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）

• 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
• 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

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等的经典介入研究表明，在没有月经周期不规律史的正常女性中，显著增加运动可引起月经周期功能障碍，从黄体期短或不足到无排卵和闭经，这被称为下丘脑闭经（hypothalamic amenorrhea， 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主要集中在运动和营养的作用上，但某种程度的压力也可能对研究结果有所贡献，因为这项研究是在一个营地进行的，生活环境的变化本身与周期紊乱的发作有关，典型的例子是大学一年级的年轻女性。增加运动和减少营养摄入的关联在其他多个横断面研究中得到证实。Loucks和他的同事量化了能量摄入和能量消耗之间的相互作用，导致GnRH分泌中断。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控制良好的研究中，他们证明了能量可用性的阈值，在该阈值下，在卵泡早期（EFP）经历了5天能量可用性下降的健康女性中，脉动性LH分泌（作为GnRH脉冲频率的标志）发生了改变。在这些研究中，与中性能量利用率45 kcal/kg LBM*day或30 kcal/kg LBM*day 67相比，黄体生成素脉冲与每天20和10 kcal/kg瘦体重（LBM*day）的能量利用率相关。进一步的研究表明，在3个月的时间里，能量摄入量分别为0%、-8%、-22%和-42%与月经周期中断有关，表现为黄体期不足、间歇排卵和闭经。综上所述，这些研究表明，当能量剥夺更为慢性时，短期能量剥夺时LH脉冲频率的变化预示着月经周期紊乱，尽管周期紊乱所需的最低慢性能量不足程度（-22%）可能比短期能量不足研究预测的要小，因此。短期研究的结果将提供潜在风险的保守标记。