The impact of birth weight on cardiovascular disease risk in the Women's Health Initiative.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is among the leading causes of morbidity and mortality worldwide. Traditional risk factors predict 75-80% of an individual's risk of incident CVD. However, the role of early life experiences in future disease risk is gaining attention. The Barker hypothesis proposes fetal origins of adult disease, with consistent evidence demonstrating the deleterious consequences of birth weight outside the normal range. In this study, we investigate the role of birth weight in CVD risk prediction. METHODS AND RESULTS: The Women's Health Initiative (WHI) represents a large national cohort of post-menopausal women with 63,815 participants included in this analysis. Univariable proportional hazards regression analyses evaluated the association of 4 self-reported birth weight categories against 3 CVD outcome definitions, which included indicators of coronary heart disease, ischemic stroke, coronary revascularization, carotid artery disease and peripheral arterial disease. The role of birth weight was also evaluated for prediction of CVD events in the presence of traditional risk factors using 3 existing CVD risk prediction equations: one body mass index (BMI)-based and two laboratory-based models. Low birth weight (LBW) (<6 lbs.) was significantly associated with all CVD outcome definitions in univariable analyses (HR = 1.086, p = 0.009). LBW was a significant covariate in the BMI-based model (HR = 1.128, p < 0.0001) but not in the lipid-based models. CONCLUSION: LBW (<6 lbs.) is independently associated with CVD outcomes in the WHI cohort. This finding supports the role of the prenatal and postnatal environment in contributing to the development of adult chronic disease.

The positive predictive value of cervical smears in previously screened postmenopausal women: the Heart and Estrogen/progestin Replacement Study (HERS).

BACKGROUND: The benefits and risks of performing annual cervical smears on postmenopausal women are not well defined. The independent effect of hormone replacement therapy on development of cytologic abnormalities is unknown. OBJECTIVE: To determine the positive predictive value of cervical smears in previously screened postmenopausal women and to determine the effect of oral estrogen plus progestin on incident cervical cytologic abnormalities. DESIGN: Prospective cohort study (incidence) and randomized, double-blind, placebo-controlled trial (hormone therapy). SETTING: 20 U.S. outpatient and community clinical centers. PARTICIPANTS: 2561 women with a uterus and normal cytologic characteristics at baseline. INTERVENTIONS: Annual smears; oral conjugated equine estrogens, 0. 625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or identical placebo. MEASUREMENTS: Incident cytologic abnormalities (atypical squamous cells of undetermined significance, atypical glandular cells of undetermined significance, low-grade squamous epithelial lesion, and high-grade squamous epithelial lesion) and final histologic diagnoses. RESULTS: The incidence of new cytologic abnormalities in the 2 years following a normal smear was 110 per 4895 person-years (23 per 1000 person-years [95% CI, 18 to 27 per 1000 person-years]). Among the 103 women with known histologic diagnoses, one had mild to moderate dysplasia. The positive predictive value of any smear abnormality identified 1 year after a normal smear, therefore, was 0% (CI, 0% to 5.0%) (0 of 78 women); the positive predictive value of abnormalities found within 2 years was 0.9% (CI, 0.0% to 3.0%) (1 of 110 women). In hormone-treated compared with non-hormone-treated women, the incidence of cytologic abnormalities was nonsignificantly higher (relative hazard, 1.36 [CI, 0.93 to 1.99]), largely because of a nonsignificant 58% greater incidence of atypical squamous cells of undetermined significance (relative hazard, 1.58 [CI, 0.99 to 2.52]). CONCLUSIONS: Because of a poor positive predictive value, cervical smears should not be performed within 2 years of normal cytologic results in postmenopausal women. Therapy with oral estrogen plus progestin does not significantly affect the incidence of cytologic abnormalities.

Plasma homocysteine in women taking hormone replacement therapy: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.

