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Influence of Hormones on the Development of Eating Disorders
CHAPTER 12
Influence of Hormones on the Development of Eating Disorders KATHERINE A. THOMPSON, MA • ALEXANDRA J. MILLER, BS • JESSICA H. BAKER, PHD
INTRODUCTION This chapter discusses the role of reproductive and appetite hormones in the etiology of eating disorders (EDs). We focus on the reproductive hormones estrogen and progesterone and the appetite hormones leptin and ghrelin in adult female populations, given that research to date has focused here. Although other hormones have been examined,1 more research is needed about their functions in EDs and obesity during childhood and adolescence. We describe the child and adolescent literature where available.
REPRODUCTIVE HORMONES Reproductive hormones act on human behavior in an organizational-activational manner. Organizational effects occur by shaping the growth and patterns of neural circuits during development (i.e., in utero and during adolescence) and are considered stable and permanent. Activational effects occur by stimulating, regulating, or inhibiting behaviors associated with the presence or absence of the hormones within the existing circuits and can be less permanent since they influence behavior only after the neural circuits in the brain are developed.
Estradiol and Progesterone Early data regarding the link between estradiol (primary estrogen–based hormone) and eating behaviors showed that ovariectomized animals experienced significant increases in food intake, meal size, and body weight,2 which were reversed upon estradiol administration.3 Thus, estradiol has an inhibiting effect on food intake. In contrast, progesterone (primary progestogen steroid) does not have a direct effect on eating behaviors: ovariectomized animals
show no changes in food intake with progesterone administration.4
Eating disorders Research examining the role of reproductive hormones in the etiology of EDs has generally explored connections at the symptom level. Initial studies that examined whether ED symptoms fluctuate over the menstrual cycle indicated that binge eating and emotional eating are higher during the midluteal and premenstrual phases of the cycle compared with the follicular and ovulatory phases. Additionally, psychological symptoms including body dissatisfaction and weight preoccupation fluctuate during the menstrual cycle, with the highest levels during the premenstrual and menstrual phases.4 There are also significant associations between hormone concentrations and ED symptoms. In women with bulimia nervosa (BN) binge eating and purging behaviors increase when estradiol concentrations diminish.5 Similarly, animal models show an increase in the consumption of highly palatable foods in ovariectomized rats compared with nonovariectomized rats.6 There are also negative associations between decreased estradiol and psychological symptoms of EDs in humans including body dissatisfaction, weight/shape concerns, drive for thinness, and preoccupation with weight.4 In regard to progesterone, a positive relationship has been observed with binge eating in women with BN5 and with body dissatisfaction and drive for thinness in young adults.4 Progesterone also has indirect effects on ED symptoms when considered in the presence of estradiol simultaneously: emotional eating increases when both progesterone and estradiol levels are elevated. However, the independent effect of progesterone is not significant.7 Some have also explored hormone administration as a supplement to standard ED treatments. For
Eating Disorders and Obesity in Children and Adolescents. https://doi.org/10.1016/B978-0-323-54852-6.00012-4 Copyright © 2019 Elsevier Inc. All rights reserved.
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example, physiological doses of estradiol improve bone mass density in adolescent girls with anorexia nervosa (AN).8 Additionally, a 3-month administration of an estradiol-based oral contraceptive among women with BN showed a reduction in compensatory behaviors, meal-related hunger, and gastric distention9—although conclusions are limited given this was not a randomized trial. Estradiol and progesterone may serve a beneficial function for ED treatments.
