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51 巻, 9 号
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市丸 俊三1975 年 51 巻 9 号 p. 693-704
発行日: 1975/09/20
公開日: 2012/09/24
ジャーナル フリーTo investigate the metabolic pathway from dehydroepiandrosterone sulfate (DHAS) to estriol (E3) in late human pregnancy, DHAS (50 to 100 mg) was given intravenously or intraamniotically to 13 volunteers (from cases of normal pregnant women, pregnant women with a live anencephalic fetus, intrauterine fetal death or hydatidiform mole and a patient complicated with cancer of the cervix). Urinary estrogens, serum unconjugated estrogens and urinary dehydroepiandrosterone (DHA) and 16α-hydroxydehydroepiandrosterone (16α-OH-DHA) were measured before and after injection.
Brown's method (1955) has been used to measure urinary three fractions of estrogens, estrone (E1), estradiol (E2) and estriol (E3). Serum unconjugated estrogens, estrone (SE1), estradiol (SE2) and estriol (SE3) were determined by a raioimmunoassay technique (a modification of the method of Makino, 1973). Urinary DHA and 16α-OH-DHA were separated by a modification of the method of Lakshmanan and Lieberman (1954) and by thin layer chromatography, and estimated by the method of Oertel and Eiknes (1959).
Results obtained were as follows :
(1) In seven cases of pregnancy with a live anencephalic fetus the excretion of urinary estriol was very low and the ratio of E3/E1 E2 was much less than that in normal pregnancy.
(2) In five women with a live anencephalic fetus the effect of intravenously injected DHAS was studied. In each case there was a remarkable in urinary E3, E1 and E2, while no remarkable differnce between the ratio of E3/E1+E2 before and after administration of DHAS was found.
(3) DHAS was given intraamniotically to two women with a live anencephalic fetus. A greater rise of the ratio of E3/E1 +E2 after administration of DHAS was found, compared to the control.
(4) DHAS circulating in the maternal organism is converted to E3 largely via a phenolic pathway (DHAS-E1-E3), whereas DHAS circulating within the feto-placental compartment is converted to E3 via both phenolic and neutral interemediates (DHAS-16α-OH-DHAS-E3).
(5) The ratio of urinary 16α-OH-DHA/DHA in pregnancy with a live anencephalic fetus was greater than that in non-pregnant woman. This suggests that 16α-hydroxylase activity in pregnancy is elevated.
(6) Increases in serum unconjugated E1, E2 and E3 after intravenous administration of DHAS in three pregnant women with a live anencephalic fetus were found.抄録全体を表示PDF形式でダウンロード (1317K) -
本庄 英雄1975 年 51 巻 9 号 p. 705-723
発行日: 1975/09/20
公開日: 2012/09/24
ジャーナル フリーToday, ENT is a popular synthetic progestogen for clinical use, and is well known to have some estrogenic activity. Estradiol-17β (E2) or 17α-ethynyl estradiol (EE2) binding to the specific protein in the nuclear fraction of hypothalamus were examined by 3H-E2 exchange assay reported by Anderson. The possible mode of the estrogenic actions of ENT are as follows : 1) Conversion of ENT to EE2. 2) Estrogenic of ENT per se without changing the chemical structure. 3) Conversion of ENT to other estrogenic compounds except for EE2.