Elevated plasma homocysteine levels have been associated with increased atherosclerotic disease risk. Estrogen and estrogen/progestin replacement therapy have been suggested to lower plasma homocysteine levels in postmenopausal women. To assess the impact of hormone replacement therapy (HRT) on plasma homocysteine, levels were measured in samples from adherent women randomized to placebo (n = 34), conjugated equine estrogens (n = 36), or continuous conjugated equine estrogens + progestin (n = 33) in the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. Homocysteine levels decreased between baseline and follow-up (12 and 36 months) in all treatment groups. The magnitude of the reduction was greater in the conjugated estrogens group at 12 months compared with placebo (p = 0.036), even when adjusted for folate and B vitamin consumption, but this difference did not persist at 36 months. These data suggest that estrogen therapy has a modest, but transient, impact on plasma homocysteine levels in women with normal homocysteine at baseline.

Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial.

OBJECTIVE: To assess pair-wise differences between placebo, estrogen, and each of three estrogen-progestin regimens on selected symptoms. METHODS: This was a 3-year, multicenter, double-blind, placebo-controlled trial in 875 postmenopausal women aged 45-64 years at baseline. Participants were assigned randomly to one of five groups: 1) placebo, 2) daily conjugated equine estrogens, 3) conjugated equine estrogens plus cyclical medroxyprogesterone acetate, 4) conjugated equine estrogens plus daily medroxyprogesterone acetate, and 5) conjugated equine estrogens plus cyclical micronized progesterone. Symptoms were self-reported using a checklist at 1 and 3 years. Factor analysis reduced 52 symptoms to a set of six symptom groups. RESULTS: In intention-to-treat analyses at 1 year, each active treatment demonstrated a marked, statistically significant, protective effect against vasomotor symptoms compared with placebo (odds ratios [ORs] 0.17-0.28); there was no additional benefit of estrogen-progestin over estrogen alone. Only progestin-containing regimens were significantly associated with higher levels of breast discomfort (OR 1.92-2.27). Compared with placebo, women randomized to conjugated equine estrogens reported no increase in perceived weight. Those randomized to medroxyprogesterone acetate reported less perceived weight gain (OR 0.61-0.69) than placebo. Anxiety, cognitive, and affective symptoms did not differ by treatment assignment. Analyses restricted to adherent women were not materially different than those using intention-to-treat, except that women adherent to medroxyprogesterone acetate and micronized progesterone regimens reported fewer musculoskeletal symptoms (OR 0.62-0.68). CONCLUSION: These results confirm the usefulness of post-menopausal hormone therapy for hot flashes, show convincingly that estrogen plus progestin causes breast discomfort, and demonstrate little influence of postmenopausal hormones on anxiety, cognition, or affect.

Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/Progestin Interventions Trial.

BACKGROUND: Transvaginal ultrasonography is a noninvasive procedure that may be used to detect endometrial disease. However, its usefulness in screening for asymptomatic disease in postmenopausal women before or during treatment with estrogen or estrogen-progesterone replacement is not known. METHODS: We compared the sensitivity and specificity of transvaginal ultrasonography and endometrial biopsy for the detection of endometrial disease in 448 postmenopausal women who received estrogen alone, cyclic or continuous estrogen-progesterone, or placebo for three years. RESULTS: Concurrent ultrasonographic and biopsy results were available for 577 examinations in the 448 women, 99 percent of whom were undergoing routine annual follow-up. Endometrial thickness was less than 5 mm in 45 percent of the examinations, 5 to 10 mm in 41 percent, more than 10 mm in 12 percent, and not measured in 2 percent, and it was higher in the women receiving estrogen alone than in the other groups. Biopsy detected 11 cases of serious disease: 1 case of adenocarcinoma, 2 cases of atypical simple hyperplasia, and 8 cases of complex hyperplasia. Biopsy also detected simple hyperplasia in 20 cases. At a threshold value of 5 mm for endometrial thickness, transvaginal ultrasonography had a positive predictive value of 9 percent for detecting any abnormality, with 90 percent sensitivity, 48 percent specificity, and a negative predictive value of 99 percent. With this threshold, a biopsy would be indicated in more than half the women, only 4 percent of whom had serious disease. CONCLUSIONS: Transvaginal ultrasonography has a poor positive predictive value but a high negative predictive value for detecting serious endometrial disease in asymptomatic postmenopausal women.

