Biomedical subjects
Publications and source records attributed to S Takayasu.
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The pilosebaceous tumor spontaneously developed on the sidegland of an old male Suncus murinus was serially transplanted into male nude athymic (BALB/c-nu/nu) mice. By the 18th generation, tumor growth occurred in about 70% of them. The transplantability of the tumor maintained in these male mice to female or castrated male nude mice was less than 35%. The histological features of the tumor did not differ by the hormonal status of hosts. Tumor growth started later and was slower in females than in males. This androgen dependency seems to be restricted to an initial period of growth, since the transplantability to males was decreased by castration within a week after grafting. The tumors grown in males possessed both cytoplasmic and nuclear androgen receptors and those in females cytoplasmic androgen receptor only. The latter tumors were found androgen-sensitive, because treatment with testosterone propionate significantly increased tumor size. In addition, after [3H]-testosterone administration, bound radioactivity was detected in the nuclear fraction from female as well as male hosts. Although the mechanism responsible for the development of these androgen-independent sensitive cells is unknown, the variance in transplantability to female hosts suggests that the original tumor was composed of androgen-dependent and androgen-independent cells.
Following administration of [3H]testosterone to castrated male Japanese house musk shrews (Suncus murinus), radioactive metabolites were detected in sidegland nuclei and the major one of them was dihydrotestosterone (DHT). The androgen binding capacity of the cytoplasmic fraction of sideglands was measured in vitro by the use of [3H]R1881 as a ligand. The binding showed a high affinity for R1881 (Kd = 6.2 X 10(-10) M) and a low capacity (Bmax = 22 fmol/mg protein). Sucrose density gradient centrifugation brought about a peak of [3H]R1881 in the 7S region in low ionic strength buffer. Their characteristics as described above are consistent with those of other androgen target organs. A cutaneous pilosebaceous tumor, which spontaneously developed on the sidegland of old male S. murinus, was transplanted to nude athymic mice. It grew in males only and failed to grow in females and castrated males. A specific androgen binding was found in this tumor (Kd = 7.8 X 10(-10) M, Bmax = 100 fmol/mg protein). Therefore, this transplantable pilosebaceous tumor is androgen-dependent and can be utilized as a new suitable model in the study of the mechanism of androgen on tumor development.
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The activity of 3 beta-hydroxysteroid dehydrogenase delta 4-5 isomerase (3 beta-HSD) was assayed in various tissues microdissected from the freeze-dried human skin of 13 subjects. The sebaceous gland possessed the highest activity of 3 beta-HSD in the skin, while the apocrine sweat gland showed only one fourth of that activity. The vellus hair follicle showed nearly one half of the activity of the sebaceous gland, whereas the terminal hair follicle exhibited much lower activity. The activity of the epidermis and of the dermis were negligible. Incubation of fresh whole skin of the forehead with 7 alpha-3H-DHA and subsequent isolation of various tissues revealed that the metabolites identified in the sebaceous gland were androstanedione and androstenedione, whereas testosterone and/or dihydrotestosterone were not detected.
The effect of castration on total 5 alpha-reductase activity in transforming testosterone to 5 alpha-reduced metabolites was studied in the sebaceous gland of male hamsters. The mean enzyme activity increased to more than twice the control level as early as 4 days after castration and this increase remained almost unchanged at 14, 21 and 63 days after castration. The administration of testosterone propionate or 5 alpha-dihydrotestosterone to castrates led to a complete inhibition of the increase in enzyme activity and this inhibitory effect was blocked by cyproterone acetate. These data indicate that androgens may be regulators of 5 alpha-reductase activity in the sebaceous gland of hamsters.
The activity of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) was assayed in various tissues microdissected from the freeze-dried human skin of fourteen subjects. The apocrine sweat gland, sebaceous gland and hair follicle possessed a high activity of 17 beta-HSD. The enzyme activity was negligible in the epidermis, except that the scalp epidermis showed much the same activity as the hair follicle. The demis showed variable activity because of contamination with other components.
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In order to know the distribution of testosterone 5 alpha-reductase activity in human skin, we developed a micro-method, in which we used 20-50 micrograms of various tissues microdissected from freeze-dried sections. The characteristics of this enzyme in the sebaceous gland are briefly described, as follows: the identified 5 alpha-reduced metabolites are 5 alpha-dihydrotestosterone, 5 alpha-androstane-3 beta, 17 beta-diol and 5 alpha-androstanedione; the optimal pH is about 7.5; and the apparent Km is approximately 2.4 x 10(-5) M. The measurement of 5 alpha-reductase activity of various components of the skin obtained from 7 men and 5 women revealed that the sweat gland (probably apocrine) in the axillary skin possessed the highest activity of 5 alpha-reductase: the value was nearly 400 pmoles/mg dry weight/hr in the standardized condition. The sebaceous gland also showed a high activity of 85-261 pmoles/mg/hr. The hair follicles exhibited a significantly lower activity than the sebaceous gland. The enzyme activity was negligible in the epidermis, while it was detected in the dermis though the values determined were variable probably because of contamination with other components such as sweat glands and hair follicles. Thus, the present study demonstrates that the 5 alpha-reductase activity is mainly located in the apocrine sweat gland and sebaceous gland. This suggests that 5 alpha-reduction of testosterone is an important step in mediating the action of androgens in these tissues.