Obesity Estradiol can be linked to obesity indirectly via eating behaviors and through direct effects on adiposity. A review of the literature described that estrogen levels are higher in nonobese compared with obese premenopausal women as well as an association between diminished levels of estrogens during menopause and increased total obesity.10,11 Although menopause is markedly distinct from childhood, menopause provides a quasi-experimental design to examine the influence of changing reproductive hormones on obesity that may extrapolate to adolescence. Once puberty is transversed, adolescent estrogen levels may have a direct impact on obesity. Indeed, estradiol administration in animals increases carbohydrate and lipid metabolism, thus the effect of estrogen on obesity could be a result of metabolic capacity and stimulation.12 Regarding progesterone, animal models indicate that progesterone interacts with estrogen to effect obesity such that progesterone administration negates the metabolic effects of estrogen by decreasing the capacity for carbohydrate and lipid metabolism. Thus, increased concentrations of progesterone result in a metabolic state that is similar to metabolic syndrome—in which fat concentrations increase and the body is unable to process them.12 Taken together, estradiol appears to have a direct, activational effect on ED symptoms and obesity. Specifically, lower levels of estradiol are associated with more binge eating, increased ED symptoms, and increased body fat. Progesterone primarily assumes a moderating role such that increasing levels of progesterone may counteract the protective effect of increasing estradiol. Progesterone additionally limits metabolic capacity increasing the likelihood of obesity.
APPETITE HORMONES Leptin Leptin is an appetite suppressant, which regulates satiety and increases energy expenditure. Following a meal, leptin secretion increases, signaling fullness.
Eating disorders Leptin concentrations are lower in individuals with AN and BN compared with healthy controls. One explanation for decreased leptin in AN is the direct link between leptin and body mass index (BMI): decreased leptin levels are a consequence of the low BMIs characteristic of individuals with AN. Corroborating this, food deprivation for several days or weeks results in a significant decline in leptin levels,13 and leptin concentrations increase once body weight is restored in AN.1 However, leptin administration in rats with activity-based AN suppresses hyperactivity, suggesting that decreased leptin may have an etiological role in excessive exercise often observed in AN.14 Moreover, leptin might influence AN outcome and relapse, such that higher leptin levels at discharge from inpatient treatment increase risk, albeit inconsistently,15 for a poorer treatment outcome.16 Regarding BN, decreased leptin may contribute to binge eating and decreased metabolic rates,1 whereas children and adolescents who experience loss of control eating episodes have higher fasting leptin levels than those who do not.17
Obesity Obese adolescents exhibit higher levels of leptin relative to nonobese adolescents. Despite leptin’s influence on decreasing caloric intake and increasing energy expenditure, increasing leptin fails to prevent progression of obesity. Consequently, obesity is thought to be, in part, the result of leptin resistance. For example, high levels of leptin in children at increased risk for adult obesity (i.e., the child was overweight and/or had overweight parents) predicts future weight gain.18 Furthermore, leptin administration is ineffective for weight loss in obese individuals.19 Thus, leptin resistance may promote and maintain obesity regardless of age.
Ghrelin Ghrelin acts as an appetite stimulant and rises before a meal, reduces feelings of satiety, increases caloric intake, and decreases after meals in healthy adults. Conversely, some data show that children’s ghrelin levels remain stable in response to meals,20 whereas others indicate ghrelin decreases after eating, staying constant over the next 2 h.21
Eating disorders Adolescent females with AN have significantly higher levels of ghrelin than healthy controls. This may be a consequence of both ghrelin’s reliance on energy stores and meal status since ghrelin levels tend to normalize once body weight is restored.1 Further, ghrelin levels increase when individuals intentionally eat less,22
CHAPTER 12 Influence of Hormones on the Development of Eating Disorders and food restriction and losing weight by dieting have been linked to rises in ghrelin.23 However, individuals with AN may have a reduced sensitivity to ghrelin signals such that individuals with AN do not experience an increase in appetite, hunger, or GH receptor response upon ghrelin administration as compared with constitutionally thin or normal weight individuals.1 Although a small pilot study observed increased food intake after administration of ghrelin in AN,24 the small sample size and lack of randomization hamper the conclusions that can be drawn. Associations between ghrelin and BN are less consistent. However, the ghrelin response may be blunted in individuals with BN compared with healthy controls such that it fails to decrease as expected following a standardized meal.25 This suggests that ghrelin may play a role in binge episodes due to deficiencies in postmeal satiety. Testing this hypothesis, Monteleone et al.26 presented individuals with BN and healthy controls a meal—who were allowed to smell and chew the food but not swallow it—and found that individuals with BN had greater ghrelin increases than controls and binge-purge frequency was positively associated to this increase.
