Biomedical subjects

B R Carr

Publications and source records attributed to B R Carr.

At least 109 records · Page 6Linked to original sources

PubMed1986

The role of calcium in steroidogenesis in fetal zone cells of the human fetal adrenal gland.

The human fetal adrenal gland is composed primarily of fetal zone (FZ) cells, which have a high rate of steroidogenesis. The purpose of this study was to examine the role of calcium in the regulation of steroidogenesis by FZ cells. Dispersed FZ cells were incubated in Krebs-Ringers medium at 37 C for 3 h in the presence of ACTH, (Bu)2cAMP, or forskolin in addition to various drugs. The medium contents of dehydroepiandrosterone sulfate (DS), cortisol (F), and cAMP were quantified by RIA. After the addition of ACTH (10(-10)-10(-5) M), DS and cAMP secretion increased. The addition of EGTA to the medium inhibited ACTH- and forskolin-stimulated DS, F, and cAMP secretion by 50% as well as (Bu)2cAMP-stimulated steroidogenesis. The addition of calcium (10(-5)-10(-2) M) had only a slight effect on the secretion of DS or F in the absence of ACTH or (Bu)2cAMP. In the presence of ACTH and (Bu)2cAMP, however, increasing amounts of calcium resulted in a 2- to 3-fold increase in the rates of DS and F secretion. The addition of either A23187, a calcium ionophore, or verapamil, a calcium channel blocker, inhibited ACTH-stimulated DS and F secretion by 90%. The rate of cAMP formation was greater after ACTH plus verapamil treatment than after ACTH treatment alone, whereas A23187 inhibited ACTH-stimulated cAMP secretion to basal levels. Both A23187 and verapamil inhibited ACTH- and cAMP-stimulated pregnenolone secretion. The metabolism of 22R-hydroxycholesterol to pregnenolone was inhibited by A23187 and verapamil. In conclusion, our results suggest that extracellular calcium is important for activation of the human adrenal FZ cell adenylate cyclase system, while intracellular calcium plays a multifaceted role in controlling steroid production.

Adenylyl Cyclases↗

PubMed1986

The action of phorbol ester on steroidogenesis in cultured human fetal adrenal cells.

The potent mitogen and tumor promoter, phorbol 12-myristate 13-acetate (PMA), has a primary action via activation of calcium-dependent protein kinase C. The treatment of monolayer cultures of human fetal adrenal neocortex (HFA) cells with PMA (50-250 nM) stimulated basal dehydroepiandrosterone sulfate (DS) secretion 2-3 fold. ACTH-treated HFA cells secreted amounts of DS and cortisol (F) 10-50 fold greater than basal secretions. PMA (250 nM) addition with ACTH to HFA cells decreased DS and F secretions at least 75% on days 2 and 3 of treatment. Treatment of HFA cells with 4 alpha-phorbol, which does not activate calcium-dependent protein kinase C, did not inhibit steroidogenesis. The attenuated rates of steroidogenesis after PMA treatment correlated with the decreased amounts of steroid 11 beta, 17 alpha- and 21-hydroxylase cholesterol side-chain cleavage steroid dehydrogenase and sulfotransferase activities. The decrease of steroid 17 alpha-hydroxylase activity correlated with the decreased amount of cytochrome P-450(17) alpha as determined after protein immunoblotting of NaDodSO4 cell lysates. After PMA treatment the ACTH-promoted increases of hydroxysteroid sulfotransferase and dehydrogenase activities of HFA cells were suppressed. PMA (50 nM) inhibited cAMP accumulation in ACTH-treated HFA cells, while 4 alpha-phorbol had no effect. Importantly, dibutyryl cAMP (0.2 mM) treatment of HFA cells did not reverse phorbol ester-promoted attenuation of steroidogenesis. We conclude that, in the presence of ACTH, phorbol ester chronically inhibits both cAMP synthesis and cAMP-dependent protein kinase action with resultant decreased steroidogenic enzyme synthesis and steroid production. This may be a consequence of activation, migration and a slow degradation of protein kinase C activity. These multifaceted actions of phorbol ester and associated protein kinase C activation may have critical effects on the ontogeny of fetal adrenal function.

Adrenal Cortex↗

PubMed1986

Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deficiency and X-linked ichthyosis.

