[Acid secretion and hormone levels after several weeks of omeprazole administration].
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Adult↗
Biomedical subjects
T Rabe
Publications and source records attributed to T Rabe.
Inhibition of human placental progesterone and estrogen synthesis in early human gestation by aminoglutethimide in vivo.
The inhibitory effect of d,l-aminoglutethimide (AG) on the synthesis of progesterone and estradiol in early human pregnancy (8th-12th week of gestation) was investigated in volunteers; control group (n = 11), AG group [1000 mg AG orally at test begin (n = 6)]. Venous blood samples were taken at the beginning of the test and 0.5, 1, 2, 4, 8 and 24 h thereafter. In controls, no significant changes in serum progesterone and estradiol could be observed during 24 h. In the AG group, a decrease in progesterone and estradiol could be observed within 1 h after the test began; lowest serum steroid concentrations were reached after 4 h. Relative to the initial values taken as 100%, the greatest decrease in progesterone ranged between 37 and 83%, 62 +/- 15% (means +/- SD)(n = 6); the greatest decrease in estradiol ranged between 32 and 78%, 51 +/- 17% (means +/- SD)(n = 6). Twenty four hours after AG treatment, both steroids reached similar concentrations to those found at test begin. No clinical signs (e.g. uterine bleeding, contractions) for the abortifacient action of AG were observed. In conclusion, a single dose of AG (1000 mg given orally) cannot induce a therapeutic abortion in early pregnancy. In accordance with in vitro studies, the inhibitory effect of AG on placental progesterone formation is due to an inhibition of mitochondrial cholesterol side chain cleavage. The decrease in estradiol is thought to be related to an inhibition of placental aromatase.
Aminoglutethimide↗
Characterization of human cholesterol side chain cleavage enzyme (EC 1.14.15x) of human term placental mitochondria.
The cholesterol side chain cleavage enzyme (EC 1.14.15x) in mitochondria of a human term placenta was partially characterized. Enzyme activity was determined by separation of [26-14C]-cholesterol and [5-14C]-isocaproic acid formed by side chain cleavage. Since the amounts of unlabeled cholesterol were too large, a KM of cholesterol could not be determined. The apparent KM value of NADPH is 6.25 x 10(-4) M. A pH optimum was found at pH 9.5 (Tris buffer) and a temperature optimum at 40 C. The metal ions Sr2+ and Ba2+ showed no inhibition at 1 and 10 mM and a moderate inhibition at 100 mM. In low concentrations (1 mM), Mg2+ and Ca2+ slightly stimulated the enzyme whereas in higher concentrations (100 mM) an inhibitory effect was observed. A strong inhibition was achieved with 1 mM Zn2+, Cd2+, Cu2+ and by 10 and 100 mM Fe2+, Mn2+, Co2+ and Ni2+. During preincubation of the enzyme without radioactive substrate, a rapid loss in enzyme activity in relation to enzyme concentration was observed (initial activity = 100%) (preincubation time in hours): 0.5 h (97%), 1 h (55%) and 1.5 h (34%). A dose-dependent inhibition of the enzyme by the following proteins was achieved: bovine serum protein, human serum protein, human immunoglobulin G and ovalbumin. Furthermore, a dose-dependent inhibition was found with the membrane lipids lecithin and sphingosine.
Cholesterol Side-Chain Cleavage Enzyme↗
Inhibition of human placental progesterone synthesis and aromatase activity by synthetic steroidogenic inhibitors in vitro.
The inhibitory effect in vitro of four synthetic steroids on enzyme systems of placental progesterone synthesis at term was analyzed. Cholesterol side chain cleavage enzyme (CSCC) was not influenced by azastene, trilostane, and WIN 32,729. A 50% inhibition of CSCC was found by 10 microM cyanoketone. The 3 beta-hydroxysteroid dehydrogenase was dose-dependently inhibited by azastene (I50 = 1 microM, trilostane (I50 = 4 nM), cyanoketone (I50 = 3 nM), and WIN 32,729 (I50 = 5 nM). A competitive inhibition of the 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSDH) by azastene (I50 = 0.6 microM), trilostane (I50 = 4.1 microM), cyanoketone (I50 = 0.6 microM), and WIN 32,729 (I50 = 1.5 microM) was observed. No difference in the effect of steroids on the 20 alpha-HSDH of early gestational and term placenta was found. The four steroidogenic inhibitors did not affect the activity of placental aromatase in vitro. Our results allow a comparison of inhibitory potencies of four steroidogenic inhibitors on different steroidogenic enzymes in vitro.
