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Biomedical subjects

A R Glass

Publications and source records attributed to A R Glass.

At least 37 records · Page 2Linked to original sources
PubMed1986

Fertility onset, spermatogenesis, and pubertal development in male rats: effect of graded underfeeding.

Undernutrition has proven to be a useful model for exploring the relationship between growth and pubertal development in female rats, such as the "critical body weight" hypothesis of pubertal timing, but corresponding studies in the male have been hampered by lack of specific discrete markers of puberty similar to vaginal opening or first estrus in females. In the current study, we explored the effect of five different levels of food intake (as low as one-third of normal) beginning at weaning on pubertal development and timing in male rats, using the date of the initial successful conception with normal females as a discrete marker for puberty in males. In underfed males, there was a weak inverse correlation (r = -0.31, p less than 0.05) between the age at puberty and the growth rate, the latter being used as an index of the degree of underfeeding. In contrast, there was a strong direct correlation (r=0.78, p less than 0.001) between body weight at puberty and growth rate. In the most severely underfed groups, the Lee index of body fat remained subnormal before and after puberty. Initial litter size also tended to be reduced when the males were underfed. At age 51 days (prior to puberty), graded underfeeding led to progressive reductions in serum luteinizing hormone and follicle-stimulating hormone levels as well as in parameters of androgen status (serum and testicular testosterone, prostate, and seminal vesicle weights). Testicular size was also reduced, but daily sperm production rate was not greatly affected by underfeeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1986

Decreased serum 3,5,3'-triiodothyronine (T3) and abnormal serum binding of T3 in calorie-deficient rats: adaptation after chronic underfeeding.

Both starvation and feeding of a low protein diet have dramatic effects on serum thyroid hormone concentrations and on the serum binding proteins for thyroid hormones in rats. We examined whether similar changes might be seen in another model of undernutrition, namely underfeeding without alteration of dietary composition, and in particular whether such changes would disappear after prolonged alteration in diet (adaptation). Male rats aged 21 days were put on five different levels of intake of a diet of normal composition (18% protein, 70% carbohydrate), and animals from each dietary group (n = 8-10) were killed after 30, 60, or 100 days of underfeeding. After 30 or 60 days of underfeeding, significant direct correlations were observed between growth rate (used as an index of the degree of underfeeding) and serum T3 (RIA), percent free T3 (equilibrium dialysis), and serum free T3 (T3 X percent free T3). When underfeeding was prolonged to 100 days, however, there was no correlation between growth rate and percent free T3, while the correlation between growth rate and serum free T3 was weak (r = 0.33). Qualitatively similar changes were seen when animals given five different levels of food intake were killed at three body weight milestones rather than three separate age milestones. Polyacrylamide gel electrophoresis of serum thyroid-binding proteins revealed that the low percent free T3 in underfed rats seen after 60 days of underfeeding was associated with the development of a thyroid-binding globulin not normally found, but this had disappeared by 100 days of underfeeding. We conclude that nutrition-related changes in serum thyroid hormone variables show adaptation over time. Because of changes in serum binding of thyroid hormones caused by undernutrition, total serum thyroid hormone concentrations may not be an accurate reflection of thyroid status in any investigational study in which an experimental treatment leads to decreased food intake.

Aging↗
PubMed1986

Ketoconazole-induced reduction in serum 1,25-dihydroxyvitamin D.

The antimycotic agent ketoconazole is known to inhibit several cytochrome P450-dependent enzymes involved in the biosynthesis of steroid hormones from cholesterol. Since 1,25-dihydroxyvitamin D is also a sterol synthesized by cytochrome P450-dependent enzymes, we assessed whether ketoconazole would lower serum 1,25-dihydroxyvitamin D levels. In nine normal men, administration of ketoconazole for 1 week in doses of 300-1200 mg/day led to a dose-dependent reduction in serum 1,25-dihydroxyvitamin D levels (r = -0.64; P less than 0.001). At the highest dose taken by each man (1200 mg/day in six, 900 mg/day in one, and 600 mg/day in two), serum levels of 1,25-dihydroxyvitamin D fell significantly compared to baseline [14 +/- 1 (+/- SEM) vs. 39 +/- 3 pg/ml; P less than 0.001), but there was no change in serum levels of 25-hydroxyvitamin D, PTH, calcium, phosphate, or alkaline phosphatase. Ketoconazole may be potentially useful in exploring the pathogenetic role of 1,25-dihydroxyvitamin D in disorders of calcium metabolism and in treatment of patients with hypercalcemic disorders or renal stone disease.