Obesity Obese children and adults have diminished concentrations of ghrelin compared with nonobese individuals. For obese children specifically, this diminishment of ghrelin persists after weight loss.27 Interestingly, animal studies suggest that mice with a ghrelin deficiency administered high-fat diets at a young age develop a resistance to obesity.28 A ghrelin “vaccine” created to elicit antibodies against ghrelin tested on diet-induced obese mice demonstrated reductions in weight gain by decreasing body fat accumulation and increasing energy expenditure.29 Thus, low ghrelin levels may play a protective role in obesity—in converse, high levels may elevate risk. Taken together, it is uncertain whether leptin and ghrelin are involved in the etiology of an ED. In particular, decreased leptin levels may be a consequence of reduced body fat percentage and malnutrition characteristics of AN. However, both leptin and ghrelin may contribute to ED maintenance and/or relapse. Leptin and ghrelin may also play an indirect role in etiology via reproductive hormones. Estradiol attenuates the potency of ghrelin such that exogenous ghrelin administration is less potent in intact female rats compared with ovariectomized rats, whereas leptin sensitivity is impaired in ovariectomized rats.30 Thus, changes in estradiol that occur with EDs could influence the
75
production of and sensitivity to appetite hormones. In contrast, both seem to have a direct role in obesity: obesity is thought to be in part due to leptin resistance, whereas ghrelin-deficient animals develop a resistance to obesity.
PUBERTY Eating Disorders Puberty is a risk period for the onset of an ED and is a period of dramatic hormonal changes. For example, not only do estrogen and progesterone increase, leptin plays a crucial role in pubertal onset by informing the brain the amount of fat required for the onset of puberty. A preponderance of data indicates that puberty is associated with ED onset, and one mechanism explaining this link is reproductive hormones.31 Following organizationalactivational effects, it is theorized that the genetic effects for EDs that organize during the prenatal period become activated during puberty via reproductive hormones to increase risk for EDs in girls. In line with this, the heritability of ED symptoms among girls before puberty is roughly 0% yet increases to more than 50% during and after puberty.31 Estradiol may be an important moderator for these effects as estradiol increases markedly during puberty and regulates several genes that have been linked to EDs. Thus, puberty and the changes in estradiol that occur during puberty may activate the prenatally organized genetic risk for an ED in adolescents with a genetic vulnerability.
Obesity Approximately, 50% of adult body weight is gained during the pubertal transition between childhood and adolescence. During puberty girls experience an increase in percent body fat and fat mass due to interactions between estradiol and growth hormones. There is also an increase and redistribution of adipose tissue thought to be due to increasing estrogen.10 Thus, pubertal timing may be important in the development of obesity. For example, age of menarche is inversely related to BMI among girls suggesting that experiencing early-onset menarche (<11 years) increased the risk for having a BMI > 75th percentile by more than 1.75 times.32 Importantly, however, obesity can also lead to early-onset puberty. Taken together with observations of the association between reproductive hormones and obesity, it is possible that puberty is a period of risk for obesity and that once puberty is complete reproductive hormones play an important role in etiology.
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CONCLUSION The adult female literature indicates reproductive hormones and puberty play a role in the etiology of EDs and obesity, whereas the direct influence of appetite hormones is less clear. Although studies of children and adolescence are limited, we conclude the following: reproductive hormones, estradiol in particular, (1) activate the genetic risk for EDs at puberty,31 (2) cause transient changes in ED symptoms across the menstrual cycle, (3) slow down metabolism, and (4) may increase fat mass and decrease lean mass concentrations during puberty and play a causal role in obesity once puberty is complete. Regarding leptin and ghrelin, (1) differences observed between individuals with an ED or obesity and healthy controls may be a consequence of the disorder, (2) changes in leptin and ghrelin may impact maintenance and relapse in EDs, (3) leptin resistance is involved in obesity, whereas ghrelin deficiency is protective, and (4) the impact of appetite hormones on an ED may be mediated through reproductive hormones.
