A factor analysis approach to examining relationships among ovarian steroid concentrations, gonadotrophin concentrations and menstrual cycle length characteristics in healthy, cycling women

STUDY QUESTION: How are ovarian steroid concentrations, gonadotrophins and menstrual cycle characteristics inter-related within normal menstrual cycles? SUMMARY ANSWER: Within cycles, measures of estradiol production are highly related to one another, as are measures of progesterone production; however, the two hormones also show some independence from one another, and measures of cycle length and gonadotrophin concentrations show even greater independence, indicating minimal integration within cycles. WHAT IS KNOWN ALREADY: The menstrual cycle is typically conceptualized as a cohesive unit, with hormone levels, follicular development and ovulation all closely inter-related within a single cycle. Empirical support for this idea is limited, however, and to our knowledge, no analysis has examined the relationships among all of these components simultaneously. STUDY DESIGN, SIZE, DURATION: A total of 206 healthy, cycling Norwegian women participated in a prospective cohort study (EBBA-I) over the duration of a single menstrual cycle. Of these, 192 contributed hormonal and cycle data to the current analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Subjects provided daily saliva samples throughout the menstrual cycle from which estradiol and progesterone concentrations were measured. FSH and LH concentrations were measured in serum samples from three points in the same menstrual cycle and cycle length characteristics were calculated based on hormonal data and menstrual records. A factor analysis was conducted to examine the underlying relationships among 22 variables derived from the hormonal data and menstrual cycle characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Six rotated factors emerged, explaining 80% of the variance in the data. Of these, factors representing estradiol and progesterone concentrations accounted for 37 and 13% of the variance, respectively. There was some association between measures of estradiol and progesterone production within cycles; however, cycle length characteristics and gonadotrophin concentrations showed little association with any measure of ovarian hormone concentrations. LIMITATIONS, REASONS FOR CAUTION: Our summary measures of ovarian hormones may be imprecise in women with extremely long or short cycles, which could affect the patterns emerging in the factor analysis. Given that we only had data from one cycle on each woman, we cannot address how cycle characteristics may covary within individual women across multiple cycles. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are generalizable to other healthy populations with typical cycles, however, may not be applicable to cycles that are anovulatory, extreme in length or otherwise atypical. The results support previous findings that measures of estradiol production are highly correlated across the cycle, as are measures of progesterone production. Estradiol and progesterone concentrations are associated with one another, furthermore. However factor analysis also revealed more complex underlying patterns in the menstrual cycle, highlighting the fact that gonadotrophin concentrations and cycle length characteristics are virtually independent of ovarian hormones. These results suggest that despite integration of follicular and luteal ovarian steroid production across the cycle, cycle quality is a multi-faceted construct, rather than a single dimension. STUDY FUNDING/COMPETING INTEREST(S): The EBBA-I study was supported by a grant from the Norwegian Cancer Society (49 258, 05087); Foundation for the Norwegian Health and Rehabilitation Organizations (59010-2000/2001/2002); Aakre Foundation (5695-2000, 5754-2002) and Health Region East. The current analyses were completed under funding from the National Institutes of Health (K12 ES019852). No competing interests declared.Anthropolog

Disparate Effects of Atorvastatin Compared With Simvastatin on C-Reactive Protein Concentrations in Patients With Type 2 Diabetes

OBJECTIVE - Reduction in LDL and high sensitivity (hs) C-reactive protein (CRP) are independent indicators of successful cardiovascular risk reduction with statins. This study compared the effect of equivalent LDL-lowering doses of simvastatin and atorvastatin on hsCRP in type 2 diabetic patients. RESEARCH DESIGN AND METHODS - A crossover study of 26 patients with type 2 diabetes taking either 40 mg simvastatin or 10 mg atorvastatin was undertaken. After 3 months on one statin, lipids and hsCRP were measured on 10 occasions over a 5-week period. The same procedure was then followed taking the other statin. RESULTS - LDL was comparable on either treatment: atorvastatin 2.2 +/- 0.2 vs. 2.1 +/- 0.3 mmol/l (mean +/- SD; P = 0.19). CRP of individuals taking atorvastatin was significantly lower than when they were taking simvastatin (median 1.08 vs. 1.47 mg/l, P = 0.0002) and was less variable (median SD of logCRP 0.0036 vs. 0.178, P = 0.0001). CONCLUSIONS - Compared with simvastatin, atorvastatin reduced hsCRP and its variability in type 2 diabetic patients. This enhanced anti-inflammatory effect may prove beneficial if lower CRP is associated with improved cardiovascular risk

Blood Pressure and Hypertension in Adults Permanently Living at High Altitude: A Systematic Review and Meta-Analysis.