Enhanced twin pregnancy detection within an open neural tube defect and Down syndrome screening protocol using free-beta hCG and AFP.

We have applied our multimarker approach of maternal serum alpha-fetoprotein (AFP) and free-beta human chorionic gonadotropin (hCG) for Down syndrome screening to multiple gestations to assess its efficacy for improved detection of twin and triplet pregnancies. This study matched 225 cases of twin pregnancy and 39 cases of triplet pregnancy each with ten singleton pregnancies based on gestational week, race, time to receive sample, time of year of sample, and geographical area. The ratios of the MOM for each group at the tenth, 50th, and 90th percentiles were compared by the Wilcoxon test. Risks for twins were calculated using Bayes' rule, the age-related incidence of twins, and the levels of AFP and free-beta hCG. The tenth, 50th and 90th percentiles of free-beta hCG MOMs in twin and triplet cases were 0.85, 1.99, and 4.51, and 1.38, 2.78, and 4.07, respectively. For AFP, the MOMs at these percentiles were 1.26, 1.91, and 2.99, and 2.02, 2.68, and 5.30, respectively. The twin and triplet distributions for each marker were statistically significantly different from the singleton distributions (P < 0.0001) and from each other (P = 0.0012). At a twin risk cut-off of 1 in 50, 77.4 per cent of all twin gestations can be detected in a second-trimester AFP and free-beta hCG screening protocol with 5.1 per cent of singleton pregnancies falsely identified as at risk for twins. Our dual marker protocol for mid-trimester pregnancy screening combining AFP and free-beta hCG can identify over 77 per cent of twin pregnancies in women less than 35 years of age. This benefit may contribute to an improved outcome of pregnancy by early detection of multiple gestation.

Advent of maternal serum markers for Down syndrome screening.

Trisomy 21, or Down syndrome, is the most common serious autosomal chromosome aberration in which affected individuals survive beyond infancy. The association between advancing maternal age and increased risk of trisomy 21 is well known, and pregnant women older than 35 years at delivery are routinely offered invasive prenatal diagnostic testing. More recently, the use of maternal serum markers in the second trimester of pregnancy to predict the risk of trisomy 21 for women under the age of 35 has received intensive analysis. Maternal serum alpha-fetoprotein (MSAFP) was the first of these markers to be identified, and an inverse correlation between MSAFP level and risk of trisomy 21 was noted. A second marker, unconjugated estriol (uE3), has also been studied, and a correlation between low uE3 and trisomy 21 has been demonstrated, with a high level of correlation between AFP and uE3. The addition of uE3 to the screening protocol has not consistently improved detection rates, possibly because of its high correlation with AFP. A strong association of human chorionic gonadotropin (hCG) and Down syndrome was reported. This analyte is the most sensitive one in use today, although controversy exists regarding the best form of the analyte to use for trisomy 21 prediction. Several groups of investigators advocate measurement of total hCG, while others feel that measurement of the free-beta subunit of the molecule offers greater detection ability. The maximum detection rate that has been reported is 80 percent with a 5 percent false-positive rate using a combination of MSAFP, free-beta hCG, and maternal age.(ABSTRACT TRUNCATED AT 250 WORDS)

Flow cytometric evaluation of epithelial ovarian cancer.

