Neuroendocrinology of nutritional infertility.
01 Dec 2004-American Journal of Physiology-regulatory Integrative and Comparative Physiology (American Physiological Society)-Vol. 287, Iss: 6
TL;DR: A working hypothesis is proposed in which any activity or condition that limits the availability of oxidizable fuels can inhibit both gonadotropin-releasing hormone (GnRH)/luteinizing hormone secretion and female copulatory behaviors, and disruption of these signaling processes allows normal reproduction to proceed in the face of energetic deficits.
Abstract: Natural selection has linked the physiological controls of energy balance and fertility such that reproduction is deferred during lean times, particularly in female mammals. In this way, an energetically costly process is confined to periods when sufficient food is available to support pregnancy and lactation. Even in the face of abundance, nutritional infertility ensues if energy intake fails to keep pace with expenditure. A working hypothesis is proposed in which any activity or condition that limits the availability of oxidizable fuels (e.g., undereating, excessive energy expenditure, diabetes mellitus) can inhibit both gonadotropin-releasing hormone (GnRH)/luteinizing hormone secretion and female copulatory behaviors. Decreases in metabolic fuel availability appear to be detected by cells in the caudal hindbrain. Hindbrain neurons producing neuropeptide Y (NPY) and catecholamines (CA) then project to the forebrain where they contact GnRH neurons both directly and also indirectly via corticotropin-releasing hormone (CRH) neurons to inhibit GnRH secretion. In the case of estrous behavior, the best available evidence suggests that the inhibitory NPY/CA system acts primarily via CRH or urocortin projections to various forebrain loci that control sexual receptivity. Disruption of these signaling processes allows normal reproduction to proceed in the face of energetic deficits, indicating that the circuitry responds to energy deficits and that no signal is necessary to indicate that there is an adequate energy supply. While there is a large body of evidence to support this hypothesis, the data do not exclude nutritional inhibition of reproduction by other pathways and processes, and the full story will undoubtedly be more complex than this.
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TL;DR: The female athlete triad (Triad) refers to the interrelationships among energy availability, menstrual function, and bone mineral density, which may have clinical manifestations including eating disorders, functional hypothalamic amenorrhea, and osteoporosis.
Abstract: The female athlete triad (Triad) refers to the interrelationships among energy availability, menstrual function, and bone mineral density, which may have clinical manifestations including eating disorders, functional hypothalamic amenorrhea, and osteoporosis. With proper nutrition, these same relationships promote robust health. Athletes are distributed along a spectrum between health and disease, and those at the pathological end may not exhibit all these clinical conditions simultaneously. Energy availability is defined as dietary energy intake minus exercise energy expenditure. Low energy availability appears to be the factor that impairs reproductive and skeletal health in the Triad, and it may be inadvertent, intentional, or psychopathological. Most effects appear to occur below an energy availability of 30 kcal.kg(-1) of fat-free mass per day. Restrictive eating behaviors practiced by girls and women in sports or physical activities that emphasize leanness are of special concern. For prevention and early intervention, education of athletes, parents, coaches, trainers, judges, and administrators is a priority. Athletes should be assessed for the Triad at the preparticipation physical and/or annual health screening exam, and whenever an athlete presents with any of the Triad's clinical conditions. Sport administrators should also consider rule changes to discourage unhealthy weight loss practices. A multidisciplinary treatment team should include a physician or other health-care professional, a registered dietitian, and, for athletes with eating disorders, a mental health practitioner. Additional valuable team members may include a certified athletic trainer, an exercise physiologist, and the athlete's coach, parents and other family members. The first aim of treatment for any Triad component is to increase energy availability by increasing energy intake and/or reducing exercise energy expenditure. Nutrition counseling and monitoring are sufficient interventions for many athletes, but eating disorders warrant psychotherapy. Athletes with eating disorders should be required to meet established criteria to continue exercising, and their training and competition may need to be modified. No pharmacological agent adequately restores bone loss or corrects metabolic abnormalities that impair health and performance in athletes with functional hypothalamic amenorrhea.
1,349 citations
TL;DR: The IOC expert working group introduces a broader, more comprehensive term for the condition previously known as ‘Female Athlete Triad’, ‘Relative Energy Deficiency in Sport’ (RED-S), and recommends practical clinical models for the management of affected athletes.
Abstract: Protecting the health of the athlete is a goal of the International Olympic Committee (IOC). The IOC convened an expert panel to update the 2005 IOC Consensus Statement on the Female Athlete Triad. This Consensus Statement replaces the previous and provides guidelines to guide risk assessment, treatment and return-to-play decisions. The IOC expert working group introduces a broader, more comprehensive term for the condition previously known as ‘Female Athlete Triad’. The term ‘Relative Energy Deficiency in Sport’ (RED-S), points to the complexity involved and the fact that male athletes are also affected. The syndrome of RED-S refers to impaired physiological function including, but not limited to, metabolic rate, menstrual function, bone health, immunity, protein synthesis, cardiovascular health caused by relative energy deficiency. The cause of this syndrome is energy deficiency relative to the balance between dietary energy intake and energy expenditure required for health and activities of daily living, growth and sporting activities. Psychological consequences can either precede RED-S or be the result of RED-S. The clinical phenomenon is not a ‘triad’ of the three entities of energy availability, menstrual function and bone health, but rather a syndrome that affects many aspects of physiological function, health and athletic performance. This Consensus Statement also recommends practical clinical models for the management of affected athletes. The ‘Sport Risk Assessment and Return to Play Model’ categorises the syndrome into three groups and translates these classifications into clinical recommendations.
