A phase 1b study of erlotinib and momelotinib for the treatment of EGFR-mutated, tyrosine kinase inhibitor-naive metastatic non-small cell lung cancer.

INTRODUCTION: Preclinical evidence suggests the feedforward cytokine loop of interleukin-6/Janus kinases (JAK)/STAT3 plays a role in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance in EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In this phase 1b study, the JAK1/2 and TANK-binding kinase 1 (TBK1) inhibitor momelotinib was evaluated in combination with erlotinib in patients with EGFR TKI-naive, EGFR-mutated NSCLC. After erlotinib lead-in (50, 75, 100, or 150 mg oral daily [QD]), momelotinib was combined and dose escalated in a 3 + 3 study design. The primary endpoint of maximum tolerated dose (MTD) of momelotinib was determined based on the incidence of dose-limiting toxicities (DLTs) during the first 28-day cycle. Secondary endpoints included efficacy and pharmacokinetics (PK). RESULTS: Eleven patients were enrolled across 3 dose levels of momelotinib (100 mg QD, 200 mg QD, and 100 mg twice daily [BID]). The MTD was momelotinib 200 mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100 mg BID. Most common treatment-emergent adverse events included diarrhea, dry skin, fatigue, and decreased appetite; the vast majority being grades 1-2. The overall response rate was 54.5% (90% CI 27.1-80.0; all partial) and median progression-free survival was 9.2 months (90% CI 6.2-12.4). Momelotinib did not affect the PK of erlotinib. CONCLUSIONS: The JAK1/2 and TBK1 inhibitor momelotinib in combination with erlotinib did not appear to enhance benefit over the historical data of erlotinib monotherapy in patients with EGFR-mutated NSCLC. CLINICALTRIALS. GOV IDENTIFIER: NCT02206763.

IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC.

INTRODUCTION: We report the final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP [experimental arm]) and OS data with approximately 39.8 months of median follow-up with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) versus bevacizumab-carboplatin-paclitaxel (BCP) in chemotherapy-naive patients with metastatic nonsquamous NSCLC in the phase 3 IMpower150 study (NCT02366143). METHODS: In this randomized, open-label study (N = 1202), coprimary end points included investigator-assessed progression-free survival and OS in intention-to-treat (ITT) wild-type (WT; no EGFR or ALK alterations) patients. Secondary and exploratory end points included OS in ITT and programmed death-ligand 1 (PD-L1) subgroups defined by the VENTANA SP142 and SP263 immunohistochemistry assays. RESULTS: At the final analysis with ACP versus BCP (data cutoff: September 13, 2019; minimum follow-up: 32.4 mo), ACP had numerical, but not statistically significant, improvements in OS (ITT-WT: median OS = 19.0 versus 14.7 mo; hazard ratio = 0.84; 95% confidence interval: 0.71-1.00). OS benefit was sustained with ABCP versus BCP (ITT-WT: 19.5 versus 14.7 mo; hazard ratio = 0.80; 95% confidence interval: 0.67-0.95). Exploratory analyses in the SP142-defined PD-L1 subgroups revealed longer median OS with ABCP and ACP versus BCP in PD-L1-high and PD-L1-positive subgroups; in the PD-L1-negative subgroups, median OS was similar with ACP and ABCP versus BCP. Safety was consistent with that in earlier analyses (data cutoff: January 22, 2018). CONCLUSIONS: At the final IMpower150 OS analysis, ACP had numerical, but not statistically significant, OS improvement versus BCP. Updated data with an additional 20 months of follow-up revealed continued OS improvement with ABCP versus BCP in all patients.

Phase 1B Study of Momelotinib Combined With Trametinib in Metastatic, Kirsten Rat Sarcoma Viral Oncogene Homolog-Mutated Non-Small-Cell Lung Cancer After Platinum-Based Chemotherapy Treatment Failure.

