Search PubMed⌕ Search

Biomedical subjects

C Longcope

Publications and source records attributed to C Longcope.

At least 127 records · Page 7Linked to original sources
PubMed1987

Sex steroids and bone mass. A study of changes about the time of menopause.

To examine the relationships between bone loss and sex steroids, 84 peri- and postmenopausal women were studied at 4-mo intervals for 3 yr. At each visit, measurements were made of bone mass at the midshaft and distal radius, of steroids, of gonadotropins, and of bone gla protein (BGP). Bone loss was approximately 1% per yr among late perimenopausal and postmenopausal groups, whereas the early perimenopausal group lost no bone. Mean serum estrogen and BGP concentrations predicted rates of bone loss. BGP was negatively correlated with the rate of bone loss (r = -0.45) and with mean estrogen concentrations (r = -0.40). Multivariate regressions showed estrogen concentrations to be strong independent predictors of the slope of bone mass over time. When BGP concentrations were added to the models, the significance of estrogen was reduced, suggesting that a portion of the estrogen effect was mediated through effects on rates of bone remodelling.

Adult↗
PubMed1987

Aromatase activity in a rat Leydig cell tumor.

Male Wistar-Furth rats bearing the transplantable LTW(m) Leydig cell tumor have elevated serum estradiol (E2) concentrations. We measured the ability of these tumors to aromatize testosterone (T) to E2 by two methods. First, tumor minces were incubated with [7-3H]T, and the resultant [3H]E2 and [3H]estrone were purified and measured. In addition, tumor cell cultures were incubated with [1 beta-3H]T, and the resultant [3H]H2O was determined as a measure of aromatization. Tumor minces aromatized more actively than normal rat testicular tissue (3.30 +/- 0.15% of the T added was converted to E2 by the tumor vs. 0.30 +/- 0.25% by normal testis). Most of the aromatizing actitivity was localized to the microsomes. Using cell cultures the maximum velocity was 6.1 pmol/h X 5 X 10(5) cells, and the Km was 98 nM. In neither minces nor cell cultures were we able to show stimulation of aromatization with hCG, (Bu)2cAMP, or phorbol esters, although we could show stimulation by these agents in normal testicular cells. We were unable to inhibit the aromatase activity with human beta-endorphin or stimulate it with naloxone. However, we were able to inhibit the aromatase activity with 4-hydroxy-4-androstene-3,17-dione. We conclude that the LTW(m) rat Leydig cell tumor has an active autonomous aromatase system that is not responsive to compounds affecting the adenylate cyclase-cAMP system. It can be inhibited by 4-hydroxy-4-androstene-3,17-dione, a competitive-suicide inhibitor of the aromatase enzyme(s).

Androstenedione↗
PubMed1987

Free estradiol, free testosterone, and sex hormone-binding globulin in perimenopausal women.

To determine whether menstrual status had an effect on plasma sex hormone-binding globulin (SHBG) capacity and nonprotein-bound estradiol (% free E2) and testosterone (% free T), we measured these as well as plasma FSH, total E2, and T and the MCRs of E2 and T in a group of 78 perimenopausal women. The women were allocated to 4 groups: women with cycles whose plasma FSH level was less than 40 mIU/mL (A; n = 16), women with cycles whose plasma FSH level was greater than 40 mIU/mL (B; n = 19), women who were amenorrheic for less than 1 yr (C; n = 13), and women who were amenorrheic for more than 1 yr (D; n = 30). The mean plasma SHBG values were 51.4 +/- 5.7 (+/- SE), 48.3 +/- 4.3, 45.9 +/- 5.4, and 51.1 +/- 3.7 nM in groups 1-4 respectively, and were not significantly different from one another. The mean % free E2 and % free T values also were not different between the groups. However, the mean total E2 and free E2 (% free E2 X E2/100) concentrations were significantly (P less than 0.05) higher in both groups A and B than in groups C and D. The E2 concentration was also higher in group A than in group B. There were strong correlations between the E2 and free E2 concentrations between the T and free T (% free T X T/100); (P less than 0.0001) concentrations, between SHBG capacity and weight, and between the MCRs of both E2 and T and % free E2 and % free T. In normal women, the menopause is not associated with changes in SHBG or % free steroids. Hence, the measurement of E2 could be used to predict the mass of free E2 in these women.

