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Homogenates of cerebral metastatic chorionepithelioma tissue were incubated with labelled dehydroepiandrosterone, pregnenolone or 20α-hydroxypregn-4-en-3-one. The metabolites of dehydroepiandrosterone which were isolated and identified were androstenedione, testosterone, oestrone and oestradiol; no oestriol was detected. The only metabolite of pregnenolone and 20α-hydroxypregn-4-en-3-one isolated and identified was progesterone. No conversion of C-21 to C-19 steroids occurred in the metastatic chorionepithelioma tissue.

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Department of Obstetrics and Gynecology, Kumamoto University Medical School, Kumamoto 860, and *Department of Obstetrics and Gynecology, Miyazaki Medical College, Japan

(Received 11 February 1976)

It has been reported that 20α-hydroxysteroid dehydrogenase (20α-HSD), catalysing the oxidation of 20α-hydroxy-4-pregnen-3-one (20α-OHP) to progesterone with NAD+ is mainly associated with the mitochondrial fraction of endometrial cells and increases progressively from the early proliferative phase until the late secretory phase (Maeyama, Nakahara, Sudo & Mori, 1973; Tseng & Gurpide, 1974). Recently Collins & Jewkes (1974) and Pollow, Lübbert, Boquoi & Pollow (1975) showed that human endometrial carcinomata do not produce significantly more 20α-OHP than proliferative endometrium and that the specific activity of 20α-HSD decreases with decreasing differentiation of the tumour. The present study was on the effect of combined administration of progestagen and oestrogen on the conversion of 20α-OHP to progesterone in human endometrial carcinomata.

Tissues of endometrial carcinomata were obtained by total hysterectomy

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Dehydroepiandrosterone sulphate (DHAS) was injected intravenously or intra-amniotically into eight volunteers carrying live anencephalic foetuses (including one microcephalic foetus). Urinary and unconjugated serum oestrone, oestradiol and oestriol were measured before and after DHAS administration. In seven pregnant women with live anencephalic foetuses the urinary excretion of oestriol was very low, and the ratio of oestriol to oestrone+ oestradiol was much less than that during normal pregnancy. Increases of urinary oestrone and oestradiol but no significant change in the ratio of oestriol to oestrone + oestradiol were observed 24 h after i.v. administration of DHAS to five patients. In three patients, between 1 and 12 h after i.v. administration of DHAS (100–200 mg), the concentrations of serum oestrone, oestradiol and oestriol increased to 13·5, 6·8 and 3·1 times the control values, respectively. After injection of DHAS (200 mg) intra-amniotically into two patients, the urinary excretion of all three oestrogens increased much more on day 2 than on day 1, and the ratio of urinary oestriol to oestrone + oestradiol rose greatly. On the other hand, the concentrations of unconjugated serum oestrogens in these patients increased progressively between 1 and 12 h or more after DHAS administration, and the maximal level of serum oestriol was 9·8 times the control value while those of oestrone and oestradiol were 4·6 times and 5·0 times the control values, respectively. These results suggest that in late human pregnancy DHAS in the circulation of the mother is converted to oestriol largely via the phenolic pathway (DHAS → oestrone → oestriol), whereas DHAS circulating within the foeto-placental compartment is converted to oestriol via both the phenolic and the neutral intermediates.

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T Hayashida, K Nakahara, MS Mondal, Y Date, M Nakazato, M Kojima, K Kangawa, and N Murakami

Ghrelin, a 28 amino acid peptide, has recently been isolated from the rat stomach as an endogenous ligand for the GH secretagogue receptor. The fact that administration of ghrelin, centrally or peripherally, stimulates both food intake and GH secretion suggests that stomach ghrelin has an important role in the growth of rats. We used immunohistochemistry and radioimmunoassay to determine the age at which ghrelin-immunostained cells begin to appear in the rat stomach. Ghrelin-immunoreactive cells were found to be expressed in the fetal stomach from pregnancy day 18. The number of ghrelin-immunoreactive cells in the fetal stomach increased as the stomach grew. The amount of ghrelin in the glandular part of the rat stomach also increased, in an age-dependent manner, from the neonatal stage to adult. Eight hours of milk restriction significantly decreased the ghrelin concentration in the stomachs of 1-week-old rats, and increased the ghrelin concentration in their plasma. Administration of ghrelin to 1- and 3-week-old rats increased plasma GH concentrations. The daily subcutaneous administration of ghrelin to pregnant rats from day 15 to day 21 of pregnancy caused an increase in body weight of newborn rats. In addition, daily subcutaneous administration of ghrelin to neonatal rats from birth advanced the day of vaginal opening from day 30.7+/-0.94 to day 27.9+/-0.05. These results suggest that ghrelin may be involved in neonatal development.