In this experiment, 3H-ENT or 3H-testosterone (3H-T) was incubated with human placental microsomes and NADPH generating system for 1 hr at 37°C, 3H-Δ4AD, 3H-T and 3H-ENT were incubated also with homogenates of rat hypothalamus under the same conditions. Isolation and purification of the metabolites were performed by using phenolic separation and paper chromatography. Identification of EE2, a metabolite of ENT, was established by measuring the radiochemical homogenity with the authentic standard on paper chromatography. In another experiment where alkali was not used during the extraction procedure to avoid making artificial products, the conversion rate of ENT to EE2 was measured. This experimental data indicated that ENT was converted to 1β-OH-ENT and to EE2 by human placental microsomes. The former compound was easily converted to EE2 in the presence of NaOH or by incubation with bile. In the incubation with hypothalamic preparation neither aromatization nor 1β-hydroxylation of Δ4AD, T and ENT were detected. In the exchange assays of E2 receptor, the animals were killed 1 hr after the administration of 25μg of various steroids. The hypothalamic nuclear fraction was incubated with various 3H-steroids for 30 min at 37°C. After washing this nuclear pellet, the radioactivity was counted. Administration of E2 in vivo resulted in the increase of the amount of 3H-EE2 bound to the nuclear fraction in vitro. But only a small increase of binding was observed in the similar experiment with 3HENT. 3H-EE2 was exchanged more abundantly after ENT administration than after EE2 injection. From the above results, it was concluded that the estrogenic effect of ENT is attributed to the EE2 converted in vivo. In addition, a possibility was proposed that ENT or its metabolites other than EE2 could regulate some step in the mechanism of estrogen action.抄録全体を表示PDF形式でダウンロード (1965K) -
奥村 次郎1975 年 51 巻 9 号 p. 724-739
発行日: 1975/09/20
公開日: 2012/09/24
ジャーナル フリーIt is reasonable to presume that the metabolism of the steroid hormones in the liver may play an important role in elucidating their physiologic significance.
Although there are many methods by which the intrahepatic metabolism of the steroid hormones can be evaluated, little has been reported on a method to elucidate simultaneously such dynamic factors as metabolic rate, quantities passing through the liver, structural change, conjugation and the like.
In this paper, comparative studies on the methods for the investigation of steroid hormone metabolism in the liver were carried out.
These include batch incubation, dialysis, continuous flow perfusion, portal vein injection and the “tissue column method” which was newly designed in order to search for the dynamic factors described above in a simple system, simultaneously.
In the “tissue column method” studied here, cell suspension of the rabbit liver mixed with Sephadex G 75 gel (4 : 1 in volume) was packed at the height of 4 cm in a glass column (internal diameter ; 1.5 cm).
After an isotopically labelled steroid was placed on the tissue column, this column was perfused with oxygenated extracellular fluid (pH 7.4), keeping the perfusion system at 37°C.
The perfusion was continued for 60 min. and the perfusate was collected in 5 fractions. Flow rate was kept at 2 ml/min.
When the perfusion was stopped, the cells were rapidly homogenized. The concentrations of the radioactivity in each perfusate, and in the final cells were measured. The amount of entry into the liver cells were calculated.
The compounds in the perfusate and in the cells were separated by alumina column chromatography for analyzing the metabolites.
Based on these experiments, the following conclusions were drawn ;
1) Usual methods with liver slices and homogenates can clarify only the metabolic pathway.
2) To examine the amount of entry of steroids into the liver, portal vein injection as well as the “tissue column method” are preferable to the methods of dialysis and batch incubation. It seemed probable that the entry of steroids into the liver might not be explained simply on the basis of passive transfusion.
3) Incubation of slices and homogenate are of great advantage in studying the metabolic transformation in a specific organ. However, portal vein injection as well as the “tissue column method” are much more preferable to investigate the conjugation of steroids in the liver.
4) Continuous flow perfusion reported by Elrio Gurpide is suitable to examine the metabolism and the entry of steroids in a specific organ, but it is disadvantageous for investigating the conjugation of steroids because of its low production rate of conjugated steroids.
5) The portal injection method is intricate, troublesome and expensive, but this method provides a situation similar to in vivo circumstances.
6) It is evident that despite its simplicity, the newly designed “tissue column method” is of great worth in obtaining summarized information of the entry, metabolic pathway, metabolic rate, structural change and conjugation of the steroid hormones in the liver.抄録全体を表示PDF形式でダウンロード (1596K) -
猿田 享男, 近藤 和興, 斉藤 郁夫, 三角 二郎, 中村 隆一, 城所 澄江, 松木 駿1975 年 51 巻 9 号 p. 740-744
発行日: 1975/09/20
公開日: 2012/09/24
ジャーナル フリーIn order to study the control system of plasma aldosterone in human, we examined the effects of low salt plus upright posture, angiotensin II, ACTH and potassium upon plasma renin activity, aldosterone and cortisol in five subjects who were supposed to be normal. All of the procedures, low salt diet with below 3 g of salt and 2 hr-upright posture, 0.25 mg of Cortrosyn, angiotensin infusion to increase 20 mmHg of diastolic pressure for an hour, and 30 mEq of potassium infusion stimulated plasma aldosterone significantly. Furthermore, in each subject the degrees of response to each of these stimulations were almost same.