Adult↗
PubMed1987

The effect of a low fat diet on estrogen metabolism.

Women who consume a diet low in fat are at lower risk for breast cancer than women whose diet is relatively high in fat. To investigate the effects of a low fat diet on estrogen metabolism, six normal young women were studied while eating a Western-style high fat diet and again after 2 months of consuming a defined low fat diet. Both studies involved the simultaneous administration of [3H]estradiol [( 3H]E2) orally and [14C]E2 iv and the subsequent collection of multiple blood samples and urine for 96 h. The blood samples were analyzed for radioactivity as estrone (E1), E2, their glucuronides, and E1 sulfate. An aliquot of the pooled 96-h urine was analyzed for radioactivity as the glucuronides and sulfates of E1, E2, estriol, 16 alpha-hydroxyestrone (16 alpha-OHE1), and the catechol estrogens, i.e. 2-hydroxy and 2-methoxy metabolites of E1 and E2. The low fat diet resulted in a consistent and significant (P less than 0.05) decrease in urinary excretion of both 16-hydroxylated metabolites, estriol and 16 alpha-OHE1, expressed as a percentage of administered dose of [3H]E2 and [14C]E2, and an increase in the excretion of the catechol estrogens. These changes in metabolite excretion were not, however, mirrored by changes in the MCRs or conversion ratios of either [3H]E2 or [14C]E2. Thus, while neither the clearance of E2 from the blood nor its absorption from the intestinal tract was altered by a relatively short term decrease in dietary fat, there was a shift in the pattern of urinary metabolites away from the purported carcinogenic estrogen (16 alpha-OHE1) and toward the less active catechol estrogens. This may represent an important mechanism whereby low fat diets decrease the risk of breast cancer.

Adult↗
PubMed1987

Effect of menstrual cycle phase on plasma lipids.

The effect of endogenous sex hormone fluctuations on plasma lipoprotein levels was studied in 15 young women. Plasma samples were taken during the follicular, ovulatory, and luteal phases of the menstrual cycle while the women were consuming a defined diet, similar to the average American diet. No significant effect of menstrual cycle phase on plasma total cholesterol or cholesterol lipoprotein subfraction levels was found; however, a 34% increase in total plasma triglycerides associated with an increased very low density lipoprotein triglyceride fraction was found during the ovulatory phase. These data indicate that menstrual cycle phase can have a significant effect on plasma triglyceride levels, but not on plasma cholesterol or lipoprotein fractions.

Adult↗
PubMed1987

5 alpha-reductase activity in rat adipose tissue.

We measured the 5 alpha-reductase activity in isolated cell preparations of rat adipose tissue using the formation of [3H]dihydrotestosterone from [3H]testosterone as an endpoint. Stromal cells were prepared from the epididymal fat pad, perinephric fat, and subcutaneous fat of male rats and from perinephric fat of female rats. Adipocytes were prepared from the epididymal fat pad and perinephric fat of male rats. Stromal cells from the epididymal fat pad and perinephric fat contained greater 5 alpha-reductase activity than did the adipocytes from these depots. Stromal cells from the epididymal fat pad contained greater activity than those from perinephric and subcutaneous depots. Perinephric stromal cells from female rats were slightly more active than those from male rats. Estradiol (10(-8) M), when added to the medium, caused a 90% decrease in 5 alpha-reductase activity. Aromatase activity was minimal, several orders of magnitude less than 5 alpha-reductase activity in each tissue studied.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1986

Androgen and estrogen metabolism: relationship to obesity.