962 citations
TL;DR: The IOC RED-S consensus authors have reconvened to provide an update summary of the interim scientific progress in the field of relative energy deficiency with the ultimate goal of stimulating advances inRED-S awareness, clinical application and scientific research to address current gaps in knowledge.
Abstract: In 2014, the IOC published a consensus statement entitled ‘Beyond the Female Athlete Triad: Relative Energy Deficiency in Sport (RED-S)’. The syndrome of RED-S refers to ‘impaired physiological functioning caused by relative energy deficiency and includes, but is not limited to, impairments of metabolic rate, menstrual function, bone health, immunity, protein synthesis and cardiovascular health’. The aetiological factor of this syndrome is low energy availability (LEA).1
The publication of the RED-S consensus statement stimulated activity in the field of Female Athlete Triad science, including some initial controversy2 3 followed by numerous scientific publications addressing:
1. The health parameters identified in the RED-S conceptual model (figure 1).1 4
2. Relative energy deficiency in male athletes.
3. The measurement of LEA.
4. The performance parameters identified in the RED-S conceptual model (figure 2).1 4
The IOC RED-S consensus authors have reconvened to provide an update summary of the interim scientific progress in the field of relative energy deficiency with the ultimate goal of stimulating advances in RED-S awareness, clinical application and scientific research to address current gaps in knowledge.
Figure 1
Health consequences of Relative Energy Deficiency in Sport (RED-S) showing an expanded concept of the Female Athlete Triad to acknowledge a wider range of outcomes and the application to male athletes (*Psychological consequences can either precede RED-S or be the result of RED-S).1 4
Figure 2
Potential Performance consequences of Relative Energy Deficiency in Sport (*Aerobic and anerobic performance).1 4
### Low energy availability
LEA, which underpins the concept of RED-S, is a mismatch between an athlete’s energy intake (diet) and the energy expended in exercise, leaving inadequate energy to support the functions required by the body to maintain optimal health and performance. Operationally, energy availability (EA) is defined as:
![Formula][1]
where exercise energy expenditure (EEE) is calculated as the additional energy expended above that of …
[1]: /embed/mml-math-1.gif
476 citations
TL;DR: The variety and physiological importance of what has been learned so far warrant intensifying basic, translational, and clinical research on sex differences in eating.
Abstract: Hypothalamic-pituitary-gonadal (HPG) axis function fundamentally affects the physiology of eating. We review sex differences in the physiological and pathophysiological controls of amounts eaten in rats, mice, monkeys, and humans. These controls result from interactions among genetic effects, organizational effects of reproductive hormones (i.e., permanent early developmental effects), and activational effects of these hormones (i.e., effects dependent on hormone levels). Male-female sex differences in the physiology of eating involve both organizational and activational effects of androgens and estrogens. An activational effect of estrogens decreases eating 1) during the periovulatory period of the ovarian cycle in rats, mice, monkeys, and women and 2) tonically between puberty and reproductive senescence or ovariectomy in rats and monkeys, sometimes in mice, and possibly in women. Estrogens acting on estrogen receptor-α (ERα) in the caudal medial nucleus of the solitary tract appear to mediate these effects in rats. Androgens, prolactin, and other reproductive hormones also affect eating in rats. Sex differences in eating are mediated by alterations in orosensory capacity and hedonics, gastric mechanoreception, ghrelin, CCK, glucagon-like peptide-1 (GLP-1), glucagon, insulin, amylin, apolipoprotein A-IV, fatty-acid oxidation, and leptin. The control of eating by central neurochemical signaling via serotonin, MSH, neuropeptide Y, Agouti-related peptide (AgRP), melanin-concentrating hormone, and dopamine is modulated by HPG function. Finally, sex differences in the physiology of eating may contribute to human obesity, anorexia nervosa, and binge eating. The variety and physiological importance of what has been learned so far warrant intensifying basic, translational, and clinical research on sex differences in eating.
384 citations
Cites background from "Neuroendocrinology of nutritional i..."
...Finally, the many physiological interactions between leptin and gonadal steroids, for example, in the early development of neural architecture controlling adult behavior (493, 667, 805), in pubertal development (187, 563), and in nutritional infertility (645, 769, 787), certainly justify further investigation of their interactions in the control of normal eating and adiposity (see Ref....
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TL;DR: It is argued that the concept of energy availability is more useful than the idea of energy balance for managing the diets of athletes.
Abstract: This review updates and complements the review of energy balance and body composition in the Proceedings of the 2003 IOC Consensus Conference on Sports Nutrition. It argues that the concept of energy availability is more useful than the concept of energy balance for managing the diets of athletes. It then summarizes recent reports of the existence, aetiologies, and clinical consequences of low energy availability in athletes. This is followed by a review of recent research on the failure of appetite to increase ad libitum energy intake in compensation for exercise energy expenditure. The review closes by summarizing the implications of this research for managing the diets of athletes.
