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Biomedical subjects

F W George

Publications and source records attributed to F W George.

At least 37 records · Page 2Linked to original sources
PubMed1989

Testosterone synthesis and adenylate cyclase activity in the early human fetal testis appear to be independent of human chorionic gonadotropin control.

Androgen secretion by the fetal testis is essential for male phenotypic differentiation. In the human fetus testosterone formation is initiated soon after the differentiation of the testis (approximately 8 weeks of gestation), and the maximal testosterone content in fetal testes is achieved between 10 and 15 weeks of fetal life. The testosterone content of the fetal testis declines at the beginning of the third trimester and remains low until after birth. In an effort to understand the regulation of the onset of testosterone formation in the human fetal testis we measured adenylate cyclase activity in response to hCG stimulation in homogenates of fetal testes obtained from first and second trimester human abortuses. Basal adenylate cyclase activity was 50 pmol/mg protein.min at 10 weeks gestation, the peak activity was 137 pmol/mg protein.min at 12 weeks gestation, and activity declined thereafter to 8 pmol/mg protein.min by 16 weeks gestation. NaF-stimulated (0.6 mmol/L) and forskolin-stimulated (50 mumol/L) activities were 4- to 8-fold greater than basal adenylate cyclase activities. The maximal forskolin-stimulated activity occurred at 11 weeks (803 pmol/mg protein.min), and it fell to 35 pmol/mg protein.min by 17 weeks gestation. In contrast, hCG-stimulated (1 mumol/L) adenylate cyclase activity was only slightly greater than basal rates at all ages examined. In addition, hCG did not stimulate baseline testosterone formation in minces of testes obtained between 12 and 18 weeks of gestation. These findings suggest that the onset of testosterone formation in human fetal testes may be independent of gonadotropin control.

Adenylyl Cyclases↗
PubMed1989

Suppression of experimental uveitis in rats by anti-I-A antibodies.

I-region-associated (Ia) class II major histocompatibility complex (MHC) products are known to play a major role in autoimmunity. Effects of anti-I-A and anti-I-E monoclonal antibodies on development of experimental autoimmune uveitis (EAU) were investigated in Lewis rats. Prior to sensitization with S-antigen, seven groups of rats, six in each group, were injected intraperitoneally with one of the following agents. Groups 1, 2, and 3 (controls) received saline, RPMI and mouse immunoglobulin G (IgG), respectively. Groups 4 and 5 were injected with anti-I-E antibodies, 80 micrograms and 1000 micrograms, respectively. Similarly, groups 6 and 7 received anti-I-A, 100 micrograms and 750 micrograms, respectively. The treatments were repeated on days 1, 2, 5, 8, and 11 after S-antigen injection. All these animals were killed on day 18. In addition, two groups of rats sensitized with S-antigen were treated with 750 micrograms anti-I-A antibodies on days 5, 6, and 7 (group 8) and on days 7, 8 and 9 (group 9). An additional group (group 10) of Lewis rats was treated with 750 micrograms anti-I-A 1 day prior to and on days 1 and 2 after S-antigen injection. These group-10 animals were killed on day 31. Histopathologically, the enucleated globes of animals treated with high dose anti-I-A revealed marked suppression or inhibition of uveitis development. Such inhibition was virtually complete when the antibody was administered within a week of S-antigen injection, and the inhibitory effect lasted for at least 31 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Partial characterization of the androgen receptor of the newborn rat gubernaculum.

Androgen receptors were measured by sucrose density gradient techniques in low-salt and high-salt extracts of gubernaculum, urogenital sinus, and bladder from 3- to 5-day-old male rats. Specific 5 alpha-[3H] dihydrotestosterone binding was present in both the low-salt and high-salt extracts of gubernacular tissue. The total amount of receptor in gubernaculum was approximately one-fifth the total amount of androgen binding measured in the urogenital sinus (119 fmol/g tissue in gubernaculum vs. 562 fmol/g tissue in urogenital sinus). No androgen receptor was detected in bladder. A 10-fold excess of nonradioactive 5 alpha-dihydrotestosterone competed well for 5 mM 5 alpha-[3H]-dihydrotestosterone binding, whereas 10-fold molar excesses of testosterone, estradiol, and progesterone were ineffective. These results suggest that the gubernaculum may be a target tissue for androgens.

Animals↗
PubMed1988

5 alpha-dihydrotestosterone formation is necessary for embryogenesis of the rat prostate.