20-Hydroxysteroid Dehydrogenases↗
Inhibition of human placental progesterone synthesis by danazol in vitro.
In vitro, danazol showed a slight dose-dependent inhibition of the mitochondrial cholesterol side chain cleavage enzyme isolated from early gestational (8th to 12th week of gestation) placenta. In the presence of 100 microM danazol, the enzyme activity was 65% of controls. Danazol inhibits dose-dependently the mitochondrial 3 beta-hydroxysteroid dehydrogenase (I50 = 3.1 microM; Ki = 1 microM) (noncompetitive inhibition) and the cytoplasmic 20 alpha-hydroxysteroid dehydrogenase (I50 = 1.4 microM; Ki = 2.6 microM) (competitive inhibition). The inhibition of human placental progesterone synthesis by danazol in vitro is a further example for the direct interference of danazol with steroidogenesis.
20-Hydroxysteroid Dehydrogenases↗
[Regulation of human placental progesterone synthesis].
The steroid hormone progesterone is necessary for the maintenance of human pregnancy. It protects the uterus against the labour-inducing effect of prostaglandins and oxytocine. Before the 8.-9th week of gestation progesterone is produced by the corpus luteum and thereafter by the human placenta. The progesterone production of the human placenta is widely independent of endocrine organs of the mother and the foetus and controlled by autoregulation. Progesterone is formed from cholesterol taken up from the maternal circulation in the form of lipoprotein complexes. After side-chain cleavage of cholesterol pregnenolone is formed, which is converted by a 3 beat-hydroxysteroid dehydrogenase, delta 4-5 isomerase to progesterone. Progesterone is released partly to the mother and via the umbilical cord to the foetus. In the foetus a high conversion to 20 alpha-dihydroprogesterone takes place and this compound is transported to the placenta and recycled to progesterone. The steroidogenic enzymes of the progesterone pathway are controlled by various feedback inhibitions; activators could not be isolated so far.
Cholesterol↗
Diagnosis of intrauterine fetal growth retardation (IUGR) and placental insufficiency by a dehydroepiandrosterone sulfate (DHAS) loading test.
Chronic placental insufficiency results in intrauterine fetal growth retardation (IUGR). The IUGR can be diagnosed by clinical signs (follow-up of maternal weight, fundus height, abdominal circumference), ultrasound examination (biparietal and thoracic diameters, circumferences of the head and the trunk), and by endocrinologic tests (estrogen determination in serum and urine without and after performance of a DHAS loading test). The different ways of performing the DHAS loading test reported in the literature are reviewed. The DHAS loading test measures the aromatization capacity of the human placenta and indirectly its metabolic exchange capacities. After DHAS loading, estrogens (estrone, estradiol, estriol), DHAS and DHA can be determined in blood and urine; furthermore, changes in urine total estrogen excretion can be evaluated. In conclusion, the best parameter for diagnosing IUGR seems to be the determination of the DHAS half-life after DHAS loading. A prolongation of DHAS half-life (greater than 4.7 h) after DHAS loading (50 mg i.v.) is a good index of IUGR.
Circadian Rhythm↗
Sulfatase deficiency in the human placenta: clinical findings.
Sulfatase and aromatase are the key enzymes of estrogen biosynthesis in the human placenta. A total of 76 pregnancies with sulfatase deficiency have been reported. Reduced sulfatase activity occurs in 1:2000 of 1:6000 pregnancies. It can be suspected in patients with low urinary excretion or low serum estriol levels. The sulfatase deficiency can be detected during pregnancy by a prolongation of the half-life of dehydroepiandrosterone sulfate (DHAS) after venous DHAS loading (50 or 100 mg). Post partum the placental sulfatase deficiency can be demonstrated in vitro by nonconversion of radioactive DHAS to DHA. Only 7 of the 76 pregnancies described ended with an uncomplicated vaginal delivery after spontaneous onset of labor. A cesarian section was required in 18 cases. The other case reports mostly concern patients associated with a prolonged pregnancy, lack of cervical dilatation, or absent induction of labor. All 76 newborns were male. Sulfatase deficiency is probably a congenital, sex-specific, X-linked placental enzyme defect. A special therapy is not necessary but the antepartum diagnosis is important because this benign disorder has to be discriminated from the more serious fetal adrenal hypoplasia.
