Rose G. Radin

African Ancestry and Genetic Risk for Uterine Leiomyomata

Rates of uterine leiomyomata (UL) are 2-3 times higher in African Americans than in European Americans. It is unclear whether inherited factors explain the ethnic disparity. To investigate the presence of risk alleles for UL that are highly differentiated in frequency between African Americans and European Americans, the authors conducted an admixture-based genome-wide scan of 2,453 UL cases confirmed by ultrasound or surgery in the Black Womens Health Study (1997-2009), a national prospective cohort study. Controls (n = 2,102) were women who did not report a UL diagnosis through 2009. Mean percentage of European ancestry was significantly lower among cases (20.00%) than among controls (21.63%; age-adjusted mean difference = -1.76%, 95% confidence interval: -2.40, -1.12; P < 0.0001), and the association was stronger in younger cases. Admixture analyses showed suggestive evidence of association at chromosomes 2, 4, and 10. The authors also genotyped a dense set of tag single nucleotide polymorphisms at different loci associated with UL in Japanese women but failed to replicate the associations. This suggests that genetic variation for UL differs in populations with and without African ancestry. The admixture findings further indicate that no single highly differentiated locus is responsible for the ethnic disparity in UL, raising the possibility that multiple variants jointly contribute to the higher incidence of UL in African Americans.

A Prospective Study of Diabetes, Lifestyle Factors, and Glaucoma Among African-American Women

PURPOSE To evaluate the association of self-reported type 2 diabetes, anthropometric factors, alcohol consumption, and cigarette smoking with risk of primary open-angle glaucoma (POAG) in a prospective cohort study of African-American women. METHODS From 1995 through 2007, 32,570 Black Womens Health Study participants aged 21 to 69 years at baseline were followed for incident POAG. Questionnaires were mailed biennially to update exposures and identify incident cases of POAG. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were derived from Cox regression models. RESULTS During 416,171 person-years of follow-up, 366 incident POAG cases were confirmed by physician report. After adjustment for potential confounders, the IRR comparing women with and without type 2 diabetes was 1.58 (95% CI, 1.17-2.13), and the IRR comparing current with never alcohol consumers was 1.35 (95% CI, 1.05-1.73). Among women younger than 50, associations with diabetes and alcohol consumption were stronger, and POAG was significantly associated with body mass index, waist circumference, waist-to-hip ratio, and both long-duration and high-intensity current smoking. CONCLUSIONS These results suggest that type 2 diabetes and current alcohol consumption are independent risk factors for POAG among African-American women, and that in addition to those factors, overall and central adiposity and smoking may be associated with increased risk of early-onset POAG.

A Prospective Study of Dairy Intake and Risk of Uterine Leiomyomata

Rates of uterine leiomyomata are 2-3 times higher among black women than white women. Dietary factors that differ in prevalence between these populations that could contribute to the disparity include dairy intake. During 1997-2007, the authors followed 22,120 premenopausal US Black Womens Health Study participants to assess dairy intake in relation to uterine leiomyomata risk. Because soy may be substituted for dairy, the effect of soy intake was also evaluated. Diet was estimated by using food frequency questionnaires in 1995 and 2001. Incidence rate ratios and 95% confidence intervals were estimated with Cox regression. There were 5,871 incident cases of uterine leiomyomata diagnosed by ultrasound (n = 3,964) or surgery (n = 1,907). Multivariable incidence rate ratios comparing 1, 2, 3, and > or =4 servings/day with <1 serving/day of total dairy were 0.94 (95% confidence interval (CI): 0.88, 1.00), 0.87 (95% CI: 0.78, 0.98), 0.84 (95% CI: 0.70, 1.01), and 0.70 (95% CI: 0.58, 0.86), respectively (P-trend <0.001). Incidence rate ratios comparing the highest (> or =2 servings/day) with the lowest (<1 serving/week) intake categories were 0.81 (95% CI: 0.66, 0.99) for high-fat dairy, 0.80 (95% CI: 0.70, 0.91) for low-fat dairy, and 0.78 (95% CI: 0.68, 0.89) for milk. Soy intake was unrelated to uterine leiomyomata risk. This large prospective study of black women provides the first epidemiologic evidence of reduced uterine leiomyomata risk associated with dairy consumption.

Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata

BACKGROUND US black women have higher rates of uterine leiomyomata (UL) and lower intakes of fruit and vegetables than do white women. Whether fruit and vegetable intake is associated with UL in black women has not been studied. OBJECTIVE We assessed the association of dietary intake of fruit, vegetables, carotenoids, folate, fiber, and vitamins A, C, and E with UL in the Black Womens Health Study. DESIGN In this prospective cohort study, we followed 22,583 premenopausal women for incident UL (1997-2009). Diet was estimated by using food-frequency questionnaires in 1995 and 2001. Cox regression was used to derive incidence rate ratios (IRRs) and 95% CIs for the association between each dietary variable (in quintiles) and UL. RESULTS There were 6627 incident cases of UL diagnosed by ultrasonography (n = 4346) or surgery (n = 2281). Fruit and vegetable intake was inversely associated with UL (≥4 compared with <1 serving/d; IRR: 0.90; 95% CI: 0.82, 0.98; P-trend = 0.03). The association was stronger for fruit (≥2 servings/d compared with <2 servings/wk; IRR: 0.89; 95% CI: 0.81, 0.98; P-trend = 0.07) than for vegetables (≥2 servings/d compared with <4 servings/wk: IRR: 0.97; 95% CI: 0.89, 1.05; P-trend = 0.51). Citrus fruit intake was inversely associated with UL (≥3 servings/wk compared with <1 serving/mo: IRR: 0.92; 95% CI: 0.86, 1.00; P-trend = 0.01). The inverse association for dietary vitamin A (upper compared with lower quintiles: IRR: 0.89; 95% CI: 0.83, 0.97; P-trend = 0.01) appeared to be driven by preformed vitamin A (animal sources), not provitamin A (fruit and vegetable sources). UL was not materially associated with dietary intake of vitamins C and E, folate, fiber, or any of the carotenoids, including lycopene. CONCLUSION These data suggest a reduced risk of UL among women with a greater dietary intake of fruit and preformed vitamin A.

Hypertension and risk of uterine leiomyomata in US black women

BACKGROUND Previous studies have found a positive association between hypertension and risk of hysterectomy-confirmed uterine leiomyomata (UL). The association of hypertension with UL confirmed by ultrasound or other surgery is less clear. METHODS The present study evaluated the association of hypertension with UL incidence according to confirmation method (hysterectomy, other surgery or ultrasound) in the Black Womens Health Study, 1997-2007. We collected prospective data every 2 years on physician-diagnosed hypertension and UL in 22 530 premenopausal women. Validation sub-studies confirmed 99 and 96% of hypertension and UL self-reported diagnoses, respectively. Cox regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association of hypertension and UL, adjusting for potential confounders. RESULTS During 172 162 person-years of follow-up, there were 6447 incident cases of UL confirmed by ultrasound (n = 5111), hysterectomy (n = 670) or other surgery (n = 666). Treated hypertension was associated with UL confirmed by hysterectomy (IRR = 1.32, 95% CI: 1.06, 1.63), but it was not associated with UL confirmed by ultrasound (IRR = 1.05, 95% CI: 0.96, 1.16) or other surgery (IRR = 1.13, 95% CI: 0.88, 1.46). CONCLUSIONS Treated hypertension was associated with UL confirmed by hysterectomy, but not UL confirmed by other methods (other surgery or ultrasound). These data suggest it is premature to conclude that hypertension is related to an increased risk of UL. Additional studies are needed to assess whether the association with hysterectomy-confirmed UL can be explained by other sources of bias, such as patient or physician preferences for specific types of medical care.

