Estrogen is of vital importance for the development and control of reproductive functions. Until recently, estrogen was believed to regulate complex programs of gene expression by binding to an unique nuclear receptor belonging to the superfamily of ligand-dependent transcription factors. However, the identification of a second estrogen receptor, referred to as ER beta, is leading to a re-evaluation of estrogen signaling and physiology.

Animals↗

PubMedDate not supplied

EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium.

Breast cancer is the most frequent cancer in women while it is the second cause of cancer death. Estrogens are well recognized to play the predominant role in breast cancer development and growth and much efforts have been devoted to the blockade of estrogen formation and action. The most widely used therapy of breast cancer which has shown benefits at all stages of the disease is the use of the antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and antagonist activity and major efforts have been devoted to the development of compounds having pure antiestrogenic activity in the mammary gland and endometrium. Such a compound would avoid the problem of stimulation of the endometrium and the risk of endometrial carcinoma. We have thus synthesized an orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ER alpha and ER beta compared to any of the other antiestrogens tested. An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ER alpha and ER beta while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors. AF1 activity is constitutive, ligand-independent and is responsible for mediation of the activity of growth factors and of the ras oncogene and MAP-kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ER alpha and ER beta and blocks SRC-1-stimulated activity of the two receptors. EM-652 was also found to block the recruitment of SRC-1 at AF1 of ER beta, this ligand-independent activation of AF1 being closely related to phosphorylation of the steroid receptors by protein kinase. Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER beta activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression. In fact, the absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of tamoxifen observed up to 5 years become negative at longer time intervals and why resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat, a well-recognized model of human breast cancer. It is of interest that the addition of dehydroepiandrosterone, a precursor of androgens, to EM-800, led to complete inhibition of tumor development in this model. Not only the development, but also the growth of established DMBA-induced mammary carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also observed when medroxyprogesterone was added to treatment with EM-800. Uterine size was reduced to castration levels in the groups of animals treated with EM-800. An almost complete disappearance of estrogen receptors was observed in the uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. (ABSTRACT TRUNCATED)

Animals↗

PubMedDate not supplied

Familial resemblance in fatness indicators.

Family resemblance in fatness has been studied in 481 individuals from 114 families of French descent living in the greater Quebec city area. Subjects were measured for the following fatness indicators: triceps, biceps, subscapular, suprailiac, abdominal and medial calf skinfolds. The sum of these six skinfolds as well as a prediction of percent body fat (Durnin and Rahaman 1967) were also considered. Data were standardized for appropriate age and sex classes yielding SS scores. The influence of relevant lifestyle variables (energy intake, energy expenditure and socioeconomic status) were statistically removed from SS yeilding residual scores (RS) that were then submitted to familial analyses. Analyses of variance indicate that there is a larger between family variation than within (P less than or equal to 0.01) for SS when considering either the whole nuclear family or sibships; in these instances, the intra-class correlation ranges from 0.15 to 0.26. There was, however, no significant resemblance among spouses for the SS fatness indicators. Similar values were essentially found for RS fatness indicators. Furthermore, husband-wife inter-class correlations were not significant with the exception of subscapular and calf skinfold RS. Covariations between biological relatives are however significant (0.16 less than or equal to r less than or equal to 0.24, P less than or equal to 0.01) for SS and remain essentially unchanged after statistical control over the lifestyle variables (0.16 less than or equal to r less than or equal to 0.40, P less than or equal to 0.01). The findings that spouses do not covary significantly in fatness, while biological relatives of traditional nuclear families exhibit a significant degree of resemblance even after statistical control over daily energy intake, daily energy expenditure and socioeconomic status provide evidence supporting the hypothesis that there is a substantial genetic effect in human fatness.

Adolescent↗

PubMedDate not supplied

Submaximal power output in adopted and biological siblings.

Submaximal power output was determined in relative steady state on a bicycle ergometer at a heart rate of 150 beats per minute (PWC150). PWC150 was measured in 880 individuals, 9 to 26 years of age, belonging to 46 sibships of adopted sibs, 66 sibships of unrelated individuals including adoptees, 33 sibships of first-degree cousins, 225 sibships of biological sibs, 56 sibships of DZ twins and 54 sibships of MZ twins. PWC150, PWC150/kg of body weight, PWC150/kg lean body mass, PWC150/cm of height and PWC150/m2 of body surface area were submitted to analysis of variance and correlation analysis after statistical control over age and sex of subjects. Few significant resemblances were found in PWC measurements for adoptive siblings, unrelated sibs and cousins. Sibling resemblance was, however, significant for the sibships of biological sibs, and of DZ and MZ twins. Interclass correlations reached significance only in pairs of biological brothers and sisters, and in pairs of DZ and MZ twins. Estimates of total genetic effect in PWC150/kg in a population of free-living children, adolescents and young adults vary from 0.30 to 0.48. It is concluded that submaximal power output is only moderately affected by the genotype.

Adolescent↗

PubMedDate not supplied

Genetic and environmental sources of variation in physical fitness.

