Premenopausal bone loss--a risk factor for osteoporosis.
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Adult↗
Biomedical subjects
C Longcope
Publications and source records attributed to C Longcope.
Relationships of estrogen to breast cancer, of diet to breast cancer, and of diet to estradiol metabolism.
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Breast Neoplasms↗
Predictors of bone mass in perimenopausal women. A prospective study of clinical data using photon absorptiometry.
STUDY OBJECTIVE: To determine whether clinically available data on risk factors are adequate to identify perimenopausal women with either low or high bone mass. DESIGN: Cross-sectional observational study of a cohort of perimenopausal women (mean age, 50.8 years). SETTING: Community volunteers in a university hospital. SUBJECTS: One hundred twenty-four white volunteers established as perimenopausal by history and serum concentrations of estrogens and follicle-stimulating hormone. MEASUREMENTS AND MAIN RESULTS: Models were constructed to predict bone mass in the radius, lumbar spine, and hip using risk factors (age, height, weight, calcium and caffeine intake, alcohol and tobacco use, and urinary markers of bone turnover). Although highly significant predictive models were developed for all skeletal sites, none of the models correctly identified more than 70% of women with low bone mass at any site. However, for the radius, a model was constructed that never overestimated bone mass by more than 0.10 g/cm. A small subgroup (7%) with short stature, low body weight, low calcium intake, and who were heavy smokers always had low radial bone mass. Using these models, about 30% of our population could be assessed without bone mass measurements. Predictions for the spine and femur were less efficient, suggesting that direct measurements are required if therapy decisions are to be based on bone mass at these sites. CONCLUSIONS: Risk factors for osteoporosis are of limited use in identifying women with low bone mass around the time of menopause. Measurements of bone mass are probably necessary if the risk for osteoporosis is to be the basis for deciding on estrogen replacement therapy.
Absorptiometry, Photon↗
Androgen and estrogen dynamics: stability over a two year interval in peri-menopausal women.
As part of a study on hormones and bone density in peri-menopausal women, metabolic clearance rates (MCR), and interconversions of androgens and estrogens and the peripheral aromatization of androgens were measured twice 2 yr apart. Measurements of clearance rates and interconversions were made from blood samples obtained during constant infusions of [3H]androgens and [14C]estrogens. Measurements of peripheral aromatization were made from the estrogen glucuronides in a pooled 4-day urine collection timed from the start of the infusions. The women were divided into 3 groups: Group A (n = 15) were having menstrual cycles throughout the 2 yr interval; Group B (n = 11) were having menstrual cycles at the time of Study 1 but had been amenorrheic for at least 1 yr at the time of Study 2; Group C (n = 28) were amenorrheic for at least 1 yr at the time of Study 1 and had remained amenorrheic through Study 2. The MCRs for testosterone, androstenedione, estrone and estradiol were not different for Study 1 and Study 2 in any of the groups. The interconversions of the androgens were similar in both studies for all groups. The conversion of estrone to estradiol decreased in Group A, otherwise the interconversions of the estrogens did not vary between the studies for the other groups. The peripheral aromatization of androstenedione, but not of testosterone, was significantly greater at study 2 compared to Study 1 for all groups. We conclude that the MCRs and interconversions of androgens and of estrogens are stable over time, but that the peripheral aromatization of androstenedione increases over a 2 yr interval. This increase may be menopausal and/or age related.
Androgens↗
Estrogen metabolism as measured in blood and urine in female rhesus monkeys.
