Inhibition of p-450 aromatase prevents feminisation and induces protection during cysticercosis.

Cysticercotic male mice undergo an impressive feminisation process, characterised by 200 times increased serum 17beta-estradiol levels while testosterone and dihydrotestosterone are 90% reduced, which results in elevated parasite burden. Administration of Fadrozole (an aromatase inhibitor) in male and female mice suppressed the production of 17beta-estradiol, accompanied with a 70% reduction in parasite burden. This protective effect was associated in male mice with a recovery of the specific cellular immune response. Interleukin-6 (IL-6) serum levels, and its production by splenocytes, was augmented by 80%, together with a 10-fold increase in its expression in testes of infected male mice. Fadrozole treatment returned these levels to baseline values. Aromatase expression in the testes of infected male mice was not affected by Fadrozole. These results suggest that aromatase and IL-6 are key molecules in the production of the feminisation undergone by infected male mice and to Fadrozole treatment as a possible new therapeutic approach to cysticercosis.

Immunoendocrine interactions during chronic cysticercosis determine male mouse feminization: role of IL-6.

Taenia crassiceps cysticercosis results in an impressive feminization in male mice during chronic infection, characterized by increased serum estradiol levels 100 times their normal values, while those of testosterone and dihydrotestosterone are decreased by 85 and 95% respectively. Concomitantly, the levels of follicle-stimulating hormone and IL-6 are increased 70 and 90 times their normal values in the infected male mice. Since a specific Th1/Th2 shift of the immune response has been previously reported during the chronic infection, and this shift may be associated with the feminization process, we proposed that this shift is induced by immunoendocrine interactions during the disease, and this gives way to a change in the initial resistance to the infection in the male mice, which become as susceptible as female mice. To confirm this hypothesis, we depleted immune system activity in two different ways: total body irradiation and neonatal thymectomy. Our results show that when immune system activity is depleted using either strategy, the male mice do not feminize, and the levels of follicle-stimulating hormone and IL-6 are inhibited. Depletion of IL-6 using IL-6(-/-) knockout mice does not produce the feminization process stated above, while restitution of the IL-6(-/-) knockout, irradiated, and thymectomized mice with murine recombinant IL-6 restores the feminization process. Expression of the IL-6 gene was found only in the testes and spleen of infected animals. Our results illustrate the importance of immunoendocrine interactions during a parasitic disease and show a possible new mechanism of parasite establishment in an initially resistant host.

Bone marrow hypoplasia in a feminized dog with an interstitial cell tumor.

Bone marrow hypoplasia and feminization developed in a 10-year-old male German Shepherd Dog with interstitial cell tumor. Clinical abnormalities included pyrexia, pale mucous membranes, signs of abdominal pain, large left testis, atrophied right testis, and feminization. Abnormal laboratory findings included pancytopenia, bacteremia, bacteriuria, and pyuria. Results of cytologic examination of a bone marrow aspirate were consistent with aplastic anemia. Serum estradiol concentration was high, and serum testosterone concentration was low, compared with normal values for male dogs. The left testicular mass was identified as an interstitial cell tumor. Other causes of the aplastic anemia or feminization were not found.

[Feminizing adrenocortical tumor].

Feminizing adrenocortical tumor is rare. Three patients with feminizing adrenocortical tumor (2 males and 1 female) were treated surgically. The age of the patients was 11, 21 and 32 years old respectively. The removed tumors weighing 70 g, 250g and 31g respectively and they all were adrenocortical adenoma. The chief symptoms of the patients were gynecomastia, orchiatrophy and sexual inadequacy. The results of follow-up for 1-11 years showed no recurrence in all 3 patients. We consider that the tumor should be resected as soon as the diagnosis was established and long-term follow-up should be made after operation.

Effects of feminization of male F344 rats on induction of tumors and on nucleic acid alkylation by nitrosobis-(2-oxopropyl)amine.

Groups of male and female F344 rats were treated twice weekly by gavage with 2.5 mg of nitrosobis-(2-oxopropyl)amine (BOP) for 35 weeks. Additional groups given the same treatment were male rats castrated at birth, male rats bearing an implant of a pellet containing estradiol and castrated male rats bearing an estradiol pellet. Most rats died with tumors related to the treatment; intact male rats survived the least well of the five groups. Most rats in all groups had alveolar/bronchiolar neoplasms of the lung. Many of the male rats also had follicular cell neoplasms of the thyroid and transitional cell neoplasms of the urinary bladder and kidney pelvis; there were no liver tumors in intact male rats. Almost all female rats and castrated male rats had liver neoplasms, including hepatocellular, cholangiocellular and hemangiosarcomatous neoplasms, but few neoplasms of the thyroid, kidney or bladder. The male rats feminized with estradiol, intact or castrated, had liver neoplasms, mainly cholangiocellular, and also neoplasms of the thyroid. Two rats of each of the five groups were treated at 20 weeks of age with [14C]BOP. As measured by respiration of 14CO2, metabolism of BOP was faster in the two groups of male rats with the estradiol implant than in the other groups. DNA and RNA of the liver were isolated 6 h after treatment. The extent of methylation of liver DNA as 7-methylguanine and O6-methylguanine was higher in the females and in the feminized males than in the intact male rats, but when normalized to the dose of nitrosamine per unit body weight there was little difference among the five groups.