Adipose tissue contains both aromatase and 17 beta-steroid dehydrogenase activity. Therefore, to see whether there was a relationship between obesity and certain parameters of androgen and estrogen metabolism we infused 88 women, mean age 51.1 +/- 0.3 years and mean weight 140 +/- 3 lbs, with 3H-testosterone (T)/14C-estradiol (E2) and 3H-androstenedione (A)/14C-estrone (E1) on separate occasions. Blood samples were obtained during the infusion and all urine was collected for 4 days following the start of the infusion. The blood samples were analyzed for radioactivity as A, T, E1, E2, and dihydrotestosterone (DHT) and the urines were analyzed for radioactivity as E1 and E2. From these data we calculated the percent of A converted to T ([rho]A,TBB = percent of A infused measured as T in the blood), [rho]T,ABB [rho]E1,E2BB, and [rho]E2,E1BB. We also measured the ratio of radioactivity as 3H-DHT to radioactivity as 3H-A (CRA,DHT) and 3H-T (CRT,DHT) during the respective androgen infusions. From the ratio of 3H/14C as estrone or estradiol in the urine following 3H-A or 3H-T infusions, we calculated the percent of A or T that was aromatized to E1 or E2 ([rho]A,E1BM; [rho]T,E2BM). When the data from these women were related to weight or Quetelet's Index (QI = wt/ht2) by unweighted linear regression, the only values that were significantly correlated with weight and QI were [rho]T,E2BM and [rho]A,E1BM; for all other [rho] and CR values there was no correlation with weight or QI. We conclude that peripheral aromatization is positively correlated with adiposity but androgen interconversions and estrogen interconversions are not related to adiposity.

17-Hydroxysteroid Dehydrogenases↗
PubMed1986

Steroid and gonadotropin levels in women during the peri-menopausal years.

We obtained blood samples from 88 women 45-58 yr old who were having cyclic menses every 1-2 mth (37 women, 133 samples) or were amenorrheic for greater than 3 mth (51 women, 310 samples). Samples were obtained at intervals of 3-4 mth and analyzed for estrogens, androgens and gonadotropins using radioimmunoassay techniques. There was a gradual decline in the concentrations of estrone (E1), estradiol (E2), estrone sulfate (E1SO4) and progesterone (P) as the time from the last menses increased. A relatively stable concentration was reached in 12 mth for E1, E2, and E1SO4 and in 2 mth for P. The concentrations of testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate remained relatively constant as the time from the last menses increased. There was no apparent difference in the mean values of any of these hormones for any time interval from the last menses. The concentrations of both luteinizing hormone (LH) and follicle stimulating (FSH) were noted to increase initially but they appeared to become stable after 12 mth for FSH and after only 6 mth for LH. Using only the measurements made on the initial blood samples obtained in all patients, we found significant correlations between FSH concentrations and the concentrations of E1, E2 and E1SO4 for women who were less than 3 mth from a menses as well as those whose last menses had occurred 3 or more mth previously. The correlations were generally not significant for LH in either groups of women.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗
PubMed1986

Adrenal and gonadal androgen secretion in normal females.

Both the adrenal and the ovary contain the biosynthetic pathways necessary for androgen synthesis and secretion. The fetal ovary is not very active but the fetal adrenal is an important source of DHAS. However the secretion of DHAS declines markedly after birth and until puberty there is little androgen secretion by either the adrenal or the ovary. Post-pubertally, the adrenal secretes DHAS, DHA, delta 4-A and T from the reticularis and probably the fasciculata. This secretion is under ACTH control, at least in part, but apparently also under control of another pituitary polypeptide tentatively called 'adrenal androgen secretory hormone'. THe adrenal secretion rates are in the range of 7-14 mg/day for DHAS, 3-4 mg/day for DHA, 1-1.5 mg/day for delta 4-A and 50 micrograms/day for T. Androgen secretion from the ovary arises in part from the theca cells of the follicle, the corpus luteum and the stromal cells, under LH control, and will vary somewhat during the normal menstrual cycle. The ovarian secretion rate in the follicular phase is 1-2 mg/day for DHA, 1-1.5 mg/day for delta 4-A and about 50 micrograms/day for T. In the peri-ovulatory period the secretion rate of delta 4-A can rise to 3-3.5 mg/day but there appears to be little change in the secretion of DHA and T. The normal ovary does not secrete significant amounts of DHAS. In about 50% of post-menopausal women the ovaries continue to secrete some T but little delta 4-A or DHA.