Estriol↗
Influence of human lipoproteins on the progesterone synthesis of human term placenta in organ culture.
In the presence of LDL (200 micrograms/ml) and HDL (400 micrograms/ml), the uptake of radioactive cholesterol by a human term placenta in organ culture was enhanced by about 1.5 and 2.5, respectively, after 24-h incubation. Using cholesterol linoleate, the ratio was 1.0 and 1.5, and the tissue concentration of progesterone was 5-fold higher in the presence of LDL (600 micrograms/ml) than in the presence of HDL (4.4 mg/ml). A dose-dependent increase in medium progesterone was found using either LDL or HDL in combination with cholesterol or cholesterol linoleate, respectively. In human term placenta in organ culture, the human lipoproteins LDL and HDL both have a carrier function for cholesterol and cholesteryl linoleate, stimulate the uptake of these steroids in the placental tissue, and enhance placental progesterone formation. Furthermore, the lipoproteins facilitate progesterone release from the placental tissue.
Cholesterol↗
Partial characterization of the cytoplasmic 20 alpha-hydroxysteroid dehydrogenase (EC 1.1.1.149) of the human placenta at term.
The 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSDH) is a key enzyme in human fetal and maternal progesterone metabolism. In this paper, the cytoplasmic 20 alpha-HSDH of human term placenta is partially characterized in vitro. A 14-fold concentration of the 20 alpha-HSDH was prepared by ultracentrifugation and ammonium sulfate precipitation. The apparent Km values for the substrates progesterone (Km: 4.8 x 10(-5) M) and 20 alpha-DHP (Km: 6.2 x 10(-5) M) and for the cofactors NADPH (Km: 1.9 x 10(-4)) and NADH (Km: 2.6 x 10(-4)) were determined. The temperature optimum for the oxidation of 20 alpha-DHP is 40--50 degrees C. The pH optimum for the reduction of progesterone was found to be pH 6.2 and for the oxidation of 20 alpha-DHP pH 6.5. The addition of glycerol (3 M) to the incubation medium inhibited the conversion rate of 20 alpha-HSDH by 70%. No influence of EDTA could be found. Various bivalent metal ions (1--100 mM) showed a dose-dependent inhibition of 20 alpha-HSDH; a complete inhibition was achieved at 100 mM: Cu2+, Zn2+, Cd2+, Fe2+ and Ni2+.
20-Hydroxysteroid Dehydrogenases↗
Endogenous inhibition of the 20 alpha-hydroxysteroid dehydrogenase (EC 1.1.1.149) in the human term placenta in vitro.
Human placental 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSDH) interconverts progesterone and 20 alpha-dihydroprogesterone (20 alpha-DHP). In this study, an endogenous inhibitor of the cytoplasmic 20 alpha-HSDH isolated from human term placenta is demonstrated. Characterization of the endogenous inhibitor was carried out by adding heat-denatured fractions of the 20 alpha-HSDH enzyme stock solution to the incubations. The aqueous phase of the 20 alpha-HSDH (after diethylether extraction) using 8-fold concentration of the enzyme inhibited the 20 alpha-HSDH activity by 50%. After ultrafiltration of the aqueous phase, this inhibitory effect (50%) was found in the aqueous fraction with a molecular weight above 12,800. No inhibition of the 20 alpha-HSDH was shown using the ether phase or the aqueous ultrafiltrate with a molecular weight below 12,800. The 20 alpha-HSDH was stimulated by human and bovine serum albumins up to 290% and 420% respectively. Bovine serum albumin showed a higher stimulatory effect on the oxidative (420%) than on the reductive (190%) pathway of the 20 alpha-HSDH. Ovalbumin and immunoglobulin G had no effect. The endogenous inhibitor of the cytoplasmic 20 alpha-HSDH isolated from the human term placenta is heat stable (100 degrees C), water soluble, not soluble in diethylether and has a molecular weight above 12,800. The stimulatory effect of serum albumins in 20 alpha-HSDH may be caused by binding and inactivation of the endogenous inhibitor.
20-Hydroxysteroid Dehydrogenases↗
New aromatase assay and its application for inhibitory studies of aminoglutethimide on microsomes of human term placenta.