Mild androgen insensitivity presenting with sexual dysfunction.

A man presented with sexual dysfunction and was found to have elevated serum levels of both gonadotropins and T, suggesting AIS. Small external genitalia were the only phenotypic abnormality. Serum T levels increased appropriately in response to hCG and CC, but the patient was severely oligospermic, and testicular biopsy study revealed profoundly impaired spermatogenesis. Studied on androgen receptors in genital skin fibroblasts were normal. PAIS with a virtually normal male phenotype can present in adulthood with sexual dysfunction as well as infertility. As with the syndrome of complete AIS, androgen receptor studies indicate that this is a heterogeneous group of disorders.

Constitutional factors in alcoholic cirrhosis.

The different sensitivity of the male and the female liver is well established, but there is an obvious difference in male livers as well. One possible explanation for these differences might be the existence of genetic peculiarities among patients with alcoholic cirrhosis. In the early twentieth, Chvostek in Vienna was the first to draw attention to a constitutional element which he believed to be fundamental: Absent body hair, absent or extremely spare hair on the limbs, and pubic hair of the female type, i.e. with horizontal upper border (1) (Fig. 1). Chvostek laid special stress on the fact that these anomalies were of genetic origin and were not a secondary phenomenon do to alcoholism or cirrhosis. The feminine pattern of hair distribution, the so-called "Chvostek's habitus", is a frequently seen condition but the statistical proof of its association with alcoholic cirrhosis in man is still missing. The purpose of our study was to investigate if the feminine pattern of hair distribution in male patients with alcoholic cirrhosis is a genetic characteristic, this anomaly is more frequently encountered in the alcoholic type than in the post-hepatitis type of cirrhosis, the reported discrepancies of HLA frequencies are due to genetic differences.

Bilateral incipient germ cell tumours of the testis in the incomplete testicular feminization syndrome.

The presence of bilateral incipient germ cell tumours in the testes of two cases of the incomplete testicular feminization syndrome (TFS) is reported and found to resemble that occurring in the testes of infertile men. Both the nature and nomenclature of the lesion is discussed, as is its relevance in the early diagnosis and improved therapy of testicular tumours, which occur frequently in TFS. Suggestions are made for a more complete postpubertal surveillance in these patients, including assay of tumour markers and bilateral biopsies in cases of complete TFS. In this condition the removal of the testes is usually delayed until the twenties when total feminization is achieved, thus increasing the chances of tumour development.

Progestin binding in testes from three siblings with the syndrome of male pseudohermaphroditism with testicular feminization.

We have found a specific binding protein for synthetic progestins 6,7-[3H]methyltrienolone (R1881) and 17,21-dimethyl-19-norpregna-4,9-diene-3,20-dione (R5020) and in the testis cytosol from three "sisters" with the complete form of the testicular feminization syndrome. The binding component sediments in the 8S region of sucrose gradients. It is saturable. The apparent affinity constant (Ka) for R5020 was determined in two cases and found to be 1.8 and 0.6 X 10(8) M-1. The number of binding sites calculated from Scatchard plots is relatively high: 572 and 826 fmol/mg protein. Competition studies indicate that this putative receptor is specific for natural and synthetic progestins but not for 5 alpha-dihydrotestosterone and cortisol. Similar progestin binding could not be found in normal human and rat testes.

Massive extranglandular aromatization of plasma androstenedione resulting in feminization of a prepubertal boy.

This report describes the mechanism of origin and the quantity of estrogen produced in a prepubertal boy who developed severe feminization at 8 yr of age as the result of a heretofore undescribed metabolic abnormality. The clinical findings were gynecomastia and accelerated linear growth and bone maturation. At the time feminization developed, there were no signs of growth or development of the otherwise normal prepubertal male external genitalia or any increase of muscle mass that normally accompanies male puberty. The hyperestrogenism was found to be the consequence of massive extraglandular conversion of plasma androstenedione to estrone. During a 6-mo period of study, the plasma production rate of androstenedione ranged from 1.2 to 1.6 mg/day. More than 55% of plasma androstenedione was metabolized by aromatization to estrone which, in turn, was extensively sulfurylated in the tissue sites of aromatization before its entry into the blood. Thus, estrone sulfate was the final product in the aromatizing sites, and the plasma production rate of estrone sulfate derived from plasma androstenedione was 782 mug/24 h. The extent of extraglandular conversion of plasma androstenedione to estrone measured in this boy was 50 times that observed in two normal prepubertal boys. Moreover, 94% of the extraglandular aromatization occurred in extrahepatic sites. The metabolic clearance rate of plasma androstenedione, 2,380 liters/day per m(2), was markedly increased in this boy. Approximately 1,500 liters of plasma androstenedione clearance was accounted for by extrahepatic, extraglandular aromatization. The fractional conversion of testosterone to estradiol, 0.16, was 50 times greater in this boy than that observed in normal young adult men. The total extent of aromatization of plasma prehormones was even greater in this boy inasmuch as evidence was obtained that aromatization of 16-hydroxysteroids, e.g. 16alpha-hydroxy androstenedione and 16alpha-hydroxy dehydroisoandrosterone (sulfate), resulted in estriol formation independent of estrone formation. Thus, extensive extrahepatic, extraglandular aromatization resulted in advanced feminization in this prepubertal boy by a previously undescribed metabolic abnormality.