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PubMed1997

Assessment of androgen receptor function in genital skin fibroblasts using a recombinant adenovirus to deliver an androgen-responsive reporter gene.

Mutations of the androgen receptor (AR) cause defects in virilization and can result in a spectrum of phenotypic abnormalities of male sexual development that includes patients with a completely female phenotype (complete testicular feminization) and individuals with less severe defects of virilization, such as Reifenstein syndrome. These phenotypes are not specific for mutations of the AR gene, however, and defects in other genes can also result in similar abnormalities of male development. For this reason, the diagnosis of an AR defect is laborious and requires data from endocrine studies, the family history, and in vitro binding experiments. To assist in the evaluation of patients with possible AR defects, we previously employed the use of a recombinant adenovirus to deliver an androgen-responsive gene into fibroblast cultures to assay AR function in normal subjects and patients with complete forms of androgen resistance. Although these studies demonstrated measurable differences between these two groups of subjects, we did not assay samples from patients with partial defects of androgen action. In the current study, we have modified this method to examine AR function in three groups of patients with known or suspected defects of AR function: patients with Reifenstein syndrome, patients with spinobulbar muscular atrophy, and patients with severe forms of isolated hypospadias. When assayed using this method, the AR function of patients with Reifenstein syndrome was intermediate between that of normal control subjects and that of patients with complete testicular feminization. Using the parameters established by the aforementioned experiments, we found that defective AR function can be detected in fibroblasts established from patients with spinobulbar muscular atrophy and in some patients with severe forms of isolated hypospadias, including two with a normal AR gene sequence. These results suggest that this method may have some utility in screening samples to detect defects of AR function, particularly when viewed in the context of other AR assays results.

Adenoviridae↗

PubMed1994

Identification of a candidate primary sex determination locus, fox-1, on the X chromosome of Caenorhabditis elegans.

Sex in Caenorhabditis elegans (XX hermaphrodite, XO male) is determined by the X:A ratio, which is the ratio of X chromosome number to autosomal set number. Recent genetic results with X chromosome duplications have suggested that there may be only a small number of major numerator sites on the X chromosome that contribute to this ratio. Mapping of duplication endpoints delimited a region of less than 300 kb, likely to contain one such element. Cosmid clones from this region were tested for numerator activity by constructing transgenic lines carrying extra copies of each tested cosmid. Most cosmid arrays have no effect on the viability of either XX or XO animals. One cosmid array was found to be viable in XX animals, but lethal and feminizing in XO animals, consistent with it containing a major numerator element. Further experiments defined a region of 12-30 kb with apparent numerator activity, which is designated fox-1, 'Feminizing locus On X'. A cDNA clone hybridizing across part of this region encodes a predicted RNA-binding protein.

Amino Acid Sequence↗

PubMed1975

On the modulating effects of ovaries on neonatal androgen programming of rat liver enzymes.

The metabolism of 4-[4-14C]androstene-3,17-dione in rat liver microsomal and cytosol fractions was investigated in adult female rats treated with 1.45 mumole of testosterone propionate at birth. The effects of ovariectomy at 14 and 43 days of age on neonatal testosterone imprinting of enzyme levels were studied. Animals spayed 14 days after birth showed a typical masculinized hepatic enzyme activity pattern with a decreased level of the 5alpha-reductase activity and increased level of 5beta-reductase, 16alpha-hydroxylase and 17alpha- and 3beta-hydroxysteroid reductase levels. The pattern was essentially the same in testosterone propionate-treated rats spayed 43 days after birth - with the exception of a feminized 5alpha-reductase activity - whereas a completely feminized ("de-imprinted") pattern of enzyme activities was found in the rats with intact ovaries at the time of death. It is concluded that de-imprinting action of ovaries is mainly of a reversible nature.

Androstanes↗

PubMed1982

The effects of pituitary hormones on hepatic drug metabolism in the rat.

Sex differences exist in the hepatic microsomal metabolism of drugs in the rat. These differences have been shown to be related to the presence of androgen in the male and the pituitary gland in the female. The present study was designed to identify the pituitary 'feminizing factor' by continuously infusing hormones via an osmotic mini-pump. Rat somatotropin and prolactin mimicked somewhat the 'feminizing' effect of pituitary extract infused into male animals while human somatotropin, which binds to both lactogenic and somatogenic receptors in rat liver, completely reversed the effect of hypophysectomy of female rats with respect to most of the parameters studied. It thus appears that the somatogenic/lactogenic receptors in the rat liver are involved in the maintenance of the sex differences in drug metabolism but the identity of the hormone that normally acts on these receptors in the rat is still uncertain.