INTRODUCTION: Specific treatment options are lacking for Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated non-small-cell lung cancer (NSCLC) despite treatment advances in other mutation-driven subgroups. PATIENTS AND METHODS: In this study we evaluated the multitargeted Janus kinase/TANK-binding kinase 1 (TBK1) inhibitor momelotinib combined with the mitogen/extracellular signal-related kinase (MEK)1/MEK2 inhibitor trametinib in patients with platinum-treated, refractory, metastatic, KRAS-mutated NSCLC. Dose escalations (3 + 3 design) were conducted with momelotinib in combination with trametinib 1.0 mg once daily, then with trametinib in combination with the maximum tolerated dose (MTD) of momelotinib. MTD was determined from dose-limiting toxicity (DLT) during patients' first 28-day cycle. Safety was the primary end point, and efficacy parameters, including disease control rate (DCR) at 8 weeks, were secondary end points. RESULTS: Twenty-one patients were enrolled (median age: 68 years; 14 [66.7%] female). The MTD was momelotinib 150 mg twice daily in combination with trametinib 1.0 mg once daily. DLTs that determined the MTD were increased alanine aminotransferase and fatigue. The most common adverse events of any grade were nausea (n = 14 [66.7%]), diarrhea (n = 11 [52.4%]), and fatigue (n = 11 [52.4%]). The most common Grade ≥3 event was hypoxia (n = 3 [14.3%]). No patients achieved objective response. DCR at 8 weeks was 12 patients (57.1%) (90% confidence interval [CI], 37.2%-75.5%). Median progression-free and overall survival were 3.6 months (90% CI, 2.2-5.6 months) and 7.4 months (90% CI, 4.0-15.3 months), respectively. Maximum momelotinib plasma concentrations were reached 1 to 2 hours after dosing, but were insufficient to achieve significant TBK1 inhibition. CONCLUSION: The additional use of momelotinib with trametinib does not improve on the activity of single-agent trametinib in KRAS-mutated NSCLC on the basis of historic data.

A semiparametric imputation approach for regression with censored covariate with application to an AMD progression study.

This research is motivated by studying the progression of age-related macular degeneration where both a covariate and the response variable are subject to censoring. We develop a general framework to handle regression with censored covariate where the response can be different types and the censoring can be random or subject to (constant) detection limits. Multiple imputation is a popular technique to handle missing data that requires compatibility between the imputation model and the substantive model to obtain valid estimates. With censored covariate, we propose a novel multiple imputation-based approach, namely, the semiparametric two-step importance sampling imputation (STISI) method, to impute the censored covariate. Specifically, STISI imputes the missing covariate from a semiparametric accelerated failure time model conditional on fully observed covariates (Step 1) with the acceptance probability derived from the substantive model (Step 2). The 2-step procedure automatically ensures compatibility and takes full advantage of the relaxed semiparametric assumption in the imputation. Extensive simulations demonstrate that the STISI method yields valid estimates in all scenarios and outperforms some existing methods that are commonly used in practice. We apply STISI on data from the Age-related Eye Disease Study, to investigate the association between the progression time of the less severe eye and that of the more severe eye. We also illustrate the method by analyzing the urine arsenic data for patients from National Health and Nutrition Examination Survey (2003-2004) where the response is binary and 1 covariate is subject to detection limit.

Conditional modeling of longitudinal data with terminal event.

We consider a random effects model for longitudinal data with the occurrence of an informative terminal event that is subject to right censoring. Existing methods for analyzing such data include the joint modeling approach using latent frailty and the marginal estimating equation approach using inverse probability weighting; in both cases the effect of the terminal event on the response variable is not explicit and thus not easily interpreted. In contrast, we treat the terminal event time as a covariate in a conditional model for the longitudinal data, which provides a straight-forward interpretation while keeping the usual relationship of interest between the longitudinally measured response variable and covariates for times that are far from the terminal event. A two-stage semiparametric likelihood-based approach is proposed for estimating the regression parameters; first, the conditional distribution of the right-censored terminal event time given other covariates is estimated and then the likelihood function for the longitudinal event given the terminal event and other regression parameters is maximized. The method is illustrated by numerical simulations and by analyzing medical cost data for patients with end-stage renal disease. Desirable asymptotic properties are provided.

Antimüllerian hormone among women with and without type 1 diabetes: the Epidemiology of Diabetes Interventions and Complications Study and the Michigan Bone Health and Metabolism Study.