Adrenal Glands↗
PubMed1985

The metabolism of estradiol; oral compared to intravenous administration.

We administered [6,7-3H]estradiol p.o. and [4-14C]estradiol i.v. simultaneously to 5 women 22-35 years of age. Fourteen blood samples were collected over 480 min, and all urine was collected for 96 h. The blood samples were analyzed for radioactivity as estradiol, estrone, estrone-sulfate and estradiol glucuronide. The urine samples were analyzed for radioactivity as the glucuronide and pH 1 hydrolyzable conjugates of estradiol, estrone, estriol, 16 alpha-hydroxy-estrone, 2-hydroxy-estrone, 2-hydroxy-estradiol, 2-methoxy-estradiol and 2-methoxy-estrone. The major circulating estrogen, after either estradiol, p.o. or i.v. administration, was estrone sulfate; approximately 50% of estradiol administered by either route being converted to and measured as estrone sulfate in the blood. Following oral administration about twice as much estradiol was converted to and measured as estradiol glucuronide in the blood as after i.v. administration. Of the estradiol administered p.o., only 10% was absorbed into the blood as estradiol the rest being metabolized prior to absorption. After estradiol, p.o., the major radioactive compounds in the urine were the glucuronides of estrone and estradiol, but after estradiol, i.v., the conjugates of estrone, estradiol and estriol were present to about the same extent as the conjugates of the 2-oxygenated compounds. Following p.o., considerable metabolism of estradiol administration occurs in the splanchnic tissue, much of it in the intestinal wall.

Administration, Oral↗
PubMed1985

Production and metabolism of dihydrotestosterone in peripheral tissues.

The production and metabolism of dihydrotestosterone (DHT) was studied in 10 normal men using constant infusions of [7-3H]-delta 4 -androstenedione (A)/[4-14C]DHT (6 men) or of [7-3H]testosterone (T)/[4-14C]DHT (4 men) with measurement of radioactivity as precursor and product in the brachial artery, and a superficial vein (draining primarily adipose tissue) and deep vein (draining primarily muscle) in the arm opposite to the infusion. The metabolic clearance rates (MCR) were (mean +/- SE) 560 +/- 55, 1620 +/- 80, and 790 +/- 65, 1/day for DHT, A and T respectively. The overall conversions (percent of A or T infused which was measured as DHT in arterial blood) were 2.3 +/- 0.8% and 2.7 +/- 0.5% for A to DHT and T to DHT. Of the DHT entering the adipose tissue 13.8 +/- 3.4% was metabolized and of that entering muscle 5.8 +/- 1.8% was metabolized. On the basis of assumed blood flows, adipose tissue and muscle metabolism each carry out approx. 7-8% of the overall metabolism of DHT. Of the A entering the forearm adipose tissue 1.9 +/- 0.5% was converted to DHT. Extrapolated to the body's adipose tissue, this represents 14% of the total A converted to DHT. Of the T entering the forearm adipose tissue 1.2 +/- 0.3% was converted to DHT. Extrapolated to the body's adipose tissue, this represents 6% of the total T converted to DHT. In three out of six subjects infused with A/DHT and in three out of four subjects infused with T/DHT small gradients indicating conversion of A and T to DHT by tissues drained by the deep vein were found. The mean value for the conversion of A to DHT across the deep vein tissues was 0.84 +/- 0.51% and for T to DHT was 0.28 +/- 0.12%. Both adipose tissue and muscle metabolize DHT but only adipose tissue appears to play a role in the conversion of A and T to DHT.

Adipose Tissue↗
PubMed1985

Bone mass and sex steroid concentrations in postmenopausal Caucasian diabetics.

