Caloric Restriction, Environment, and Fitness: Reproductive Effects Evaluation Study (CaREFREE Study)

热量限制、环境和健康：生殖影响评估研究（CaREFREE 研究）

基本信息

批准号：
10928607
负责人：
Janet Hall
金额：
$ 27.86万
依托单位：
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10928607
关键词：
Acute Adipose tissue Affect Age Algorithms Amenorrhea Anovulation Attitude Biochemical Markers Biological Markers Body Composition Body Weight decreased Body mass index Breast Feeding Caloric Restriction Cerebrospinal Fluid Characteristics Chronic Clinical Clinical Markers Conjugated Estrogens Controlled Study Cross-Sectional Studies Delayed Puberty Desire for food Dose Energy Intake Energy Metabolism Environment Equilibrium Etiology Evaluation Studies Exercise Exposure to Family Family history of Fasting Follow-Up Studies Frequencies Functional disorder GNRH1 gene Glucose Goals Gonadotropins Height Homeostasis Hormone secretion Hydrocortisone Hypothalamic structure Individual Infertility Insulin Intake Intervention Intervention Studies Interview Laboratories Length Leptin Life Style Link Longterm Follow-up Luteal Phase Manuscripts Measures Mediating Medical History Menarche Menstrual cycle Metabolic Metabolic hormone Metabolism Mutation Neurons Neurosecretory Systems Nutritional Outcome Measure Ovulation Oxygen Consumption Parents Pathway interactions Patients Physiologic pulse Pituitary Gland Plasma Play Predictive Factor Predisposition Pregnancy Pregnanediol Questionnaires Recording of previous events Regulation Reproduction Reproductive History Rest Risk Role Sampling Satiation Serum Signal Transduction Sleep Somatotropin Stomach Stress System Thyroid Function Tests Thyroid Hormones Urine VO2max Visit Woman adipokines adiponectin college deprivation dietary energy balance environmental stressor fitness ghrelin hormonal signals improved lean body mass men nutrition peptide hormone physiologic stressor primary outcome proliferative phase Menstrual cycle receptor reproductive reproductive axis reproductive function response restrictive eating secondary outcome stressor young woman

