BACKGROUND:Recent randomized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease (CHD). In this report, we provide the final results with regard to estrogen plus progestin and CHD from the Women's Health Initiative (WHI).METHODS:The WHI included a randomized primary-prevention trial of estrogen plus progestin in 16,608 postmenopausal women who were 50 to 79 years of age at base line. Participants were randomly assigned to receive conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The primary efficacy outcome of the trial was CHD (nonfatal myocardial infarction or death due to CHD).RESULTS:After a mean follow-up of 5.2 years (planned duration, 8.5 years), the data and safety monitoring board recommended terminating the estrogen-plus-progestin trial because the overall risks exceeded the benefits. Combined hormone therapy was associated with a hazard ratio for CHD of 1.24 (nominal 95 percent confidence interval, 1.00 to 1.54; 95 percent confidence interval after adjustment for sequential monitoring, 0.97 to 1.60). The elevation in risk was most apparent at one year (hazard ratio, 1.81 [95 percent confidence interval, 1.09 to 3.01]). Although higher base-line levels of low-density lipoprotein cholesterol were associated with an excess risk of CHD among women who received hormone therapy, higher base-line levels of C-reactive protein, other biomarkers, and other clinical characteristics did not significantly modify the treatment-related risk of CHD.CONCLUSIONS:Estrogen plus progestin does not confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women, especially during the first year after the initiation of hormone use. This treatment should not be prescribed for the prevention of cardiovascular disease.

We used complex segregation analysis to compare the genetic transmission of overweight in randomly selected black (N = 60) and white (N = 961) families. In both groups we found evidence for polygenic transmission. Major gene inheritance was strongly supported in whites and was marginally supported in blacks. Parameter estimates for black and white families were similar, suggesting that overweight is similarly transmitted in the black and white families we observed. There was evidence in both black and white families for high gene frequency and recessive gene expression. Extreme phenotypes common in black families may be the result of interactions between major genotype and polygenic or environmental factors; alternative explanations for differences in black and white families' transmission patterns are discussed. Replication with a larger group of black families is needed to confirm our findings.

We studied 3925 individuals in 961 families to determine the mode of inheritance of overweight. As an index of overweight, we examined body mass index. Our analyses indicate that the most likely genetic model for susceptibility to overweight included moderate polygenic inheritance (34% of variance resulting from many genes with small effects) and common (21% frequency) recessively expressed major genes (a few genes with large effects on the individuals who possess them). Standard statistical criteria for accepting both polygenic and major gene inheritance were met, including tests of Mendelian transmission. These results suggest that recessive major gene inheritance of overweight may be common and that homozygosity for overweight susceptibility alleles often results in overweight. Clinical, biologic, and empirical observations all suggest genetic heterogeneity, that is, more than one predisposing gene.

A single 51‐member kindred, ascertained on the basis of a normotriglyceridemic proband with depressed high‐density lipoprotein cholesterol (HDL‐C) and myocardial infarctions at ages 40 and 42, was studied with respect to quantitative variation in HDL‐C and apolipoprotein (apo) AI and AII levels. The results of bivariate segregation analysis suggest that the etiology of depressed HDL‐C involves one or possibly two major loci: one has a pleiotropic effect on apo AI and apo AII levels and, possibly another one that affects apo AI levels. Both the major loci were characterized as having a dominant allele leading to depression of the respective trait(s). In addition, analysis of the cosegregation of HDL‐C and apo AI levels gave evidence of residual nonfamilial factors common to both traits, leading to a positive covariance between them. This could reflect the role of apo AI in the transformation of nascent HDL‐C particles into mature ones via its cofactor activity to lecithin cholesterol acyltransferase. The proposed two‐locus model represents one possible etiology for the heterogeneous disorder of hypoal‐phalipoproteinemia. This analysis of a single pedigree does not completely define the genetic mechanism, but it does illustrate a useful new analytic approach.

To the Editor.— Our paper (Pediatrics 1986; 78:338) was seriously flawed by unintentional errors, which we profoundly regret. The committee that reviewed the patient charts found errors and inconsistencies in our use of some of the lipid data but not the height and weight data. When we corrected the errors, they were found to be nonsystematic and random. The clarified data led to the same conclusion as the original paper: long-term therapy with cholesterol-lowering diet and/or bile acid-binding resin did not affect normal growth and development in children.