Aryal, Nirmal, Mark Weatherall, Yadav Kumar Deo Bhatta, and Stewart Mann. Blood pressure and hypertension in adults permanently living at high altitude: a systematic review and meta-analysis. High Alt Med Biol. 17:185-193, 2016.-The objective of this study was to estimate the associations between altitude and mean blood pressure (BP) (or prevalence of hypertension [HT]) in adults who live permanently at high altitude. A literature search was conducted in December 2014 using PubMed, Scopus, and OvidSP (MedLine and EMBASE) databases to identify relevant observational studies. Inclusion criteria were reports of studies in populations permanently living at an altitude of ≥2400 m and in those 18 years or older. Meta-regression was used to estimate the association between average BP and HT and altitude. We identified 3375 articles and inclusion criteria were met for 21 reports, which included a total of 40,854 participants. Random-effects meta-regression estimated that for every 1000 m elevation the average systolic BP (SBP) (95% confidence interval [CI]) increased by 17 mmHg (0.2 to 33.8), p = 0.05 and diastolic BP (DBP) by 9.5 mmHg (0.6 to 18.4), p = 0.04 in participants with Tibetan origin. By contrast, in participants with non-Tibetan origin, average SBP decreased by 5.9 mmHg (-19.1 to 7.3), p = 0.38 and DBP by 4 mmHg (-13 to 5), p = 0.38. The odds ratios (95% CI) for the proportion of participants with HT per 1000 m increment in the altitude were 2.01 (0.37 to 11.02), p = 0.446 and 4.05 (0.07 to 244.69), p = 0.489 for Tibetan and non-Tibetan participants, respectively. Sensitivity analysis excluding two studies with older participants (≥60 years) reversed the direction of this effect in non-Tibetans with odds ratio (95% CI) of 0.10 (0.004 to 2.22) per 1000 m, p = 0.143. Overall, this review suggests weak association between BP and altitude in Tibetan origin populations

17-beta-Estradiol in relation to age at menarche and adult obesity in premenopausal women

BACKGROUND: We hypothesize that premenopausal endogenous estradiol may be associated with age at menarche and adult overweight and obesity, potentially contributing to breast cancer risk. METHODS: We assessed age at menarche by questionnaire among 204 healthy Norwegian women, aged 25 – 35 years. Measures of body composition included body mass index (BMI, kg/m2), waist circumference (WC, cm), waist-to-hip ratio (WHR) and fat percentage dual energy X-ray absorptiometry, (DEXA). Daily salivary 17-b-estradiol (E2) concentrations were collected throughout one entire menstrual cycle and assessed by radioimmunoassay (RIA). Linear regression analyses and linear mixed models for repeated measures were used and potential confounding factors and effect modifiers were tested. RESULTS: Among women with an early age at menarche (12 years), the overall mean salivary E2 concentration increased by 3.7 pmol/l (95% confidence interval, 1.8 – 5.7 pmol/l) with each 9.8 cm (1 SD) increase in WC, which represents a 20.7% change in the mean for the total group. Among the same early maturers, a 1 SD (0.06) change in WHR was directly associated with a 24.0% change in mean E2 concentration for the total group. CONCLUSIONS: Our findings support the hypothesis that early age at menarche, together with adult overweight and obesity, result in high levels of 17-b-estradiol throughout the menstrual cycle.AnthropologyHuman Evolutionary Biolog

Supporting Parental Decisions About Genomic Sequencing for Newborn Screening: The NC NEXUS Decision Aid

Advances in genomic sequencing technology have raised fundamental challenges to the traditional ways genomic information is communicated. These challenges will become increasingly complex and will affect a much larger population in the future if genomics is incorporated into standard newborn screening practice. Clinicians, public health officials, and other stakeholders will need to agree on the types of information that they should seek and communicate to parents. Currently, few evidence-based and validated tools are available to support parental informed decision-making. These tools will be necessary as genomics is integrated into clinical practice and public health systems. In this article we describe how the North Carolina Newborn Exome Sequencing for Universal Screening study is addressing the need to support parents in making informed decisions about the use of genomic testing in newborn screening. We outline the context for newborn screening and justify the need for parental decision support. We also describe the process of decision aid development and the data sources, processes, and best practices being used in development. By the end of the study, we will have an evidenced-based process and validated tools to support parental informed decision-making about the use of genomic sequencing in newborn screening. Data from the study will help answer important questions about which genomic information ought to be sought and communicated when testing newborns

