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：
10252597
负责人：
Janet Hall
金额：
$ 56.62万
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/10252597
关键词：
Acute Adipose tissue Affect Age Algorithms Amenorrhea Anovulation Attitude Biochemical Markers Biological Markers Body Composition Body Weight decreased Breast Feeding Caloric Restriction Cerebrospinal Fluid Characteristics Chronic Clinical Clinical Markers Conjugated Estrogens Controlled Study Cross-Sectional Studies Delayed Puberty Desire for food Diet 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 energy balance environmental stressor ghrelin hormonal signals improved lean body mass men nutrition peptide hormone physiologic stressor primary outcome proliferative phase Menstrual cycle receptor reproductive reproductive axis reproductive fitness 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，在没有循环不规则史的正常妇女中，运动的显着增加可能会引起月经周期功能障碍，从短期或不足的黄体相和缺乏症和闭经性，这被称为下丘脑闭经（HA）。这项研究还表明，减肥和运动的结合比单独运动更有害。尽管这项研究的结论集中在运动和营养的作用上，但随着研究是在营地进行的，生活情况的变化本身可能与发作周期障碍有关，可能还会导致一定程度的压力。，一个经典的例子是大学一年级的年轻女性。在其他多项横断面研究中，证实了运动增加和营养摄入量减少的关联。 Loucks及其同事量化了导致GNRH分泌破坏的能量摄入与能量消耗之间的相互作用。作者开发了能源可用性的概念，他们将其定义为饮食能量摄入量减去锻炼能量消耗。在实验室环境中良好控制的研究中，他们证明了能量可用性的阈值，在该脉动LH分泌物被用作GnRH脉冲频率的标记中，在早期卵泡期降低能量可用性的健康女性中，其健康女性发生了变化（EFP）。在这些研究中，LH脉冲与每天20 kcal/kg/kg的能量可利用性下降，而中性能量的可利用性为45 kcal/kg lbm*day或30 kcal/kg lbm*，每天降低了20 kcal/kg/kg的瘦体重（LBM*天）。第67天。进一步的研究表明，在3个月内暴露于0％，-8％，-8％，-22％和-42％的能源摄入量与月经周期的破坏相关，以不足的黄体相，间歇性排卵和闭经性。综上所述，这些研究表明，短期能量剥夺的LH脉冲频率变化会预测月经周期扰动时，尽管能量剥夺更慢性，尽管循环干扰所需的最小慢性能量缺陷程度可能小于（-22％）短期的能源不足研究将预测。短期研究的结果将提供潜在风险的保守标志。将能量可利用性降低和应力与GNRH的抑制联系起来的机制能源可利用性降低 - 下丘脑的主要功能是体内平衡的调节。在能源供应减少的情况下，由于营养不足或能源消耗的增加，可以通过下丘脑配位对各种神经内分泌轴的配位来实现能量的保护，以将可用的能量重定向至关键的生存系统。此外，与体重减轻本身相比，能量不足的大小更能预测抑制生殖功能。在女性中，有充分的文献证明，生殖功能是通过破坏GNRH分泌而被抑制能量剥夺的最早抑制系统之一。假设由于怀孕和母乳喂养的高能量需求，短期生存优先于繁殖。随着能源剥夺，能源摄入的动力增加，而能量消耗减少以恢复平衡。瘦素，生长素蛋白和脂联素是高度特异性的信号，不仅是在下丘脑水平上的能量可用性，作为对恢复能量平衡的自适应反应的一部分，而且还与GNRH的控制有关。瘦素在能量平衡与下丘脑繁殖控制之间提供了至关重要的联系。然而，尚未确定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。肽激素的生长素素主要由胃分泌，与BMI成反比，在下丘脑上起作用，以刺激食欲和生长激素分泌，并且在短期和长期调节的能量调节中起着重要作用稳态。对于这项研究，最重要的是，生长素释放蛋白给健康女性的给药会导致平均LH和LH脉冲频率显着降低，但对于瘦素，尚不清楚能量可用性变化引起的绝对生长素蛋白浓度还是诱导的生长素素的变化可以预测个体的敏感性生殖轴降低了能量可用性。像瘦素一样，脂联素是脂肪组织分泌的脂肪细胞因子。脂联素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。脂联素不会受到餐食的急剧影响，因此可能是更稳定的生物标志物，可以与能量降低的易感性相关联。现在有大量证据通过压力与抑制生殖信号传导联系着神经内分泌机制的激活，只有其中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力轴的激活与剂量反应性的急性能量剥夺有关。但是，更多的慢性能量缺陷并非如此。与正常骑自行车对照相比，HA女性的血清，尿液和脑脊髓液中的皮质醇水平更大。在对HA患者的长期随访研究中，循环皮质醇和LH水平与未恢复生殖功能的女性之间存在反比关系，而禁食等离子体皮质醇水平明显高于那些康复的女性。皮质醇也随运动而增加，并且在运动症中最高。皮质醇和瘦素在HA中呈成反比，但是瘦素给药的健康男性皮质醇水平没有变化，并且显着改善了女性的生殖功能，而皮质醇水平没有变化。因此，在HA病因学中涉及应力途径的大量信息。此外，应激途径也可能参与营养缺陷对中央生殖功能的抑制作用。似乎与繁殖有关的其他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。卡路里剥夺加剧月经周期对睡眠的影响 2。响应热量剥夺的代谢激素稳态 3。热量限制对甲状腺激素动力学的影响