PSD-X-linked ichthyosis are manifestations of a similar disorder of an inborn error of metabolism characterized by a deficiency of steroid sulfatase. The decreased enzyme activity is due to the absence of the expression of enzyme (steroid sulfatase) protein. Affected individuals with this disorder are males (X-linked inheritance) with a frequency of 1/2000 to 1/6000 births. Homozygous females from cosanguineous marriages have been reported with this disorder. The diagnosis is suspected and confirmed by: Low estriol excretion; Negative DHEAS loading test Increased DHEAS in amnionic fluid; Normal DHEAS in cord plasma; Possible delayed or abnormal labor patterns; Decreased sulfatase activity in the placenta, fibroblast, erythrocytes, lymphocytes or leukocytes of affected individuals; Development of ichthyosis in male infants at 2 to 3 months of age.

Chromosome Mapping↗

PubMed1986

Ovarian and tubal inguinal hernia.

An inguinal hernia containing an ovary and fallopian tube is an extremely rare occurrence in a woman of reproductive age. When ovarian and fallopian tube inguinal hernias are found, they are commonly associated with defects in genital tract development. In this report a woman with primary amenorrhea, 46XX karyotype, mullerian agenesis, and an inguinal hernia consisting of an ovary and a fallopian tube is presented. The defect in embryologic development that leads to this disorder and a review of previous reports of ovarian and tubal inguinal hernias are discussed.

Adult↗

PubMed1985

3-Hydroxy-3-methylglutaryl coenzyme A reductase in anencephalic and normal human fetal liver.

In previous investigations, we have found that the liver appears to be the major source of cholesterol in the human fetus, and, in particular, a principal source of circulating low density lipo-protein-cholesterol (LDL-C). LDL-C plasma levels are low in the normal fetus, most likely due to the rapid uptake and metabolism by the fetal adrenal as precursor for steroid hormone biosynthesis. In contrast, in the anencephalic fetus the adrenals are atrophic, the rate of estrogen and glucocorticoid production is low, and the levels of LDL-C in fetal plasma are high. The purpose of the present investigation was to determine the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the primary rate-limiting enzyme of cholesterol biosynthesis, in anencephalic liver and normal fetal liver. We found that the specific activity of HMG-CoA reductase in normal fetal liver microsomes was 0.428 +/- 0.054 nmol mevalonate formed times mg-1 protein X min-1 (mean +/- SE, n = 9). The rate of HMG-CoA reductase in anencephalic liver microsome preparations was 10-fold less (0.040 +/- 0.003) (mean +/- SE, n = 7) P less than 0.001. Furthermore, we detected HMG-CoA reductase (97,000-mol wt protein) in normal human fetal liver after SDS PAGE and immunoblotting by using a monoclonal antibody directed against HMG-CoA reductase. We were unable to detect any significant quantity of HMG-CoA reductase protein in anencephalic fetal liver, which indicates that low reductase activity was due to low amounts of enzyme protein rather than inactive enzyme. In summary, we conclude that the low levels of cholesterol synthesis observed in anencephalic fetal liver are probably due to both the high levels of LDL-C in fetal plasma as well as the presence of low circulating levels of estrogens and glucocorticoids and that these factors regulate cholesterol synthesis both in vivo and in vitro in fetal liver. This occurs most probably by the modulation of the amount of HMG-CoA reductase, a primary rate-limiting and regulatory enzyme of the cholesterol biosynthetic sequence.

Anencephaly↗

PubMed1985

Factors affecting the conversion of androstenedione to estrogens by human fetal hepatocytes in monolayer culture.