REFERENCES 1. Culbert KM, Racine SE, Klump KL. Hormonal factors and disturbances in eating disorders. Curr Psychiatry Rep. 2016;18(7):65. 2. Wade GN. Some effects of ovarian hormones on food intake and body weight in female rats. J Comp Physiol Psychol. 1975;88(1):183–193. 3. Geary N, Asarian L. Cyclic estradiol treatment normalizes body weight and test meal size in ovariectomized rats. Physiol Behav. 1999;67(1):141–147. 4. Baker JH, Girdler SS, Bulik CM. The role of reproductive hormones in the development and maintenance of eating disorders. Expert Rev Obstet Gynecol. 2012;7(6):573–583. 5. Edler C, Lipson SF, Keel PK. Ovarian hormones and binge eating in bulimia nervosa. Psychol Med. 2007;37(1):131– 141. 6. Klump KL, Suisman JL, Culbert KM, Kashy DA, Keel PK, Sisk CL. The effects of ovariectomy on binge eating proneness in adult female rats. Horm Behav. 2011;59(4):585–593. 7. Klump KL, Keel PK, Racine SE, et al. The interactive effects of estrogen and progesterone on changes in emotional eating across the menstrual cycle. J Abnorm Psychol. 2013;122(1):131–137. 8. Misra M, Katzman D, Miller KK, et al. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J Bone Miner Res. 2011;26(10):2430–2438. 9. Naessén S, Carlström K, Byström B, Pierre Y, Hirschberg AL. Effects of an antiandrogenic oral contraceptive on appetite and eating behavior in bulimic women. Psychoneuroendocrinology. 2007;32(5):548–554.
10. Leeners B, Geary N, Tobler PN, Asarian L. Ovarian hormones and obesity. Hum Reprod Update. 2017;28:1–15. 11. Mayes JS, Watson GH. Direct effects of sex steroid hormones on adipose tissues and obesity. Obes Rev. 2004;5(4):197–216. 12. Campbell SE, Febbraio MA. Effects of ovarian hormones on exercise metabolism. Curr Opin Clin Nutr Metab Care. 2001;4(6):515–520. 13. Wolfe BE, Jimerson DC, Orlova C, Mantzoros CS. Effect of dieting on plasma leptin, soluble leptin receptor, adiponectin and resistin levels in healthy volunteers. Clin Endocrinol. 2004;61(3):332–338. 14. Exner C, Hebebrand J, Remschmidt H, et al. Leptin suppresses semi-starvation induced hyperactivity in rats: implications for anorexia nervosa. Mol Psychiatry. 2000;5(5):476–481. 15. Seitz J, Bühren K, Biemann R, et al. Leptin levels in patients with anorexia nervosa following day/inpatient treatment do not predict weight 1 year post-referral. Eur Child Adolesc Psychiatry. 2016;25(9):1019–1025. 16. Holtkamp K, Hebebrand J, Mika C, Heer M, Heussen N, Herpertz-Dahlmann B. High serum leptin levels subsequent to weight gain predict renewed weight loss in patients with anorexia nervosa. Psychoneuroendocrinology. 2004;29(6):791–797. 17. Miller R, Tanofsky-Kraff M, Shomaker LB, et al. Serum leptin and loss of control eating in children and adolescents. Int J Obes. 2014;38(3):397–403. 18. Fleisch AF, Agarwal N, Roberts MD, et al. Influence of serum leptin on weight and body fat growth in children at high risk for adult obesity. J Clin Endocrinol Metab. 2007;92(3):948–954. 19. Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. J Am Med Assoc. 1999;282(16):1568–1575. 20. Lomenick JP, Clasey JL, Anderson JW. Meal-related changes in ghrelin, peptide YY, and appetite in normal weight and overweight children. Obesity. 2008;16(3):547–552. 21. Maffeis C, Bonadonna RC, Consolaro A, et al. Ghrelin, insulin sensitivity and postprandial glucose disposal in overweight and obese children. Eur J Endocrinol. 2006;154(1):61–68. 22. Schur EA, Cummings DE, Callahan HS, Foster-Schubert KE. Association of cognitive restraint with ghrelin, leptin, and insulin levels in subjects who are not weight-reduced. Physiol Behav. 2008;93(4–5):706–712. 23. Leidy HJ, Gardner JK, Frye BR, et al. Circulating ghrelin is sensitive to changes in body weight during a diet and exercise program in normal-weight young women. J Clin Endocrinol Metab. 2004;89(6):2659–2664. 24. Hotta M, Ohwada R, Akamizu T, Shibasaki T, Takano K, Kangawa K. Ghrelin increases hunger and food intake in patients with restricting-type anorexia nervosa: a pilot study. Endocr J. 2009;56(9):1119–1128.