Animals↗

PubMed1990

Effect of cis-platinum on heme, drug, and steroid metabolism pathways: possible involvement in nephrotoxicity and infertility.

cis-Platinum, a coordination complex of platinum, is highly effective against a number of human tumors, including steroid-dependent tumors such as testicular and prostatic cancers. It is generally assumed that DNA is the cellular target responsible for the antitumor activity of the drug. Much evidence, however, has been gathered in recent years suggesting that cis-platinum has major effects on the endocrine system, particularly the hypothalamic-pituitary-testis steroidogenesis axis, and severely disrupts the normal production of testosterone. In the axis, testis is the prime target, where the LH receptor-binding capacity of Leydig cells is decreased by nearly 80%. Within the testis, the mitochondrial cytochrome P-450scc and side-chain cleavage activity are markedly depressed and the microsomal 17 alpha-hydroxylase activity and cytochrome P-450 concentration are decreased; side-chain cleavage activity is rate-limiting in testosterone production. The effects are not limited to the testis cytochrome P-450, but extend to other organs including the liver and the kidney cytochromes. In the liver, a feminization of the cytochromes P-450 profile is produced, and hence the biotransformation of endogenous steroids as well as that of exogenous chemicals is affected. In the kidney, cis-platinum appears to be the most effective inducer of cytochrome P-450, whereby the biotransformation of the prostaglandins and fatty acids could be altered. The spectrum of the effects of cis-platinum on cytochrome P-450-dependent drug metabolism and steroid hydroxylation activity mimic those produced by hypophysectomy and are for the most part reversed by the anterior pituitary hormones. These findings suggest the possibility that general feminization of steroidogenesis caused by cis-platinum may significantly contribute to the activity of cis-platinum against hormone-dependent tumors.

Animals↗

PubMed2004

When most doctors are women: what lies ahead?

The profession of medicine is becoming feminized: The number of women enrolled in medical school and residency programs has increased dramatically over the past several decades. Some researchers have examined how women are faring in the profession, but few have considered how feminization of the profession will affect patient care and health care systems, as well as the profession itself. We predict that notable changes may emerge in 4 domains: the patient-physician relationship, the local delivery of care, the societal delivery of care, and the medical profession itself. We also consider the potential positive and negative consequences of a predominantly female physician workforce on these domains.

Delivery of Health Care↗

PubMedDate not supplied

Estrogen in autoimmunity: expression of estrogen receptors in thymic and autoimmune T cells.

OBJECTIVE: To identify the targets of estrogen in immune system lymphocytes and to examine gender differences in autoimmunity. DESIGN: RNA samples from purified lymphocyte subsets were analyzed for the presence of mRNA for estrogen receptor alpha and beta (ER alpha and ER beta). Groups of male, female, and testicular-feminized mice were compared for autoantibody production. SUBJECTS: Autoimmune-prone lpr (Fas-deficient), testicular-feminized (Tfm, androgen receptor-deficient) and wild-type mice were studied. METHOD: Lymphocyte subsets were purified by fluorescence-activated cell sorting (FACS) and RNA was assessed for the presence of estrogen receptor sequences using specific oligonucleotide primers and the reverse transcription-polymerase chain reaction (RT-PCR). Spontaneous and induced antibody production in mice was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: ER alpha was expressed in all lymphocyte subsets examined. ER beta was expressed at low levels in thymic CD4/CD8- T cells in wild-type mice and at high levels in the peripheral CD4-/CD8- T cells in lpr mice. Both spontaneous and induced autoantibody production was higher in female lpr mice than in male lpr mice. CONCLUSIONS: The presence of ERs in lymphocytes indicates that estrogen may affect immune cells during their development and mature function. The selective expression of ER beta may help explain some of the physiological effects of estrogen and its pharmacologic analogues and may lead to means to direct estrogen analogues to such cells. Such effects may be explored in lpr mice, given the enhanced capacity of female lpr mice for autoantibody production.

Androgen-Insensitivity Syndrome↗

PubMedDate not supplied

[Surgical tactics for sex correction of patients with testicular forms of hermaphroditism].

On the basis of own material (43 patients) the author presents surgical tactics towards the testes in patients with testicular forms of hermaphroditism depending on the form of the disease. The authors consider that in the syndrome of dysgenesia of the testes the latter should be removed from the abdominal cavity (oncological danger!): when female sex is chosen--castration, and male--fixation of the testes under abdominal skin is indicated. In case of the syndrome of testicular feminization the testicles should be fixated under the abdominal skin by the authors' method. In case of the syndrome of incomplete masculinization (eunichoid form) the tactics is the same as in testicular feminization; in android form the testicles can be placed into the scrotum. Biopsy of the testes is necessary in all forms of hermaphroditism.