We have evaluated radial bone mass and sex steroid concentrations in a group of postmenopausal white type 2 diabetics, that group at greatest risk of developing osteoporosis. The linear regression of midshaft bone mass on age for 79 patients showed a rate of loss about half the rate for normals. These data suggest that bone is lost at a slower rate by this group, and the difference cannot be explained by obesity or glucose control alone. A subset of 40 of these subjects was chosen for further study. As expected, these women had significantly higher bone mass than normals; in addition, they were significantly heavier (82.4 +/- 2.7 kg v 65.3 +/- 1.8 kg, P less than .001), and had higher body mass index (32.1 +/- 1.0 kg/m2 v 25.2 +/- 0.6 kg/m2, P less than .001), than controls. Serum estrone concentrations were higher (49.8 +/- 3.7 pg/mL v 28.5 +/- 1.8 pg/mL, P less than .001); serum androstenedione (0.28 +/- 0.03 ng/mL v 0.51 +/- 0.04 ng/mL, P less than .001), and serum testosterone (0.18 +/- 0.02 ng/mL v 0.26 +/- 0.02 ng/mL, P less than .02) concentrations were lower among diabetics than controls. Serum estradiol (15.1 +/- 1.7 pg/mL v 15.3 +/- 1.0 pg/mL, P greater than .5) was not significantly different. Multiple regression analysis indicates that the excess level of estrone concentration among diabetics increased with the degree of obesity. The explanation for the lower concentration of the other sex steroids among diabetics is not known.

Aged↗
PubMed1985

Catecholestrogen regulation of prolactin synthesis in pituitary cell culture.

The 2-hydroxycatecholestrogens, 2-hydroxyestradiol [1,3,5-(10)estratriene-2,3,17 beta-triol] (2-OHE2) and 2-hydroxyestrone [2,3-dihydroxy-1,3,5-(10)-estratriene-17-one] (2-OHE1) were tested for their ability to alter PRL production and PRL messenger RNA (mRNA) levels in rat pituitary cell cultures. Treatment of cells with 10(-8) M 2-OHE1 or 2-OHE2 resulted in increased PRL secretion at 24 and 48 h (to 167% and 211% of control, respectively), but not at 4 h. Metabolism studies of radioactive 2-OHE1 and 2-OHE2 in parallel cultures demonstrated that the major metabolite at all times for either compound was the 2-methoxy derivative. After 24 h of treatment, nearly 40% of each compound was the original catecholestrogen, and at no time was there any detectable conversion to estradiol or estrone. Treatment of pituitary cells for 48 h with increasing concentrations of 2-OHE1 or 2-OHE2 resulted in a biphasic PRL dose response. PRL secretion was increased 3.6-fold for 2-OHE2 and 2.4-fold for 2-OHE1 between 10(-10) M and 10(-8) M. At concentrations above 5 X 10(-8) M, however, both compounds decreased PRL levels until, at 10(-6) M 2-OHE1 or 2-OHE2, PRL levels were 40-70% of control. Changes in PRL mRNA levels paralleled those of secretion. Treatment of pituitary cells with 10(-8) M of either 17 beta-estradiol (E2), 2-OHE1, or 2-OHE2 resulted in 2- to 5-fold increases in translatable and hybridizable PRL mRNA. The addition of 10(-7) M E2 plus 10(-8) M 2-OHE1 or 2-OHE2 resulted in PRL secretion and PRL mRNA levels equal to those resulting from E2 stimulation alone. The inhibition in PRL secretion and PRL mRNA levels caused by 10(-6) M 2-OHE1 or 2-OHE2 was partially overcome by coincubation of cultures with E2. Thus, 2-OHE1 and 2-OHE2 at low concentrations (less than 10(-8) M) can act on the pituitary as E2 agonists to increase PRL synthesis but at high concentrations may act as inhibitors of PRL production.