The purpose of the present investigation was to characterize and determine what hormones affect the activity of aromatase in human fetal hepatocytes maintained in primary monolayer culture. The major product of aromatization of androstenedione was estrone sulfate. Optimal conditions for assay of aromatase activity in fetal liver cells were determined. The apparent Km for androstenedione was 50 nM. Aromatase activity was stimulated by glucocorticoids in the presence of fetal calf serum. The concentration of dexamethasone required for half-maximal stimulation was 10(-8) M, similar to the concentration required for half-maximal binding to glucocorticoid receptors. This action of dexamethasone was inhibited by cortisol 21-mesylate, a glucocorticoid antagonist. Aromatase activity was also stimulated by (Bu)2cAMP and cholera toxin, and was inhibited by fetal calf serum. This effect of fetal calf serum was mimicked by epidermal growth factor. However, epidermal growth factor did not mimic the permissive action of serum to stimulate aromatase activity by dexamethasone. In these respects, the regulation of aromatase activity of human fetal hepatocytes is similar to that of human adipose stromal cells. A polycyclic hydrocarbon, benzo(a)pyrene, which causes induction of aryl hydrocarbon hydroxylase activity in fetal hepatocytes, inhibited the stimulation of aromatase activity by dexamethasone. Of a number of hormones tested, including glucagon, insulin, angiotensin II, ACTH, hCG, GH, PRL, and T3, only glucocorticoids were effective in stimulating aromatase activity of human fetal hepatocytes. These results emphasize the complex and multiparameter nature of the regulation of aromatase activity in this as in other tissues.

Androstenedione↗

PubMed1985

Adenylate cyclase activity in neocortex and fetal zone membrane fractions of the human fetal adrenal gland.

Whether peptide hormones other than ACTH may be responsible for the difference in size or rate and pattern of steroidogenesis of the fetal zone (FZ) compared to those of the neocortex (NC) of the human fetal adrenal gland is controversial. In the present investigation, the activity of adenylate cyclase in membrane fractions of separated zones of the human fetal adrenal gland was determined. Basal adenylate cyclase activity was 2- to 3-fold greater in NC than in FZ membrane fractions. The addition of ACTH-(1-24) stimulated adenylate cyclase activity in both zones, but the activity was more sensitive to ACTH (10(-10) M) in NC fractions than in FZ fractions (10(-7) M). In addition to ACTH-(1-24), the effect of other ACTH-related peptides on the activity of adenylate cyclase in the separated zones of the adrenal gland was investigated. 16K fragments 2-36, gamma 3MSH, alpha MSH, beta-endorphin, leu-enkephalin, and met-enkephalin, as well as hCG, FSH, prostaglandin E2, prostaglandin F2 alpha, epinephrine, and norepinephrine did not stimulate adenylate cyclase activity in either zone. It is concluded that basal and ACTH-(1-24)-stimulated adenylate cyclase activities are greater in NC than in FZ membrane fractions. In addition, the results of the present investigation do not support the concept that other ACTH-related peptides or peptide or protein hormones increase steroidogenesis by stimulating adenylate cyclase activity in the human fetal adrenal gland.

Adenylyl Cyclases↗

PubMed1984

Umbilical cord plasma concentrations of deoxycorticosterone sulfate in anencephalic fetuses.

In the present investigation, we determined the levels of deoxycorticosterone sulfate in mixed umbilical cord plasma of anencephalic abortuses and newborn infants. The anencephalic fetus is an interesting model with respect to the production of deoxycorticosterone and deoxycorticosterone sulfate on several accounts. There is profound adrenal atrophy in most such fesuses, and, in consequence, there also is relatively profound hypoestrogenism. This is an important consideration in the formation of deoxycorticosterone and deoxycorticosterone sulfate since it is known that estrogen acts to stimulate extra-adrenal steroid 21-hydroxylase and 21-hydroxysteroid sulfotransferase activities. The plasma levels of deoxycorticosterone sulfate in 22 anencephalic abortuses and newborn infants delivered between 21.5 and 45.5 weeks of gestation ranged from 1.8 to 30.3 ng/ml. The concentrations of deoxycorticosterone sulfate in umbilical cord plasma of anencephalic fetuses and newborn infants were not related to gestational age or method of delivery and, at term, were less than 13% of those in umbilical cord plasma of normal newborn infants. These data can be interpreted to indicate (1) that deoxycorticosterone sulfate normally is secreted directly by the fetal adrenal or (2) that placental estrogen normally derived largely from fetal adrenal dehydroisoandrosterone sulfate is essential for the maintenance of plasma deoxycorticosterone sulfate levels in the fetus by stimulating extra-adrenal deoxycorticosterone sulfate production from plasma progesterone, or both.

Abnormalities, Multiple↗

PubMed1984

Cholesterol synthesis by human fetal hepatocytes: effect of lipoproteins.