OBJECTIVE: To compare concentrations of antimüllerian hormone (AMH) in women with and without type 1 diabetes. DESIGN: Cross-sectional analysis of longitudinal studies, adjusting for repeated measures. SETTING: Not applicable. PATIENT(S): Women aged 30-45 years who had not undergone oophorectomy, hysterectomy, or natural menopause at the time of AMH measurement were included (n = 376 in the Michigan Bone Health and Metabolism Study and n = 321 in the Epidemiology of Interventions and Complications Study). Linear mixed regression was used to evaluate whether AMH concentrations differed by diabetes status, adjusting for repeated measurements of AMH within individual women, body mass index, smoking status, and oral contraceptive use. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of AMH. RESULT(S): In unadjusted comparisons, women with and without diabetes had similar median AMH values before 35 years of age, although women with type 1 diabetes had a lower proportion of women with elevated AMH concentrations (≥5.0 ng/dL). After adjustment for covariates and multiple observations per woman, log AMH concentrations were significantly lower among women with type 1 diabetes compared with women without diabetes (ß-coefficient -1.27, 95% confidence interval [-2.18, -0.36] in fully adjusted models) before 35 years of age. CONCLUSION(S): Before 35 years of age, women with type 1 diabetes have lower AMH levels than women without diabetes. Further investigation is needed to determine the etiologies of this difference and how it may contribute to reproductive disorders among women with type 1 diabetes.

Endogenous Sex Steroid Hormones, Lipid Subfractions, and Ectopic Adiposity in Asian Indians.

BACKGROUND: Estradiol, testosterone (T), and sex hormone binding globulin (SHBG) levels are associated with lipid subfractions in men and women. Our objective was to determine if associations are independent from adipose tissue area among Asian Indians. METHODS: We used data from 42 women and 57 Asian Indian men who did not use exogenous steroids or lipid-lowering medications. Lipoprotein subfractions including low-density lipoprotein cholesterol (LDL), very low-density lipoprotein cholesterol (VLDL), and intermediate density lipoprotein (IDL) were assessed by ion mobility spectrometry. Intra-abdominal adiposity was assessed by computed tomography. Multivariable regression models estimated the association between sex hormones with lipoprotein subfractions before and after adjustment for adiposity. RESULTS: Among women, lower logSHBG levels were associated with smaller logLDL particle size and higher logtriglycerides, logVLDL, and logIDL, although these associations were attenuated with adjustment for visceral adiposity in particular. Among women, lower logSHBG levels was significantly associated with lower logmedium LDL and logsmall LDL concentrations even after consideration of visceral and hepatic adiposity and insulin resistance as represented by the homeostasis model assessment of insulin resistance (HOMA-IR). Among men, lower logSHBG was also associated with smaller logLDL peak diameter size and higher logtriglycerides and logVLDL, even after adjustment for HOMA-IR and adiposity. Relationships between sex steroids and lipid subfractions were not significant among women. Among men, higher total testosterone was associated with higher logHDL and logLDL particle size, and lower logtriglycerides and logVLDL, but these associations were partially attenuated with adjustment for adiposity and HOMA-IR. CONCLUSIONS: Among Asian Indians, SHBG is associated with more favorable lipid subfraction concentrations, independent of hepatic and visceral fat.

Sex differences in the association of fasting and postchallenge glucose levels with grip strength among older adults: the Rancho Bernardo Study.

OBJECTIVE: Persons with diabetes have accelerated muscle loss. The association of fasting and postchallenge glucose levels per se to grip strength, a clinical marker of poor physical function, and potential sex differences in this relationship has not been previously described. DESIGN: Longitudinal cohort. SETTING: USA. PARTICIPANTS: Participants were community-dwelling older adults (mean age 71.3 years) without self-reported diabetes and/or use of diabetes medication with glucose measured at baseline (1992-1996). MEASUREMENTS: Fasting plasma glucose (FPG) was measured in 1019 women and 636 men. Two-hour glucose (2HG) levels after a 75 g oral glucose tolerance test were also available (women, n=870; men, n=559). Dominant hand grip strength was assessed using a hand-held dynamometer at 3.0±1.6 visits over a median 7.0 years. Mixed linear models examined the association of baseline glucose levels with grip strength, accounting for repeated visits, and adjusting for covariates. RESULTS: Sex-specific FPG quartiles were associated with unadjusted differences in grip strength among women (p=0.03) but not men (p=0.50). However, in men, adjusting for age, education, height, weight, peripheral neuropathy, physical activity, and comorbidities, each SD (SD=17 mg/dL) higher FPG was associated with persistently lower grip strength (-0.44±0.22 kg, p=0.049); 2HG (SD=50 mg/dL) was unrelated to grip strength (-0.39±0.25 kg, p=0.13). In women, neither FPG (SD=16 mg/dL) nor 2HG (SD=45 mg/dL) was associated with grip strength (0.02±0.12 kg, p=0.90; and -0.20±0.14 kg, p=0.14; respectively) after adjustment. The rate of change in grip strength did not differ across FPG or 2HG quartiles in either sex. CONCLUSIONS: In age-adjusted analyses, elevated fasting glucose levels are associated with persistently lower grip strength in older men, but not women. Future studies are needed to elucidate reasons for these sex differences and may provide further insight into accelerated loss of muscle function as a complication of diabetes in older adults.