Adolescent↗
PubMed1986

Ketoconazole-induced stimulation of gonadotropin output in men: basis for a potential test of gonadotropin reserve.

The antifungal drug ketoconazole is known to inhibit testosterone biosynthesis and decrease serum testosterone concentrations. To assess whether the ketoconazole-induced reduction in serum testosterone might stimulate LH and FSH output in a manner suitable as a test of pituitary gonadotropin reserve, we gave normal men ketoconazole every 8 h for 1 week in dosages of 300-1200 mg/day. Ketoconazole administration caused a dose-dependent reduction in serum testosterone which correlated inversely with serum ketoconazole (r = -0.82; P less than 0.001). This fall in serum testosterone stimulated increases in serum LH and FSH which were maximal at a ketoconazole dose of 900 mg/day [LH increase, 127 +/- 27% (+/- SEM); FSH increase, 63 +/- 15%]. Ketoconazole tended to blunt the LH and FSH responses to LHRH. Ketoconazole increased serum 17-hydroxyprogesterone, reflecting blockade of 17,20-desmolase by the drug, while having inconsistent effects on serum estradiol. I conclude that ketoconazole administration for 1 week to normal men stimulates LH and FSH output in a fashion that makes it potentially suitable, after additional verification in subjects with normal and abnormal pituitary-testicular function, as a test of pituitary gonadotropin reserve.

17-alpha-Hydroxyprogesterone↗
PubMed1986

Comparative antiandrogenic potency of spironolactone and cimetidine: assessment by the chicken cockscomb topical bioassay.

Spironolactone and cimetidine are effective antiandrogens in vivo, although they differ by five orders of magnitude in affinity for androgen receptors in vitro. To explore this discrepancy, we directly compared the antiandrogenic potency of these two compounds in vivo using the chicken cockscomb topical bioassay. In this assay, the growth of the androgen sensitive cockscomb of immature chicks after stimulation by various doses of androgen (dihydrotestosterone 5, 20, or 100 micrograms/day sc) is inhibited by antiandrogens in cream vehicle applied topically to the cockscomb itself. At low levels of androgen stimulation (5 micrograms/day), 0.5% topical cimetidine produced maximal suppression of cockscomb growth, while at high levels of androgen stimulation 100 micrograms/day), topical cimetidine in concentrations as high as 4% did not suppress cockscomb growth. In contrast, topical spironolactone in concentrations as low as 0.06% produced maximal inhibition of cockscomb growth at all androgen doses. Using an intermediate androgen dose (20 micrograms/day), the minimally effective antiandrogenic concentration of topical cimetidine was between 0.5 and 1.0%, while that for topical spironolactone was less than 0.001%. We conclude that the chicken cockscomb topical bioassay is a useful method for assessing relative potency of antiandrogens. With this method, spironolactone appears to be at least 500 times as strong an antiandrogen in vivo as cimetidine.

Administration, Topical↗
PubMed1985

Hypogonadotropic hypogonadism in nephrotic rats: increased sensitivity to negative feedback effects of testosterone.

Pituitary-testicular function was examined in adult male rats with aminonucleoside-induced nephrotic syndrome as a model for similar disease in humans. Nephrotic rats developed androgen deficiency, as manifested by decreased prostate and seminal vesicle weights, lower serum total and free testosterone levels, and reduced testosterone release from testes incubated in vitro. Despite hypoandrogenism, the weight and histologic appearance of the testes (light microscopy) were not affected in nephrotic rats. This androgen deficiency seemed to be a consequence of decreased gonadotropin output rather than primary testicular failure, since both pituitary gonadotropin content and serum gonadotropin levels (basally and after luteinizing hormone releasing factor; LHRH) were reduced in nephrotic rats. In addition, the percentage increase in testosterone release by testes incubated in vitro after addition of exogenous gonadotropin was similar in nephrotic and control groups. However, gonadotropin output in nephrotic rats was not impaired in the absence of testis, since no reduction was seen in either post-castration serum gonadotropin levels in vivo or gonadotropin release from pituitaries incubated in vitro. This presumed inhibitory effect of the testis on gonadotropin output in nephrotic rats was confirmed directly by demonstrating an increased sensitivity to testosterone-mediated suppression of gonadotropins in castrate animals in vivo. The presence or absence of albumin also seemed to modulate the suppressive effect of testosterone on gonadotropin output from normal pituitaries incubated in vitro. We conclude that nephrotic male rats develop hypogonadotropic hypogonadism secondary to an increase in sensitivity of the pituitary to the negative feedback effects of testosterone.