Complex segregation analysis with the unified mixed model in white families from nine lipid research clinics was carried out to delineate the mode of familial transmission of plasma high-density-lipoprotein cholesterol (HDL-C). Three groups of families from the collaborative Lipid Research Clinics Program Family Study were assessed: 1,146 selected at random, 483 obtained through hypercholesterolemic probands, and 177 selected from the random sample because a number had low HDL-C, the sample sizes being 4,279, 1,807 and 735, respectively. The data were first transformed and adjusted for effects of covariates. Analyses were performed within clinic and selection strata and also pooled across clinics within strata. The results were consistent across strata and identified two major HDL-C clusters with means separated by approximately 3 SD. There was significant evidence of transmission of a major factor for low HDL-C, but transmission did not conform to Mendelian segregation expectations. There was also evidence of significant multifactorial transmission. Since low HDL-C levels are a major independent risk factor for coronary heart disease, the association of a major factor with familial aggregation of low HDL-C emphasizes the importance of detailed within-family sampling for low HDL-C after identifying a proband whose predominant dyslipoproteinemia is low HDL-C.

ABSTRACT. To test the hypothesis that chronic furosemide treatment in otherwise healthy newborn animals may lead to lowered bone mineral [calcium (Ca) and magnesium (Mg)] content, healthy littermates within each litter of Sprague-Dawley rat pups were randomly assigned to three groups: control, low dose furosemide (5 mg/kg/day), and high dose furosemide (15 mg/kg/day). The pups were treated between days 4 and 28 postnatally. The wet and dry weights of kidneys and tibiae significantly correlated with body weights at sacrifice. Furosemide-treated pups demonstrated a dose-dependent growth delay, decreased total bone (tibiae) Ca and Mg, increased urine Ca and Mg concentration, and a significant inverse correlation between bone Ca and urine Ca concentration. There was no significant difference among the groups when bone Ca and Mg were normalized to per gram of bone dry weight. There were no significant differences among the groups with respect to bone phosphorus or urinary phosphorus concentration; kidney and serum Ca and Mg; or serum sodium, potassium, alkaline phosphatase and immunoreactive parathyroid hormone concentration. We conclude that chronic furosemide therapy leads to growth failure and to increased urinary losses of Ca and Mg. Total bone Ca and Mg in the furosemide-treated pups were diminished in proportion to growth retardation but the bone mineral content per unit of dry weight remained similar to control pups.

Our aim in the current study of 20 normal controls, 28 overweight, and 26 severely overweight (obese) subjects was to assess interrelationships of obesity, endogenous estradiol (E2) and testosterone (T), and the E2/T ratio with major independent explanatory variables for coronary heart disease (CHD), including lipids, lipoproteins, and apolipoproteins. Most of the lipid and lipoprotein variables (total, high-, low-, and very-low-density lipoprotein cholesterols) as well as apolipoproteins A1, A2, and B did not vary significantly with the presence of obesity. With increasing relative ponderosity, there were, however, increasing levels of total triglycerides and VLDL triglyceride. Levels of FSH, LH, prolactin, and testosterone did not differ significantly with obesity. The obese subjects had the highest E2 and E2/T levels; overweight subjects had intermediate levels which were also significantly higher than in the controls. Using multiple regression analyses, in obese subjects increasing T was associated with increasing apo B, and increasing E2 was correlated with decreasing apo A1. Opposite relationships were found in the normal controls where increasing T and increasing Quetelet indices were associated with diminished apo B and increasing E2 was associated with increasing A1. Obesity's association with increased CHD risk may be mediated through increasing E2 and apo B and reducing apo A1. Since obese subjects have higher E2 levels and often have lower T, they are likely to have a pattern of endogenous sex hormones (higher E2, lower T, higher E2/T ratios) similar to those observed in young men with premature myocardial infarction.