We investigated the prognostic significance of deoxyribonucleic acid content and proliferative activity of tumor cell populations as measured by flow cytometry of the tumor specimens from 115 women with epithelial ovarian cancer. Deoxyribonucleic acid aneuploidy was found in 87 of 115 (76%) of these cancers with a mean deoxyribonucleic acid index of 1.6 and S-phase fraction of 14.7%. The S-phase fraction of the 28 (24%) diploid tumors was 7.0%. Deoxyribonucleic acid ploidy was significantly correlated with survival. S-phase fraction was significantly correlated with ploidy, residual tumor, histology, grade, ascites, time to recurrence, and survival. Diploidy versus aneuploidy were the best discriminating values for deoxyribonucleic acid index and an S-phase fraction of greater or less than 18% for that parameter. Multivariate analysis revealed stage, S-phase fraction, residual tumor, and grade to be independently associated with time to recurrence, and stage, age, S-phase fraction, and largest metastases were factors associated with survival. Deoxyribonucleic acid ploidy did not significantly improve either model. These results suggest that abnormalities of deoxyribonucleic acid content and the proliferative activity of tumor cell populations are reflective of their biologic activity.

X;Y translocation in a female with streak gonads, H-Y- phenotype, and some features of Turner's syndrome.

In women X;Y translocations usually arise as Xp-Yq exchanges. We describe a 17-year-old female with streak gonads, some minor features of Turner's syndrome, and an X;Y translocation involving an exchange between Xq and Yq. Histological examination of the gonads revealed a fibrous stroma with prominent hilar cells. Cultured fibroblasts and peripheral lymphocytes were typed H-Y-. Examination of a buccal smear revealed a single intranuclear structure with the appearance of both a Barr body and a fluorescent Y body. This finding was consistent with the results of BrdU studies showing that the translocation X chromosome had been inactivated in all cells analyzed.

Isodicentric X chromosome in a girl with gonadal dysgenesis.

Chromosomal analysis on a 15-year-old girl with amenorrhea and lack of secondary sexual development showed a normal X chromosome and an isodicentric X chromosome, 46,X, idic(x) (pter leads to q23::q23 leads to pter). Thus the patient has duplicated and deleted X chromosome material. There was no evidence of 45,X mosaicism. Brd U-labeling revealed the abnormal X to be late-replicating.

Chromosomal breakage and sister chromatid exchange in peripheral blood lymphocytes and lymphoblastoid cell lines in the X-linked lymphoproliferative syndrome.

The frequencies of chromosomal aberrations and sister chromatid exchange (SCE) were measured in lymphoblastoid cell lines (LCLs) and in phytohemagglutinin (PHA)- and pokeweed mitogen (PWM)-stimulated lymphocytes from males with X-linked lymphoproliferative (XLP) syndrome, their obligate carrier mothers, and control subjects. We observed an increased frequency of chromosomal aberrations including increased polyploidy in LCLs derived from families with XLP with time in culture. The SCE rate in LCLs (mean of 3.89 SCEs per cell) was much lower than that in PHA- or PWM-stimulated lymphocytes: PWM-stimulated lymphocytes showed 9.58 SCEs per cell and PHA-stimulated cells had 11.38 SCEs per cell. A greater number of chromosomal gaps and breaks in the D-group chromosomes of LCLs of affected males and carrier females were identified compared to the number expected, based on chromosomal length and the number of aberrations seen in PHA-stimulated cell cultures. No differences in the frequency of SCEs or chromosomal aberrations were found in control subjects and affected males or carrier females in the peripheral lymphocytes stimulated by PHA. Phenotypes of XLP appear to arise from failure of immune responses to Epstein-Barr virus (EBV) and not from intrinsic chromosomal breakage or instability.

A possible exception to the critical region hypothesis.

Cytogenetic studies were done on a 5-year-old female with multiple congenital anomalies and mental retardation, revealing an unbalanced X/11 translocation. Her mother and phenotypically normal sister carry the balanced form of the translocation, while her brother has a normal 46,XY karyotype. Banding studies showed the breakpoints to be Xq22 and 11q13. These are remarkable for the following reasons: (1) the X breakpoint is within the critical region of the X chromosome, yet the balanced carrier does not manifest gonadal dysgenesis; and (2) the proband was trisomic for most of the long arm of chromosome 11. Late-replication studies of cells from the two balanced carriers showed inactivation of the normal X.