Androgens↗
PubMed1984

Androgen receptor abnormalities in identical twins with oligospermia. Clinical and biochemical studies.

Identical twin brothers presented with oligospermia, small testes, normal male phenotypes, elevated serum luteinizing hormone levels, and normal or elevated serum testosterone levels. Both men had low to low-normal cytosol androgen receptor binding capacity in cultured fibroblasts from pubic skin biopsy specimens. Qualitative abnormalities of cellular androgen receptors were suggested by low-normal or low nuclear androgen uptake in fibroblasts from both brothers as well as abnormal thermolability and subnormal molybdate stabilization of androgen receptors from one brother. In vivo androgen sensitivity was assessed in one twin following administration of testosterone or the non-aromatizable androgen fluoxymesterone. Fluoxymesterone suppressed serum luteinizing hormone and serum testosterone/estradiol-binding globulin, and although testosterone suppressed both serum luteinizing hormone and serum follicle-stimulating hormone, the suppression of serum luteinizing hormone by testosterone was subnormal. Both subjects showed marked exaggeration of the serum 17-hydroxyprogesterone increase after administration of human chorionic gonadotropin, despite normal serum testosterone increases, suggesting a block in testicular 17,20-desmolase, which converts 17-hydroxyprogesterone to testosterone. These studies suggest that oligospermia and block of the enzyme 17,20-desmolase may be the earliest manifestations of androgen resistance, and the finding of the syndrome of oligospermia, normal male phenotype, and androgen receptor abnormalities in identical twins indicates a genetic etiology of this disorder.

17-alpha-Hydroxyprogesterone↗
PubMed1984

Low serum thyroxine and high serum triiodothyronine in nephrotic rats: etiology and implications for bioavailability of protein-bound hormone.

Traditionally, it has been thought that the bioavailable fraction of circulating serum hormones, i.e. that which is available for cellular uptake and is physiologically active, is limited to the free (nonprotein bound) hormone. However, recent evidence, based on acute organ uptake of labeled hormone, suggests that the amount of hormone which is bioavailable in vivo may exceed that which is calculated to be free in vitro. To explore the bioavailability of circulating protein-bound thyroid hormones under steady state conditions in vivo, we altered serum thyroid hormone-binding proteins in rats by inducing nephrotic syndrome with puromycin aminonucleoside. Nephrotic rats (serum albumin, 1.1 g/dl) were found to have a marked reduction in serum T4 [2.1 +/- 0.2 (SEM) vs. 6.5 +/- 0.3 microgram/dl; P less than 0.01] and an elevation of serum T3 [141 +/- 8 vs. 51 +/- 2 ng/dl; P less than 0.01]. Estimated T4 production rate was normal in nephrotic rats, and the 3- to 4-fold increase in T4 MCR appeared to account for the marked reduction in serum T4. By contrast, increased serum T3 levels in nephrotic rats reflected both a reduction (55%) in T3 MCR and an increased rate of peripheral conversion of T4 to T3. A circulating inhibitor of T4 binding to serum proteins appeared to be present in nephrotic rats. The changes in the various serum components of thyroid hormone [T4-binding prealbumin (TBPA)-bound, albumin-bound, free] produced by nephrotic syndrome were compared with the corresponding changes in indices of thyroid hormone bioavailability (MCR, urinary excretion, hepatic content, TSH suppression, single pass extraction by liver). These comparisons suggested that nephrotic syndrome results in increased bioavailability of circulating T4 and decreased bioavailability of circulating T3. The bioavailable fraction of circulating T3 in vivo seemed to include both free T3 and that which is albumin bound in vitro. The bioavailable fraction of circulating T4 resembled free T4 more than non-TBPA-bound T4 (= albumin bound + free), although a nephrosis-induced increase in bioavailability of TBPA-bound T4 was also possible. We conclude that nephrotic rats have low serum T4, which is related to accelerated T4 clearance, and high serum T3, which is related both to decreased T3 clearance and increased peripheral conversion of T4 to T3. Under steady state conditions in vivo, bioavailable circulating T3 appears to include both free T3 and the T3 that is bound to albumin in vitro.

