Expanding the Concept of Translational Research: Making a Place for Environmental Health Sciences.

SUMMARY: The National Institute of Environmental Health Sciences (NIEHS) introduces a new translational research framework that builds upon previous biomedical models to create a more comprehensive and integrated environmental health paradigm. The framework was developed as a graphical construct that illustrates the complexity of designing, implementing, and tracking translational research in environmental health. We conceptualize translational research as a series of concentric rings and nodes, defining "translation" as movement either from one ring to another or between nodes on a ring. A "Fundamental Questions" ring expands upon the research described in other frameworks as "basic" to include three interrelated concepts critical to basic science research: research questions, experimental settings, and organisms. This feature enables us to capture more granularity and thus facilitates an approach for categorizing translational research and its growth over time. We anticipate that the framework will help researchers develop compelling long-term translational research stories and accelerate public health impacts by clearly mapping out opportunities for collaborations. By using this paradigm, researchers everywhere will be better positioned to design research programs, identify research partners based on cross-disciplinary research needs, identify stakeholders who are likely to use the research for environmental decision-making and intervention, and track progress toward common goals. https://doi.org/10.1289/EHP3657.

Endocrinology of the Menopause.

In women, age-related changes in ovarian function begin in the mid-30s with decreased fertility and compensatory hormonal changes in the hypothalamus-pituitary-gonadal axis that maintain follicle development and estrogen secretion in the face of a waning pool of ovarian follicles. The menopause transition is characterized by marked variability in follicle development, ovulation, bleeding patterns, and symptoms of hyper- and hypoestrogenism. The menopause, which is clinically defined by the last menstrual period, is followed by the consistent absence of ovarian secretion of estradiol.

Metabolic activity in the insular cortex and hypothalamus predicts hot flashes: an FDG-PET study.

CONTEXT: Hot flashes are a common side effect of adjuvant endocrine therapies (AET; leuprolide, tamoxifen, aromatase inhibitors) that reduce quality of life and treatment adherence in breast cancer patients. Because hot flashes affect only some women, preexisting neurobiological traits might predispose to their development. Previous studies have implicated the insula during the perception of hot flashes and the hypothalamus in thermoregulatory dysfunction. OBJECTIVE: The aim of the study was to understand whether neurobiological factors predict hot flashes. DESIGN: [18F]-Fluorodeoxyglucose (FDG) positron emission tomography (PET) brain scans coregistered with structural magnetic resonance imaging were used to determine whether metabolic activity in the insula and hypothalamic thermoregulatory and estrogen-feedback regions measured before and in response to AET predict hot flashes. Findings were correlated with CYP2D6 genotype because of CYP2D6 polymorphism associations with tamoxifen-induced hot flashes. OUTCOME MEASURES: We measured regional cerebral metabolic rate of glucose uptake (rCMRglu) in the insula and hypothalamus on FDG-PET. RESULTS: Of 18 women without hot flashes who began AET, new-onset hot flashes were reported by 10 (55.6%) and were detected objectively in nine (50%) participants. Prior to the use of all AET, rCMRglu in the insula (P ≤ 0.01) and hypothalamic thermoregulatory (P = 0.045) and estrogen-feedback (P = 0.007) regions was lower in women who reported developing hot flashes. In response to AET, rCMRglu was further reduced in the insula in women developing hot flashes (P ≤ 0.02). Insular and hypothalamic rCMRglu levels were lower in intermediate than extensive CYP2D6 metabolizers. CONCLUSIONS: Trait neurobiological characteristics predict hot flashes. Genetic variability in CYP2D6 may underlie the neurobiological predisposition to hot flashes induced by AET.

Inverse relationship between luteinizing hormone and body mass index in polycystic ovarian syndrome: investigation of hypothalamic and pituitary contributions.

CONTEXT: Patients with polycystic ovarian syndrome (PCOS) have increased LH relative to FSH, but LH is modified by body mass index (BMI). OBJECTIVE: The objective of the study was to determine whether the impact of BMI on neuroendocrine dysregulation in PCOS is mediated at the hypothalamic or pituitary level. PARTICIPANTS/INTERVENTIONS/SETTING: Twenty-four women with PCOS across a spectrum of BMIs underwent frequent blood sampling, iv administration of GnRH (75 ng/kg), and sc administration of the NAL-GLU GnRH antagonist (5 microg/kg) in the General Clinical Research Center at an academic hospital. MAIN OUTCOME MEASURES: LH pulse frequency and LH response to submaximal GnRH receptor blockade were used as measures of hypothalamic function; LH response to GnRH was used as a measure of pituitary responsiveness. RESULTS: BMI was negatively correlated with mean LH, LH/FSH, and LH pulse amplitude. There was no effect of BMI on LH pulse frequency. Percent inhibition of LH was decreased in PCOS, compared with normal women (53.9 +/- 1.5 vs. 63.1 +/- 4.1, respectively; P < 0.01), suggesting an increase in the amount of endogenous GnRH, but was not influenced by BMI. Pituitary responsiveness to GnRH was inversely correlated with BMI (peak LH, R = -0.475, P < 0.02; and LH area under the curve R = -0.412, P < 0.02). CONCLUSIONS: LH pulse frequency and quantity of GnRH are increased in PCOS, but there is no influence of BMI on either marker of hypothalamic function. The pituitary response to a weight-based dose of GnRH is inversely related to BMI in PCOS. These studies suggest that the effect of BMI on LH is mediated at a pituitary and not a hypothalamic level in PCOS.

Control of follicle-stimulating hormone by estradiol and the inhibins: critical role of estradiol at the hypothalamus during the luteal-follicular transition.

To test the hypothesis that estradiol, inhibin A, and inhibin B contribute differentially to FSH negative feedback in specific phases of the menstrual cycle, daily blood samples were obtained across a control cycle and after selective estrogen blockade with tamoxifen. To examine the site of estradiol-negative feedback in control and tamoxifen treatment cycles, early follicular phase GnRH (free alpha-subunit) pulse frequency was assessed in normal women, and FSH levels were examined in GnRH-deficient women in whom hypothalamic output was fixed with GnRH administration. FSH was higher in the early follicular phase in the presence of estrogen receptor blockade (15.7 +/- 3.1 vs. 13.2 +/- 1.9 IU/liter; P < 0.05) but was not increased in the late follicular phase. In the luteal phase, FSH was elevated (10.1 +/- 0.7 vs. 7.3 +/- 0.6 IU/liter; P < 0.01). In normal women, free alpha-subunit pulse frequency increased (7.3 +/- 0.4 vs. 4.8 +/- 0.4 pulses per 8 h; P < 0.003), but in GnRH-deficient women, there was no FSH increase (11.1 +/- 1.6 vs. 12.5 +/- 3.6 IU/liter) in the early follicular phase in the presence of estrogen blockade. In conclusion, estradiol exerts a greater role over inhibin in FSH-negative feedback regulation during the luteal phase and the luteal-follicular transition. In contrast, inhibin A and/or B plays a more critical role as the follicular phase progresses. In addition, these studies support a primary if not exclusive hypothalamic site of estrogen-negative feedback in the early follicular phase.