Animals↗
PubMed1985

The effects of the aromatase inhibitor delta 1-testolactone on gonadotropin release and steroid metabolism in polycystic ovarian disease.

This study was designed to examine the importance of aromatization in the gonadotropin secretory dynamics of polycystic ovarian disease (PCOD) by using the aromatase inhibitor delta 1 testolactone (TL) as a probe and to determine the effects of TL on steroid metabolism in vivo and in vitro. The pulsatile patterns of gonadotropin secretion and peripheral steroid levels were studied in eight women with PCOD before and during TL administration. There was a significant fall in peripheral estrone (E1) levels, a rise in peripheral androstenedione levels, and an increase in the androstenedione/E1 ratio during TL administration in these women. Isotopic determinations of androgen and estrogen production and metabolism before and during TL administration in two women confirmed a 90-95% decrease in the overall rate of aromatization. One patient also had an increase in the production and clearance rates of estradiol and E1 during TL administration, suggesting resistance to TL of the ovarian aromatase enzyme system. There were significant increases in both mean LH pulse amplitude [1.2 +/- 0.3 (SE) mIU/ml LER-907 before vs. 1.7 +/- 0.3 mIU/ml LER-907 during TL, P less than 0.05, paired t test] and frequency per 6 h (median: 3 before vs. 4 during TL, P less than 0.05, Wilcoxon signed rank test). Mean levels of LH and FSH did not, however, change significantly during TL administration. TL maximally inhibited neonatal rat hypothalamic aromatase in vitro at concentrations of 200 microM, a level theoretically obtainable during pharmacological therapy. These data suggest that: 1) in humans TL is a potent inhibitor of peripheral but not ovarian aromatase, and of hypothalamic aromatase in rats; 2) TL administration increases LH pulse amplitude and frequency in PCOD, either directly via hypothalamic aromatase inhibition, or indirectly by alterations in gonadal steroid metabolism; and 3) because of the multiple potential actions of TL, its usefulness as a probe in studies of gonadotropin secretion in PCOD is limited.

Adult↗
PubMed1985

Early menopausal changes in bone mass and sex steroids.

Eighty-four healthy perimenopausal and early postmenopausal women were divided into four groups: group A, those with slightly irregular menstrual periods and plasma FSH below 40 mIU/ml; group B, those with irregular periods and FSH above 40 mIU/ml; group C, those whose last menstrual period was within 1 yr of study; and, group D, those whose last menstrual period was between 12 and 55 months before the study. Plasma concentrations of estrone and estradiol progressively decreased in groups B, C and D compared to those in A in parallel with a decrease in the production rates, and FSH and LH were significantly increased. There was little change in the concentration of androstenedione or testosterone. Vertebral bone mass was significantly decreased in groups B, C, and D compared to that in A, and radial bone mass was decreased in group D. There was a significantly positive correlation between plasma estrone and estradiol and bone mass at both the radius and vertebra. Increased bone remodeling was suggested by increases in serum calcium and bone gla protein. These data suggest that bone loss, at least from the spine, may begin before menses cease and is correlated with decreases in estrogen production and increases in bone remodeling.

Adult↗
PubMed1985

Clinical, biochemical, and ovarian morphologic features in women with acanthosis nigricans and masculinization.

Nine women with acanthosis nigricans and masculinization, who did not appear to have any of the reported syndromes associated with acanthosis nigricans, were studied to characterize the clinical, biochemical, and ovarian morphologic features of their disorders. These patients had the clinical and biochemical profiles of polycystic ovarian disease. All acanthosis nigricans subjects had significant insulin resistance when insulin binding to both circulating monocytes and erythrocytes was compared to the control subjects. Microscopic examination of the ovaries revealed no evidence of recent normal ovulation, sclerosis of the ovarian cortex, follicle cysts, and stromal hyperthecosis. The authors conclude that ovarian stromal hyperthecosis and insulin resistance are consistent findings in the present type of patient. This study provides further evidence supporting a relationship between insulin resistance and human ovarian function.

Acanthosis Nigricans↗