Dataset Information

Estradiol Priming Improves Gonadotrope Sensitivity and Pro-Inflammatory Cytokines in Obese Women.

ABSTRACT: Obesity is associated with a pro-inflammatory state and relative hypogonadotropic hypogonadism. Estrogen (E2) is a potential link between these phenomena because it exhibits negative feedback on gonadotropin secretion and also inhibits production of pro-inflammatory cytokines.We sought to examine the effect of estrogen priming on the hypothalamic-pituitary-ovarian axis in obesity.This was an interventional study at an academic center of 11 obese and 10 normal-weight (NW) women.A frequent blood-sampling study and one month of daily urinary collection were performed before and after administration of transdermal estradiol 0.1 mg/d for one entire menstrual cycle.Serum LH and FSH before and after GnRH stimulation, and urinary estrogen and progesterone metabolites were measured.E2 increased LH pulse amplitude and FSH response to GnRH (P = .048, and P < .03, respectively) in obese but not NW women. After E2 priming, ovulatory obese but not NW women had a 25% increase in luteal progesterone (P = .01). Obese women had significantly higher baseline IL-6, IL-10, TGF-?, and IL-12 compared with NW (all P < .05); these levels were reduced after E2 (-6% for IL-1?, -21% for IL-8, -5% for TGF-?, -5% for IL-12; all P < .05) in obese but not in NW women.E2 priming seems to improve hypothalamic-pituitary-ovarian axis function and systemic inflammation in ovulatory, obese women. Reducing chronic inflammation at the pituitary level may decrease the burden of obesity on fertility.

SUBMITTER: Al-Safi ZA

PROVIDER: S-EPMC4702462 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Estradiol Priming Improves Gonadotrope Sensitivity and Pro-Inflammatory Cytokines in Obese Women.

Al-Safi Zain A ZA Liu Huayu H Carlson Nichole E NE Chosich Justin J Lesh Jennifer J Robledo Celeste C Bradford Andrew P AP Gee Nancy A NA Phang Tzu T Santoro Nanette N Kohrt Wendy W Polotsky Alex J AJ

The Journal of clinical endocrinology and metabolism 20151001 11

<h4>Context</h4>Obesity is associated with a pro-inflammatory state and relative hypogonadotropic hypogonadism. Estrogen (E2) is a potential link between these phenomena because it exhibits negative feedback on gonadotropin secretion and also inhibits production of pro-inflammatory cytokines.<h4>Objective</h4>We sought to examine the effect of estrogen priming on the hypothalamic-pituitary-ovarian axis in obesity.<h4>Design, setting, and participants</h4>This was an interventional study at an ac ...[more]

PMID: 26425884

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Project description:BACKGROUND:Posttraumatic stress disorder (PTSD) is associated with disturbed sleep and elevated levels of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Studies in animals and healthy humans have also shown that disrupted sleep elevates pro-inflammatory cytokines, including IL-6 and TNF-α. A better understanding of overnight cytokine levels and sleep might shed light on possible mechanisms for elevated inflammation in PTSD. Thus, we investigated overnight levels of IL-6 and TNF-α in individuals with and without PTSD while recording sleep polysomnography (PSG). METHOD:Serum samples were collected from otherwise healthy, medication-free participants with chronic PTSD (n = 44; 50% female; M age = 30.34 ± 8.11) and matched controls (n = 49; 53% female; M age = 30.53 ± 6.57) during laboratory PSG. Levels of IL-6 and TNF-α were measured at hours 0, 2, 4, 6, and 8 after typical sleep onset time using serial serum samples. Plasma IL-6 and TNF-α levels were quantified using enzyme-linked immunosorbent assays. RESULTS:Growth model analysis indicated a significantgroup by time interaction for IL-6 (t[247] = -2.92, p = .005) and a significant group by sex by time interaction for TNF-α (t[275] = 2.02, p = .04). PTSD positive men and women initially had higher IL-6 and TNF-α at sleep onset, but not at the end of their sleep cycle. Men with PTSD showed a peak of TNF-α at the end of the sleep cycle, whereas male control subjects demonstrated an inverted U-shaped profile. There were no significant differences in TNF-α levels overnight between women with and without PTSD. CONCLUSION:To our knowledge, this is the largest study to examine IL-6 overnight in a PTSD sample and the first study to examine overnight TNF-α in PTSD. Overnight IL-6 and TNF-α levels may be altered in individuals with PTSD compared to those without PTSD, and TNF-α trajectories also differed by sex. The current findings highlight the need to consider sex, sleep, time of day, and circadian variation when examining inflammation in PTSD. Additional research in broader study samples will be necessary to clarify associations between disrupted sleep, cytokines, and increased risk for disease in PTSD.