To determine the role of 5 alpha-dihydrotestosterone (DHT; 17 beta-hydroxy-5 alpha-androstan-3-one) in formation of the embryonic prostate, we quantitated prostatic development in urogenital tracts of control male newborn and offspring of rats treated with a specific 5 alpha-reductase inhibitor (L652,931; Merck, Sharp, and Dohme) during prostate morphogenesis. Treatment with the 5 alpha-reductase inhibitor (50 mg/kg.day) from days 14-22 of gestation impaired development of the prostate and virilization of the external genitalia in male offspring compared to those in control animals. However, virilization of the internal genitalia (seminal vesicles, epididymis) was unaffected. Simultaneous administration of DHT (50 mg/kg.day) with the 5 alpha-reductase inhibitor restored prostate development and anogenital distances of males to normal and virilized the external genitalia of females. We conclude that DHT is the active androgen responsible for prostatic development in the rat.

5-alpha Reductase Inhibitors↗
PubMed1988

The androgen receptor in the fetal epididymis is similar to that in the mature rabbit.

To provide insight into the mechanism of wolffian duct virilization the androgen receptor has been characterized in pooled epididymal tissue from Day 27 rabbit embryos. Although the receptor is present at levels about a tenth that of other androgen target tissues in rabbit embryos, it appears to be a typical androgen receptor in regard to sedimentation characteristics and preferential binding of 5 alpha-dihydrotestosterone over testosterone. Thus, the mechanism by which testosterone virilizes the wolffian duct cannot be explained by unique binding characteristics of the androgen receptor in tissues derived from the wolffian ducts.

Animals↗
PubMed1987

Vasoactive intestinal peptide enhances aromatase activity in the neonatal rat ovary before development of primary follicles or responsiveness to follicle-stimulating hormone.

We have investigated the factors that regulate aromatase activity in fetal-neonatal rat ovaries. Ovarian aromatase activity (assessed by measuring the amount of 3H2O) formed from [1 beta-3H]testosterone) is low prior to birth (less than 0.5 pmol/hr per mg of protein) and increases to values greater than 30 pmol/hr per mg of protein between days 8 and 12 after birth. The appearance of ovarian aromatase (postnatal days 2-4) coincides with the development of primordial follicles. Fetal-neonatal ovaries maintained in serum-free organ culture do not develop aromatase activity at the expected time. Ovine follicle-stimulating hormone (0.1-1 microgram/ml), ovine luteinizing hormone (0.1 microgram/ml), or their combination failed to induce the enzyme activity in cultured fetal ovaries, whereas follicle-stimulating hormone is effective in preventing the decline in aromatase activity when postnatal day 8 ovaries are placed in culture. In contrast to follicle-stimulating hormone, dibutyryl-cAMP markedly enhances ovarian aromatase in cultured fetal ovaries. Likewise, enhancement of endogenous cAMP formation with forskolin or cholera toxin caused an increase in enzyme activity within 24 hr. Vasoactive intestinal peptide, a peptide known to occur in ovarian nerves, caused a dose-dependent increase in aromatase activity in fetal ovaries prior to folliculogenesis. Of related peptides tested, only the peptide having N-terminal histidine and C-terminal isoleucine amide was capable of inducing aromatase activity in fetal ovaries. The fact that VIP can induce aromatase activity in fetal rat ovaries prior to follicle formation and prior to responsiveness to follicle-stimulating hormone suggests that this neuropeptide may play a critical role in ovarian differentiation.

Animals↗
PubMed1987

Changes in amount and intracellular distribution of androgen receptor in human foreskin as a function of age.

To provide insight into the factors that control growth of the penis we measured the amount and intracellular distribution of specific high affinity androgen receptor in foreskins obtained at circumcision from 49 males varying in age from newborn to 59 yr. Total (cytosolic plus nuclear extract) androgen receptor decreased from approximately 40 fmol/g tissue weight in newborn foreskins to approximately 25 fmol/g by 1 yr of age. The amount of receptor rose in childhood to approximately 180 fmol/g in the late teenage years and fell thereafter to approximately 20-40 fmol/g in men older than 40 yr. The amount of receptor in the nuclear fraction increased at the time of puberty and subsequently decreased in parallel with the decline in total receptor level. These changes in androgen-receptor amount are similar when expressed per milligram DNA or per milligram protein.

Age Factors↗
PubMed1987

5 alpha-reduced androgens in the human fetal testis.