Androgen-Insensitivity Syndrome↗

PubMed2003

Effects of environmental endocrine disruptors on the sex differentiation in Korean rockfish, Sebastes schlegeli.

The effects of estradiol-17beta, methyltestosterone, tributyltin, bisphenol A and 2,4-dinitrophenol on sex differentiation were investigated in the Korean rockfish, Sebastes schlegeli. The 51 day-old fry with undifferentiated gonads were fed with food containing the chemicals at 0.05, 0.5, 5, 50 and 100 micro/g diet for 29 days. Sex ratio and gonadal abnormality after the chemical treatment were determined by histological examination of gonads. In control group, the sex ratio of fry was 1:1.3 (female:male), and more males than females appeared. The sex of fry fed with estradiol-17beta at 5, 50 and 100 micro/g diet was all females. Feminization of the fry was induced by exogenic estradiol-17beta. In the methyltestosterone group, sex ratio of fry was 1:10.2 in 0.05 micro/g diet, 1:2.4 in 0.5 micro/g diet, 1:3.1 in 5 micro/g diet, 1:1.2 in 50 micro/g diet and 1:2.3 in 100 micro/g diet. Masculinization of the fry was induced by methyltestosterone at the lowest concentration. Furthermore, intersex of the fry was observed. The number of intersex fry was 23.3, 25.0 and 35.3 at 0.5, 5 and 50 micro/g diet of methyltestosterone, respectively. Sex ratio of bisphenol A group showed no difference with that of the control. The sex of fry fed with 2,4-dinitrophenol at 5, 50 and 100 micro/g diet was all females. 2,4-dinitrophenol should be considered as a new member of endocrine disruptors. In tributyltin group, the sex ratio of fry at 100 micro/g diet of tributyltin was 5.4:1. Tributyltin induced the feminization of the fry at the highest dose. Tributyltin showed an estrogenic effect in the Korean rockfish in contrast to an androgenic effect in gastropods.

Administration, Oral↗

PubMed1992

[A laboratory test for the detection of androgen resistance using sex hormone-binding globulin].

A simple laboratory test for disclosure of peripheral androgen insensitivity has been suggested. The test is based on determination of sex hormone-binding globulin (SHBG) following single administration of testosterone preparation (Testoviron Depot, Schering, 2 mg/kg of body weight). The kinetics of SHBG response to exogenous testosterone was investigated first in a group of 5 healthy male volunteers. The highest highly significant decrease of SHBG level occurred 7th day after drug administration. The method of choice for SHBG determination is an immunoradiometric assay (IRMA). The test was used for a group of 15 children and young people suspected for androgen sensitivity disorder. In all cases, besides SHBG on days 0 and 7 testosterone, dihydrotestosterone and LH were measured, too. In three instances the response was negative: in the case of male Turner syndrome, with very low basal SHBG levels, in one case of confirmed diagnosis of testicular feminization and in the third case of suspected testicular feminization, which has not yet been concluded. In all other patients a significant decrease (in average to 62.8% of the basal level) was in agreement with clinical findings.

Adolescent↗

PubMed2005

Development of on-site fish exposure system placed in water quality monitoring stations along a river.

Estrogen-like substances have been suspected to cause feminization of wild fish in rivers in Japan. To elucidate the influence of estrogen-like substances on fish in river, we have started to develop the on-site continuous fish exposure system using medaka Oryzias latipes that were placed in water quality monitoring stations along a river. Adult male medaka were exposed to the river water in a glass exposure tank placed in the monitoring stations. Flow rate of water and water temperature were controlled at 30 L/hour and 26 degrees C respectively, and a light: dark cycle was maintained 16:8 hours. A commercial diet free from phytoestrogens was fed 4 times in a day using automatic feeder. After 2-week exposure, hepatic vitellogenin concentration of each male medaka was measured. The exposure tests were repeatedly performed at both the upstream and the downstream of sewage treatment plants along the River Tama which is a representative urbanized river in Japan. At the control site Haijimabashi monitoring station, vitellogenin was not detected in male medaka. On the other hand, at the Ishihara monitoring station which is the most downstream in this test area, every male medaka were produced vitellogenin in the test performed in the spring of 2004. As the results of the water quality analysis, it could be inferred that the estrone derived from effluents of sewage treatment plants caused the feminization of male medaka. The reason why the concentrations of the estrone and the estrogenic activity using DNA recombinant yeast varied in proportion to the electric conductivity of river water measured at the water quality monitoring station. Furthermore, after continuous 2-week exposure, the vitellogenin production of male medaka was reduced similar to the decrease of the concentrations of the estrone and the estrogenic activity of river water.