Project description:BackgroundOverweight and obese (OW/OB) body mass index (BMI) is associated with greater inflammation and poorer outcomes in breast cancer (BC). Stress management interventions using cognitive behavioral therapy (CBT) and relaxation training (RT) have reduced inflammation in BC patients but have not been tested specifically in OW/OB patients undergoing primary treatment. We developed brief CBT and RT-based group interventions and tested their effects (vs time-matched Health Education [HE] control) on serum inflammatory cytokines (IL-6, IL-1β and TNF-α) in OW/OB vs normal weight (NW) BC patients during primary treatment. We hypothesized OW/OB women would show higher levels of inflammatory cytokines, and that stress management would decrease these cytokines more in OW/OB women than in NW women.MethodsStage 0 - III BC patients were enrolled post-surgery and before initiating adjuvant therapy, were randomized to either 5 weeks of CBT, RT, or HE, and provided questionnaires and blood samples at baseline and 6-months. Serum cytokine levels were measured by ELISA. Repeated measures analysis of variance tested the interaction of condition by BMI by time in predicting cytokine levels over 6 months, controlling for age, stage, ethnicity, and income.ResultsThe sample (N = 153) majority was OW/OB (55.6%). We found differences in baseline IL-6 and IL-1β across BMI categories, with greater IL-6 (p < 0.005) and IL-1β (p < 0.04) in OW and OB vs NW women, but no difference between OW and OB women. There were no differences in baseline TNF-α among BMI groups. BMI category moderated the effect of brief stress management interventions on IL-6 changes over 6-months (p = 0.028): CBT/RT vs HE decreased IL-6 in OW/OB (p = 0.045) but not in NW patients (p = 0.664). There were no effects on IL-1β or TNF-α. Results could not be explained by differences in receipt of adjuvant therapy, prescription medications, or changes in physical activity.ConclusionsOW/OB women with newly diagnosed BC had significantly greater serum IL-6 and IL-1β than NW women post-surgery. Brief stress management delivered with primary treatment among OW/OB patients may reduce the increases in inflammatory markers known to accompany adjuvant treatments and could thus promote better outcomes.Clinical trial registrationNCT02103387.

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Project description:BackgroundUdder infections with environmental pathogens like Escherichia coli are a serious problem for the dairy industry. Reduction of incidence and severity of mastitis is desirable and mild priming of the immune system either through vaccination or with low doses of immune stimulants such as lipopolysaccharide LPS was previously found to dampen detrimental effects of a subsequent infection. Monocytes/macrophages are known to develop tolerance towards the endotoxin LPS (endotoxin tolerance, ET) as adaptation strategy to prevent exuberant inflammation.We have recently observed that infusion of 1 μg of LPS into the quarter of an udder effectively protected for several days against an experimentally elicited mastitis. We have modelled this process in primary cultures of mammary epithelial cells (MEC) from the cow. MEC are by far the most abundant cells in the healthy udder coming into contact with invading pathogens and little is known about their role in establishing ET.ResultsWe primed primary MEC cultures for 12 h with LPS (100 ng/ml) and stimulated three cultures either 12 h or 42 h later with 107/ml particles of heat inactivated E. coli bacteria for six hours. Priming-related alterations in the global transcriptome of those cells were quantified with Affymetrix microarrays. LPS priming alone caused differential expression of 40 genes and mediated significantly different response to a subsequent E. coli challenge of 226 genes. Expression of 38 genes was enhanced while that of 188 was decreased. Higher expressed were anti-microbial factors (β-defensin LAP, SLPI), cell and tissue protecting factors (DAF, MUC1, TGM1, TGM3) as well as mediators of the sentinel function of MEC (CCL5, CXCL8). Dampened was the expression of potentially harmful pro-inflammatory master cytokines (IL1B, IL6, TNF-α) and immune effectors (NOS2, matrix metalloproteases). Functional network analysis highlighted the reduced expression of IL1B and of IRF7 as key to this modulation.ConclusionLPS-primed MEC are fitter to repel pathogens and better protected against misguided attacks of the immune response. Attenuated is the exuberant expression of factors potentially promoting immunopathological processes. MEC therefore recapitulate many aspects of ET known so far from professional immune cells.

Dataset Information

Estradiol Priming Improves Gonadotrope Sensitivity and Pro-Inflammatory Cytokines in Obese Women.

Publications

Estradiol Priming Improves Gonadotrope Sensitivity and Pro-Inflammatory Cytokines in Obese Women.

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