In an old woman aged 68, responses to all of stimulations were significantly lower than those in other subjects.
Plasma cortisol was significantly stimulated by ACTH, but slightly reduced by potassium infusion. From these results, it is certain that plasma aldosteron levels are easily affected by a small amount of changes in angiotensin, ACTH, potassium and sodium. However, responses of aldosterone to these changes seem to be decreased in old subjects.抄録全体を表示PDF形式でダウンロード (506K) -
小林 俊子, 紫芝 良昌1975 年 51 巻 9 号 p. 745-748
発行日: 1975/09/20
公開日: 2012/09/24
ジャーナル フリーTanned red cell hemagglutination has been widely accepted for use in the detection of anti-thyroglobulin antibodies. The interpretation, however, especially when the hemagglutination was observed at a low titer of serum dilution, has remained equivocal. In order to separate specific and non-specific hemagglutination, we tried to concentrate serum IgG to compare the hemagglutination titer at various concentrations of IgG. If the hemagglutination is specific for the presence of antithyroglobulin antibodies, the hemagglutination titer would increase as the IgG concentration rises. On the contrary, when the hemagglutination is non-specific and irrelevant to the presence of anti-thyroglobulin antibodies, the hemagglutination titer is expected not to increase while the IgG concentration rises. Based on this hypothesis, sera which showed various hemagglutination titer for anti-thyroglobulin antibodies were studied to examine the parallelism between hemagglutination titer and IgG concentration.
IgG was concentrated with the method of ammonium sulfate precipitation. The grade of concentrate was examined by the IgG determination with the method of immunodiffusion technique employing the kit distributed by Behringwerke. The hemagglutination test was performed with the Boyden's method using the kit distributed by the Wellcome Company.
The results showed that 4 out of 15 sera whose original hemagglutination titer was 1 : 3 failed to show increase in hemagglutination titer even at the 2 to 4 fold concentration of IgG. On the contrary, only 2 out of 26 sera whose hemagglutination titer was more than 1 : 6, failed to increase the titer at the IgG concentrate to the same degree. Thus, it is possible to conclude that the hemagglutination observed at 1 : 3 dilution of the serum is highly non-specific, while that observed at a serum dilution of more than 1 : 6 is thought to be specific.抄録全体を表示PDF形式でダウンロード (449K) -
-臨床観察ならびに実験的考察-長谷川 恭一, 森脇 要, 五十嵐 暢, 菅瀬 透, 川上 房男, 伊藤 芳晴, 西川 光夫1975 年 51 巻 9 号 p. 749-759
発行日: 1975/09/20
公開日: 2012/09/24
ジャーナル フリーSix cases of Cushing's syndrome with adrenocortical tumors which showed a variety of responsiveness to ACTH were investigated in relation to their clinical pictures and laboratory findings. Abnormal responses to ACTH in tumors was analyzed by in vitro experiments with surgically obtained tumor tissues, and the ACTH responsive mechanism of the tumors was discussed.
An 8 hour intravenous ACTH infusion test showed that three of these patients were ACTH responsive, and the other three unresponsive. Histological observation of the tumors revealed that ACTH responsive tumors were adenomas and that ACTH unresponsive tumors were “black adenomas” in two and a carcinoma in one.
To investigate possible factors which might account for these differences in ACTH responsiveness, tumor specimens of each one of the responsive and unresponsive adenomas, and a carcinoma were subjected to in vitro studies. When incubated with ACTH or cyclic AMP, tissue sections of a responsive adenoma enhanced cortisol secretion, while that of a black adenoma failed to show any change. Steroidogenesis by carcinoma sections were significantly suppressed in the presence of ACTH or cyclic AMP.
Cycloheximide abolished a stimulatory effect of ACTH and cyclic AMP on steroidogenesis in a responsive adenoma without affecting its basal secretion of cortisol. Steroidogenesis by unresponsive tumors (an adenoma and a carcinoma) were decreased by cycloheximide.