Weight loss increases follicle stimulating hormone in overweight postmenopausal women [corrected].

OBJECTIVES: To examine the impact of a weight loss intervention upon follicle stimulating hormone (FSH) levels in postmenopause. METHODS: Participants were postmenopausal, overweight, glucose-intolerant women not using exogenous estrogen (n = 382) in the Diabetes Prevention Program. Women were randomized to intensive lifestyle change (ILS) with the goals of weight reduction of at least 7% of initial weight and 150 min per week of moderate-intensity exercise, metformin 850 mg twice a day, or placebo administered twice a day. RESULTS: Randomization to ILS led to small increases in FSH between baseline and 1-year follow-up vs. placebo (2.3 IU/l vs. -0.81 IU/l, P < 0.01). Increases in FSH were correlated with decreases in weight (r = -0.165, P < 0.01) and estradiol (E2) (r = -0.464, P < 0.0001) after adjustment for age, race/ethnicity, and randomization arm. Changes in FSH were still significantly associated with changes in weight even after adjustment for E2 levels. Metformin users had reductions in weight but non-significant changes in FSH and E2 levels vs. placebo. CONCLUSIONS: Weight loss leads to small increases in FSH among overweight, postmenopausal women, potentially through pathways mediated by endogenous estrogen as well as other pathways.

Reproductive history and chronic hepatic steatosis in the Michigan Study of Women's Health Across the Nation.

BACKGROUND: Reproductive history, particularly maternal age at most recent birth, may reflect lower risk for chronic disease and mortality due to socioeconomic factors, lifestyle behaviors, or genetics. Reproductive history has not been examined with respect to hepatic steatosis, the most common liver disease in the United States. Our objective was to examine the association between reproductive history and hepatic steatosis. METHODS: We examined the association between reproductive history characteristics--specifically age at most recent birth--and the odds of moderate to severe hepatic steatosis using a population-based retrospective cohort study of women who underwent hepatic ultrasound at the Michigan site of the Study of Women's Health Across the Nation (n=331). RESULTS: Women who gave birth at ≥ 35 years of age comprised 19% of the study population and were similar to other women regarding sociodemographic history and health behaviors. In multivariable analyses adjusting for age, race/ethnicity, chronic disease, and medications associated with hepatic steatosis, age at birth ≥ 35 years was associated with significantly decreased odds of hepatic steatosis (adjusted odds ratio [OR] 0.41, 95% confidence interval [CI] 0.20-0.87), which was attenuated after adjustment for waist circumference (OR 0.51, 95% CI 0.24-1.10). Other reproductive factors including gravidity, parity, miscarriages and abortions, recall of gestational weight gain, breastfeeding, age at first birth, and age at final menstrual period were not associated with hepatic steatosis. CONCLUSIONS: Women who were older at their most recent birth had a reduced odds of hepatic steatosis, possibly associated with their lower waist circumference.

Non-Asymptotic Oracle Inequalities for the High-Dimensional Cox Regression via Lasso.

We consider finite sample properties of the regularized high-dimensional Cox regression via lasso. Existing literature focuses on linear models or generalized linear models with Lipschitz loss functions, where the empirical risk functions are the summations of independent and identically distributed (iid) losses. The summands in the negative log partial likelihood function for censored survival data, however, are neither iid nor Lipschitz.We first approximate the negative log partial likelihood function by a sum of iid non-Lipschitz terms, then derive the non-asymptotic oracle inequalities for the lasso penalized Cox regression using pointwise arguments to tackle the difficulties caused by lacking iid Lipschitz losses.

Does hormone therapy affect blood pressure changes in the Diabetes Prevention Program?