CHAPTER 12 Influence of Hormones on the Development of Eating Disorders 25. Kojima S, Nakahara T, Nagai N, et al. Altered ghrelin and peptide YY responses to meals in bulimia nervosa. Clin Endocrinol. 2005;62(1):74–78. 26. Monteleone P, Serritella C, Scognamiglio P, Maj M. Enhanced ghrelin secretion in the cephalic phase of food ingestion in women with bulimia nervosa. Psychoneuroendocrinology. 2010;35(2):284–288. 27. Soriano-Guillén L, Barrios V, Chowen JA, et al. Ghrelin levels from fetal life through early adulthood: relationship with endocrine and metabolic and anthropometric measures. J Pediatr. 2004;144(1):30–35. 28. Wortley KE, del Rincon JP, Murray JD, et al. Absence of ghrelin protects against early-onset obesity. J Clin Invest. 2005;115(12):3573–3578.
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29. Azegami T, Yuki Y, Sawada S, et al. Nanogel-based nasal ghrelin vaccine prevents obesity. Mucosal Immunol. 2017;10(5):1351–1360. 30. Brown LM, Clegg DJ. Central effects of estradiol in the regulation of food intake, body weight, and adiposity. J Steroid Biochem Mol Biol. 2010;122(1–3):65–73. 31. Klump KL. Puberty as a critical risk period for eating disorders: a review of human and animal studies. Horm Behav. 2013;64(2):399–410. 32. Ahmed ML, Ong KK, Dunger DB. Childhood obesity and the timing of puberty. Trends Endocrinol Metab. 2009;20(5):237–242.
Influence of Hormones on the Development of Eating Disorders KATHERINE A. THOMPSON, MA • ALEXANDRA J. MILLER, BS • JESSICA H. BAKER, PHD
INTRODUCTION This chapter discusses the role of reproductive and appetite hormones in the etiology of eating disorders (EDs). We focus on the reproductive hormones estrogen and progesterone and the appetite hormones leptin and ghrelin in adult female populations, given that research to date has focused here. Although other hormones have been examined,1 more research is needed about their functions in EDs and obesity during childhood and adolescence. We describe the child and adolescent literature where available.
REPRODUCTIVE HORMONES Reproductive hormones act on human behavior in an organizational-activational manner. Organizational effects occur by shaping the growth and patterns of neural circuits during development (i.e., in utero and during adolescence) and are considered stable and permanent. Activational effects occur by stimulating, regulating, or inhibiting behaviors associated with the presence or absence of the hormones within the existing circuits and can be less permanent since they influence behavior only after the neural circuits in the brain are developed.