The purpose of the present investigation was to determine the effect of various lipoproteins on the rate of cholesterol synthesis of human fetal liver cells maintained in culture. This was accomplished by measuring the rate of incorporation of tritium from tritiated water or carbon 14-labeled acetate into cholesterol in human fetal liver cells. Optimal conditions for each assay were determined. When human fetal liver cells were maintained in the presence of low-density lipoprotein, cholesterol synthesis was inhibited in a concentration-dependent fashion. Intermediate--density lipoprotein and very-low-density lipoprotein also suppressed cholesterol synthesis in human fetal liver cells. In contrast, high-density lipoprotein stimulated cholesterol synthesis in human fetal liver cells. The results of the present as well as our previous investigations suggest that multiple interrelationships exist between fetal liver cholesterol synthesis and lipoprotein-cholesterol utilization by the human fetal adrenal gland and that these processes serve to regulate the lipoprotein-cholesterol levels in fetal plasma.

Acetates↗

PubMed1984

The effect of hypertension in pregnant women on fetal adrenal function and fetal plasma lipoprotein-cholesterol metabolism.

In the present investigation, we evaluated the effect(s) of long-term hypertension and pregnancy-induced hypertension in women on the activity of the adrenals of their fetuses. We measured dehydroisoandrosterone sulfate, cortisol, and lipoprotein-cholesterol in umbilical cord plasma of newborn infants delivered (30 to 41 weeks' gestation) of 120 women whose pregnancies were uncomplicated and of 98 women with pregnancy-induced or long-term hypertension. Umbilical cord plasma levels of cortisol were similar in both groups of newborn infants at each gestational period. Fetal plasma levels of dehydroisoandrosterone sulfate also were similar in both groups at 30 to 33 weeks of gestation but were significantly reduced in newborn infants of hypertension women who were delivered between 34 and 41 weeks of gestation compared with those of newborn infants of normal women who were delivered at a similar gestational age. At term, umbilical cord plasma levels of total cholesterol and low-density lipoprotein-cholesterol were significantly higher in the newborn infants of hypertensive women compared with those levels in newborn infants of normotensive women; fetal plasma levels of high-density lipoprotein-cholesterol and very low-density lipoprotein-cholesterol were similar in both groups of newborn infants. The lowest plasma levels of dehydroisoandrosterone sulfate and the highest plasma levels of total cholesterol and low-density lipoprotein-cholesterol were found in newborn infants of women with the most severe pregnancy-induced hypertension. Based on these findings, we conclude that maternal hypertension effects a decrease in the rate of steroidogenesis of the fetal zone of the fetal adrenal cortex but does not act in a similar manner to effect steroidogenesis of the neocortical zone and leads to hypercholesterolemia in the fetus as a consequence of reduced adrenal utilization of low-density lipoprotein-cholesterol. In addition, the effects of pregnancy-induced hypertension appear to be manifest in the fetus late in pregnancy at a time when the fetal adrenal normally undergoes an accelerated rate of growth and steroid biosynthesis.

Adrenal Glands↗

PubMed1984

Cholesterol synthesis by human fetal hepatocytes: effects of hormones.

In previous investigations, we found high rates of cholesterol synthesis in human fetal liver tissue, second only to rates in fetal adrenal tissue. Previous estimates of the amount of cholesterol in the fetus derived from the maternal compartment are in the range of 20%. Thus, the liver may be the principal source of circulating lipoproteins in the human fetus, as is true in the human adult. Low density lipoprotein is the major source of cholesterol used for fetal adrenal steroidogenesis; therefore, it follows that factors regulating cholesterol synthesis in the human fetal liver may indirectly control the rate of steroid secretion by the adrenal cortex. The purpose of the present investigation was to determine if hormones, particularly those produced by the fetal-placental unit, might serve to stimulate cholesterol synthesis in the human fetal liver. The rate of cholesterol biosynthesis was determined by measuring the rate of incorporation of [3H]water into [3H]cholesterol in hepatocytes maintained in culture or by determination of the specific activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase in microsomal preparations from human fetal liver. The addition of dexamethasone (10(-10) - 10(-6)M) stimulated cholesterol synthesis up to 2- to 4-fold between days 2 and 6 of exposure. When human fetal liver cells were maintained in the presence of dexamethasone (10(-7)M), the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase in microsomal fractions was stimulated 4-fold compared to that in control cells. Cortisol also stimulated cholesterol biosynthesis in a concentration-dependent manner. The addition of 17 beta-estradiol (E2) to the culture medium resulted in stimulation of cholesterol biosynthesis in a concentration-dependent manner from 10(-10) - 10(-7)M. The rate of cholesterol synthesis when E2 was present (10(-7)M) was 4-fold greater than that in untreated cells. Stimulation of cholesterol synthesis by E2 was maintained between 2-7 days of incubation with E2. Estrone, estriol, and E2 (10(-6)M) caused similar increases (3- to 4-fold) in the rates of cholesterol synthesis in human fetal hepatocytes. Finally, progesterone in concentrations greater than 10(-6) M significantly stimulated cholesterol synthesis in human fetal liver cells. In contrast, other hormones and factors, including insulin, glucagon, PRL, GH, dehydroepiandrosterone and its sulfate, epidermal growth factor, fibroblast growth factor, T3, (Bu)2cAMP, and cholera toxin, had no effect on the rate of cholesterol synthesis in human fetal liver cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Cells, Cultured↗