In order to measure the interconversions of estrone (E1) and estradiol (E2) and their conversion to the 16 alpha-hydroxylated estrogens, 16 alpha-hydroxy estrone (16 alpha-OHE1) and estriol (E3), we infused 11 female rhesus monkeys with [3H]E2 and [14C]E1 and measured radioactivity in the blood as E1, E2 and 16 alpha-OHE1 (n = 9) and in the urine as the glucuronides of E1, E2, 16 alpha-OHE1, and E3 (n = 11). The mean conversion of E1 to E2 as measured in blood (percent of infused E1 measured in blood as E2, [rho]1.2BB) was 29.2 +/- 1.6% and as measured in the urine of the same animals, [rho]1.2BM, was 77.4 +/- 5.9%. The mean conversion of E2 to E1, [rho]2.1BB was 21.5 +/- 1.0% and as measured in urine, [rho]2.1BM was 67.7 +/- 4.6%. Thus for both estrone and estradiol only 30-35% of the interconversions occurred in pools which were in equilibrium with the blood pool of these estrogens. The remaining 65-70% occurred in a pool, probably liver, in which glucuronidation occurred immediately after conversion. The conversion ratios (the ratio of the concentration in the blood of radioactivity as 16 alpha-OHE1 to its precursor, CRPrec,16 alpha-OHE1) was 0.036 +/- 0.008 for CRE1,16 alpha-OHE1 and 0.0039 +/- 0.0010 for CRE2,16 alpha-OHE1. The percentages of administered E1 excreted in the urine as the glucuronides of E1, E2, 16 alpha-OHE1 and E3 were 20.1 +/- 1.5, 1.6 +/- 0.2, 0.96 +/- 0.20 and 0.76 +/- 0.07 respectively. The percentages of administered E2 excreted in the urine as E1, E2, 16 alpha-OHE1 and E3 were 14.4 +/- 1.0, 2.2 +/- 0.3, 0.57 +/- 0.05 and 0.68 +/- 0.11 respectively. Thus there are minor differences in the patterns of excreted metabolites of E1 and E2. Furthermore, 16 alpha-OHE1 and E3 are not major metabolites of E1 or E2 in the female rhesus monkey.
Animals↗
Aromatase activity in human adipose tissue stromal cells: effect of growth factors.
Adipose tissue is a major, nonglandular site for the aromatization of androgens to estrogens. In this tissue, the aromatase activity resides primarily in the stromal cells, and we have used cultures of stromal cells to study the effects of insulin and insulin-like growth factor I (IGF-I) on aromatase activity. Adipose tissue, obtained during indicated surgery, was digested with collagenase, and the stromal cells were isolated and cultured. Aromatase activity was determined by measuring the tritiated water (3H2O) in the medium after incubating stromal cells with [1 beta-3H]androstenedione. Insulin and IGF-I had no effect on the aromatase activity in cultured adipose stromal cells at concentrations of 10 to 1,000 microU/ml. However, insulin (100 to 1,000 microU/ml) and IGF-I (500 ng/ml) markedly attenuated the stimulatory effect of (Bu)2cAMP, but significantly augmented the dexamethasone-stimulated aromatase activity. The greater effects of IGF-I compared with the effect of insulin are compatible with both effects being mediated through the IGF-I compared with the effect of insulin are compatible with both effects being mediated through the IGF-I receptor. In addition, the effects of insulin in attenuating the aromatase activity in adipose tissue could potentiate its role in hyperandrogenic syndromes in women.
Adipose Tissue↗
Effects of serum proteins on estrogen action in the perfused rat liver.
To determine the effects of serum proteins on the biologic activity of estrogens, we perfused isolated livers from ovariectomized female rats with oxygenated Krebs-Henseleit-bicarbonate buffer (KHBB), with and without 4% human serum albumin (4% HSA), with and without added estrogens, or with charcoal-stripped human serum (CSHS) with and without added estradiol. At the end of the perfusions, the cytosolic and nuclear estrogen receptors were measured by an exchange assay. When added to KHBB, estradiol 10(-9) or 10(-8) M or estrone 10(-8) M did not cause any significant increase in the percent of receptors measured in the nucleus. When the livers were perfused with KHBB containing 4% HSA and estradiol 10(-9) to 10(-7) M or estrone 10(-8) M, there was an increase in nuclear receptors. Perfusion with estradiol 10(-8) M in CSHS resulted in significantly less receptor in the nucleus than after estradiol in KHBB plus 4% HSA. We conclude that the presence of 4% HSA in the perfusion medium increases the biologic activity of estradiol and estrone on the isolated rat liver, and this increase is inhibited in the presence of sex hormone-binding globulin. The exact mechanism by which HSA increases the biologic activity is uncertain, but may be due in part to better diffusion of estrogen through the liver.
Animals↗
Biochemical and immunohistochemical analyses of estrogen and progesterone receptors in the rhesus monkey uterus during the proliferative and secretory phases of artificial menstrual cycles.
On day 9 of an artificial menstrual cycle (28 day) in the rhesus monkey, endometrial epithelia and stroma and myometrial smooth muscle cells showed positive immunoreactivity for estradiol (E2) and progesterone (P) receptor. On day 23 a reduction of staining for E2 and P receptor was observed for epithelial cells in endometrial zones I, II, and III with a pronounced loss of E2 receptor staining in stromal cells. Glandular epithelial cells in zone IV retained strong positive staining for both E2 and P receptor. Cytosolic and occupied nuclear E2 receptor analyzed biochemically were significantly reduced on day 23. These data suggest that P induces a zonal-dependent distribution of immunoreactive E2 and P receptor and that epithelial cells of zone IV are distinguished by the combined presence of strong immunoreactive staining for both receptors.