The androgen content was measured in testes from 34 male and in ovaries from 30 female embryos that varied in age from less than 12 to approximately 20 weeks. The 5 alpha-reduced androgens dihydrotestosterone and 3 alpha-androstanediol were found in testes at a level of about a 30th of that of testosterone at all ages examined, whereas very little or no testosterone, androstenedione, or either of the 5 alpha-reduced androgens were detected in the ovaries. Whether dihydrotestosterone plays a role in the development of the testes is unknown.

Androstane-3,17-diol↗
PubMed1986

Characterization of the testicular abnormality in 5 alpha-reductase deficiency.

The testes of five phenotypic women (from four families) with 5 alpha-reductase deficiency were studied. In one of the patients, the enzyme deficiency was similar in the testis and epididymis and in fibroblasts cultured from the labia majora. In testes from four of the patients, the concentrations of the 5 alpha-reduced steroids dihydrotestosterone and 3 alpha-androstanediol were less than 10% of those in normal subjects. We conclude that the testis is involved in 5 alpha-reductase deficiency. Impaired spermatogenesis was evident in testicular biopsies from all five subjects, and in two, sperm production, as estimated in testicular homogenates, was less than 10% of normal. The extent to which spermatogenic arrest is due to 5 alpha-reductase deficiency or testicular maldescent is not clear.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1985

The synthesis and metabolism of gonadal steroids in pouch young of the opossum, Didelphis virginiana.

We have measured steroid hormone biosynthesis from pregnenolone in ovaries and testes, aromatization of testosterone in gonads and peripheral tissues, and 5 alpha-reduction of testosterone in peripheral tissues of developing opossum pouch young. Sex of the newborn opossums is discernible grossly with development of the pouch in females and the scrotum in males approximately 10 days after birth. Differentiated endocrine function of ovaries and testes was demonstrable as soon as development of the pouch or scrotum was apparent. The testes synthesized testosterone, and ovaries aromatized androgens to estrogens as assessed by the conversion of [1 beta-3H] testosterone to 3H2O. This endocrine differentiation of the gonads occurs days or weeks before differentiation of the male and female urogenital tracts. As in other species, 5 alpha-reduction of [1 beta-3H] testosterone was high in urogenital sinus and urogenital tubercle. However, 5 alpha-reductase activity was highest in mesonephros and structures derived from the mesonephros. In wolffian and mullerian ducts of pouch young less than 10 days old, 5 alpha-reductase activity was greater than 50 pmol/h . mg protein and decreased by 19 days of age to approximately 3 pmol/h . mg protein, a pattern different than in eutherian mammals in which testosterone itself appears to mediate virilization of the wolffian ducts. These studies provide the framework for studies of the endocrine control of phenotypic sexual differentiation in the opossum.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1985

The lixiscope. Use in examination and surgery.

The lixiscope is a portable, low-intensity fluoroscopic device, which provides convenience and safety for doctor and patient in examination and surgery. It gives a real time image which allows motion of the object to be observed and manipulation or surgical procedures to be performed under continuous visual monitoring. By changing lines of perspective, an appreciation of the object can be gained in three dimensions. This is especially important in visualizing geometry-dependent flaws, such as fractures, or in bringing out low-contrast objects from the background by relative motion. lixiscopic foot surgery is a new kind of foot surgery, opening up previous "closed" or minimal incision surgery. It has the benefits of the previous minimal incision surgery, with direct visualization of sophisticated procedures for consistent results. Future directions in this technology may include a lixiscope which will not require isotope replacement, true stereoscopic vision, and specialized devices for various branches of medicine.

Ambulatory Surgical Procedures↗
PubMed1984

Treatment-related morbidity in phase III RTOG studies of extended-field irradiation for carcinoma of the prostate.

The incidence, severity, time of onset, and clinical course of complications of treatment have been reviewed in the RTOG studies of extended field irradiation in carcinoma of the prostate. A total of 526 patients, entered between 1976 and 1980 and followed for a minimum of 18 months, comprised the study population. In most instances of treatment-related morbidity, the symptoms were recorded during the first several months to 1 year following completion of treatment. Late occurrences, however, were not uncommon in certain types of radiation-produced injuries, such as proctitis, hematuria, and urethral strictures. Resolution of symptoms has been observed in a large proportion of patients including those with late occurrences of treatment-related morbidity, although the probability and the pattern of resolution differed considerably from one type of morbidity to another. Symptoms of cystitis are more likely to abate than those of proctitis. In patients who develop symptoms of proctitis the probability of persistence of symptoms beyond the second year following occurrence has been estimated at 20%-30%. Hematuria and symptoms secondary to urethral strictures seem to be even more likely to recur or persist, while genital and leg edema remain chronic in the majority of patients.