Animals↗
PubMed1984

Relationship between pubertal timing and body size in underfed male rats.

A direct connection has been proposed between body size and sexual maturation by the critical body weight and critical body fat hypotheses. To test these theories in male rats, we compared the degree of sexual maturation in animals with reduced growth rate due to undernutrition with that in weight-matched but normally fed rats. Underfed rats had significantly larger prostate, seminal vesicle, and testis weights than the weight-matched normally fed controls at the three time points studied: the early pubertal period (approximate time of onset of rising serum testosterone), late pubertal period (approximate time of appearance of mature spermatids), and young adult period. At the first time point, testes of underfed rats, but not those of normally fed, weight-matched controls, showed mature step 19 spermatids, and serum testosterone was significantly higher in the underfed animals. At all time points, serum LH levels were similar in both groups, while serum FSH levels were significantly lower in the underfed rats at all points. The Lee index, an index of fatness, was significantly lower in the underfed rats. The current study indicates that underfed rats are more sexually mature than normally fed controls of the same weight despite having a lower percentage of body fat. These findings do not support the critical body weight or critical body fat hypotheses of puberty in male rats.

Adipose Tissue↗
PubMed1984

Circadian rhythm of serum cortisol in Cushing's disease.

Two women with typical clinical and biochemical features of pituitary-dependent Cushing's disease each underwent hourly blood sampling for 24 h on two separate occasions for measurement of serum cortisol. The 24-h mean serum cortisol concentrations (17.7 and 15.4 micrograms/dl in patient 1; 19.0 and 15.8 micrograms/dl in patient 2) were elevated (normal level, less than 12.5 micrograms/dl), as expected. Cosinor analysis of the patients' serum cortisol patterns revealed statistically significant circadian rhythms on all four profiles. The amplitude of the rhythm on both occasions in patient 1 (5.8 and 6.6 micrograms/dl) and on one of two occasions in patient 2 (7.2 and 10.5 micrograms/dl) fell in the range for the amplitude of the cortisol circadian rhythm in normal subjects (2.2-8.6 micrograms/dl). In contrast to commonly held belief, some patients with Cushing's disease may exhibit circadian variation of serum cortisol.

Adult↗
PubMed1982

Testicular dysfunction in untreated Hodgkin's disease.

Gonadal function was examined in 19 young men with Hodgkin's disease before therapy and compared with that of 11 men with other malignancies, 13 men with primary testicular failure, and 19 normal men of similar age. Total (p less than 0.01) and free (p less than 0.05) testosterone levels were decreased in Hodgkin's disease. In those with advanced (stage III + IV) and symptomatic (B), Hodgkin's disease serum testosterone levels were indistinguishable from those in primary testicular failure, yet serum levels of luteinizing hormone were normal. Moreover, the acute response of serum testosterone to exogenous human chorionic gonadotropin (HCG) was significantly greater in Hodgkin's disease than in primary testicular failure (p less than 0.03). These data and the finding that basal serum follicle-stimulating hormone levels are significantly lower than normal in Hodgkin's disease (p less than 0.05) suggest that the cause of pretreatment hypogonadism in Hodgkin's disease is not simple primary testicular failure. Total sperm count was decreased in 40 percent of men with Hodgkin's disease but in none of the men with other malignancies (p less than 0.05), suggesting specific seminiferous tubular dysfunction in Hodgkin's disease. However, motility was abnormal in 69 percent of men with Hodgkin's disease and 60 percent of those with other malignancies, suggesting that this is a nonspecific effect of cancer. Serum prolactin levels were significantly higher than normal in Hodgkin's disease (p less than 0.05) but not in other malignancies. Our findings suggests that the cause of testicular dysfunction that is present before treatment of Hodgkin's disease is complex, perhaps involving both pituitary and gonadal abnormalities.

Adult↗
PubMed1982

Investigations into the etiology of elevated serum T3 levels in protein-malnourished rats.

