Prenatal diethylstilbestrol exposure and risk of obesity in adult women.

Diethylstilbestrol (DES) is a non-steroidal estrogen that was commonly prescribed during pregnancy from the late 1940s to 1971. A potent endocrine disruptor, prenatal DES exposure has been linked with reproductive tract malformations, adverse pregnancy outcomes, cancer, infertility and earlier menopause. DES was used for years as a growth promoter in animal production. Some animal studies suggest that prenatal DES exposure is associated with obesity and metabolic disturbances. Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between DES and adult obesity, weight gain from age 20 to mid-life, central adiposity and height among 2871 prenatally exposed and 1352 unexposed women between 23 and 52 years of age (median 41.5) at baseline in 1994. DES exposure status was confirmed by prenatal medical record review. We used multivariable log-binomial models to calculate risk ratios (RRs) for obesity in 2006, and linear regression to calculate mean differences in body mass index, weight gain, waist circumference and height. The adjusted RR for DES and obesity was 1.09 [95% confidence interval (CI): 0.97, 1.22], and RRs were 1.23 (CI: 1.07, 1.42) and 1.05 (CI: 0.91, 1.20) for low and high estimated total DES dose, respectively, compared with no exposure. DES-exposed women gained slightly more weight than unexposed women [mean difference, 0.70 kg (CI: -0.27, 1.66)]. This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity.

Practices and perceptions among pediatricians regarding adolescent contraception with emphasis on intrauterine contraception.

STUDY OBJECTIVE: This study was conducted to characterize pediatricians' current practice patterns and perceived barriers related to adolescent contraception counseling with an emphasis on intrauterine contraception (IUC). DESIGN: We performed a mailed survey study to 400 general pediatricians. SETTING: Surveys were mailed to pediatricians at their individual office locations. PARTICIPANTS: General pediatricians belonging to the Massachusetts Pediatric Society were included in the study. INTERVENTIONS: The survey instrument assessed current practice patterns and perspectives as related to contraception counseling for adolescents. MAIN OUTCOME MEASURES: Use of contraception among adolescent patients, policy to recommend IUC to adolescents in various clinical scenarios, and barriers to adolescent contraceptive counseling. RESULTS: Over 50% of pediatricians considered abstinence their favored method of contraception for adolescents, while fewer than 20% reported discussing IUC as an option. Female pediatricians were more likely to discuss IUC (25% vs 8%, P = .01), as were younger pediatricians (28% vs 14%, P = .13). Given 8 clinical scenarios suitable for IUC use, less than 25% of pediatricians would offer IUC to a teen unless she had a history of a vaginal delivery or abortion. Seventy percent of pediatricians reported lack of training with IUC, and more than 30% reported legal, fertility and parental concerns as barriers to discussing IUC with adolescents. CONCLUSIONS: Efforts are warranted to improve the education of pediatricians regarding the most current guidelines for proper IUC use in adolescents with the goal to increase the frequency with which this effective contraceptive method is discussed with this vulnerable population.

Novel measurements of mammary stem cells in human umbilical cord blood as prospective predictors of breast cancer susceptibility in later life.

BACKGROUND: The size of the breast stem-cell pool could underlie the intrauterine roots of breast cancer. We studied whether breast stem cells exist in umbilical cord blood and if they correlate with hematopoietic stem-cell measurements that have been positively associated with perinatal risk factors for breast cancer. SUBJECTS AND METHODS: We isolated mononuclear cells from umbilical cord blood of 170 singleton full-term pregnancies and determined, by reverse transcription polymerase chain reaction, the presence of genes of putative breast epithelial stem-cell/progenitor markers [including epithelial cell adhesion molecule (EpCAM), CD49f (α6-integrin), CD117 (c-kit receptor), CD24, and CD29 (ß1-integrin)]. By immunocytochemistry, we colocalized protein expressions of EpCAM+CD49f+, CD49f+CD24+, and CD24+CD29+. We correlated concentrations of putative breast stem-cell/progenitor subpopulations, quantified by flow cytometry, with concentrations of hematopoietic stem cells. RESULTS: Mammary stem-cell phenotypes were identified in umbilical cord blood. The measured EpCAM+ subpopulation was positively correlated with concentrations of CD34+ and CD34+CD38- hematopoietic stem cells (both P=0.006). Additionally, EpCAM+CD49f+ and CD49f+CD24+ subpopulations were positively correlated to the CD34+ cells (P=0.03 and 0.008, respectively). CONCLUSION: The positive association between measurable breast and hematopoietic stem cells in human umbilical cord blood suggests plausible mechanisms for a prenatal influence on breast cancer risk.

Admission uric acid levels and length of expectant management in preterm preeclampsia.