The hypothesis of this study was that pharmacologic doses of calcitriol (1,25-dihydroxyvitamin D3) would result in elevated levels of serum osteocalcin, the major noncollagenous bone protein, and calcium in infants of very low birth weight (less than 1500 g). Twenty-four infants of very low birth weight but of the appropriate weight for gestational age were matched in 250-g weight ranges and randomized into calcitriol treatment and control groups on the first day after birth. Treated infants received 4 micrograms/kg of calcitriol intravenously on entry and on the second and third study days. Controls did not receive calcitriol. Four infants from each group were hypocalcemic (serum calcium level, less than 7.0 mg/dL [less than 1.75 mmol/L]) on entry (five to 20 hours after birth) to the study. Seven infants received calcium replacement; data analyses with and without these infants were similar. Of the remaining 17 infants, eight were in the treatment group and nine were in the control group. Calcitriol significantly increased serum calcium and osteocalcin concentrations on days 2, 3, and 4 after birth compared with the control group. None of eight treated infants manifested hypocalcemia after calcitriol vs eight of nine controls. There were no acute changes in heart rate, respiratory rate, systolic blood pressure, or urinary calcium loss nor were there changes at the infusion site, but the diastolic blood pressure increased with treatment. Although high doses of calcitriol may elevate serum calcium concentrations in infants of very low birth weight, we suggest that the long-term or subtle biologic effects of high doses of calcitriol remain to be studied and that its routine use not be recommended at present.

The effects of increasing two dietary polyunsaturated fatty acids, eicosapentaenoic and linoleic, on the glomerulonephritis induced by repeated injections of apoferritin in the mouse were studied. Urinary protein excretion was measured serially; serum creatinine, aortic and renal production of eicosanoids and kidney histology were measured at sacrifice at 8 weeks. Both high EPA and LA feedings were associated with lesser proteinuria, normalization of renal function and profound changes in the tissue production of prostaglandin and thromboxane, which may explain their protective effect in this model of renal disease.

Evening primrose oil, safflower oil, and salmon oil, all with high polyunsaturated fatty acid content, were fed to partially nephrectomized rats; the effects were compared to those of feeding beef tallow. All three oils had favorable effects on progression on renal failure, salmon oil on kidney histology as well. The changes induced in platelet production of thromboxane A2, and in the renal production of various eicosanoids may explain the protective role of these oils.

A comparison of blacks and whites 6 to 49 years old revealed striking differences between races with respect to the prevalence of various dyslipoproteinemias and mean plasma lipid levels. Compared with whites, juvenile and adult blacks of both sexes had higher mean levels of high-density lipoprotein cholesterol (HDL-C), with correspondingly higher prevalences of the hyperHDL and hypoLDL (low-density lipoprotein) phenotypes. In contrast, whites showed a much higher prevalence of type IV hyperlipoproteinemia and higher mean triglyceride levels in most age-sex groups. Although juvenile blacks had higher mean levels of LDL-C than did whites, this race difference was reversed in men, while women showed inconsistent differences between races. Adult black men and juvenile blacks of both sexes had a somewhat higher prevalence of the type IIA phenotype than whites. The distribution of major HDL-C predictors in this population could not account for the difference in prevalence of hyperHDL between races. These findings suggest that health professionals may find differences in plasma lipid and lipoprotein patterns between their black and white patients, but additional research is needed to ascertain the disease risks associated with dyslipoproteinemia among blacks.

Few studies have simultaneously examined the relationship of triglyceride levels with a wide variety of potential covariates. Thus, the present study was designed to assess in a large, free-living population the association of fasting plasma triglyceride values with selected demographic, behavioral, biochemical, and dietary measures. These analyses were done using data obtained from 5189 white men and women aged 20 to 69 years who participated in the Lipid Research Clinics Program Prevalence Study. Of the eight nondietary factors examined, age, Quetelet Index, fasting plasma glucose, and cigarette smoking were strongly, positively associated (p less than 0.0001) with triglycerides in men and in women not using gonadal hormones. Among women using oral contraceptives or estrogens, only Quetelet Index (p less than 0.01) and cigarette smoking (p = 0.01) were significantly related to triglyceride values. Physical activity was inversely associated (p less than 0.0001) and use of diuretic medications was positively related (p less than 0.01) to triglycerides only in men. Results of analyses of triglycerides and six selected dietary measures varied by age, sex, and hormone-use subgroups. Although none of the dietary variables showed consistent associations with triglycerides across all of the subgroups, triglycerides tended to be inversely associated with total calories per kilogram of body weight and the percentage of calories as dietary fat.