Thyroid function studies and the peripheral metabolism of thyroid hormone were examined in rats fed a low protein diet (9% casein) for 4-8 wk. Compared to animals fed a normal protein diet ad libitum, both the low protein rats and a pair-fed control group weighed less at the end of the study. However, serum total T3 levels were significantly higher only in the protein deficient rats. The elevated serum T3 was not explainable by enhanced peripheral T4 to T3 conversion, as there was no evidence of any change in hepatic or renal 5'-deiodinase activity when homogenates were examined for conversion of T4 to T3, reverse T3 to 3,3'-diiodothyronine, or 3',5'-diiodothyronine to 3'-monoiodothyronine. Neither was there an effect on hepatic T3 receptor maximal binding capacity (204 +/- 24 versus 168 +/- 15 fmol/mg DNA control) or binding affinity (2.07 +/- 0.38 versus 2.49 +/- 0.24 x 10(-10) M control). In two separate experiments the dialyzable fraction of T3 was significantly lower in the low protein group while free T3 concentrations were unchanged or reduced. In contrast, serum total and free T4 were either normal or reduced and dialyzable T4 was unaffected by protein deficiency. We conclude that while serum total T3 is elevated in rats chronically fed a low protein diet, this elevation is not due to enhanced T4 to T3 conversion. Rather, the increased T3 levels can be accounted for by a striking alteration in protein binding to T3. Moreover, the failure to demonstrate similar changes in serum total and dialyzable T4 suggests that in the rat, protein deficiency has different effects on binding to the two major thyroid hormones. Dietary induced changes in serum thyroid hormone binding must be kept in mind in nutrition studies in the rat.

Animals↗
PubMed1982

Testicular reserve of testosterone precursors in primary testicular failure.

To explore the abnormal steroidogenesis in subjects with primary testicular failure, we measured serum levels of testosterone (T) and its precursors androstenedione (delta 4A) and 17-hydroxyprogesterone (17-OHP) in the basal state and after stimulation by human chorionic gonadotropin (hCG) for 4 hours (acute reserve) or 72 hours (chronic reserve). Subjects with primary testicular failure had decreased mean basal serum T, decreased mean chronic T reserve, and absent mean acute T reserve. In contrast, these subjects had normal mean basal serum 17-OHP and delta 4A, normal chronic 17-OHP reserve, and non-zero mean acute 17-OHP and delta 4A reserve, although mean chronic delta 4A reserve was reduced. Heterogeneity of biochemical abnormalities depending on the etiology of testicular failure was apparent. In primary testicular failure, the testicular reserves of the T precursors 17-OHP and delta 4A are better maintained than is the reserve of T itself, raising the possibility that this disorder might be associated with biochemical blocks in conversion of T precursors to T.

Adolescent↗
PubMed1982

Identical twins discordant for the "rudimentary testes" syndrome.

A 20-year-old man was found to have rudimentary testes, microphallus and minimal evidence of sexual maturation, along with low serum testosterone and high serum gonadotropin levels, consistent with the syndrome of rudimentary testes and microphallus. His identical twin brother was unaffected, confirming that this unusual congenital disorder does not have a genetic basis in all cases.

Adult↗
PubMed1982

Pituitary-testicular function in protein-deficient rats. Follicle-stimulating hormone hyperresponse to castration and supersensitivity of gonadotropin secretion to androgen negative feedback.

Previous studies have shown that weanling male rats fed a low protein diet ad libitum develop hypogonadotropic hypogonadism. Two unusual features of this state were 1) subnormal serum FSH in noncastrate rats but not in castrate rats, suggesting that FSH was being suppressed by a testicular factor, and 2) serum FSH increases after castration that were greater in protein-deficient rats than in controls. In the current study, protein-deficient rats showed FSH hyperresponse to castration, compared to either ad libitum or pair-fed controls, after periods of low protein feeding from 1-8 weeks and periods of castration from 1-8 weeks. FSH hyperresponse to castration was rapidly induced after the start of low protein feeding and was present whether castration was performed before or after low protein feeding was begun. In none of these circumstances did protein-deficient rats show LH hyperresponse to castration. Inhibin production of Sertoli cell cultures prepared from protein-deficient rats was less (P less than 0.02) than in ad libitum or pair-fed controls, suggesting that inhibin overproduction was not the cause of subnormal serum FSH in noncastrate protein-deficient rats. However, castrated rats fed a low protein diet were more sensitive to the negative feedback effects of testosterone on gonadotropin secretion than were ad libitum or pair-fed controls. We conclude that low serum gonadotropins in protein-deficient male rats may be related to hypersensitivity of these animals to the negative feedback effects of testosterone on gonadotropin secretion. In addition, FSH hyperresponse to castration, without corresponding LH hyperresponse, seems to be typical of protein deficiency, suggesting that protein deficiency may be a useful model for exploring the differential control of gonadotropin secretion.

Animals↗