Polymorphisms in the estrogen receptor alpha gene (ESR1), daily cycling estrogen and mammographic density phenotypes

Background Single nucleotide polymorphisms (SNPs) involved in the estrogen pathway and SNPs in the estrogen receptor alpha gene (ESR1 6q25) have been linked to breast cancer development, and mammographic density is an established breast cancer risk factor. Whether there is an association between daily estradiol levels, SNPs in ESR1 and premenopausal mammographic density phenotypes is unknown. Methods We assessed estradiol in daily saliva samples throughout an entire menstrual cycle in 202 healthy premenopausal women in the Norwegian Energy Balance and Breast Cancer Aspects I study. DNA was genotyped using the Illumina Golden Gate platform. Mammograms were taken between days 7 and 12 of the menstrual cycle, and digitized mammographic density was assessed using a computer-assisted method (Madena). Multivariable regression models were used to study the association between SNPs in ESR1, premenopausal mammographic density phenotypes and daily cycling estradiol. Results We observed inverse linear associations between the minor alleles of eight measured SNPs (rs3020364, rs2474148, rs12154178, rs2347867, rs6927072, rs2982712, rs3020407, rs9322335) and percent mammographic density (p-values: 0.002–0.026), these associations were strongest in lean women (BMI, ≤23.6 kg/m2.). The odds of above-median percent mammographic density (>28.5 %) among women with major homozygous genotypes were 3–6 times higher than those of women with minor homozygous genotypes in seven SNPs. Women with rs3020364 major homozygous genotype had an OR of 6.46 for above-median percent mammographic density (OR: 6.46; 95 % Confidence Interval 1.61, 25.94) when compared to women with the minor homozygous genotype. These associations were not observed in relation to absolute mammographic density. No associations between SNPs and daily cycling estradiol were observed. However, we suggest, based on results of borderline significance (p values: 0.025–0.079) that the level of 17β-estradiol for women with the minor genotype for rs3020364, rs24744148 and rs2982712 were lower throughout the cycle in women with low (28.5 %) percent mammographic density, when compared to women with the major genotype. Conclusion Our results support an association between eight selected SNPs in the ESR1 gene and percent mammographic density. The results need to be confirmed in larger studies

Ovarian hormones and reproductive risk factors for breast cancer in premenopausal women: the Norwegian EBBA-I study

BACKGROUND: Ovarian hormones, parity and length of 'menarche-to-first birth' time interval are known risk factors for breast cancer, yet the associations between I 7$\beta$-estradiol, progesterone and these reproductive factors remain unclear. METHODS: A total of 204 women (25-35 years) who participated in the Norwegian EBBA-I study collected daily saliva samples for one complete menstrual cycle, and filled in a reproductive history questionnaire. Anthropometry was measured and saliva samples were analyzed for ovarian hormones. Associations between parity, the interval and ovarian hormones, and effects of hormone-related lifestyle factors were studied in linear regression models. RESULTS: Mean age was 30.7 years, and age of menarche 13.1 years. Parous women had on average 1.9 births, and age at first birth was 24.5 years. No association was observed between parity and ovarian steroids. In nulliparous women, higher waist circumference ($\ge$)77.75 cm) and longer oral contraceptive (OC) use ($\ge$)3 years) were associated with higher levels of I 7$\beta$-estradiol. Short (13.5 years) 'menarche-to-first birth' interval was associated with higher overall mean (P$_{trend}$ = 0.029), 47% higher maximum peak and 30% higher mid-cycle levels of I 7$\beta$-estradiol. We observed a 2.6% decrease in overall mean salivary I 7$\beta$-estradiol with each 1-year increase in the interval. CONCLUSIONS: Nulliparous women may be more susceptible to lifestyle factors, abdominal overweight and past OC use, influencing metabolic and hormonal profiles and thus breast cancer risk. Short time between 'menarche-to-first birth' is linked to higher ovarian hormone levels among regularly cycling women, suggesting that timing of first birth is related to fecundity.Human Evolutionary Biolog