项目摘要

The classic interventional studies of Bullen et al demonstrated that in normal women with no history of cycle irregularity a significant increase in exercise could induce menstrual cycle dysfunction ranging from short or inadequate luteal phases to anovulation and amenorrhea, which is termed hypothalamic amenorrhea (HA). This study also showed that the combination of weight loss and exercise was more deleterious than exercise alone. While the conclusions of this study focused on the role of exercise and nutrition, it is likely that some degree of stress also contributed to the findings as the study was conducted at a camp and changes in living situations per se are associated with the onset cycle disturbances, with the classic example being young women in their freshman year in college. The association of increased exercise and decreased nutritional intake was confirmed in multiple other cross-sectional studies. Loucks and colleagues quantified the interaction between energy intake and energy expenditure that resulted in disrupted GnRH secretion. The authors developed the concept of energy availability which they defined as dietary energy intake minus exercise energy expenditure. In well-controlled studies in a laboratory setting they demonstrated a threshold of energy availability at which pulsatile LH secretion, used as a marker of GnRH pulse frequency, was altered in healthy women who had undergone 5 days of decreased energy availability during their early follicular phase (EFP). In these studies, LH pulse decreased in conjunction with an energy availability of 20 and 10 kcal/kg lean body mass per day (LBM*day) compared with neutral energy availability of 45 kcal/kg LBM*day or 30 kcal/kg LBM*day 67. Further studies showed exposure to energy intakes of 0%, -8%, -22% and -42% over 3 months was associated with menstrual cycle disruption in the form of inadequate luteal phases, intermittent ovulation and amenorrhea. Taken together, these studies suggest that the change in LH pulse frequency with short-term energy deprivation predicts menstrual cycle disturbance when energy deprivation is more chronic although the minimum degree of chronic energy deficit required for cycle disturbance (-22%) may be less than would have been predicted by the short-term energy deficit studies and thus. the results of short-term studies would provide a conservative marker of potential risk. Mechanisms Linking Decreased Energy Availability and Stress to Inhibition of GnRH Decreased Energy Availability - The primary function of the hypothalamus is the regulation of homeostasis. In the setting of decreased energy availability, due to a nutritional deficit or an increase in energy expenditure, conservation of energy is achieved by hypothalamic coordination of various neuroendocrine axes to redirect the available energy towards the crucial systems for survival. Moreover, the magnitude of energy deficit is more predictive of suppression of reproductive function than weight loss per se. It is well documented in women that reproductive function is one of the first systems to be suppressed in association with energy deprivation via disruption of GnRH secretion. It is hypothesized that short-term survival is prioritized over reproduction due to the high energy demands of pregnancy and breastfeeding. With energy deprivation, the drive for energy intake is increased while energy expenditure is decreased in an attempt to restore balance. Leptin, ghrelin and adiponectin are highly specific signals that not only signal energy availability at the level of the hypothalamus as part of an adaptive response to restore energy balance, but are also linked to control of GnRH. Leptin provides a crucial link between energy balance and the hypothalamic control of reproduction; however, individual susceptibility of the reproductive axis to absolute leptin concentrations or changes in leptin induced by changes in energy availability has not been determined. Ghrelin, a peptide hormone, is primarily secreted by the stomach, is inversely related to BMI, acts at the hypothalamus to stimulate both appetite and growth hormone secretion, and appears to play a significant role in both short- and long-term regulation of energy homeostasis. Most importantly for this study, ghrelin administration to healthy women results a significant decrease in mean LH and LH pulse frequency, but as for leptin, it is unknown whether absolute ghrelin concentrations or changes in ghrelin induced by changes in energy availability can predict individual susceptibility of the reproductive axis decreased energy availability. Like leptin, adiponectin is adipocytokine secreted by adipose tissue. Adiponectin increases satiety and reduces energy expenditure. Adiponectin receptors are present on GnRH neurons and adiponectin inhibits GnRH secretion and thereby inhibits GnRH-stimulated LH secretion. Adiponectin is not acutely affected by meals and may thus be a more stable biomarker to associate with susceptibility to reduced energy intake. There is now considerable evidence linking activation of neuroendocrine mechanisms by stress to inhibition of reproductive signaling, only some of which is mediated by the inhibitory effects of cortisol on gonadotropin secretion at the pituitary level. Activation of the stress axis as evidenced by increased cortisol is associated with acute energy deprivation in a dose responsive fashion; however this is not the case for more chronic energy deficits. Cortisol levels in serum, urine and cerebral spinal fluid are greater in women with HA compared to normally cycling controls. In a long term follow-up study of women with HA, there was an inverse relationship between circulating cortisol and LH levels and those women who had not recovered reproductive function had significantly higher fasting plasma cortisol levels than those women who had recovered. Cortisol is also increased with exercise and is highest in exercising amenorrheic women. Cortisol and leptin are inversely related in HA, however leptin administration caused no change in cortisol levels in healthy men and significantly improves reproductive function in women, with no change in cortisol levels. There is, thus, considerable information implicating stress pathways in the etiology of HA. In addition, stress pathways may also be involved in inhibitory effects of nutritional deficits on central reproductive function. Other hormonal signals that appear to be involved in linking metabolism to reproduction include the thyroid hormone axis and insulin. There are a number of manuscripts being prepared for submission: 1. Caloric Deprivation Exacerbates the Effect of the Menstrual Cycle on Sleep 2. Metabolic Hormone Homeostasis in Response to Caloric Deprivation 3. Effect of Caloric Restriction on Thyroid Hormone Dynamics

