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Progestin released from the ovaries of pregnant rabbits consists of 20α-hydroxypregn-4-en-3-one (20α-dihydroprogesterone) and progesterone (Hafez, Tsutsumi & Kahn, 1965; Okano, Matsumoto, Kotoh, Endo & Seki, 1966). Because corpora lutea (c.l.), follicles and interstitial tissue are normally present in the ovaries of pregnant rabbits, it has been difficult to determine whether interstitial tissue and c.l. both secrete both steroids (Dorrington & Kilpatrick, 1965), or whether, as is frequently assumed, 20α-dihydroprogesterone comes predominantly from interstitial tissue and progesterone from c.l. (Hilliard, Archibald & Sawyer, 1963; Hilliard, Spies, Lucas & Sawyer, 1968). Recently it has been shown that progesterone comes from c.l. and not from interstitial tissue by experiments using unilaterally X-irradiated ovaries of pregnant rabbits: these contained either c.l. and interstitial tissue or interstitial tissue alone (Keyes & Nalbandov, 1968). In this paper, further evidence of the site of progesterone secretion is reported from experiments using normal ovaries of pregnant rabbits.


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The compound, 2-methyl-1,2-bis-(3-pyridyl)-1-propanone (SU 4885) is regarded as a relative specific inhibitor of hydroxylation at C 11β of the steroid nucleus (Liddle, Island, Lance & Harris, 1958). Recently, however, evidence has accumulated suggesting an inhibitory action of SU 4885 on oestrogen biosynthesis (Kahnt & Neher, 1962; Griffiths, 1963; Giles & Griffiths, 1964; Földes, Koref, Fehér & Steczek, 1964). In the present study an attempt was made to obtain evidence for an effect of SU 4885 on oestrogen synthesis in vivo.

Six female rats of the Wistar strain with a regular oestrous cycle, weighing 130–170 g., were injected s.c. with 10 mg. SU 4885 as the ditartrate salt, twice daily for nine consecutive days. They all showed continuous dioestrus from the 5th to 9th day after injection, when they were killed. In another experiment four female rats of the same strain, weighing 130–150 g., were given SU 4885 orally at a

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Over 50% of men having paraplegia due to traumatic lesions of the spinal cord or cauda equina show decreased spermatogenesis in varying degrees (Paulsen, 1968). The commonest pathology is arrested spermatogenesis with generalized hypoplasia of the germinal epithelium. Leydig cells usually appear normal, but the presence of nodular hyperplasia has been reported (Horne, Paull & Munro, 1948; Keye, 1956). Androgen production has been considered essentially normal judging from clinical symptoms, though most testes become smaller. Although urinary gonadotrophin excretion is reported to be low or absent in the majority of paraplegic men (Paulsen, 1968) and women (Durkan, 1968), there are no reports of plasma androgen concentrations. The concentration of testosterone in peripheral plasma from 51 paraplegic men after spinal cord injuries was therefore measured and compared with that of normal men.

The patients studied (aged 18–66 yr, average 37 yr) had been admitted to Osaka Labour Injury Hospital and the

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A Shirakami, T Toyonaga, K Tsuruzoe, T Shirotani, K Matsumoto, K Yoshizato, J Kawashima, Y Hirashima, N Miyamura, CR Kahn, and E Araki

Insulin receptor substrate 1 (IRS-1) gene polymorphisms have been identified in type 2 diabetic patients; however, it is unclear how such polymorphisms contribute to the development of diabetes. Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. GTG injection resulted in approximately 30% weight gain in IRS-1(+/-) and wild type (WT) mice, compared with saline-injected controls. There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. The islets of obese IRS-1(+/-) were 1.4-fold larger than those of obese WT. The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity.

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K Matsumoto, R Morishita, N Tomita, A Moriguchi, K Yamasaki, M Aoki, T Nakamura, J Higaki, and T Ogihara

We have previously reported that a decrease in hepatocyte growth factor (HGF), which has many protective functions against endothelial damage by high d-glucose, might be a trigger of endothelial injury. However, the regulation of vascular HGF in diabetes mellitus (DM) has not been clarified in vivo, although vascular disease is frequently observed in DM patients. In addition, our previous report revealed that a prostaglandin I(2) (PGI(2)) analogue prevented endothelial cell death through the induction of vascular HGF production in cultured human epithelial cells. Thus, in this study, we examined the effects of a PGI(2) analogue in the regulation of the local HGF system using DM rats. A PGI(2) analogue (beraprost sodium; 300 and 600 micro g/kg per day) or vehicle was administered to 16-week-old DM rats induced by administration of streptozotocin for 28 days. Endothelial function was evaluated by the vasodilator response to acetylcholine, and the expression of vascular HGF mRNA was measured by Northern blotting. Of importance, expression of HGF mRNA was significantly decreased in the blood vessels of DM rats as compared with non-DM (P<0.01). In addition, the in vitro vasodilator response of the abdominal aorta to acetylcholine was markedly impaired in DM rats. Importantly, the vasodilator response was restored by PGI(2) treatment in a dose-dependent manner (P<0.01), whereas N(omega)-nitro-l-arginine methyl ester inhibited the restoration of endothelial function. Of particular interest, vascular HGF mRNA and protein were significantly increased in the blood vessels of DM rats treated with PGI(2) as compared with vehicle. Similarly, an increase in HGF protein was also confirmed by immunohistochemical analysis. In addition, the specific HGF receptor, c-met, was also increased by PGI(2) treatment. Overall, this study demonstrated that treatment with a PGI(2) analogue restored endothelial dysfunction in DM rats, accompanied by the induction of vascular HGF and c-met expression. Increased local vascular HGF production by a PGI(2) analogue may prevent endothelial injury, potentially resulting in the improvement of endothelial dysfunction.

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T Yoshimoto, M Naruse, Z Zeng, T Nishikawa, T Kasajima, H Toma, S Yamamori, H Matsumoto, A Tanabe, K Naruse, and H Demura

To explore the clinical significance of p53 in the pathogenesis of adrenal neoplasms, we investigated the incidence of p53 gene mutations in functioning human adrenal tumours using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique to screen p53 exons 4 to 9. We examined 29 adrenocortical adenomas (primary aldosteronism, n=17; Cushing's syndrome, n=12, all benign), and 33 phaeochromocytomas (benign solitary, n=18; benign multiple, n=5; malignant, n=10) in Japanese and Chinese patients. PCR-SSCP did not show any abnormal band-shifts in any of the adrenocortical adenoma and benign solitary phaeochromocytoma tissues. In contrast, six phaeochromocytoma tissues (two cases benign multiple, four cases malignant) showed PCR-SSCP band-shifts. Subsequent DNA sequencing analysis of the shifted bands revealed six cases with nine mutations or intronic sequence alterations: three cases contained sequence alterations within intronic regions, three cases with silent mutation (sequence alteration in codon without amino acid alteration), and three cases contained missense mutations (one case each in exons 5, 6 and 9). Immunohistochemical staining demonstrated that two of three cases with missense mutations and one case with an intronic sequence alteration over-expressed p53 protein in tumour cell nuclei. We observed no association between p53 gene mutation and p21/WAF1/Cip-1 expression. The relatively high incidence of p53 gene mutations or intronic sequence alteration in multiple and malignant phaeochromocytomas, but not in benign solitary cases, suggests that p53 mutation could play some role in the pathogenesis of multiple and/or malignant phaeochromocytomas.