PubMed1983

Ontogeny of human fetal plasma progesterone, deoxycorticosterone, and deoxycorticosterone sulfate.

The concentrations of progesterone, deoxycorticosterone (DOC), and deoxycorticosterone sulfate (DOC-SO4) were determined in mixed umbilical cord plasma of abortuses and newborn infants delivered between 18 and 42 weeks' gestation. A wide range of values among individual samples was found for progesterone (224 to 2,152 ng/ml), DOC (1.6 to 10.4 ng/ml), and DOC-SO4 (17 to 154 ng/ml). Levels of progesterone and DOC in mixed umbilical cord plasma were not correlated; those of DOC and DOC-SO4 were positively correlated significantly (r = 0.3945, P less than 0.001). Whereas the mean plasma levels of DOC were similar throughout gestation, significant variation, as a function of gestational age, was found for progesterone and DOC-SO4, with levels of these steroids generally being higher near term than earlier in gestation. The administration of glucocorticosteroids to the mother resulted in a significant decrease (p less than 0.001) in plasma concentrations of DOC and DOC-SO4 in the newborn infant; levels of progesterone in umbilical cord plasma were not affected by maternal glucocorticosteroid treatment. These results suggest that the fetal adrenal glands play a direct, or possibly an indirect, role in the production of the DOC and DOC-SO4 that is present in the fetal compartment. In addition, since fetal plasma levels of progesterone are quite high throughout gestation, the potential exists for circulating progesterone to serve as a precursor for adrenal and extra-adrenal production of DOC and DOC-SO4.

Desoxycorticosterone↗

PubMed1983

Extra-adrenal deoxycorticosterone production in hypoestrogenic pregnancies: Serum concentrations of progesterone and deoxycorticosterone in anencephalic fetuses and in women pregnant with an anencephalic fetus.

In a continuing effort to define the origin of and the regulation of the production of deoxycorticosterone, we measured deoxycorticosterone and progesterone in the umbilical cord plasma of 16 anencephalic fetuses and newborn infants (21 to 45 weeks' gestation) and deoxycorticosterone, progesterone, 17 beta-estradiol, and estriol in the plasma of 18 women pregnant (16 to 45 weeks) with an anencephalic fetus. Whereas umbilical cord plasma levels of progesterone in the anencephalic fetuses were similar to those of normal abortuses and newborn infants, those of deoxycorticosterone (1.3 +/- 0.21 ng/ml, mean +/- SE) were significantly lower (P less than 0.001) than those in normal abortuses and newborn infants delivered between 31 and 42 weeks' gestation (3.94 +/- 0.26 ng/ml). We found that plasma levels of deoxycorticosterone were significantly correlated (P less than 0.001) to those of progesterone in women pregnant with an anencephalic fetus, as well as in women pregnant with a normal fetus. Plasma levels of deoxycorticosterone (range = 0.14 to 0.92 ng/ml) in women pregnant with an anencephalic fetus were significantly lower than those in women pregnant with a normal fetus; plasma levels of progesterone were similar in both groups. The plasma levels of 17 beta-estradiol and of estriol were extremely low in women pregnant with an anencephalic fetus compared with those in women with a normal fetus and did not vary as a function of gestational age. In one subject who was pregnant with an anencephalic fetus, we found that estrogen treatment (100 mg of diethylstilbestrol/day) for 6 days caused a progressive increase in the serum levels of deoxycorticosterone and in the ratio of the concentration of concentration of deoxycorticosterone to that of progesterone in serum. Both the serum levels of deoxycorticosterone and the ratio of the concentration of deoxycorticosterone and in the ratio of the concentration of deoxycorticosterone to that of progesterone declined after cessation of estrogen treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Glands↗