A new, simple, fast and highly practicable aromatase assay and its application is described. This test depends on the release of tritiated water after aromatization of [1 beta,2 beta-3H]- or [1,2-3H]-androstendione or testosterone. In tests with [1 beta,2 beta-3H]-androstendione, nonradioactivity labeled estrogens are formed whereas in tests using [1,2-3H]-androstendione as substrate both estrogens and water contain tritium atoms. Tritiated water is determined by a two-phase scintillation technique depending on the limited emulsifying capacity of dioxane-based scintillation solution for water. A small volume (0.1 ml) of water is completely emulsified by the scintillation solution (10 ml) and all tritium-labeled substances can be measured. After addition of 2 ml distilled water 95% of the tritiated water is partitioned in the aqueous phase and only (1 beta,2 beta-3H]-androstendione or [1,2-3H]-androstendione and tritium labeled estrogens can be counted. The amount of tritiated water in each test can be calculated by impulse differences before and after addition of 2 ml distilled water. This aromatase assay using [1,2-3H]-androstendione was compared to a method described by Thompson and Siiteri [1] depending on extraction of steroids prior to scintillation counting. A good agreement of both methods was found. In tests with human term placenta aromatase in microsomes the apparent Km of androstendione was determined to be 8.9 nM. Aminoglutethimide showed a 50% inhibition of the placental microsomal aromatase at 0.6 microM.
Aminoglutethimide↗
Partial characterization of placental 3 beta-hydroxysteroid dehydrogenase (EC 1.1.1.145), delta 4-5isomerase (EC 5.3.3.1) in human term placental mitochondria.
A partial characterization of human term placental 3 beta-HSDH in mitochondria is reported. Apparent KM of pregnenolone: 70 nM. A dose-dependent stimulation of 3 beta-HSDH by NAD+ or NADP+ was observed in the range from 10(-6) to 10(-3) M (KM value of NAD+: 20 microM). At equimolar concentrations NAD+ is more than 10-fold as effective a cofactor of the 3 beta-HSDH than NADP+. pH optimum: 9.5 (glycine-NaOH buffer). Temperature optimum 40-45 degrees C. A rapid loss of 3 beta-HSDH activity was found after preincubation of the enzyme at 37 degrees C after 30 min; less than 50% of initial enzyme activity is present. No inhibition was obtained by Mg2+, Ca2+ Sr2+ and Ba2+ (1-100 mM). A strong inhibition was achieved with 1 mM Zn2+, Cd2+, Cu2+ and 10 mM and 100 mM Fe2+, Mn2+, Co2+ and Ni2+.
3-Hydroxysteroid Dehydrogenases↗
Diagnosis of intrauterine fetal growth retardation by prolongation of dehydroepiandrosterone sulfate (DHAS) half-life after DHAS loading.
In the last trimester of pregnancy, a correlation was established between the serum dehydroepiandrosterone sulfate (DHAS) half-life of the mother (n = 40) after DHAS loading (50 mg i.v.) and the birth weight percentile of the newborn. The DHAS half-life in pregnancies with normal fetal growth (greater than 10th percentile) was found to be 3.76 +/- 0.91 h (mean +/- SD) (n = 29) and in pregnancies with small-for-date babies (less than 10th percentile) was assessed to be 6.03 +/- 0.63 h (mean +/- SD) (n = 10) (P less than 0.001). Retrospective diagnosis of an intrauterine fetal growth retardation or normal fetal growth was based on a DHAS halflife threshold of 4.7 h. Retarded fetal growth was detected in all cases (10/10) by prolonged DHAS half-life (greater than r.7 h). Regular fetal growth was diagnosed in 90% of the cases (27/30) by a DHAS half-life of less than 4.7 h. In two out of these 30 pregnancies, an unexpected prolongation of DHAS half-life (greater than 4.7 h) led to the false diagnosis of poor fetal growth. In one patient, no DHAS half-life could be calculated due to a parabolic decline of the DHAS concentration curve. Indications for the DHAS test are diagnosis of an ultrasonographically symmetric intrauterine fetal growth retardation (biparietal and thoracic diameters) in cases with an indefinite gestational age. Furthermore, consistently low urinary excretion was clarified with particular respect to cases of placental sulphatase deficiency.
Birth Weight↗
The role of prostaglandins, cyclic nucleotides and tricarboxylic acids in the regulation of the human placental 20 alpha-hydroxysteroid dehydrogenase in vitro.