Dietary glycemic index and load in relation to risk of uterine leiomyomata in the Black Women's Health Study

BACKGROUND High dietary glycemic index (GI) and glycemic load (GL) may promote tumorigenesis by increasing endogenous concentrations of insulin-like growth factor I (IGF-I) or the bioavailability of estradiol. In vitro studies have shown that uterine leiomyoma (UL) cells proliferate in response to IGF-I and display increased IGF-I gene expression and protein synthesis. Previous epidemiologic studies suggest that a high GL is a risk factor for endometrial and ovarian cancers, which, like UL, are hormone-responsive tumors. OBJECTIVE We investigated the relation of dietary GI and GL with UL risk in the Black Womens Health Study. DESIGN In this prospective cohort study, we followed 21,861 premenopausal women for incident UL from 1997 to 2007. Diet was assessed in 1995 and 2001 with food-frequency questionnaires. We used Cox regression to estimate incidence rate ratios (IRRs) and 95% CIs, controlled for potential confounders. RESULTS During 162,604 person-years of follow-up, there were 5800 cases of UL diagnosed by ultrasound or surgery. Dietary GI was weakly associated with UL risk overall (IRR for highest compared with lowest quintile: 1.09; 95% CI: 0.99, 1.19; P for trend = 0.04). Positive associations were observed between GL and UL in women aged <35 y (IRR for highest compared with lowest quintile: 1.18; 95% CI: 1.02, 1.37; P for trend = 0.15) and between GI and UL in college-educated women (IRR for highest compared with lowest quintile: 1.17; 95% CI: 1.03, 1.34; P for trend = 0.004). CONCLUSIONS Our results suggest that high dietary GI and GL may be associated with an increased UL risk in some women. The observed associations warrant investigation in future studies.

Active and passive smoking and fecundability in Danish pregnancy planners

OBJECTIVE To investigate the extent to which fecundability is associated with active smoking, time since smoking cessation, and passive smoking. DESIGN Prospective cohort study. SETTING Denmark, 2007-2011. PATIENT(S) A total of 3,773 female pregnancy planners aged 18-40 years. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Self-reported pregnancy. Fecundability ratios (FRs) and 95% confidence intervals (CIs) were estimated using a proportional probabilities model that adjusted for menstrual cycle at risk and potential confounders. RESULT(S) Among current smokers, smoking duration of ≥10 years was associated with reduced fecundability compared with never smokers (FR, 0.85, 95% CI 0.72-1.00). Former smokers who had smoked ≥10 pack-years had reduced fecundability regardless of when they quit smoking (1-1.9 years FR, 0.83, 95% CI 0.54-1.27; ≥2 years FR, 0.73, 95% CI 0.53-1.02). Among never smokers, the FRs were 1.04 (95% CI 0.89-1.21) for passive smoking in early life and 0.92 (95% CI 0.82-1.03) for passive smoking in adulthood. CONCLUSION(S) Among Danish pregnancy planners, cumulative exposure to active cigarette smoking was associated with delayed conception among current and former smokers. Time since smoking cessation and passive smoking were not appreciably associated with fecundability.

Dietary fat intake and reproductive hormone concentrations and ovulation in regularly menstruating women

BACKGROUND Emerging evidence suggests potential links between some dietary fatty acids and improved fertility, because specific fatty acids may affect prostaglandin synthesis and steroidogenesis. OBJECTIVE The objective of this exploratory study was to evaluate associations between total and specific types of dietary fat intake and 1) hormone concentrations and 2) the risk of sporadic anovulation in a cohort of 259 regularly menstruating women in the BioCycle Study. DESIGN Endogenous reproductive hormones were measured up to 8 times/cycle for up to 2 cycles, with visits scheduled with the use of fertility monitors. Dietary intake was assessed with up to four 24-h recalls/cycle. Linear mixed models and generalized linear models were used to evaluate the associations between dietary fatty acids and both reproductive hormone concentrations and ovulatory status. All models were adjusted for total energy intake, age, body mass index, and race. RESULTS Relative to the lowest levels of percentage of energy from total fat, the highest tertile was associated with increased total and free testosterone concentrations (total: percentage change of 4.0%; 95% CI: 0.7%, 7.3%; free: percentage change of 4.1%; 95% CI: 0.5%, 7.7%). In particular, the percentage of energy from polyunsaturated fatty acids (PUFAs) in the highest tertile was associated with increases in total and free testosterone (total: percentage change of 3.7%; 95% CI: 0.6%, 6.8%; free: percentage change of 4.0%; 95% CI: 0.5%, 7.5%). The PUFA docosapentaenoic acid (22:5n-3) was not significantly associated with testosterone concentrations (P-trend = 0.86 in energy substitution models) but was associated with increased progesterone and a reduced risk of anovulation (highest tertile compared with the lowest tertile: RR: 0.42; 95% CI: 0.18, 0.95). Fat intakes were not associated with other reproductive hormone concentrations. CONCLUSIONS These results indicate that total fat intake, and PUFA intake in particular, is associated with very small increases in testosterone concentrations in healthy women and that increased docosapentaenoic acid was associated with a lower risk of anovulation.

