Anorexia nervosa: Endocrine complications and their management
- Elizabeth A Lawson, MD, MMSc
Elizabeth A Lawson, MD, MMSc
- Assistant Professor of Medicine
- Harvard Medical School
- Karen K Miller, MD
Karen K Miller, MD
- Professor of Medicine
- Harvard Medical School
- Section Editors
- Robert L Barbieri, MD
Robert L Barbieri, MD
- Editor-in-Chief — Obstetrics, Gynecology and Women's Health
- Section Editor — General Gynecology and Female Reproductive Endocrinology
- Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology
- Harvard Medical School
- Joel Yager, MD
Joel Yager, MD
- Section Editor — Eating Disorders
- Professor of Psychiatry
- University of Colorado School of Medicine
Anorexia nervosa (AN) is a disorder characterized by severe restriction of nutritional intake, despite extremely low body weight, that predominantly affects young women . In addition to restricting food intake, some women with AN binge eat and/or purge. AN is associated with significant medical complications, including endocrine dysfunction, and the highest mortality rate of any psychiatric disorder . Endocrine complications are significant and include hypothalamic-pituitary abnormalities that contribute to severe bone loss.
The pathophysiology, clinical manifestations, evaluation, and management of endocrine complications in AN are reviewed here. The medical complications of AN and their management, as well as other aspects of eating disorders and their management, are found separately. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management" and "Eating disorders: Overview of epidemiology, clinical features, and diagnosis" and "Eating disorders: Overview of treatment".)
Anorexia nervosa (AN) is associated with multiple endocrine abnormalities, primarily in neuroendocrine axes [3-5]. Some of the endocrine abnormalities in AN represent physiologic adaptive responses to chronic starvation and serve to shunt limited resources to the most essential physiologic processes. Others are present even after weight recovery, suggesting a potential role in disease pathophysiology or lagging recovery of endocrine dysregulation. Some contribute to the development of low bone density, one of the serious endocrine consequences of AN. In addition to bone loss, other important endocrine consequences of AN include amenorrhea (and as a result, anovulatory infertility) and hyper- or hyponatremia.
Hypothalamic-pituitary abnormalities — AN affects multiple hypothalamic-pituitary axes, which results in abnormal levels of several hormones.
Reproductive — Suppression of the hypothalamic-pituitary-ovarian axis results in hypogonadotropic hypogonadism with amenorrhea, estradiol deficiency, and infertility . Amenorrhea is thought to be due to the relative energy deficit associated with AN, low fat mass, and possibly changes in the hormone leptin. (See 'Appetite-regulating hormones' below.)
- Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR, 4th, American Psychiatric Association, Washington, DC 2000.
- Keel PK, Dorer DJ, Eddy KT, et al. Predictors of mortality in eating disorders. Arch Gen Psychiatry 2003; 60:179.
- Miller KK. Endocrine dysregulation in anorexia nervosa update. J Clin Endocrinol Metab 2011; 96:2939.
- Lawson EA, Klibanski A. Endocrine abnormalities in anorexia nervosa. Nat Clin Pract Endocrinol Metab 2008; 4:407.
- Singhal V, Misra M, Klibanski A. Endocrinology of anorexia nervosa in young people: recent insights. Curr Opin Endocrinol Diabetes Obes 2014; 21:64.
- Boyar RM, Katz J, Finkelstein JW, et al. Anorexia nervosa. Immaturity of the 24-hour luteinizing hormone secretory pattern. N Engl J Med 1974; 291:861.
- Devlin MJ, Walsh BT, Katz JL, et al. Hypothalamic-pituitary-gonadal function in anorexia nervosa and bulimia. Psychiatry Res 1989; 28:11.
- Katz JL, Boyar R, Roffwarg H, et al. Weight and circadian luteinizing hormone secretory pattern in anorexia nervosa. Psychosom Med 1978; 40:549.
- Biller BM, Saxe V, Herzog DB, et al. Mechanisms of osteoporosis in adult and adolescent women with anorexia nervosa. J Clin Endocrinol Metab 1989; 68:548.
- Grinspoon S, Miller K, Coyle C, et al. Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab 1999; 84:2049.