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N Murakami, T Hayashida, T Kuroiwa, K Nakahara, T Ida, MS Mondal, M Nakazato, M Kojima, and K Kangawa

Ghrelin, a 28-amino-acid peptide, has recently been isolated from the rat stomach as an endogenous ligand for the GH secretagogue receptor. We have reported previously that central or peripheral administration of ghrelin stimulates food intake, and the secretion of GH and gastric acid in rats. In the present study, we investigated how much endogenous centrally released ghrelin is involved in the control of food intake and body weight gain. We also examined the profile of ghrelin secretion from the stomach by RIA using two kinds of anti-ghrelin antiserum, one raised against the N-terminal ([Cys(12)]-ghrelin[1-11]) region and one raised against the C-terminal ([Cys(0)]-ghrelin [13-28]) region of the peptide. The former antibody recognizes specifically ghrelin with n- octanoylated Ser 3 (acyl ghrelin), and does not recognize des-acyl ghrelin. The latter also recognizes des-acyl ghrelin (i.e. total ghrelin). Intracerebroventricular treatment with the anti-ghrelin antiserum against the N-terminal region twice a day for 5 days decreased significantly both daily food intake and body weight. Des-acyl ghrelin levels were significantly higher in the gastric vein than in the trunk. Either fasting for 12 h, administration of gastrin or cholecystokinin resulted in increase of both acyl and des-acyl ghrelin levels. The ghrelin levels exhibited a diurnal pattern, with the bimodal peaks occurring before dark and light periods. These two peaks were consistent with maximum and minimum volumes of gastric content respectively. These results suggest that (1) endogenous centrally released ghrelin participates in the regulation of food intake and body weight, (2) acyl ghrelin is secreted from the stomach, (3) intestinal hormones stimulate ghrelin release from the stomach, and (4) regulation of the diurnal rhythm of ghrelin is complex, since ghrelin secretion is augmented under conditions of both gastric emptying and filling.

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A Mori-Abe, S Tsutsumi, K Takahashi, M Toya, M Yoshida, B Du, J Kawagoe, K Nakahara, T Takahashi, M Ohmichi, and H Kurachi

Proliferation of vascular smooth muscle cells (VSMC) plays a major role as an initiating event of atherosclerosis. Although estrogen directly inhibits the proliferation of VSMC, the mechanism has not been firmly established. In addition, the effect of raloxifene on VSMC remains unknown. 17Beta-estradiol (E(2)) and raloxifene significantly inhibited the growth of VSMC under growth-stimulated conditions. Since mitogen-activated protein (MAP) kinases have been implicated in VSMC proliferation, the role of MAP kinases in both the E(2)- and raloxifene-induced growth inhibition of VSMC was studied. Both E(2) and raloxifene caused rapid, transient phosphorylation and activation of p38 that was not affected by actinomycin D and was blocked by ICI 182,780. In contrast with p38 phosphorylation, extracellular signal-regulated protein kinase (ERK) phosphorylation was significantly inhibited and c-Jun N-terminal kinase (JNK) phosphorylation was not changed by E(2). Because VSMC expressed both estrogen receptor (ER) alpha and ERbeta, it is not known which of them mediates the E(2)-induced phosphorylation of p38. Although E(2) did not affect the p38 phosphorylation in A10 smooth muscle cells, which express ERbeta but not ERalpha, transfection of ERalpha expression vector into A10 cells rendered them susceptible to induction of p38 phosphorylation by E(2). We then examined whether E(2) and raloxifene induce apoptosis through a p38 cascade. Both E(2) and raloxifene induced apoptosis under growth-stimulated conditions. The p38 inhibitor SB 203580 completely blocked the E(2)-induced apoptosis. Our findings suggest that both E(2)- and raloxifene-induced inhibition of VSMC growth is due to induction of apoptosis through a p38 cascade whose activation is mediated by ERalpha via a nongenomic mechanism.