OBJECTIVE: Uric acid is known to be elevated in preeclampsia. We sought to determine if uric acid levels on admission correlate with the length of expectant management in preterm patients with preeclampsia. STUDY DESIGN: A retrospective chart review was conducted on singleton preeclamptic pregnancies delivered between 24 0/7 and 37 0/7 weeks' gestation at Tufts Medical Center between January 2005 and December 2007. Patients with a multiple gestation and those transferred or discharged before delivery were excluded. Data regarding signs and symptoms of preeclampsia, laboratory values, pregnancy complications and outcome were abstracted from the medical records. Correlation between admission uric acid level and days of expectant management was assessed. The relative risk (RR) was used to estimate the effect of uric acid levels on expectant management length >7 days. Mantel-Haenszel χ(2) values were used to construct 95% confidence intervals (CIs) around the RR. RESULT: Four hundred seventy-one charts were reviewed. Of these, 190 met inclusion criteria. In all, 55 patients (28.9%) were managed expectantly for >1 week. Admission uric acid level correlated with days of expectant management (P<0.0001). Uric acid levels at admission were categorized as ≤4.0 mg dl(-1) (low uric acid level), 4.1 to 6.0 mg dl(-1) (medium) and ≥6.1 mg dl(-1) (high). Relative to women with high uric acid levels at admission, we observed a sevenfold higher rate of extending expectant management for >1 week among women with low uric acid level (7.0; 95% CI: 3.34 to 14.68). Women with medium uric acid levels at admission also had a higher likelihood of prolonging pregnancy relative to women with high uric acid levels (RR: 2.81; 95% CI: 1.32 to 5.96) (P-value for trend <0.0001). CONCLUSION: Admission uric acid levels correlate with the length of expectant management in preterm patients with preeclampsia. Pregnancy prolongation for >1 week is significantly more likely in patients with low and medium uric acid levels at the time of admission. Uric acid levels may be helpful in assessing disease severity and counseling preeclamptic patients regarding likelihood of extended expectant management.

Correlation of umbilical cord blood haematopoietic stem and progenitor cell levels with birth weight: implications for a prenatal influence on cancer risk.

We examined the relation with birth weight and umbilical cord blood concentrations of haematopoietic stem and progenitor populations in 288 singleton infants. Across the whole range of birth weight, there was a positive relation between birth weight and CD34+CD38(-) cells, with each 500 g increase in birth weight being associated with a 15.5% higher (95% confidence interval: 1.6-31.3%) cell concentration. CD34+ and CD34+c-kit+ cells had J-shaped relations and CFU-GM cells had a U-shaped relation with birth weight. Among newborns with >or=3000 g birth weights, concentrations of these cells increased with birth weight, while those below 3000 g had higher stem cell concentrations than the reference category of 3000-3499 g. Adjustment for cord blood plasma insulin-like growth factor-1 levels weakened the stem and progenitor cell-birth weight associations. The positive associations between birth weight and stem cell measurements for term newborns with a normal-to-high birth weight support the stem cell burden hypothesis of cancer risk.

Mortality in women given diethylstilbestrol during pregnancy.

We used Cox regression analyses to assess mortality outcomes in a combined cohort of 7675 women who received diethylstilbestrol (DES) through clinical trial participation or prenatal care. In the combined cohort, the RR for DES in relation to all-cause mortality was 1.06 (95% CI = 0.98-1.16), and 1.11 (95% CI = 1.02-1.21) after adjusting for covariates and omitting breast cancer deaths. The RR was 1.07 (95% CI = 0.94-1.23) for overall cancer mortality, and remained similar after adjusting for covariates and omitting breast cancer deaths. The RR was 1.27 (95% CI = 0.96-1.69) for DES and breast cancer, and 1.38 (95% CI=1.03-1.85) after covariate adjustment. The RR was 1.82 in trial participants and 1.12 in the prenatal care cohort, but the DES-cohort interaction was not significant (P = 0.15). Diethylstilbestrol did not increase mortality from gynaecologic cancers. In summary, diethylstilbestrol was associated with a slight but significant increase in all-cause mortality, but was not significantly associated with overall cancer or gynaecological cancer mortality. The association with breast cancer mortality was more evident in trial participants, who received high DES doses.

Birth weight and breast cancer risk.

Exploring whether the positive association between birth weight and breast cancer risk differs by other breast cancer risk factors may help inform speculation about biological mechanism. In these data, high birth weight was associated with breast cancer risk in younger and in more educated women, but was not associated overall.

Tension-free vaginal tape: outcomes among women with primary versus recurrent stress urinary incontinence.

OBJECTIVE: To evaluate the outcomes of tension-free vaginal tape in the treatment of primary versus recurrent genuine stress urinary incontinence. METHODS: A retrospective, multicenter study of 245 consecutive women who were treated with tension-free vaginal tape for genuine stress urinary incontinence (157 for primary and 88 for recurrent genuine stress urinary incontinence) over a 27-month period was performed. Concurrent surgical repairs were performed as required. Subjective and objective outcome data were assessed from routine postoperative visits. Office and hospital records were reviewed to determine patient characteristics, intraoperative findings, and surgical outcomes. RESULTS: Women with recurrent genuine stress urinary incontinence were older (mean age 64.6 versus 59.4 years, P =.004) than those with primary incontinence; they were less likely to have an intact uterus (22.7% versus 66.9%, P <.001), and were more likely to have intrinsic sphincter deficiency (70.5% versus 47.1%, P <.001). The mean duration of follow-up was 38 (+/-16) weeks. Cure rates among patients with recurrent versus primary genuine stress urinary incontinence were similar (85% and 87%, respectively, P =.23). Complication rates were similarly low in both groups (4.5% versus 7.6% for recurrent and primary genuine stress urinary incontinence, respectively, P =.35). Postoperative voiding dysfunction occurred at low rates in both groups. CONCLUSION: Tension-free vaginal tape is a highly effective treatment among patients with recurrent stress incontinence, with outcomes comparable with those among patients with primary incontinence.