PubMed1983

Regulation of human fetal testicular secretion of testosterone: low-density lipoprotein-cholesterol and cholesterol synthesized de novo as steroid precursor.

The results of the present investigation support the conclusion that low-density lipoprotein (LDL)-cholesterol facilitates androgen synthesis in human chorionic gonadotropin (hCG)-treated human fetal testicular tissue in vitro. Moreover, the number of LDL receptors and the rate of de novo synthesis of cholesterol are high during the period of active fetal testicular steroidogenesis and fall with advancing gestational age, suggestive of regulation by hCG.

Androstenedione↗

PubMed1983

Decline in the concentration of low-density lipoprotein-cholesterol in human fetal plasma near term.

Fetal plasma levels of lipoprotein-cholesterol were quantified during the latter stages of normal human gestation to ascertain whether a relationship exists between fetal adrenal steroid production and the concentration of plasma lipoprotein-cholesterol. It was found that total cholesterol and low-density lipoprotein (LDL)-cholesterol levels in fetal plasma declined progressively from 33 to 42 weeks of gestation. At 41 to 42 weeks of gestation, the fetal plasma concentrations of total cholesterol (53 +/- 3 mg/dL, mean +/- SEM) and of LDL-cholesterol (28 +/- 2 mg/dL) were significantly lower (P less than 0.001) than those at 33 to 34 weeks of gestation (73 +/- 7 mg/dL and 49 +/- 6 mg/dL, respectively). However, there were no fluctuations in the plasma concentrations of high-density lipoprotein (HDL)-cholesterol during this period of fetal development. The fetal plasma levels of dehydroepiandrosterone sulfate (DS), the major secretory product of the fetal adrenals, rose significantly between 33 and 42 weeks of gestation. Since LDL-cholesterol is utilized as substrate for fetal adrenal steroidogenesis, it is suggested that the increasing rate of growth and steroid production by the fetal adrenals near term is causally related to the significant decline in the concentration of both LDL-cholesterol and total cholesterol in fetal plasma during normal human development.

Cholesterol↗

PubMed1983

Effect of prostaglandins on steroid secretion by human fetal adrenal tissue.

In the present investigation we evaluated the effect of prostaglandins on the rate of steroid secretion by human fetal adrenal (HFA) tissue. Prostaglandins F2 alpha and E2 (10 micrograms/ml) were added to the culture medium in the presence or absence of ACTH (1 micrograms/ml). The medium was assayed for content of cortisol (F), dehydroepiandrosterone sulfate (DS) and pregnenolone sulfate (PS) by radioimmunoassay. When HFA tissue fragments were maintained in the absence of ACTH, F secretion was low; PGF2 alpha but not PGE2 suppressed F secretion by 60-65%. When ACTH was added to the culture medium, the secretion rate of F increased 15-fold, whereas DS and PS secretion was maintained at or near initial rates of secretion. The addition of PGF2 alpha to the culture medium containing ACTH resulted in a 80% decrease in F secretion, but PGE2 only suppressed F secretion by 50%. In contrast, PGE2 or PGF2 alpha had little effect on the rate of DS or PS secretion either in the presence or absence of ACTH. In conclusion, prostaglandins appear to inhibit the secretion of F, but not of DS or PS by the HFA.

Adrenal Glands↗

PubMed1983

Hypercholesterolemia due to elevated low density lipoprotein-cholesterol in newborns with anencephaly and adrenal atrophy.

