis, strong cytoplasmic staining for VEGF was detected in scattered clusters of fetal zone (inner cortical compartment) cells. In contrast, cells in the outer, definitive zone of the cortex stained only weakly for VEGF. The predominant staining for VEGF in the fetal zone correlated with the extensive vasculature of this zone as detected by immunohistochemical staining for von Willebrand factor, which is specific for endothelial cells. In primary cultures of human fetal adrenal cortical cells, ACTH (1 nmol/L) and forskolin (10 micromol/L) increased the abundance of messenger ribonucleic acid transcripts encoding VEGF, as assessed by Northern and slot blot analyses. The stimulatory effect of ACTH and forskolin on VEGF gene expression occurred within 2 h of agonist exposure and persisted for at least 24 h. ACTH and forskolin also increased VEGF protein secretion by fetal adrenal cortical cells, as assessed by enzyme-linked immunosorbent assay for VEGF in fetal adrenal cortical cell-conditioned medium. A significant (P < 0.05) increase in VEGF secretion was detected as early as 8 h after ACTH or forskolin treatment. By 24 h after the addition of ACTH or forskolin, VEGF secreted from isolated human fetal adrenal cells was increased 5- to 6-fold. These data demonstrate that the human fetal adrenal cortex, particularly the cells of the inner fetal zone, express VEGF and that VEGF expression and secretion by these cells are directly regulated by ACTH and the activation of adenylate cyclase. Thus, VEGF may be a local regulator of adrenal cortical angiogenesis and an important mediator of the tropic action of ACTH, ensuring the coordination of ACTH-stimulated cortical growth and vascularization.

Adrenal Cortex↗
PubMed1998

Corticotropin-releasing hormone directly and preferentially stimulates dehydroepiandrosterone sulfate secretion by human fetal adrenal cortical cells.

Estrogens produced by the placenta play a pivotal role in the endocrine control of pregnancy and induce many of the key changes involved in parturition. The placentae of humans and higher primates use the C19 androgen dehydroepiandrosterone sulfate (DHEA-S) supplied by the fetal adrenals as the principal substrate for estrogen synthesis. Thus, secretion of androgens by the fetal adrenals may be central to the process of primate parturition. The timing of human parturition also is correlated with placental CRH concentrations in the maternal circulation. Because the mechanisms that regulate DHEA-S production by the fetal adrenals are incompletely understood, we examined whether there is a functional relationship between CRH and steroid production by human fetal adrenal cortical cells. Using Northern blot analysis, we detected messenger RNA transcripts (2.7 kb) encoding the type-1 CRH receptor in total RNA extracted from midgestation human fetal adrenals, suggesting that the fetal adrenal cortex may be directly responsive to CRH. To test this, primary cultures of human fetal adrenal cortical cells were exposed to human CRH. Human CRH increased DHEA-S production by cultured human fetal adrenal cortical cells in a dose-dependent fashion, with an ED50 of 10-100 pmol/L. Human CRH was as effective as ACTH at stimulating DHEA-S production; however, it was 70% less potent than ACTH at stimulating cortisol production, indicating that its actions were preferentially directed toward increasing DHEA-S synthesis. Consistent with this thesis, we found that CRH increased abundance of messenger RNA encoding cytochrome P450 cholesterol side-chain cleavage and 17alpha-hydroxylase/17,20 lyase but not 3beta-hydroxysteroid dehydrogenase in adrenal cells. CRH did not alter cell number, indicating that it is not mitogenic for fetal adrenal cortical cells. These data demonstrate a direct functional interaction between CRH and the fetal adrenal. Therefore, placental CRH production, which rises exponentially during human pregnancy, may play a key role in promoting DHEA-S production by the fetal adrenals, which could lead to increasing placental estrogen synthesis and contribute to the process of parturition in humans.

Adrenal Cortex↗
PubMed1992

A circadian rhythm in adrenal responsiveness to ACTH is not confirmed by in vitro studies.

From in vitro studies a circadian variation in adrenal gland response to ACTH was observed. Regulation of this circadian rhythm in adrenal responsiveness was localized to the cellular level; involving variation in either receptor density or affinity. In the present study the circadian variation in adrenal gland responsiveness was studied using an in vitro approach. Levels of corticosterone secretion during the active and inactive phases were determined using incubated rat adrenal slices in the presence and absence of submaximal stimulation by the synthetic ACTH peptide, ACTH(1-24). Initially, a circadian difference in adrenal responsiveness appeared to exist in all groups except the betamethasone pretreated. However, data expressed in terms of corticosterone secretion/mg adrenal weight proved to be misleading due to the presence of an apparent circadian pattern in adrenal gland weight; the adrenal glands from animals in the dark being significantly less in weight than those from animals in the light phase. When the data were expressed in terms of actual gland output, no circadian variation in adrenal response to exogenous ACTH(1-24) stimulation was apparent. In conclusion, the present study does not support the concept of a circadian variation in the adrenal response to ACTH(1-24) stimulation resulting from a variation in the responsiveness of the adrenal cells themselves. However, the present study does not preclude the possibility of a circadian variation due to modulation of adrenal responsiveness by humoral factor(s) other than ACTH.

Adrenal Glands↗
PubMed1989

Effect of fetal hypophysectomy on the localization of the catecholamine biosynthetic enzymes and enkephalins in the adrenal medulla of the fetal sheep.

We have investigated the effect of fetal hypophysectomy on the localization of dopamine B-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT) and enkephalin-containing peptides in the fetal sheep adrenal, using immunocytochemical techniques. Staining with anti-DBH was observed throughout the adrenal medulla in the intact (140-146 days of gestation) and hypophysectomized fetal sheep (147-164 days of gestation) and the newborn lamb (10-12 days after birth). In the adrenal medulla of the late-gestation intact fetal sheep and newborn lamb, positive staining with anti-PNMT was observed in the peripheral rim of medullary cells adjacent to the adrenal cortex. After hypophysectomy, there was intense positive staining with anti-PNMT in the peripheral adrenal medullary cells and a small and variable proportion of central adrenal medullary cells were stained with anti-PNMT. In the adrenal gland of the intact fetal sheep and the newborn lamb, there was intense staining with anti-enkephalin in the peripheral rim of adrenal medullary cells. Staining with anti-enkephalin was less intense in the central medullary cells of the adrenal gland of the intact fetal sheep and the 10- to 12-day-old newborn lamb, and many unstained central medullary cells were present. After hypophysectomy, intense positive staining with anti-enkephalin was observed throughout the entire fetal adrenal medulla. Therefore, the fetal pituitary, either directly or indirectly through the adrenal cortex, plays a role in regulating the pattern of localization of both PNMT and enkephalin in the fetal sheep adrenal.

Adrenal Medulla↗