Adenocarcinoma↗
PubMed1984

Androgen receptors are similar in fetal and adult rabbits.

In an effort to explain the separate roles of testosterone and dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) in virilizing the male fetus, we compared the binding of these androgens to cytosolic receptors from urogenital tract tissues of fetal and adult male rabbits. As measured by a direct binding assay, fetal and adult androgen receptors are similar in respect to specificity, affinity, and amount of binding. Apparent dissociation constants for dihydrotestosterone binding averaged 1.1 nM for fetal receptor and 0.8 nM for adult androgen receptors. Average apparent dissociation constants for testosterone binding were 4- to 24-fold higher than those for dihydrotestosterone in fetal and adult tissues. Nonradioactive dihydrotestosterone and testosterone competed for [3H]dihydrotestosterone binding to the androgen receptor in both adult prostate and fetal urogenital sinus in a manner consistent with their affinity for binding, whereas estradiol, progesterone, and cortisol were weak competitors for [3H]dihydrotestosterone. On sucrose density gradients, both testosterone and dihydrotestosterone were bound to a protein with a sedimentation coefficient of approximately 8S. Although androgen receptors were detectable in urogenital tubercle and urogenital sinus of both male and female fetuses on days 18 and 29 of gestation, we were unable to characterize androgen binding in fetal Wolffian ducts. The nature of the androgen receptor in this tissue remains unresolved. These findings are consistent with the hypothesis that dihydrotestosterone formation acts to amplify the androgenic signal in both the fetus and adult, but is not absolutely required for virilization.

Animals↗
PubMed1983

Characterization of the increased estrogen synthesis in skin fibroblasts from the Sebright bantam.

We have utilized the Sebright bantam chicken as a model system to explore the regulation of estrogen formation in peripheral tissues. As the result of a gene mutation, Sebright males develop a female feathering pattern associated with an increase in estrogen synthesis in skin and in fibroblasts cultured from skin. To provide insight into the mechanisms by which estrogen synthesis is increased we examined several parameters of the aromatase reaction in homogenates from control ovaries, Sebright ovaries and fibroblasts grown from Sebright skin: the pH optima; the apparent Km's for testosterone, 19-nortestosterone, androstenedione, 16-hydroxyandrostenedione, and NADPH; the apparent Ki's for 4-hydroxyandrostenedione, aminoglutethimide, dehydroepiandrosterone, and 19-hydroxytestosterone; and the inactivation of the reaction by heating. No qualitative differences were identified in the enzyme from Sebright and control birds.

Androstenedione↗
PubMed1983

Radiation therapy in bulky seminoma.

Between 1969 and 1980, 17 patients with bulky retroperitoneal seminoma and 1 patient with bulky mediastinal seminoma were treated with radiation therapy. One patient had resection of gross retroperitoneal disease, and 1 patient had resection of gross mediastinal disease. Fifteen patients received adjuvant irradiation to the mediastinum and paraclavicular lymph nodes, and 1 patient received adjuvant chemotherapy. At last follow-up, 17 of 18 patients (94%) remain free of disease. No patient has sustained treatment-related morbidity or mortality.

Dysgerminoma↗
PubMed1983

The endocrine control of male phenotypic development.

Male and female embryos develop in an identical fashion during the initial portion of gestation. If the indifferent gonad differentiates into an ovary (or if no gonad is present), a female phenotype is formed. Male phenotypic differentiation, however, requires the presence of an endocrinologically active testis. Two secretions of the foetal testis, Mullerian-inhibiting substance and testosterone, are responsible for male development. Testosterone itself is responsible for virilization of the Wolffian duct system into the epididymis, vas deferens, and seminal vesicle, whereas dihydrotestosterone induces development of the prostate and male external genitalia. Thus, impairment of dihydrotestosterone formation results in a characteristic phenotype consisting of predominantly female external genitalia but normally virilized Wolffian ducts. The molecular mechanisms by which testosterone and dihydrotestosterone act during foetal development appear to involve the same high affinity receptor, a protein that transports both testosterone and dihydrotestosterone to the nucleus of target cells. When this receptor is either absent, deficient, or structurally abnormal, the actions of both testosterone and dihydrotestosterone are impaired, and the resulting developmental anomalies involve both internal and external genital structures.

3-Hydroxysteroid Dehydrogenases↗