OBJECTIVE: This study aims to examine whether blood pressure reductions differ by estrogen use among overweight glucose-intolerant women. METHODS: We conducted a secondary analysis of Diabetes Prevention Program postmenopausal participants who used oral estrogen with or without progestogen at baseline and 1-year follow-up (n = 324) versus those who did not use oral estrogen with or without progestogen at either time point (n = 382). Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were examined by randomization arm (intensive lifestyle change [ILS], metformin 850 mg twice daily, or placebo). Associations between changes in blood pressure and changes in sex hormone-binding globulin, estradiol, testosterone, and dehydroepiandrosterone were also examined. RESULTS: Estrogen users and nonusers had similar prevalences of baseline hypertension (33% vs 34%, P = 0.82) and use of blood pressure medications at baseline (P = 0.25) and on follow-up (P = 0.10). Estrogen users and nonusers randomized to ILS had similar decreases in SBP (-3.3 vs -4.7 mm Hg, P = 0.45) and DBP (-3.1 vs -4.7 mm Hg, P = 0.16). Among estrogen users, women randomized to ILS had significant declines in SBP (P = 0.016) and DBP (P = 0.009) versus placebo. Among nonusers, women randomized to ILS had significant declines in DBP (P = 0.001) versus placebo, but declines in SBP were not significant (P = 0.11). Metformin was not associated with blood pressure reductions versus placebo regardless of estrogen therapy. Blood pressure changes were not associated with changes in sex hormones regardless of estrogen therapy. CONCLUSIONS: Among overweight women with dysglycemia, the magnitude of blood pressure reductions after ILS is unrelated to postmenopausal estrogen use.

Sex steroid levels and response to weight loss interventions among postmenopausal women in the diabetes prevention program.

OBJECTIVES: To examine whether estrogen use potentiates weight loss interventions via sex steroid levels and whether endogenous sex steroid levels predict response to weight loss interventions among women not using estrogen. METHODS: The Diabetes Prevention Program randomized overweight or obese dysglycemic participants to lifestyle change with the goals of weight reduction of >7% of initial weight and 150 minutes per week of exercise, metformin, or placebo. In this secondary analysis, we examined sex steroid levels and reductions in weight and waist circumference (WC) among postmenopausal women using (n = 324) and not using (n = 382) oral estrogen. RESULTS: Estrogen users and nonusers randomized to lifestyle change and metformin both lost significant amounts of weight compared to placebo. Reductions in weight and WC over 1 year associated with randomization arm were not associated with baseline sex steroid levels among estrogen users or nonusers. CONCLUSIONS: Among estrogen users, baseline sex steroids were not associated with reductions in weight or WC, suggesting that exogenous estrogen does not potentiate weight loss by altering sex steroids. Among nonestrogen users, baseline sex steroids were not associated with reductions in weight or WC.

Sex hormone binding globulin and sex steroids among premenopausal women in the diabetes prevention program.

CONTEXT: It is unknown whether intensive lifestyle modification (ILS) or metformin changes sex steroids among premenopausal women without a history of polycystic ovarian syndrome (PCOS). OBJECTIVES: We examined 1-year intervention impact on sex steroids (estradiol, testosterone, dehydroepiandrosterone, and androstenedione [A4]) and SHBG and differences by race/ethnicity. PARTICIPANTS: A subgroup of Diabetes Prevention Program participants who were premenopausal, not using estrogen, without a history of PCOS or irregular menses, and who reported non-Hispanic white (NHW), Hispanic, or African-American race/ethnicity (n = 301). INTERVENTIONS: Randomization arms were 1) ILS with the goals of weight reduction of 7% of initial weight and 150 minutes per week of moderate intensity exercise, 2) metformin 850 mg twice a day, or 3) placebo. RESULTS: Neither intervention changed sex steroids compared to placebo. ILS, but not metformin, increased median SHBG by 3.1 nmol/L (~11%) compared to decreases of 1.1 nmol/L in the placebo arm (P < .05). This comparison remained significant after adjustment for changes in covariates including waist circumference. However, associations with glucose were not significant. Median baseline A4 was lower in Hispanics compared to NHWs (5.7 nmol/L vs 6.5 nmol/L, P < .05) and increases in A4 were greater in Hispanics compared to NHWs (3.0 nmol/ vs 1.2 nmol/L, P < .05), and these differences did not differ significantly by intervention arm. No other racial/ethnic differences were significant. CONCLUSIONS: Among premenopausal glucose-intolerant women, no intervention changed sex steroids. ILS increased SHBG, although associations with glucose were not significant. SHBG and sex steroids were similar by race/ethnicity, with the possible exception of lower baseline A4 levels in Hispanics compared to NHWs.