Animals↗
Hormone dynamics at the menopause.
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Androgens↗
Androstenedione and estrone dynamics in hypothyroid women.
To examine the effects of hypothyroidism on androstenedione (A) and estrone (E1) metabolism, we infused eight women with [3H]androstenedione and [14C]estrone when they were hypothyroid and again when they were euthyroid after levo-T4 administration. MCRs and conversion ratios were measured using concentrations of radioactivity in the blood pools of A and E1. Peripheral aromatization was measured from the concentrations of radioactivity in the E1 glucuronide pool in the urine. After the women were euthyroid, the MCR of A had increased in seven of eight, the MCR of E1 increased in all eight, and peripheral aromatization had decreased in seven of eight. These findings indicate that hypothyroidism results in a decrease in the MCRs of A and E1 and, in most subjects, an increase in peripheral aromatization of A to E1.
Adult↗
The relationship of total and free estrogens and sex hormone-binding globulin with lipoproteins in women.
To determine whether there was a significant relationship between circulating lipids or lipoproteins and circulating estrogens or sex hormone-binding globulin (SHBG) in pre- and premenopausal women, 352 women were chosen randomly from communities in Eastern Massachusetts. These women had nonfasting blood samples drawn and analyzed for total cholesterol, high density lipoprotein cholesterol (HDL-C), HDL-2, HDL-3, apolipoprotein-A-I (apo-A-I), apo-B, triglycerides (TG), estrone, estradiol (E2), free E2, SHBG, and FSH. In addition, their body mass index (BMI; wt/ht2) was calculated, and a history of smoking, ethanol intake, current medication use, and the date of their last menstrual period was obtained. When the women were grouped according to the months from their last menses (less than 1, 1-3, and 4-11 months), those 4 months or longer since last menses had significantly lower E2 concentrations and significantly greater total cholesterol and FSH concentrations than the other two groups. However, when regressed on hormones, BMI, ethanol intake, and last menstrual period, total cholesterol was significantly related only to the time from last menses; TG, HDL-C, HDL-2, and apo-A-I were related to SHBG. Relationships between the lipids, with the exception of cholesterol and apo-B, were also noted with BMI and/or ethanol. Apo-B was related to the time from last menses. Differences in circulating estrogens appeared to be related only minimally, if at all, to the differences in total cholesterol that are seen in perimenopausal women. The relationships between lipids and lipoproteins and SHBG are probably epiphenomena as a result of similar sites of synthesis. Changes in lipids and lipoproteins that are seen at the time of the menopause are probably multifactorial in origin.
Amenorrhea↗
Hormonal regulation of prostaglandin production by rhesus monkey endometrium.
Although there have been numerous studies on the production of prostaglandins (PGs) by human endometrium in vitro during the menstrual cycle, considerable variation exists in the levels reported during the proliferative vs. the secretory phase. Such variation may be due in part to the difficulty in obtaining endometrium from a precisely known hormonal environment and in part to the use of the different culture systems employed. The aim of the present study was to develop a non-human primate model in which precisely dated endometrial tissue could be obtained reliably. Moreover, PG levels in the endometrium of the rhesus monkey or other primates have not previously been reported during the artificial menstrual cycle. An important objective in establishing such a model was to permit future manipulations of the cycle in vivo [e.g. by omitting the midcycle estradiol (E) peak] to further dissect specific roles of E and progesterone (P) in regulating PG synthesis during the menstrual cycle. Ovariectomized rhesus monkeys were maintained on a standard artificial menstrual cycle via the insertion and removal of Silastic capsules containing E or P. Samples of endometrium (approximately 50 mg) were obtained by hysterotomy under sterile conditions at predetermined stages of separate menstrual cycles: day 9 (midproliferative; n = 5), day 13 (E peak; n = 3), day 14 (1 day post-E peak; n = 5), and day 23 (midsecretory; n = 8). Measurement of the primary PGs in unextracted medium by RIA over 4 days of organ culture indicated PGF2 alpha greater than 6-keto-PGF1 alpha greater than PGE2 greater than thromboxane-B2, PGD2 greater than leukotrienes. PGF2 alpha, the most abundant PG produced on the first day of culture, was low on day 9 and increased dramatically on day 13 (P less than 0.01). On day 14, PGF2 alpha levels fell significantly only 1 day post-E peak (P less than 0.01), while on day 23, after exposure to P in vivo, PGF2 alpha was 10-fold higher (P less than 0.01) than on cycle days 9 and 14. The other PGs measured showed a lower but similar profile at the cycle stages examined. Physiological concentrations of P (5.0 ng/mL) added to cycle day 23 cultures in both the absence and presence of low or high E markedly inhibited the high levels of PGs found in day 23 cultures (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Androgens, estrogens, and sex hormone-binding globulin in middle-aged men.