This paper reports on the biological and cultural determinants of total, LDL, and HDL cholesterol, and triglyceride (TC, LDL‐C, HDL‐C, TG) levels using a general linear model on randomly selected family data collected during 1975–1978 at nine North American Lipid Research Clinics. Initially, the analyses were clinic‐specific to assess the importance of genetic and cultural transmission, marital resemblance, and other determinants of these traits and then were made jointly to identify the nature and sources of any heterogeneity between clinics. There was evidence of significant genetic and cultural factors for all traits in most clinics. Clinic heterogeneity was also significant, but excluding one clinic reduced the heterogeneity considerably. The genetic (h2) and cultural (c2) heritabilities for the remaining eight clinics were homogeneous with pooled estimates of h2 of .556 ± .028, .539 ± .028, .485 ± .029, and .358 ± .028, and of c2 of .029 ± .006, .033 ± .006, .075 ± .008, and .089 ± .009 for TC, LDL‐C, HDL‐C, and TG, respectively. Among the traits, HDL‐C exhibited the most difference among clinics, and both HDL‐C and TG showed the largest cultural heritability. The relevance of these and similar studies in a broader understanding of the determinants of plasma lipids and lipoproteins is discussed.

Five full-term infants with birth weights appropriate for gestational age presented with hypocalcemic tetany at 5 to 9 days of age. All infants had been fed Similac 20, a cow milk formula. Initial mean serum calcium (Ca), phosphorus (P), and magnesium (Mg) levels of the tetanic infants were 6.8, 9.5, and 1.6 mg/dL, respectively. The mean serum parathyroid hormone (PTH) level was elevated at 79 mu LEq/mL (adult normal values, less than or equal to 57 mu LEq/mL). Following restoration of normocalcemia with Ca supplements, feeding was reinstituted with Similac 20 in two infants and Similac PM 60/40 in three infants. Serum biochemical and hormonal values were compared with those of 18 exclusively breast-fed infants followed up from three weeks to six months and 14 Similac 20-fed full-term infants followed up from one week to six months. In tetanic infants, serum Ca concentrations became elevated (10.4 +/- 0.05 mg/dL; mean +/- SEM) by six weeks (vs 9.2 +/- 0.3 mg/dL in breast-fed infants) (P less than .001) and serum Mg concentrations (2.26 +/- 0.01 mg/dL) by four weeks (vs 1.92 +/- 0.07 mg/dL in breast-fed infants) (P less than .01). Mean serum P concentrations declined progressively. Mean serum PTH concentrations were elevated and ranged from 74 to 143 mu LEq/mL at two to 16 weeks (vs mean 28 to 35 mu LEq/mL in breast-fed infants (P less than .0001). In 14 formula-fed-nontetanic full-term infants, serum PTH concentrations were intermediate between formula-fed-tetanic and breast-fed infants, mean serum Ca concentrations ranged from 10.2 to 10.4 mg/dL, and mean serum P concentrations declined from 8.3 to 7.1 mg/dL. We speculate that acute hypocalcemic tetany in the study infants was induced by the relatively high P load in cow milk formulas (vs human milk); with the continued P load, secondary hyperparathyroidism continued, maintaining P, Ca, and Mg homeostasis.

In view of the complex, intraindividual relationships among different lipoprotein levels (LDL‐C, HDL‐C, and VLDL‐C), multivariate methods aimed at assessing joint familial associations and their possible determinants were performed in the white, random sample component of the Collaborative Lipid Research Clinics Family Study data (1,336 families with 5,097 subjects). After appropriate transformations and covariate adjustments of the data, several kinds of correlation and regression analyses were performed, taking into consideration variable family size and possible age and clinic differences. The association patterns across clinics and age strata were found to be homogeneous for the vast majority of comparisons. The results of multivariate analyses (especially the significant association of each lipoprotein among biological relatives), the persistence of parental levels as the best predictors for the same lipoprotein levels among the offspring, and the essentially unchanged partial correlation estimates as compared to ordinary correlations suggest strong influence of factors specific to each lipoprotein in the familial associations. But the highly significant intraindividual correlations and the nonnegligible cross‐correlations among relatives also suggest the additional presence of common underlying factors for the familial associations, especially between HDL‐C and VLDL‐C and to a lesser extent between LDL‐C and VLDL‐C. The issues stemming from these analyses and the directions for further analyses are discussed.