- Miller KK, Lawson EA, Mathur V, et al. Androgens in women with anorexia nervosa and normal-weight women with hypothalamic amenorrhea. J Clin Endocrinol Metab 2007; 92:1334.
- Lawson EA, Miller KK, Bredella MA, et al. Hormone predictors of abnormal bone microarchitecture in women with anorexia nervosa. Bone 2010; 46:458.
- Lawson EA, Misra M, Meenaghan E, et al. Adrenal glucocorticoid and androgen precursor dissociation in anorexia nervosa. J Clin Endocrinol Metab 2009; 94:1367.
- Jacoangeli F, Masala S, Staar Mezzasalma F, et al. Amenorrhea after weight recover in anorexia nervosa: role of body composition and endocrine abnormalities. Eat Weight Disord 2006; 11:e20.
- Gold PW, Gwirtsman H, Avgerinos PC, et al. Abnormal hypothalamic-pituitary-adrenal function in anorexia nervosa. Pathophysiologic mechanisms in underweight and weight-corrected patients. N Engl J Med 1986; 314:1335.
- Putignano P, Dubini A, Toja P, et al. Salivary cortisol measurement in normal-weight, obese and anorexic women: comparison with plasma cortisol. Eur J Endocrinol 2001; 145:165.
- dos Santos E, dos Santos JE, Ribeiro RP, et al. Absence of circadian salivary cortisol rhythm in women with anorexia nervosa. J Pediatr Adolesc Gynecol 2007; 20:13.
- Hotta M, Shibasaki T, Masuda A, et al. The responses of plasma adrenocorticotropin and cortisol to corticotropin-releasing hormone (CRH) and cerebrospinal fluid immunoreactive CRH in anorexia nervosa patients. J Clin Endocrinol Metab 1986; 62:319.
- Misra M, Miller KK, Almazan C, et al. Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 2004; 89:4972.
- Lawson EA, Donoho D, Miller KK, et al. Hypercortisolemia is associated with severity of bone loss and depression in hypothalamic amenorrhea and anorexia nervosa. J Clin Endocrinol Metab 2009; 94:4710.
- Støving RK, Veldhuis JD, Flyvbjerg A, et al. Jointly amplified basal and pulsatile growth hormone (GH) secretion and increased process irregularity in women with anorexia nervosa: indirect evidence for disruption of feedback regulation within the GH-insulin-like growth factor I axis. J Clin Endocrinol Metab 1999; 84:2056.
- Misra M, Miller KK, Bjornson J, et al. Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 2003; 88:5615.
- Støving RK, Chen JW, Glintborg D, et al. Bioactive insulin-like growth factor (IGF) I and IGF-binding protein-1 in anorexia nervosa. J Clin Endocrinol Metab 2007; 92:2323.
- Soyka LA, Misra M, Frenchman A, et al. Abnormal bone mineral accrual in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 2002; 87:4177.
- Grinspoon S, Baum H, Lee K, et al. Effects of short-term recombinant human insulin-like growth factor I administration on bone turnover in osteopenic women with anorexia nervosa. J Clin Endocrinol Metab 1996; 81:3864.
- Croxson MS, Ibbertson HK. Low serum triiodothyronine (T3) and hypothyroidism in anorexia nervosa. J Clin Endocrinol Metab 1977; 44:167.
- Leslie RD, Isaacs AJ, Gomez J, et al. Hypothalamo-pituitary-thyroid function in anorexia nervosa: influence of weight gain. Br Med J 1978; 2:526.
- Kiyohara K, Tamai H, Takaichi Y, et al. Decreased thyroidal triiodothyronine secretion in patients with anorexia nervosa: influence of weight recovery. Am J Clin Nutr 1989; 50:767.
- Onur S, Haas V, Bosy-Westphal A, et al. L-tri-iodothyronine is a major determinant of resting energy expenditure in underweight patients with anorexia nervosa and during weight gain. Eur J Endocrinol 2005; 152:179.
- Gold PW, Kaye W, Robertson GL, Ebert M. Abnormalities in plasma and cerebrospinal-fluid arginine vasopressin in patients with anorexia nervosa. N Engl J Med 1983; 308:1117.