380 citations
Cites background from "Neuroendocrinology of nutritional i..."
...Keywords: Energy availability, energy balance, diet, exercise, appetite...
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...…and energy balance In the field of bioenergetics, the concept of energy availability recognizes that dietary energy is expended in several fundamental physiological processes, including cellular maintenance, thermoregulation, growth, reproduction, immunity, and locomotion (Wade & Jones, 2004)....
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References
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Book•
15 Jan 1994
TL;DR: The gametes, fertilization and early embryogenesis the reproductive systems - the female, the male the pituitary and the hypothalmus, and the reproductive processes and their control.
Abstract: Volume 1: The gametes, fertilization and early embryogenesis the reproductive systems - the female, the male the pituitary and the hypothalmus. Volume 2: Reproductive behaviour and its control reproductive processes and their control.
7,667 citations
TL;DR: A model is described that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.
Abstract: New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.
6,178 citations
"Neuroendocrinology of nutritional i..." refers background in this paper
...Basal insulin levels are directly proportional to the body’s fat stores, and ICV infusion of insulin decreases food intake and body weight in baboons and male rats (31, 261), leading to the conclusion that the basal hypothalamus monitors insulin levels and adjusts food intake and energy expenditure such that energy stores are maintained within a particular range (219, 262)....
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TL;DR: It is proposed that regulation of the neuroendocrine system during starvation could be the main physiological role of leptin, and preventing the starvation-induced fall in leptin with exogenous leptin substantially blunts the changes in gonadal, adrenal and thyroid axes in male mice, and prevents the starve-induced delay in ovulation in female mice.
Abstract: A total deficiency in or resistance to the protein leptin causes severe obesity. As leptin levels rise with increasing adiposity in rodents and man, it is proposed to act as a negative feedback 'adipostatic signal' to brain centres controlling energy homeostasis, limiting obesity in times of nutritional abundance. Starvation is also a threat to homeostasis that triggers adaptive responses, but whether leptin plays a role in the physiology of starvation is unknown. Leptin concentration falls during starvation and totally leptin-deficient ob/ob mice have neuroendocrine abnormalities similar to those of starvation, suggesting that this may be the case. Here we show that preventing the starvation-induced fall in leptin with exogenous leptin substantially blunts the changes in gonadal, adrenal and thyroid axes in male mice, and prevents the starvation-induced delay in ovulation in female mice. In contrast, leptin repletion during this period of starvation has little or no effect on body weight, blood glucose or ketones. We propose that regulation of the neuroendocrine system during starvation could be the main physiological role of leptin.
3,017 citations
"Neuroendocrinology of nutritional i..." refers background in this paper
...The CRH/urocortin neurons then project to several forebrain sites involved in the control of estrous behavior (5) and to GnRH neurons (6)....
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...Leptin production and release from adipocytes are directly related to body fat content, and food deprivation decreases body fat content and circulating hormone levels (6, 7, 149)....
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TL;DR: The stress response is subserved by the stress system, which is located both in the central nervous system and the periphery, and the principal effectors include corticotropin-releasing hormone; arginine vasopressin; proopiomelanocortin-derived peptides alpha-melanocyte-stimulating hormone and beta-endorphin; and the glucocorticoids.
Abstract: ▪ The stress response is subserved by the stress system, which is located both in the central nervous system and the periphery. The principal effectors of the stress system include corticotropin-releasing hormone (CRH); arginine vasopressin; the proopiomelanocortin-derived peptides α-melanocyte-stimulating hormone and β-endorphin, the glucocorticoids; and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for a number of endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of the stressful events, given that prenatal life, infanc...
1,702 citations
TL;DR: It is found that both intracerebroventricular and intraperitoneal administration of ghrelin in freely feeding rats stimulated food intake and plasma growth hormone (GH) concentration increased following both i.c.v. and i.p. administration.
Abstract: Ghrelin, a novel 28 amino acid peptide found in hypothalamus and stomach, was recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). We have now found that both intracerebroventricular (ICV) and intraperitoneal (i.p.) administration of ghrelin in freely feeding rats stimulated food intake. The onset of increased feeding was rapid and after ICV administration was sustained for 24 hours. Following ICV administration of 3nmol ghrelin, the duration and magnitude of the feeding stimulation was similar to that following 5nmol neuropeptide Y (NPY). Plasma growth hormone (GH) concentration increased following both ICV and i.p. administration of ghrelin. Release of adrenocorticotrophic hormone (ACTH) was stimulated and thyroid stimulating hormone (TSH) inhibited following ICV administration of ghrelin. These data suggest a possible role for the newly identified endogenous hypothalamic peptide, ghrelin, in stimulation of feeding and growth hormone secretion.
1,588 citations
"Neuroendocrinology of nutritional i..." refers background in this paper
...Endocrine cells in the stomach secrete ghrelin during negative energy balance (94, 266), and it can act in either the hypothalamus (263) or hindbrain (60) to stimulate food intake....
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