The association of elective hormone therapy with changes in lipids among glucose intolerant postmenopausal women in the diabetes prevention program.

OBJECTIVE: It is unclear how lipids change in response to lifestyle modification or metformin among postmenopausal glucose intolerant women using and not using hormone therapy (HT). We examined the one-year changes in lipids among postmenopausal, prediabetic women in the Diabetes Prevention Program (DPP), and whether changes were mediated by sex hormones. MATERIALS/METHODS: We performed a secondary analysis of a randomized controlled trial of 342 women who used HT at baseline and year 1 and 382 women who did not use HT at either time point. Interventions included intensive lifestyle (ILS) with goals of weight reduction of at least 7% of initial weight and 150 minutes per week of moderate intensity exercise, or metformin or placebo administered 850 mg up to twice a day. Women were not randomized to HT. Main outcome measures were changes between baseline and study year 1 in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. RESULTS: Compared to placebo, both ILS and metformin significantly reduced LDL-C and raised HDL-C among HT users, changes partially explained by change in estradiol and testosterone but independent of changes in waist circumference and 1/fasting insulin. In contrast, DPP interventions had no effect on LDL-C and HDL-C among non-HT users. ILS significantly lowered triglycerides among non-users but did not significantly change triglycerides among HT users. Metformin did not significantly change triglycerides among non-users but increased triglycerides among HT users. CONCLUSIONS: The beneficial effects of ILS and metformin on lowering LDL-C and raising HDL-C differ depending upon concurrent HT use.

Reductions in glucose among postmenopausal women who use and do not use estrogen therapy.

OBJECTIVE: Among postmenopausal women who do not use estrogen therapy (ET), we have previously reported that intensive lifestyle modification (ILS) leads to increases in sex hormone-binding globulin (SHBG) and that such increases are associated with reductions in fasting plasma glucose (FPG) and 2-hour postchallenge glucose (2HG). Oral ET decreases FPG and increases 2HG while increasing both SHBG and estradiol (E2). It is unknown if ILS reduces glucose among ET users, if changes in SHBG and E2 might mediate any glucose decreases in ET users, and if these patterns differ from those in non-ET users. METHODS: We conducted a secondary analysis of postmenopausal women in the Diabetes Prevention Program who used ET at baseline and 1-year follow-up (n = 324) and who did not use ET at either time point (n = 382). Participants were randomized to ILS, metformin, or placebo administered at 850 mg BID. RESULTS: ET users were younger, more often white, and more likely to have had bilateral oophorectomy than non-ET users. Among ET users, ILS reduced FPG (P < 0.01) and 2HG (P < 0.01), and metformin reduced FPG (P < 0.01) but not 2HG (P = 0.56), compared with placebo. Associations between SHBG and total E2 with FPG and 2HG were not significant among women randomized to ILS or metformin. These patterns differed from those observed among women who did not use ET. CONCLUSIONS: We conclude that among glucose-intolerant ET users, interventions to reduce glucose are effective but possibly mediated through different pathways than among women who do not use ET.

Racial/ethnic differences in sex hormone levels among postmenopausal women in the diabetes prevention program.

CONTEXT: Sex hormones may differ by race/ethnicity in postmenopausal women. Whether racial/ethnic differences also exist among those who are overweight and glucose intolerant is not clear. OBJECTIVES: The objective of the study was to compare sex hormones by race/ethnicity [non-Hispanic white (NHW), Hispanic, African-American (AA)] in overweight, glucose-intolerant, postmenopausal women. DESIGN: This was a secondary analysis of a randomized controlled trial. PARTICIPANTS: Participants included postmenopausal glucose-intolerant women participating in the Diabetes Prevention Program. INTERVENTIONS: Interventions included intensive lifestyle modification (consisting of diet and physical activity) or metformin 850 mg twice a day vs. placebo. MAIN OUTCOME MEASURES: Baseline levels and 1-yr intervention-related changes in SHBG, total and bioavailable estradiol (E2), total and bioavailable testosterone, and dehydroepiandrosterone were measured. RESULTS: At baseline, among women not using estrogen (n = 370), NHW had higher total and bioavailable E2 and testosterone levels than Hispanics independent of age, type of menopause, waist circumference, alcohol intake, and current smoking. NHW also had higher levels of bioavailable E2 and lower levels of SHBG than AA. At baseline, among estrogen users (n = 310), NHW had higher total and bioavailable E2 than Hispanics and higher levels of SHBG than AA after adjustment. At 1 yr, among women not using estrogen, NHW had larger declines in total E2 and bioavailable E2 levels than AA after adjustment for the above covariates, changes in waist circumference, and randomization arm. At 1 yr, among estrogen users, sex hormone changes did not differ by race/ethnicity. CONCLUSIONS: Among postmenopausal women, there were significant race/ethnicity differences in baseline sex hormones and changes in sex hormones.