Animal Feed↗

PubMed1991

[Clinico-morphological signs of hormone-producing ovarian tumors].

Apparent signs of hormonal activity were observed in 65.3% of patients with hormone-producing ovarian tumors of different histology. Feminization was evident in 69.1% of cases of granulosa-stromal cell tumors: it was most often seen in patients with mixed theca-granulosa cell tumors (86.2%) but was least frequent in those with Brenner's tumor (22.2%). The occurrence of proliferative lesions of the uterus such as hyperplasia of the endometrium, cervical canal polyps and uterine myoma (81.8%) was higher in patients with granulosa-stromal cell tumors, too, the highest rate being observed for cases of mixed theca-granulosa cell tumors (93.1%) whereas the lowest--for patients with Brenner's tumor (27.8%). Various clinical signs of masculinization were most often seen in cases of androblastoma (79.2%) whereas the proliferative disorders in that group were rare (12.5%). As a result, the authors placed mixed theca-granulosa cell, theca cell, granulosa cell tumors and Brenner's tumor in the order of decreasing feminizing activity. In the granulosa-stromal cell tumor subgroup, masculinization was most often observed in granulosa cell tumor patients (12.1%).

Brenner Tumor↗

PubMed1991

[From embryogenesis to female phenotype in subjects with XY karyotype].

On the basis of the findings of their investigation of the embryogenesis of the female genital tract, the authors advance a hypothesis concerning the origin of ambiguities between the genetic sex and the gonophoric sex which determine primary sexual characteristics observed in Morris' syndrome and in gonadoblastoma. According to the authors, in gonadoblastoma there is dysgenesis or even agenesis of the gonads, with a total absence of Sertoli cells and, therefore, no secretion of anti-Müller substance and this explains the development of the Müller canals into uterus and Fallopian tubes and the presence of a vagina in an XY subject. In the syndrome of the feminizing testis, XY subjects have testes containing Sertoli cells which have produced anti-Müller substance. However, the initiation of the production of this substance is delayed and it is this delay which has permitted the tendency towards feminization of the uro-genital sinus with the formation of a vagina. The authors thus refute the theory which holds that the Müller cells are involved in the genesis of the vagina.

Female↗

PubMed1990

Alteration of plasma sex hormone levels associated with old age and its effect on hepatic drug metabolism in rats.

A mechanism of age-associated alterations in plasma sex hormone levels as well as their effect on drug metabolizing enzyme activities were studied using male and female Fischer 344 rats of ages ranging between 3 and 30 months. Plasma testosterone levels as well as the activity of the rate limiting enzyme required for testosterone production in testes, androstenedione 17 beta-oxido-reductase, decreased with senescence in parallel with the alteration of drug metabolism whereas activity of hepatic microsomal androstenedione 5 alpha-reductase, the testosterone metabolizing enzyme, increased with age. The profile of drug metabolizing activities with imipramine, diazepam, hexobarbital, lidocaine, p-nitroanisole and androstenedione as substrates in old (27-month-old) male rats was almost identical to that in young or old female rats, indicating that neonatal androgenic imprinting of drug metabolism in male rats was erased in senescence. Castration of adult (9-month-old) male rats caused a decrease in drug metabolism, but did not result in complete feminization of the profiles of drug metabolism as was observed in old male rats, indicating that neonatally imprinted male pattern of drug metabolism was still retained in the absence of testosterone in adult male rats. Testosterone administration restored completely male-level activities in castrated adult rats, but caused only a partial recovery in old male rats. It is proposed that senescence associated feminization of the drug-metabolizing ability of the male rat liver may be in part due to the decrease in testosterone levels in old age and in part to the loss of neonatal imprinting.

Aging↗

PubMed1979

The influence of oestradiol on androgen- and oestrogen-dependent enzyme activities of hepatic steroid metabolism in rats.

Five sexually differentiated enzyme activities of hepatic steroid metabolism (cytoplasmic 17 beta-hydroxysteroid dehydrogenase, 5 beta-reductase; microsomal 3 alpha- and 3 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase) were investigated in intact, gonadectomized and hypophysectomized rats after administration of a single dose of oestradiol valerate. Oestradiol administration caused a partial or complete feminization of these activities in intact male rats. The influence of oestradiol on these activities in gonadectomized rats was determined by the mode of sex hormone-dependent regulation of the individual activity: the most prominent effects were seen in the oestrogen-dependent activities (17 beta-hydroxysteroid dehydrogenase, 5 beta-reductase); no effect was seen in the completely androgen-dependent 3 alpha-hydroxysteroid dehydrogenase because gonadectomy alone was sufficient to cause complete feminization of the activity. Oestradiol administration had no effect on the activities of hypophysectomized rats. The fact that oestrogen administration to intact male rats caused greater changes than prepuberal gonadectomy demonstrates that oestrogen action is more than simple suppression of testicular function.