Estradiol and Progesterone Early data regarding the link between estradiol (primary estrogen–based hormone) and eating behaviors showed that ovariectomized animals experienced significant increases in food intake, meal size, and body weight,2 which were reversed upon estradiol administration.3 Thus, estradiol has an inhibiting effect on food intake. In contrast, progesterone (primary progestogen steroid) does not have a direct effect on eating behaviors: ovariectomized animals
show no changes in food intake with progesterone administration.4
Eating disorders Research examining the role of reproductive hormones in the etiology of EDs has generally explored connections at the symptom level. Initial studies that examined whether ED symptoms fluctuate over the menstrual cycle indicated that binge eating and emotional eating are higher during the midluteal and premenstrual phases of the cycle compared with the follicular and ovulatory phases. Additionally, psychological symptoms including body dissatisfaction and weight preoccupation fluctuate during the menstrual cycle, with the highest levels during the premenstrual and menstrual phases.4 There are also significant associations between hormone concentrations and ED symptoms. In women with bulimia nervosa (BN) binge eating and purging behaviors increase when estradiol concentrations diminish.5 Similarly, animal models show an increase in the consumption of highly palatable foods in ovariectomized rats compared with nonovariectomized rats.6 There are also negative associations between decreased estradiol and psychological symptoms of EDs in humans including body dissatisfaction, weight/shape concerns, drive for thinness, and preoccupation with weight.4 In regard to progesterone, a positive relationship has been observed with binge eating in women with BN5 and with body dissatisfaction and drive for thinness in young adults.4 Progesterone also has indirect effects on ED symptoms when considered in the presence of estradiol simultaneously: emotional eating increases when both progesterone and estradiol levels are elevated. However, the independent effect of progesterone is not significant.7 Some have also explored hormone administration as a supplement to standard ED treatments. For
Eating Disorders and Obesity in Children and Adolescents. https://doi.org/10.1016/B978-0-323-54852-6.00012-4 Copyright © 2019 Elsevier Inc. All rights reserved.
73
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example, physiological doses of estradiol improve bone mass density in adolescent girls with anorexia nervosa (AN).8 Additionally, a 3-month administration of an estradiol-based oral contraceptive among women with BN showed a reduction in compensatory behaviors, meal-related hunger, and gastric distention9—although conclusions are limited given this was not a randomized trial. Estradiol and progesterone may serve a beneficial function for ED treatments.
Obesity Estradiol can be linked to obesity indirectly via eating behaviors and through direct effects on adiposity. A review of the literature described that estrogen levels are higher in nonobese compared with obese premenopausal women as well as an association between diminished levels of estrogens during menopause and increased total obesity.10,11 Although menopause is markedly distinct from childhood, menopause provides a quasi-experimental design to examine the influence of changing reproductive hormones on obesity that may extrapolate to adolescence. Once puberty is transversed, adolescent estrogen levels may have a direct impact on obesity. Indeed, estradiol administration in animals increases carbohydrate and lipid metabolism, thus the effect of estrogen on obesity could be a result of metabolic capacity and stimulation.12 Regarding progesterone, animal models indicate that progesterone interacts with estrogen to effect obesity such that progesterone administration negates the metabolic effects of estrogen by decreasing the capacity for carbohydrate and lipid metabolism. Thus, increased concentrations of progesterone result in a metabolic state that is similar to metabolic syndrome—in which fat concentrations increase and the body is unable to process them.12 Taken together, estradiol appears to have a direct, activational effect on ED symptoms and obesity. Specifically, lower levels of estradiol are associated with more binge eating, increased ED symptoms, and increased body fat. Progesterone primarily assumes a moderating role such that increasing levels of progesterone may counteract the protective effect of increasing estradiol. Progesterone additionally limits metabolic capacity increasing the likelihood of obesity.
APPETITE HORMONES Leptin Leptin is an appetite suppressant, which regulates satiety and increases energy expenditure. Following a meal, leptin secretion increases, signaling fullness.