Since the conversion of cholesterol to pregnenolone, the rate limiting step in steroidogenesis, takes place in adrenal mitochondria, the effect of cyclic AMP on pregnenolone formation from 14C-cholesterol by mitochondrial fractions of these tumors was examined. Cyclic AMP stimulated pregnenolone formation by mitochondrial fraction of an ACTH responsive adenoma, while with that of an unresponsive adenoma pregnenolone formation was not affected. Pregnenolone formation by cancer mitochondria was significantly suppressed by cyclic AMP.
These results suggest that the unresponsiveness to ACTH of these tumors might be explained by the ineffectiveness of cyclic AMP to stimulate pregnenolone formation by tumor mitochondria, and that the steroidogenic pathway in unresponsive tumors are in an enhanced state even without cyclic AMP.
It should be mentioned that all unresponsive adenomas gave a characteristic appearance of a “black adenoma”. Histologically, tumors were composed of compact cells with abundant lipofuscin granules. The possible relationship between the ACTH responsiveness of adrenocortical tumors and some clinical pictures caused by them was also noticed. ACTH unresponsive adenomas resulted in shorter duration, severer conditions of the disease and higher 17-ketosteroid excretion than responsive adenomas. The growth of unresponsive tumors seemed faster than that of responsive ones.抄録全体を表示PDF形式でダウンロード (1669K) -
-ACTH作用機構に関する考察 その1-長谷川 恭一1975 年 51 巻 9 号 p. 760-769
発行日: 1975/09/20
公開日: 2012/09/24
ジャーナル フリーDespite the accumulation of a number of studies, the mechanism of action of ACTH remains to be clarified. Although it is now clear that cyclic AMP acts as a intracellular mediator of ACTH action, the mechanism of its action on the stimulation of steroidogenesis is not known. The present studies were carried out to test the hypothesis that cyclic AMP might act directly on adrenal mitochondrial fraction to stimulate the metabolism of cholesterol to pregnenolone and progesterone, and to determine whether Ca++ might modulate the action of cyclic AMP.
Adrenal mitochondria were obtained from male Sprague-Dawley rats pretreated with-dexamethasone. Steroidogenesis by the mitochondrial fraction from cholesterol-4-14C (0.2-0.25 μCi, 3.6-4.5 mμmole/sample) were measured in a system containing 20 mM tris-HCl buffer (pH 7.4), 11.5 mM NaCl, 15.4 mM KCl, 70 mM sucrose, 10 mM sodium succinate and mitochondrial fraction (0.16-0.22 mg protein/sample). Incubations were performed at 37°C, with shaking, in the presence or absence of cyclic AMP, cyclic GMP and cycloheximide. After incubation, the medium was extracted with chloroform, and the extracts were analyzed by thin-layer chromatography. And the radioactivity of the separated steroids was measured.
The products from cholesterol-4-14C were mainly pregnenolone and progesterone, and the other products were almost negligible. Cyclic AMP effected the formation of pregnenolone and progesterone by mitochondria. Cyclic A MP exerted its effect even at low concentrations (5×10-6-5×10-5 M), which was presumably near the intracellular level. On the other hand, cyclic GMP (5×10-6 M) failed to enhance steroidogenesis.
The effect of Ca++ on the action of various concentrations (5×10-6-3×10-3 M) of cyclic AMP was also clearly demonstrated. Addition of Ca++ (1 mM) to the incubation medium intensified the stimulatory effect of cyclic AMP in each concentration. And in the presence of Ca++, the most effective level of cyclic AMP was shifted from 5×10-4-3×10-3 M to the lower concentration (5×10-5 M). In addition, cyclic AMP action was modified by the changes in the concentration of Ca++ in the medium. At concentration of 10-6 M of Ca++, steroid formation of mitochondria was maximally activated by cyclic AMP.
These observations suggest that cyclic AMP enhances steroidogenesis by acting directly on adrenal mitochondria to stimulate pregnenolone and progesterone formation from cholesterol, and that Ca++ plays a significant role in its action.抄録全体を表示PDF形式でダウンロード (1119K)
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