Endogenous sex hormone changes in postmenopausal women in the diabetes prevention program.

CONTEXT: Whether endogenous sex hormones (ESH) [SHBG, estradiol, testosterone, and dehydroepiandrosterone (DHEA)] are altered by intensive lifestyle modification (ILS) or metformin and whether such changes affect glucose levels among dysglycemic postmenopausal women is unclear. OBJECTIVES: Our objective was to examine intervention impact on ESH and associations with fasting plasma glucose (FPG) and 2-h glucose changes among postmenopausal glucose-intolerant women. DESIGN: We performed a secondary analysis of a randomized controlled trial. PARTICIPANTS: Participants included postmenopausal, overweight, glucose-intolerant women not using exogenous estrogen (n = 382) who participated in the Diabetes Prevention Program. INTERVENTIONS: Interventions included ILS with the goals of weight reduction of at least 7% of initial weight and 150 min/wk of moderate intensity exercise or metformin or placebo administered 850 mg twice a day. MAIN OUTCOME MEASURES: Intervention-related changes in ESH and associations of changes in ESH and glucose levels were evaluated. RESULTS: ILS significantly increased SHBG and decreased DHEA before and after adjustment for changes in waist circumference and fasting insulin. ILS did not alter estradiol or testosterone. Metformin did not change any ESH. ILS-induced increases in SHBG and declines in DHEA were associated with decreases in FPG and 2-h glucose, and declines in estradiol were associated with decreases in FPG, before and after adjustment for age, FSH, race/ethnicity, changes in waist circumference, and 1/fasting insulin. CONCLUSIONS: Among postmenopausal glucose-intolerant women not using estrogen, ILS increased SHBG levels and lowered DHEA levels. These changes were associated with lower glucose independent of adiposity and insulin. Metformin effects upon ESH were not significant.

Changes in iron measures over menopause and associations with insulin resistance.

OBJECTIVES: No longitudinal studies have examined how iron measures change over menopause. Our objectives were to examine iron measures in individual women at premenopause and at postmenopause and, secondarily, to determine if any changes contributed to insulin resistance. METHODS: In a subset of participants (n=70) in a longitudinal study of menopause, we measured ferritin, transferrin, and soluble transferrin receptor (sTfR) once in the premenopause and once in the postmenopause. We also examined associations between menopausal status and change in iron markers after adjustment for age at menopause, race/ethnicity, and waist circumference. In linear regression models, we examined associations between premenopause iron measures and changes in iron markers over menopause with homeostasis model assessment of insulin resistance (HOMA-IR) changes over menopause, before and after adjustment for age at menopause, race/ethnicity, changes in waist circumference, C-reactive protein (CRP), and sex hormone-binding globulin (SHBG) levels. RESULTS: Women had lower ferritin (p<0.01), higher sTfR:ferritin levels (p<0.01), lower HOMA-IR (p=0.022), and lower glucose (p=0.05) in premenopause compared to postmenopause. After adjustment, lower premenopausal iron levels (sTfR:ferritin levels ß=11.0, 95% confidence interval [CI] 0.017-22.0) and larger increases in iron over menopause (changes in sTfR:ferritin ß=13.6, 95% CI 0.93-26.3) were associated with larger increases in HOMA-IR. CONCLUSIONS: From premenopause to postmenopause, women on average have increases in measures of iron stores. Women who had the greatest changes in iron over menopause (lower measures of premenopausal iron and greater increases in iron measures over the menopause) had the strongest associations between changes in iron and changes in insulin resistance.