Although the administration of estrogens and androgens can affect the concentrations of sex hormone-binding globulin (SHBG) in men, the relationships between endogenous estrogens and androgens and SHBG are uncertain. Therefore, in a randomly selected cohort of 1640 middle-aged men we measured androgen, estrogen, and SHBG concentrations and obtained the subjects' weight, ethanol intake, and smoking histories. The data were analyzed by stepwise multiple regression, with SHBG as the dependent variable, to compare the role of hormones with that of other factors in the control of SHBG levels. Neither estrone or estradiol nor the testosterone/estradiol ratio was predictive of SHBG levels. However, SHBG concentrations were positively correlated with total testosterone and negatively correlated with percent free and percent albumin-bound testosterone. SHBG concentrations were negatively correlated with estrone sulfate, but were positively correlated with the testosterone/estrone sulfate ratio and the concentrations of free and albumin-bound testosterone. In addition, in all models tested age and body mass index (wt/ht2), but not smoking or ethanol, were strong predictors of SHBG concentrations. Thus, when present in physiological amounts in the blood as a result of glandular secretion, there is a positive relationship between SHBG concentrations and testosterone and, to a lesser extent, free- and albumin-bound testosterone, but age and body mass index appear to be more important in predicting the SHBG concentration.
Adult↗
Aromatase activity of human adipose tissue stromal cells: effects of thyroid hormones and progestogens.
In order to determine the direct effects of thyroid hormones and progestogens on extraglandular aromatization, human adipose stromal cells in monolayer culture were used as a model system for this study on the regulation of aromatase enzyme activity. It was found that 1-thyroxine at 2- and 4-fold normal concentrations (220 and 440 nM, respectively) and triiodothyronine at 4-fold normal concentration (7.4 nM) had no effect on basal, dibutyryl cyclic AMP ((Bu)2 cAMP)-induced, or dexamethasone-induced aromatization. Medroxyprogesterone acetate at a concentration of 25.9 nM, but not progesterone, 47.7 nM, stimulated basal aromatization slightly but not significantly. In contrast, both medroxyprogesterone acetate and progesterone potentiated the effect of (Bu)2 cAMP on aromatase activity (P less than 0.05 and P less than 0.01, respectively) but had no effect on dexamethasone-stimulated aromatase activity. We concluded that (i) the increased peripheral aromatization associated with hyperthyroidism is not due to the direct effect of thyroid hormones on aromatase activity, and (ii) neither progesterone nor medroxyprogesterone acetate inhibit aromatase activity of adipose tissue stromal cells, but may stimulate this activity under certain conditions.
Adipose Tissue↗
Prognostic significance of estrogen and progesterone receptors in epithelial ovarian cancer.
Estrogen and progesterone receptor assays were analyzed from epithelial ovarian cancer in 123 patients to determine the prognostic significance of receptor results. In 110 (89%), assays were performed at diagnosis and in 13, assays were performed after previous therapy. Estrogen receptor determinations were positive (above 10 fmol/mg) in 75 cases (61%), progesterone receptor determinations were positive (above 3 fmol/mg) in 35 (28%), and both were positive in 20 (16%). Progesterone receptors were more frequently positive (53%) in tumors of endometrioid histology than with other histologic types (P = .01). Thirty-one subjects had a second assay; estrogen receptors were positive in 16 cases (52%), progesterone receptors were positive in five (17%), and both were positive in five (17%). Synchronous and metachronous assays were in agreement in 60-79% of the cases. By multivariate analysis, positive estrogen receptor, progesterone receptor, or both did not predict response to chemotherapy, negative second-look findings, or survival. Thirty-one women received hormonal therapy; one of 26 evaluable subjects had a partial response and four (13%) maintained stable disease for at least 6 months (6-21 months). Positive receptors did not predict hormonal response or disease stabilization.