Bullen等人的经典介入研究表明，在没有月经周期不规则史的正常女性中，运动量的显着增加可能会导致月经周期功能障碍，包括黄体期短或不足、不排卵和闭经，称为下丘脑闭经（HA）。这项研究还表明，减肥和运动相结合比单独运动更有害。虽然这项研究的结论集中在运动和营养的作用上，但一定程度的压力也可能对研究结果有所贡献，因为该研究是在营地进行的，而且生活环境本身的变化与周期紊乱的发生有关。，典型的例子是大学一年级的年轻女性。多项其他横断面研究证实了增加运动和减少营养摄入之间的关联。 Loucks 及其同事量化了导致 GnRH 分泌紊乱的能量摄入和能量消耗之间的相互作用。作者提出了能量可用性的概念，他们将其定义为饮食能量摄入减去运动能量消耗。在实验室环境中进行的严格对照研究中，他们证明了健康女性的能量可用性阈值，在该阈值下，脉动 LH 分泌（用作 GnRH 脉冲频率的标志）发生了变化，这些女性在早期卵泡期经历了 5 天的能量可用性下降（EFP）。在这些研究中，与 45 kcal/kg LBM*day 或 30 kcal/kg LBM* 的中性能量可用性相比，LH 脉冲随着每天 20 和 10 kcal/kg LBM*day 的能量可用性而下降。第 67 天。进一步的研究表明，3 个月内能量摄入量为 0%、-8%、-22% 和 -42% 与黄体不足导致的月经周期中断有关阶段，间歇性排卵和闭经。总而言之，这些研究表明，当能量剥夺较长期时，短期能量剥夺引起的 LH 脉冲频率的变化可预测月经周期紊乱，尽管周期紊乱所需的慢性能量缺乏的最小程度 (-22%) 可能小于短期能源赤字研究可以预测到这一点。短期研究的结果将提供潜在风险的保守标记。能量可用性下降和压力降低与 GnRH 抑制相关的机制能量可用性降低 - 下丘脑的主要功能是调节体内平衡。在由于营养不足或能量消耗增加而导致能量可用性下降的情况下，通过下丘脑协调各种神经内分泌轴将可用能量重新定向到生存的关键系统来实现能量保存。此外，能量不足的程度比体重减轻本身更能预测生殖功能的抑制。有充分证据表明，女性的生殖功能是第一个因 GnRH 分泌中断而与能量匮乏相关的系统之一。据推测，由于怀孕和母乳喂养的高能量需求，短期生存优先于繁殖。在能量匮乏的情况下，能量摄入的动力会增加，而能量消耗会减少，以试图恢复平衡。瘦素、生长素释放肽和脂联素是高度特异性的信号，不仅在下丘脑水平发出能量可用性信号，作为恢复能量平衡的适应性反应的一部分，而且还与 GnRH 的控制有关。瘦素在能量平衡和下丘脑生殖控制之间提供了重要的联系。然而，生殖轴对绝对瘦素浓度或能量可用性变化引起的瘦素变化的个体敏感性尚未确定。胃饥饿素是一种肽类激素，主要由胃分泌，与体重指数成反比，作用于下丘脑刺激食欲和生长激素分泌，似乎在短期和长期能量调节中发挥重要作用体内平衡。对于这项研究来说最重要的是，对健康女性施用生长素释放肽会导致平均 LH 和 LH 脉冲频率显着降低，但对于瘦素而言，尚不清楚生长素释放肽绝对浓度或能量可用性变化引起的生长素释放肽变化是否可以预测个体对瘦素的易感性。生殖轴降低了能量的可用性。与瘦素一样，脂联素是脂肪组织分泌的脂肪细胞因子。脂联素可增加饱腹感并减少能量消耗。脂联素受体存在于 GnRH 神经元上，脂联素抑制 GnRH 分泌，从而抑制 GnRH 刺激的 LH 分泌。脂联素不会受到膳食的严重影响，因此可能是与能量摄入减少的易感性相关的更稳定的生物标志物。现在有大量证据表明，压力引起的神经内分泌机制的激活与生殖信号的抑制有关，其中只有一些是由皮质醇对垂体水平促性腺激素分泌的抑制作用介导的。皮质醇增加所证明的应激轴的激活与剂量反应方式的急性能量剥夺有关；然而，对于更长期的能源短缺来说，情况并非如此。与正常骑行者相比，患有HA的女性血清、尿液和脑脊液中的皮质醇水平更高。在一项针对患有HA的女性的长期随访研究中，循环皮质醇和LH水平之间存在负相关关系，那些未恢复生殖功能的女性的空腹血浆皮质醇水平显着高于那些已恢复的女性。皮质醇也会随着运动而增加，并且在运动的闭经女性中最高。皮质醇和瘦素在 HA 中呈负相关，但是瘦素给药不会导致健康男性的皮质醇水平发生变化，并且显着改善女性的生殖功能，而皮质醇水平没有变化。因此，有大量信息表明 HA 病因中的应激途径。此外，应激途径也可能参与营养缺乏对中枢生殖功能的抑制作用。其他似乎参与新陈代谢与生殖联系的激素信号包括甲状腺激素轴和胰岛素。有许多手稿正在准备提交： 1.热量缺乏会加剧月经周期对睡眠的影响 2. 热量剥夺时的代谢激素稳态 3. 热量限制对甲状腺激素动态的影响