Specific dihydrotestosterone (DHT) binding was demonstrated in the whole cell sonicates obtained from serially subcultured human endometrial fibroblasts. This binding showed a high affinity and specificity for DHT (Kd=3.3 X 10(-10) M). Various kinds of excess nonradioactive steroids were arranged, as a result of competition among them, in the following decreasing order of binding affinity: DHT, testosterone, cyproterone acetate, 17 beta-estradiol, progesterone, and 5 alpha-androstane-3 alpha, 17 beta-diol. Androsterone, 5 alpha-androstanedione, cortisol, androstenedione and estrone hardly affected the binding even at 200 fold excess. Saturation analysis indicated that cultured endometrial and genital skin fibroblasts have a similar number of binding sites for DHT (14.3 +/- 8.5 vs 11.5 +/- 8.6 fmoles/mg cell protein). Sucrose density gradient centrifugation brought about a sharp peak of 3H-DHT in the 4S region in high ionic strength buffer. This binding was abolished by heating sonicates at 37 degrees C for 1 hr, treating them with pronase or adding to them excess nonradioactive DHT. Endometrial fibroblasts also contained testosterone binding components which formed a peak in the 4S region and showed a similar binding affinity to that for DHT.
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Cyproterone acetate, R 2956, Ro 7-2340 and Sch 13521 in the daily dose of 8 mg injected intramuscularly to castrated adult hamsters for 3 weeks were all found to significantly antagonize the stimulatory effect of exogenous testosterone propionate (80 microgram im, every other day) on the sebaceous gland as well as the prostate and the seminal vesicle. With a view to clarifying the mechanisms of action of these antiandrogenic drugs on the sebaceous gland, the present author carried out both in vivo and in vitro experiments and examined how they would interfere with the binding of 3H-dihydrotestosterone (DHT) to cytosol and nuclei. When 200-1000 excess quantities of the antiandrogens were administered to the experimental animals 10 min before injection of 3H-testosterone, all of them except R 2956 reduced the bound radioactivity in the nuclei of the sebaceous gland by more than 40%. Incubation of the cytosol fraction with 1 x 10(-7) M of cyproterone acetate caused a 70% decrease in radioactivity of the specific binding. In contrast, such inhibitory activities of the three other antiandrogens were less conspicuous even at 1 x 10(-6) M. In the homogenate of the sebaceous gland incubated with 1 x 10(-8) M of DHT, the other drugs than Sch 13521 curbed the characteristic binding of DHT to macromolecules of the nuclei by nearly 70% at 1 x 10(-6) M.
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A 19-year-old phenotypic female with gonadal agenesis and XY karyotype underwent an endocrinologic study. She lacked secondary sexual characteristics and there was posterior labial fusion, absence of vagina, and no gonadal or gonadal duct tissues present at laparotomy. Elevated levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responded well to intravenous injection of LH-releasing hormone (LH-RH) but did not respond to clomiphene citrate. Both OH and FSH levels were suppressed by administration of testosterone or estrogen. Low serum concentration of testosterone did not respond to human chorionic gonadotropin (hCG) injection. Dihydrotestosterone binding by cultured skin fibroblast revealed the existence of a binding component with low capacity and high affinity. This is the first report of a patient with XY gonadal agenesis in whom androgen receptors in the target cells are demonstrated.
Twenty-six patients with Ebstein's anomaly were classified into three types according to their clinical features, heart catheterization data, angiocardiographic and anatomical findings which were obtained on surgery or autopsy. The hemodynamics in each type were discussed. 1. Tricuspid Stenosis Dominant Type. Eight patients, who were cyanotic and had severe symptoms, mild to moderate cardiomegaly, and the "double-ball sign" on angiocardiography were classified into this type. A pressure gradient across the tricuspid valve was demonstrated in 5 patients. 2. Tricuspid Insufficiency Dominant Type. Four cyanotic patients, who had mild symptoms despite the severe cardiomegaly were grouped into this type. The "double-ball sign" was found in all. In three patients, incompetent tricuspid valve was observed. Tricuspid insufficiency necessitates the volume overwork of the right atrium and the functioning right ventricle, resulting in severe dilatation. 3. Mild Type. Fourteen patients who showed no or mild cyanosis, no or mild symptoms, and mild to moderate cardiomegaly, were classified into this type. It is considered that the adequate cardiac output in these patients is attributable to the good function of the tricuspid valve.
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