Adult↗
Cigarette smoking, obesity, and bone mass.
This study was designed to assess the effects of smoking on bone mass and bone loss and to ascertain whether these effects are independent of effects on adiposity and hormone concentrations. A total of 84 healthy, peri- and postmenopausal women were studied prospectively over 3 1/2 years. Heavy smokers had significantly (p less than 0.05) lower radial and vertebral bone mineral content than light or nonsmokers (who did not differ from each other). In regression models, which contained measurements of obesity, pack-years smoking remained a significant predictor of bone mass. However, there were no detectable effects of smoking on rates of bone loss at any site. Smokers appear to be at greater risk of osteoporosis due to their lower bone mass. However, this reduced bone mass is already present around the time of menopause, and rates of bone loss during this period do not appear to be influenced by smoking. Furthermore, we have previously shown in this population that menopausal serum estrogen concentrations (which determine rates of bone loss) do not differ between the smokers and nonsmokers. Further studies of larger groups are required to determine whether small differences in bone loss may exist, since the power to detect such differences was not ideal in this study.
Aging↗
Plasma lipoprotein cholesterol and endogenous sex hormones in healthy young women.
Relationships between plasma levels of lipoproteins and sex hormones were studied in 24 healthy premenopausal women with no risk factors for coronary heart disease. The women were carefully selected to remove the effects of other environmental factors, such as smoking, drugs, alcohol, and exercise, which are known to influence lipid metabolism. They all ate precisely the same Western-style diet for 1 to 2 weeks before blood samples were obtained in the follicular phase of their menstrual cycle. After adjusting for other hormones by multiple regression, significant positive partial correlations were seen between high density lipoprotein cholesterol (HDL-C) and protein bound estradiol (r = .57, P = .02), as well as between very low density lipoprotein cholesterol (VLDL-C) and protein bound estradiol (r = .63, p = .01). A significant negative partial correlation was seen between VLDL-C and free estradiol (r = -.65 P = .01). Conversely, low density lipoprotein cholesterol (LDL-C) levels were negatively correlated with protein bound estradiol (r = -.77, P less than .001) and positively correlated with free estradiol (r = .71, P less than .001). No associations between plasma lipoproteins and testosterone were seen; however, androstenedione was positively correlated with VLDL-C (r = .59, P = .01). These findings show a close link between plasma lipoproteins and sex hormones, and may help to explain the lower risk of coronary heart disease in women.
Adult↗
Radiosensitivity of human prostate cancer and malignant melanoma cell lines.
The relative radioresponsiveness of human prostate cancer compared to malignant melanoma is well known. The effects of beta-estradiol or testosterone on the X-irradiation survival of several human cell lines were studied, including: human prostate carcinoma cell lines PC3 and DU145 and human malignant melanoma cell lines A375 and A875. Lines PC3 and DU145 demonstrated 55-61 fmol per 10(6) cells of androgen receptor with no detectable estrogen or progesterone receptor. Cells were irradiated at 120 cGy/min dose rate. There was no detectable toxicity of up to 10(-4) M testosterone or beta-estradiol on PC3 or DU145 cells in the absence of X-irradiation. At plating efficiencies from 11-13%, and plating densities of 1 x 10(4) cells per 60 cm2 flask, cell lines PC3 and DU145 demonstrated a Do of 108.5 +/- 6.5, n 2.1 +/- 0.7 cGy, and Do of 143.5 +/- 1.5 cGy, n 2.4 +/- 0.5, respectively. The addition of testosterone or beta-estradiol at 10(-4) to 10(-10) M prior to or after, X-irradiation did not alter radiosensitivity. At the same dose rate of 120 cGy/min, malignant melanoma cell lines A375 and A875 had a Do of 125 +/- 2.5 cGy, n 1.56 +/- 0.8 SF2 0.65 +/- 0.03 and line A875 demonstrated a Do of 129 +/- 4.5 cGy, n 1.58 +/- 0.4 SF2 0.55 +/- 0.04, respectively. The radiosensitivity of melanoma cell lines did not decrease at low dose rate 5 cGy/min. Thus, the in vitro radiosensitivity of androgen receptor positive prostate cancer cell lines is not necessarily altered by the presence of androgen before or after irradiation. The data support the concept that all malignant melanoma cell lines do not show a broad-shouldered cell survival curve in vitro and intrinsic cellular radioresistance.
Cell Survival↗