The technique of path analysis was used to assess inherited and environmental variance components in physical fitness indicators measured in 1630 subjects from 375 families of French descent living in the greater Québec city area. For that purpose, submaximal power output (PWC150/kg), muscular endurance, muscular strength, reaction time and movement time were evaluated during a visit of the family to the laboratory. Inter-class correlations in various types of relatives were computed from scores adjusted for linear and non-linear effects of age and sex by a regression procedure (Y = age + sex + (age X sex) + age2). Correlations were then used in the path analytic BETA model which allows the partition of transmissible variance (t2) into genetic (h2) and cultural (b2) components. Results indicated that t2 accounted for 18% (movement time) to 63% (muscular strength) of the phenotypic variance. The contribution of genetic factors was found to be negligible for PWC150/kg and movement time, and accounted for about 20% of the phenotypic variance for reaction time and muscular endurance and 30% for muscular strength, while non-transmissible variance (1 - t2) accounted for 37% (muscular strength) to 82% (movement time) of the phenotypic variance. These results suggest that biological variation observed in the physical fitness level of a healthy population is mainly associated with non-transmissible environment factors and that the contribution of heredity is moderate and clearly lower than previously reported.

Adolescent↗

PubMedDate not supplied

Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease.

Several epidemiological studies have reported that the regional distribution of body fat is a significant and independent risk factor for cardiovascular disease (CVD) and related mortality. Although these associations are well established, the causal mechanisms are not fully understood. Numerous studies have, however, shown that specific topographic features of adipose tissue are associated with metabolic complications that are considered as risk factors for CVD such as insulin resistance, hyperinsulinemia, glucose intolerance and type II diabetes mellitus, hypertension, and changes in the concentration of plasma lipids and lipoproteins. The present article summarizes the evidence on the metabolic correlates of body fat distribution. Potential mechanisms for the association between body fat distribution, metabolic complications, and CVD are reviewed, with an emphasis on plasma lipoprotein levels and plasma lipid transport. From the evidence available, it seems likely that subjects with visceral obesity represent the subgroup of obese individuals with the highest risk for CVD. Although body fat distribution is now considered as a more significant risk factor for CVD and related death rate than obesity per se, further research is clearly needed to identify the determinants of body fat distribution and the causal mechanisms involved in the metabolic alterations. It appears certain, however, that an altered plasma lipid transport is a significant component of the relation between body fat distribution and CVD.

Abdomen↗

PubMedDate not supplied

Heredity and changes in plasma lipids and lipoproteins after short-term exercise training in men.

The aims of this controlled experiment were to investigate the effects of short-term aerobic exercise training on plasma lipid and lipoprotein concentrations and the role of heredity in determining the individual variation observed in the lipoprotein-lipid response. Six pairs of male monozygotic (MZ) twins were subjected to an exercise training program that induced a 22,000 kcal energy deficit after 22 consecutive days of training. This program significantly reduced body weight, percent body fat, and subcutaneous fat and significantly increased maximal oxygen consumption (VO2max) (p less than 0.005). The plasma insulin response to an oral glucose challenge was markedly reduced after training (p less than 0.001). Plasma triglyceride concentration decreased and the high density lipoprotein cholesterol (HDL-CHOL)/CHOL ratio increased with training (p less than 0.05). Subjects also displayed substantial individual variation in their response to exercise training, but the changes in plasma CHOL, apolipoprotein (apo) B low density lipoprotein cholesterol (LDL-CHOL), HDL-CHOL, and the HDL-CHOL/CHOL ratio tended to be similar within MZ twin pairs (0.67 less than or equal to ri less than or equal to 0.92; 0.05 greater than p less than 0.0001) thus indicating a significant effect of heredity on the sensitivity of plasma lipids and lipoproteins to exercise training.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Adipose tissue distribution and plasma lipoprotein levels in obese women. Importance of intra-abdominal fat.

Prospective studies have shown that excess abdominal fat is associated with an increased risk of coronary heart disease and related death. We used computed axial tomography (CAT) to assess the association between deep and subcutaneous abdominal adipose tissue and plasma lipoprotein levels in a sample of 52 premenopausal obese women aged 35.7 +/- 5.5 years (mean +/- SD). Whereas the plasma lipoprotein concentration were not significantly correlated with fat mass, the data obtained by CAT indicated that the absolute amount of deep abdominal fat was negatively correlated with high density lipoprotein cholesterol (HDL-CHOL) levels (r = -0.35, p less than 0.01), as well as with HDL-CHOL/low density lipoprotein (LDL)-CHOL, HDL-apoprotein-(apo) A-I/LDL-apo B, and HDL2-CHOL/HDL3-CHOL ratios (-0.32 less than or equal to r less than or equal to -0.40, 0.05 greater than p less than 0.01). Adipose tissue deposition at the mid-thigh region determined by CAT did not show any significant relationship with plasma lipoprotein levels. When subgroups of women with comparable ages and adiposity but with high and low intra-abdominal fat accumulation were compared, women with a high accumulation of intra-abdominal fat displayed significantly lower HDL-CHOL (p less than 0.001), HDL2-CHOL (p less than 0.001), HDL3-CHOL (p less than 0.01), and HDL-apo A-I (p less than 0.05) levels, as well as reduced HDL-CHOL/LDL-CHOL (p less than 0.01), HDL-apo A-I/LDL-apo B (p less than 0.05), and HDL2-CHOL/HDL3-CHOL ratios (p less than 0.05) in comparison with obese women with low accumulations of intra-abdominal fat.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