In the present investigation, we evaluated the relationship between plasma lipoprotein-cholesterol and adrenal steroid production in abortuses and newborns in whom the adrenal was expected to be atrophic, i.e. in anencephalics. We found that umbilical cord plasma levels of dehydroepiandrosterone sulfate (DS) in 23 anencephalics delivered between 13.5 and 45.5 weeks of gestation (mean +/- SE, 176 +/- 37 ng/ml) were significantly lower than those in normal newborns of similar gestational ages; the umbilical cord plasma concentrations of cortisol in many anencephalics, however, were within normal limits. The levels of total cholesterol (134 +/- 10 mg/dl) and low density lipoprotein (LDL)-cholesterol (94 +/- 8 mg/dl) were substantially higher (up to 4-fold) in umbilical cord plasma of anencephalics than in umbilical cord plasma of normal newborns. The mean level of high density lipoprotein-cholesterol in umbilical cord plasma of anencephalic abortuses and newborns (38 +/- 4 mg/dl) was approximately 50% higher than that in normal newborns. The lowest plasma cholesterol level (56 mg/dl) and a concentration of DS (480 ng/ml) that was among the highest seen in the group of anencephalics were found in an anencephalic newborn in whom adrenals were of near-normal weight. Plasma cholesterol levels were inversely correlated to adrenal weights and plasma DS levels, and plasma DS levels were correlated to adrenal weight. Whereas the estimated plasma pool of DS in normal newborns increased to over 300 micrograms during the latter part of gestation, that of anencephalic newborns was much lower (less than 1 to 26 micrograms) and did not appear to increase as a function of gestational age. Conversely, the estimated plasma pool of cholesterol in normal newborns appeared to decline slightly during the last 10 weeks of gestation (80 mg at term), whereas that of anencephalic newborns expanded greatly near term; levels (approximately 200 mg) were attained that were about 3 times those in normal newborns. We conclude that the hypercholesterolemia in anencephalic newborns, due primarily to extremely elevated plasma levels of LDL-cholesterol, is a result of decreased uptake and utilization of plasma LDL-cholesterol for steroid biosynthesis by the adrenals. Since hypercholesterolemia is apparently early in gestation in anencephalic abortuses, we speculate that in normally developing fetuses, plasma LDL-cholesterol is used as substrate for adrenal steroidogenesis early in gestation as well as near term when the rates of growth and steroid production by the adrenals accelerate markedly.

Adrenal Glands↗

PubMed1983

Prostaglandin secretion by the neocortex and fetal zones of the human fetal adrenal gland.

Previously, we reported that the human fetal adrenal (HFA) gland secretes various prostaglandins (PGs) in vitro and that PG secretion is inhibited by endogenously synthesized glucocorticosteroids. In this investigation, the neocortex (NC) and fetal zone (FZ) of the HFA gland were separated by microdissection and maintained as tissue fragments in organ culture. The rate of PG secretion into the culture medium was determined by measuring various PGs using specific RIAs in media collected at 24-h intervals. During the first 24 h in culture, the secretion rates of PGF2 alpha and PGE2 were 6- and 7-fold greater by NC [14 +/- 5 and 9.9 +/- 3 ng mg protein-1 24 h-1 (mean +/- SE)], respectively, than by FZ tissue (2.5 and 1.4 ng mg protein-1 24 h-1). The secretion rates of PGFM and PGD2 were 2-fold greater in NC tissue than in FZ tissue, but the secretion rates of thromboxane B2 were similar in both zones of HFA tissue. In another study, the patterns of secretion of PGF2 alpha and PGE2 were determined as a function of days in culture. The secretion rates of PGF2 alpha and PGE2 fell rapidly in NC from 19.0 +/- 11 and 38.3 +/- 9.7 ng mg protein-1 24 h-1, respectively, to 1.3 +/- 7.2 and 4.8 +/- 3.3 by day 4. In contrast, the secretion rates of PGF2 alpha and PGE2 rose 8- and 3-fold in FZ tissue (from 0.7 +/- 0.2 and 0.9 +/- 0.6 ng mg protein-1 24 h-1, respectively, to 5.9 +/- 0.5 and 3.1 +/- 1.2 by day 4). The addition of ACTH or dexamethasone inhibited PG secretion in both zones, but to a greater degree in FZ tissue than in NC tissue. In summary, the NC secretes larger quantities of PG than the FZ, and the patterns of secretion are different in the two zones. The secretion of PGs is inhibited more in FZ than in NC tissue by ACTH and glucocorticosteroids.

Adrenal Glands↗