Trying to Conceive After an Early Pregnancy Loss: An Assessment on How Long Couples Should Wait.

OBJECTIVE: To compare time to pregnancy and live birth among couples with varying intervals of pregnancy loss date to subsequent trying to conceive date. METHODS: In this secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial, 1,083 women aged 18–40 years with one to two prior early losses and whose last pregnancy outcome was a nonectopic or nonmolar loss were included. Participants were actively followed for up to six menstrual cycles and, for women achieving pregnancy, until pregnancy outcome. We calculated intervals as start of trying to conceive date minus pregnancy loss date. Time to pregnancy was defined as start of trying to conceive until subsequent conception. Discrete Cox models, accounting for left truncation and right censoring, estimated fecundability odds ratios (ORs) adjusting for age, race, body mass index, education, and subfertility. Although intervals were assessed prior to randomization and thus reasoned to have no relation with treatment assignment, additional adjustment for treatment was evaluated given that low-dose aspirin was previously shown to be predictive of time to pregnancy. RESULTS: Couples with a 0–3-month interval (n=765 [76.7%]) compared with a greater than 3-month (n=233 [23.4%]) interval were more likely to achieve live birth (53.2% compared with 36.1%) with a significantly shorter time to pregnancy leading to live birth (median [interquartile range] five cycles [three, eight], adjusted fecundability OR 1.71 [95% confidence interval 1.30–2.25]). Additionally adjusting for low-dose aspirin treatment did not appreciably alter estimates. CONCLUSION: Our study supports the hypothesis that there is no physiologic evidence for delaying pregnancy attempt after an early loss.

Serum Antioxidants Are Associated with Serum Reproductive Hormones and Ovulation among Healthy Women

BACKGROUND Evidence is growing that the equilibrium between reactive oxygen species and antioxidants plays a vital role in womens reproductive health. OBJECTIVE The objective of this study was to evaluate variations in serum antioxidant concentrations across the menstrual cycle and associations between antioxidants and reproductive hormones and anovulation among healthy women. METHODS The BioCycle Study, a prospective cohort, followed 259 women aged 18-44 y for up to 2 menstrual cycles. Serum fat-soluble vitamin and micronutrient (α-tocopherol, γ-tocopherol, retinol, lutein, lycopene, and β-carotene), ascorbic acid, and reproductive hormone concentrations were measured 5-8 times/cycle. We used weighted linear mixed models to assess associations between antioxidants and hormone concentrations, after adjustment for age, race, body mass index, parity, sleep, pain medication use, total energy intake, concurrent hormones, serum cholesterol, F2-isoprostanes, and other antioxidants. Generalized linear models were used to identify associations with anovulation. RESULTS Serum antioxidant concentrations varied across the menstrual cycle. Retinol and α-tocopherol were associated with higher estradiol [RR: 1.00 pg/mL (95% CI: 0.67, 1.34 pg/mL); RR: 0.02 pg/mL (95% CI: 0.003, 0.03 pg/mL), respectively] and testosterone [RR: 0.61 ng/dL (95% CI: 0.44, 0.78 ng/dL); RR: 0.01 ng/dL (95% CI: 0.001, 0.01 ng/dL), respectively]. Ascorbic acid was associated with higher progesterone (RR: 0.15 ng/mL; 95% CI: 0.05, 0.25 ng/mL) and with lower follicle-stimulating hormone (RR: -0.06 mIU/mL; 95% CI: -0.09, -0.03 mIU/mL). The ratio of α- to γ-tocopherol was associated with an increased risk of anovulation (RR: 1.03; 95% CI: 1.01, 1.06). CONCLUSIONS These findings shed new light on the intricate associations between serum antioxidants and endogenous hormones in healthy premenopausal women and support the hypothesis that concentrations of serum vitamins affect steroidogenesis even after adjustment for oxidative stress.