Cancer risk in men exposed in utero to diethylstilbestrol.

BACKGROUND: An association between prenatal diethylstilbestrol (DES) exposure and cancer in men, especially testicular cancer, has been suspected, but findings from case-control studies have been inconsistent. This study was conducted to investigate the association between prenatal DES exposure and cancer risk in men via prospective follow-up. METHODS: A total of 3613 men whose prenatal DES exposure status was known were followed from 1978 through 1994. The overall and site-specific cancer incidence rates among the DES-exposed men were compared with those of the unexposed men in the study and with population-based rates. The relative rate (RR) was used to assess the strength of the association between prenatal DES exposure and cancer development. All statistical tests were two-sided. RESULTS: Overall cancer rates among DES-exposed men were similar to those among unexposed men (RR = 1.07; 95% confidence interval [CI] = 0.58 to 1.96) and to national rates (RR = 0.99; 95% CI = 0.65 to 1.44). Testicular cancer may be elevated among DES-exposed men, since the RRs for testicular cancer were 3.05 (95% CI = 0.65 to 22.0) times those of unexposed men in the study and 2.04 (95% CI = 0.82 to 4.20) times those of males in the population-based rates. The higher rate of testicular cancer in the DES-exposed men is, however, also compatible with a chance observation. CONCLUSIONS: To date, men exposed to DES in utero do not appear to have an increased risk of most cancers. It remains uncertain, however, whether prenatal DES exposure is associated with testicular cancer.

The impact of age on the incidence and prognosis of initial acute myocardial infarction: the Worcester Heart Attack Study.

As part of a community-wide study examining time trends in the incidence and case-fatality rates (CFR) of patients hospitalized with acute myocardial infarction (MI) in sixteen hospitals in the Worcester, Massachusetts metropolitan area, the association of age to the incidence rates of initial acute MI and to in-hospital and long-term survival among 2115 patients with validated acute MI was examined. After selected age-specific changes in the incidence rates of initial events of acute MI between 1975 and 1981, the incidence rates of acute MI markedly declined between 1981 and 1984, resulting in decreases in the age-specific incidence rates of initial acute MI between 1975 and 1984. For the combined study periods, the in-hospital CFR of acute MI increased from 5.0% in patients less than 55 years of age to 7.9% in those 55 to 64 years, to 16.1% in those 65 to 74 years and to 32.1% in patients 75 years of age and older. Among discharged hospital survivors, increasing age was related to poorer long-term survival over a 5-year follow-up period. The results of this population-based study reinforce the need for, and importance of, modification of coronary risk factors in both young and older individuals, and of focused therapeutic efforts to salvage jeopardized myocardium in elderly patients hospitalized with acute MI.

Phosphatidic acid and phosphatidylinositol labelling in adipose tissue. Relationship to the metabolic effects of insulin and insulin-like agents.

Exposure to phospholipase C increased the incorporation of [32P]Pi into phosphatidate, CMP-phosphatidate and phosphatidylinositol in rat adipose tissue and isolated adipocytes. A similar effect was observed in response to insulin and oxytocin. Theophylline, 3-isobutyl-1-methylxanthine and adenosine deaminase decreased [32P]Pi incorporation, and adenosine and N6-phenylisopropyladenosine reversed these effects. As with insulin, exposure of adipose tissue to phospholipase C stimulated oxidation of glucose, pyruvate and leucine and activated pyruvate dehydrogenase. Oxytocin and adenosine also mimicked the effects of insulin on leucine oxidation and pyruvate dehydrogenase. However, only insulin stimulated glycogen synthase activity, indicating that the regulation of synthase may be achieved by intracellular events distinct from those regulating changes in phospholipid metabolism, sugar transport and mitochondrial enzyme activities. It is postulated that exposure to phospholipase C forms diacylglycerol, which is phosphorylated to yield phosphatidate. The increased labelling of CMP-phosphatidate and phosphatidylinositol results from the conversion of phosphatidate into these lipids. The correlation between the effects of phospholipase C on phosphatidate synthesis and changes in adipose-tissue metabolism suggests the possibility that increased phosphatidate may directly or indirectly produce changes in membrane transport and enzyme activities. The pattern of phospholipid labelling produced by insulin, adenosine and oxytocin suggests that these stimuli may also increase phosphatidate synthesis, and, if so, changes in phospholipid metabolism could account for some of the metabolic actions of these stimuli.