Eating disorders Leptin concentrations are lower in individuals with AN and BN compared with healthy controls. One explanation for decreased leptin in AN is the direct link between leptin and body mass index (BMI): decreased leptin levels are a consequence of the low BMIs characteristic of individuals with AN. Corroborating this, food deprivation for several days or weeks results in a significant decline in leptin levels,13 and leptin concentrations increase once body weight is restored in AN.1 However, leptin administration in rats with activity-based AN suppresses hyperactivity, suggesting that decreased leptin may have an etiological role in excessive exercise often observed in AN.14 Moreover, leptin might influence AN outcome and relapse, such that higher leptin levels at discharge from inpatient treatment increase risk, albeit inconsistently,15 for a poorer treatment outcome.16 Regarding BN, decreased leptin may contribute to binge eating and decreased metabolic rates,1 whereas children and adolescents who experience loss of control eating episodes have higher fasting leptin levels than those who do not.17
Obesity Obese adolescents exhibit higher levels of leptin relative to nonobese adolescents. Despite leptin’s influence on decreasing caloric intake and increasing energy expenditure, increasing leptin fails to prevent progression of obesity. Consequently, obesity is thought to be, in part, the result of leptin resistance. For example, high levels of leptin in children at increased risk for adult obesity (i.e., the child was overweight and/or had overweight parents) predicts future weight gain.18 Furthermore, leptin administration is ineffective for weight loss in obese individuals.19 Thus, leptin resistance may promote and maintain obesity regardless of age.
Ghrelin Ghrelin acts as an appetite stimulant and rises before a meal, reduces feelings of satiety, increases caloric intake, and decreases after meals in healthy adults. Conversely, some data show that children’s ghrelin levels remain stable in response to meals,20 whereas others indicate ghrelin decreases after eating, staying constant over the next 2 h.21
Eating disorders Adolescent females with AN have significantly higher levels of ghrelin than healthy controls. This may be a consequence of both ghrelin’s reliance on energy stores and meal status since ghrelin levels tend to normalize once body weight is restored.1 Further, ghrelin levels increase when individuals intentionally eat less,22
CHAPTER 12 Influence of Hormones on the Development of Eating Disorders and food restriction and losing weight by dieting have been linked to rises in ghrelin.23 However, individuals with AN may have a reduced sensitivity to ghrelin signals such that individuals with AN do not experience an increase in appetite, hunger, or GH receptor response upon ghrelin administration as compared with constitutionally thin or normal weight individuals.1 Although a small pilot study observed increased food intake after administration of ghrelin in AN,24 the small sample size and lack of randomization hamper the conclusions that can be drawn. Associations between ghrelin and BN are less consistent. However, the ghrelin response may be blunted in individuals with BN compared with healthy controls such that it fails to decrease as expected following a standardized meal.25 This suggests that ghrelin may play a role in binge episodes due to deficiencies in postmeal satiety. Testing this hypothesis, Monteleone et al.26 presented individuals with BN and healthy controls a meal—who were allowed to smell and chew the food but not swallow it—and found that individuals with BN had greater ghrelin increases than controls and binge-purge frequency was positively associated to this increase.
Obesity Obese children and adults have diminished concentrations of ghrelin compared with nonobese individuals. For obese children specifically, this diminishment of ghrelin persists after weight loss.27 Interestingly, animal studies suggest that mice with a ghrelin deficiency administered high-fat diets at a young age develop a resistance to obesity.28 A ghrelin “vaccine” created to elicit antibodies against ghrelin tested on diet-induced obese mice demonstrated reductions in weight gain by decreasing body fat accumulation and increasing energy expenditure.29 Thus, low ghrelin levels may play a protective role in obesity—in converse, high levels may elevate risk. Taken together, it is uncertain whether leptin and ghrelin are involved in the etiology of an ED. In particular, decreased leptin levels may be a consequence of reduced body fat percentage and malnutrition characteristics of AN. However, both leptin and ghrelin may contribute to ED maintenance and/or relapse. Leptin and ghrelin may also play an indirect role in etiology via reproductive hormones. Estradiol attenuates the potency of ghrelin such that exogenous ghrelin administration is less potent in intact female rats compared with ovariectomized rats, whereas leptin sensitivity is impaired in ovariectomized rats.30 Thus, changes in estradiol that occur with EDs could influence the
75
production of and sensitivity to appetite hormones. In contrast, both seem to have a direct role in obesity: obesity is thought to be in part due to leptin resistance, whereas ghrelin-deficient animals develop a resistance to obesity.