17-Hydroxysteroid Dehydrogenases↗

PubMed1987

[Androgen insensitivity syndromes].

The syndromes of androgen resistance illustrate a special field of endocrinology, that is pathology of target-tissues. These syndromes are responsible for male pseudohermaphroditism and provoke in XY subjects, with a normal testicular androgen secretion, abnormalities in the phenotype with all the possibilities from an "idealistically" female phenotype in the testicular feminization syndrome to an almost normal male phenotype in the mildest forms of the incomplete syndrome. Understanding of these syndromes has strongly benefited of progress in biochemistry and molecular biology concerning the mechanism of action of androgens. On the other hand, understanding androgen mechanism expanded markedly from parallel clinical observation and biochemical investigation permitted by methodological progress: plasma hormones assays, 5 alpha-reductase and androgen receptor qualitative and quantitative determinations. The complete form of the testicular feminization syndrome seems to be due--in most cases--to an absence of the androgen receptor whereas the incomplete forms of the syndrome are related either to insufficient amount or qualitative alteration of the receptor or to a defect of 5 alpha-reductase, the key-enzyme which transforms testosterone to its active metabolite dihydrotestosterone in androgen target-cells. In some cases (approximately equal to 10%) the mechanism of androgen insensitivity could not be identified. The abnormality might be downstream the receptor at various possible steps = binding of the complex androgen-receptor to the chromatin, transcription or post-transcription process. These cases can be useful models for understanding the ultimate steps of the androgen mechanism of action.

Androgen-Insensitivity Syndrome↗

PubMed1987

Experience with adrenocortical neoplasms in childhood.

The experience with adrenocortical neoplasms in childhood is reviewed. During three decades, ten children with adrenocortical neoplasms were seen at the authors' institution. The literature was reviewed, and 209 patients 16.5 years or younger were found. All ten patients at Vanderbilt University Hospital (VUH) presented with endocrine manifestations of the tumor. Three patients had Cushing's, two patients had virilization, and five patients had features of both. In the literature, virilization, alone or with Cushing's, was the most common mode of presentation. Feminizing tumors were uncommon and nonfunctional tumors rare. The majority of patients were female. Features associated with malignancy included 17-KS levels greater than 40 mg/24 hr, diameter greater than 6 cm, weight greater than 500 g, and histologic evidence of diffuse growth pattern, vascular invasion, and tumor cell necrosis. Although uncommon, adrenocortical neoplasms should be suspected in children with Cushing's, virilization, feminization, or a combination of these. There has been an increased incidence reported in patients with hemihypertrophy, Beckwith-Wiedemann syndrome, hemangiomas, and nevi. Following endocrinologic evaluation, imaging studies should be performed. CT scan appears to be the most useful diagnostic tool. A posterior operative approach is recommended for suspected adenomas. An anterior thoracoabdominal approach is favored for suspected malignancies with uncompromised en bloc resection. There is no evidence that adjuvant therapy provides any additional benefit.

17-Hydroxycorticosteroids↗

PubMed1979

Pituitary control of hepatic steroid metabolism.

Hypophysectomy of male animals has little effect on the hepatic 4-androstene-3,17-dione (androstenedione) metabolism except at the kinetic level where changes in the apparent Km of the 16 alpha- and 7 alpha-hydroxylases are seen. On the other hand, hypophysectomy of female animals leads to a "masculinization" of hepatic androstenedione metabolism, following the changes seen in Vmax of the respective enzymes probably due to the removal of the source of "feminizing factor" thought to maintain the female-type metabolism in the liver. There seems to be a temporal dissociation of the effects on the various enzymes indicating different cellular control mechanisms for these enzymes. Oestrogen treatment of male rats causes "feminization" of the hepatic androstenedione metabolism. The time study shows an initial increase in 17-hydroxysteroid oxidoreductase, 6 beta- and 16 alpha-hydroxylase activities followed by a decrease to the levels of females. This biphasic effect is possibly due to an initial direct effect of the oestrogen on the liver followed by an indirect effect via the hypothalamo-pituitary system. The changes in enzyme activity noted are related to changes in Vmax of the respective enzymes although changes in apparent Km are also seen.

17-Hydroxysteroid Dehydrogenases↗