The in vitro effect of non-steroidal regulators (prostaglandins, cyclic nucleotides and tricarboxylic acids) on the cytoplasmic 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSDH, EC 1.1.1.149) isolated from human early gestational and term placentas was investigated. When prostaglandins (PG) were tested at 100 microM concentrations, an inhibition of the human placental 20 alpha-HSDH by PGE1 (80% inhibition), PGE2 (70%), PGF1 alpha (40%) PGF2 alpha (30%) and 13,14-dihydro-15-keto-PGF2 (PGFM) (20%) was observed. This effect was shown to be dose-dependent. The I50 (concentration at 50% inhibition) was determined for PGE1 and PGE2 to be 11 microM and 38 microM, respectively. No effect on the activity of the 20 alpha-HSDH could be demonstrated for PGI2 and its stable metabolite 6-keto-PGF1 alpha, for the cyclic nucleotides (dbcAMP, dbcGMP) and for the tricarboxylic acids (citrate, ketoglutarate, lactate, malonate, pyruvate and succinate) when added to the incubation at 100 microM concentration. The 20 alpha-HSDH isolated from early gestational and term placentas did not respond differently to the substances tested. These results suggest that prostaglandins can have a direct, dose-dependent effect on the isolated human placental 20 alpha-HSDH without cyclic nucleotides as intermediates and thereby play a role in the regulation of human progesterone synthesis and metabolism during pregnancy and near term.
20-Hydroxysteroid Dehydrogenases↗
[Carcinomatous meningeosis during cis-platinum treatment of gynaecological cancers (author's transl)].
Two cases of carcinomatous meningeosis are reported. One occurred during cis-platinum combination treatment (PAC-scheme) for advanced ovarian carcinoma and one during the same treatment for a carcinoma of the cervix. Both patients showed no neurological problems prior to chemotherapy. The central nervous symptoms developed rapidly following the administration of small doses of cis-platinum (total dose 160 or 300 mg) and could not be controlled. In one case tumour cells were found in the cerebral spinal fluid. The cause of death could have been an unusually toxic reaction to cis-platinum. A thorough neurological examination prior and during chemotherapy with cis-platinum is necessary in order to recognize toxic side effects of the drug as soon as possible.
Adult↗
Pharmacologically induced changes in human beta-chorionic gonadotropin (beta-hCG) synthesis by human placenta in organ culture.
In organ cultures the regulation of beta-hCG formation in human placentas of early gestation (EG) and at term (T) was analyzed using the following test substances: dibutyryl cAMP (dbcAMP), theophylline, and by two drugs used to treat patients with premature labor, fenoterol hydrobromide and verapamil hydrochloride. The rapid increase in beta-hCG in culture medium beginning at 24-48 h corresponds to morphologic changes (proliferation of the cytotrophoblast). Beta-hCG synthesis of human placenta is related to an adenylate cyclase as could be shown by dose-dependent stimulation by dbcAMP (T) (after 72 h) (controls = 100%): 2 nM = 125%; 70 nM = 200%; 2 microM = 300%. Similar results were obtained using EG. First stimulation by dbcAMP was found after 2 h and may be caused by a release of intracellular beta-CG or by a direct stimulation of beta-hCG synthesis; late effects (after 48-72 h) are suspected to be due to changes in morphologic differentiation of the placenta in organ culture. Theophylline (0.1 and 1 mM) did not influence beta-hCG formation in EG, whereas in T a dose-dependent stimulation could be achieved (controls = 100%): 0.1 mM = 110%; 1 mM = 300%; and 10 mM = 160%. Fenoterol hydrobromide, a tocolytic beta 2-receptor stimulating agent showed a slight (130-160%) beta-hCG stimulation (after 72 h) (EG and T). The stimulatory effect of a high dose (1 microgram/ml) of fenoterol hydrobromide could be due to a stimulation of beta 2 receptors related to an adenylate cyclase. Dose-related changes in beta-hCG in T were found for the calcium antagonist verapamil hydrochloride (controls = 100%): 0.01 microgram/ml = 125% stimulation; 0.33 microgram/ml = 200% stimulation; 10 micrograms/ml = 100%. As indicated by verapamil tests, calcium ions may play a role in the regulation of beta-hCG production.
Bucladesine↗