PUBERTY Eating Disorders Puberty is a risk period for the onset of an ED and is a period of dramatic hormonal changes. For example, not only do estrogen and progesterone increase, leptin plays a crucial role in pubertal onset by informing the brain the amount of fat required for the onset of puberty. A preponderance of data indicates that puberty is associated with ED onset, and one mechanism explaining this link is reproductive hormones.31 Following organizationalactivational effects, it is theorized that the genetic effects for EDs that organize during the prenatal period become activated during puberty via reproductive hormones to increase risk for EDs in girls. In line with this, the heritability of ED symptoms among girls before puberty is roughly 0% yet increases to more than 50% during and after puberty.31 Estradiol may be an important moderator for these effects as estradiol increases markedly during puberty and regulates several genes that have been linked to EDs. Thus, puberty and the changes in estradiol that occur during puberty may activate the prenatally organized genetic risk for an ED in adolescents with a genetic vulnerability.
Obesity Approximately, 50% of adult body weight is gained during the pubertal transition between childhood and adolescence. During puberty girls experience an increase in percent body fat and fat mass due to interactions between estradiol and growth hormones. There is also an increase and redistribution of adipose tissue thought to be due to increasing estrogen.10 Thus, pubertal timing may be important in the development of obesity. For example, age of menarche is inversely related to BMI among girls suggesting that experiencing early-onset menarche (<11 years) increased the risk for having a BMI > 75th percentile by more than 1.75 times.32 Importantly, however, obesity can also lead to early-onset puberty. Taken together with observations of the association between reproductive hormones and obesity, it is possible that puberty is a period of risk for obesity and that once puberty is complete reproductive hormones play an important role in etiology.
76
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CONCLUSION The adult female literature indicates reproductive hormones and puberty play a role in the etiology of EDs and obesity, whereas the direct influence of appetite hormones is less clear. Although studies of children and adolescence are limited, we conclude the following: reproductive hormones, estradiol in particular, (1) activate the genetic risk for EDs at puberty,31 (2) cause transient changes in ED symptoms across the menstrual cycle, (3) slow down metabolism, and (4) may increase fat mass and decrease lean mass concentrations during puberty and play a causal role in obesity once puberty is complete. Regarding leptin and ghrelin, (1) differences observed between individuals with an ED or obesity and healthy controls may be a consequence of the disorder, (2) changes in leptin and ghrelin may impact maintenance and relapse in EDs, (3) leptin resistance is involved in obesity, whereas ghrelin deficiency is protective, and (4) the impact of appetite hormones on an ED may be mediated through reproductive hormones.
REFERENCES 1. Culbert KM, Racine SE, Klump KL. Hormonal factors and disturbances in eating disorders. Curr Psychiatry Rep. 2016;18(7):65. 2. Wade GN. Some effects of ovarian hormones on food intake and body weight in female rats. J Comp Physiol Psychol. 1975;88(1):183–193. 3. Geary N, Asarian L. Cyclic estradiol treatment normalizes body weight and test meal size in ovariectomized rats. Physiol Behav. 1999;67(1):141–147. 4. Baker JH, Girdler SS, Bulik CM. The role of reproductive hormones in the development and maintenance of eating disorders. Expert Rev Obstet Gynecol. 2012;7(6):573–583. 5. Edler C, Lipson SF, Keel PK. Ovarian hormones and binge eating in bulimia nervosa. Psychol Med. 2007;37(1):131– 141. 6. Klump KL, Suisman JL, Culbert KM, Kashy DA, Keel PK, Sisk CL. The effects of ovariectomy on binge eating proneness in adult female rats. Horm Behav. 2011;59(4):585–593. 7. Klump KL, Keel PK, Racine SE, et al. The interactive effects of estrogen and progesterone on changes in emotional eating across the menstrual cycle. J Abnorm Psychol. 2013;122(1):131–137. 8. Misra M, Katzman D, Miller KK, et al. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J Bone Miner Res. 2011;26(10):2430–2438. 9. Naessén S, Carlström K, Byström B, Pierre Y, Hirschberg AL. Effects of an antiandrogenic oral contraceptive on appetite and eating behavior in bulimic women. Psychoneuroendocrinology. 2007;32(5):548–554.
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