- Caregaro L, Di Pascoli L, Favaro A, et al. Sodium depletion and hemoconcentration: overlooked complications in patients with anorexia nervosa? Nutrition 2005; 21:438.
- Bahia A, Chu ES, Mehler PS. Polydipsia and hyponatremia in a woman with anorexia nervosa. Int J Eat Disord 2011; 44:186.
- Evrard F, da Cunha MP, Lambert M, Devuyst O. Impaired osmoregulation in anorexia nervosa: a case-control study. Nephrol Dial Transplant 2004; 19:3034.
- Chiodera P, Volpi R, Capretti L, et al. Effect of estrogen or insulin-induced hypoglycemia on plasma oxytocin levels in bulimia and anorexia nervosa. Metabolism 1991; 40:1226.
- Lawson EA, Donoho DA, Blum JI, et al. Decreased nocturnal oxytocin levels in anorexia nervosa are associated with low bone mineral density and fat mass. J Clin Psychiatry 2011; 72:1546.
- Lawson EA, Holsen LM, Santin M, et al. Oxytocin secretion is associated with severity of disordered eating psychopathology and insular cortex hypoactivation in anorexia nervosa. J Clin Endocrinol Metab 2012; 97:E1898.
- Lawson EA, Holsen LM, Santin M, et al. Postprandial oxytocin secretion is associated with severity of anxiety and depressive symptoms in anorexia nervosa. J Clin Psychiatry 2013; 74:e451.
- Grinspoon S, Gulick T, Askari H, et al. Serum leptin levels in women with anorexia nervosa. J Clin Endocrinol Metab 1996; 81:3861.
- Misra M, Miller KK, Kuo K, et al. Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents. Am J Physiol Endocrinol Metab 2005; 289:E373.
- Gendall KA, Kaye WH, Altemus M, et al. Leptin, neuropeptide Y, and peptide YY in long-term recovered eating disorder patients. Biol Psychiatry 1999; 46:292.
- Otto B, Cuntz U, Fruehauf E, et al. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 2001; 145:669.
- Misra M, Miller KK, Kuo K, et al. Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents. Am J Physiol Endocrinol Metab 2005; 289:E347.
- Misra M, Miller KK, Tsai P, et al. Elevated peptide YY levels in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 2006; 91:1027.
- Pfluger PT, Kampe J, Castaneda TR, et al. Effect of human body weight changes on circulating levels of peptide YY and peptide YY3-36. J Clin Endocrinol Metab 2007; 92:583.
- Grinspoon S, Thomas E, Pitts S, et al. Prevalence and predictive factors for regional osteopenia in women with anorexia nervosa. Ann Intern Med 2000; 133:790.
- Bredella MA, Misra M, Miller KK, et al. Distal radius in adolescent girls with anorexia nervosa: trabecular structure analysis with high-resolution flat-panel volume CT. Radiology 2008; 249:938.
- Bredella MA, Fazeli PK, Miller KK, et al. Increased bone marrow fat in anorexia nervosa. J Clin Endocrinol Metab 2009; 94:2129.
- Walsh CJ, Phan CM, Misra M, et al. Women with anorexia nervosa: finite element and trabecular structure analysis by using flat-panel volume CT. Radiology 2010; 257:167.
- Bachmann KN, Fazeli PK, Lawson EA, et al. Comparison of hip geometry, strength, and estimated fracture risk in women with anorexia nervosa and overweight/obese women. J Clin Endocrinol Metab 2014; 99:4664.
- Vestergaard P, Emborg C, Støving RK, et al. Fractures in patients with anorexia nervosa, bulimia nervosa, and other eating disorders--a nationwide register study. Int J Eat Disord 2002; 32:301.
- Rigotti NA, Neer RM, Skates SJ, et al. The clinical course of osteoporosis in anorexia nervosa. A longitudinal study of cortical bone mass. JAMA 1991; 265:1133.
- Utz AL, Lawson EA, Misra M, et al. Peptide YY (PYY) levels and bone mineral density (BMD) in women with anorexia nervosa. Bone 2008; 43:135.
- Miller KK, Grinspoon S, Gleysteen S, et al. Preservation of neuroendocrine control of reproductive function despite severe undernutrition. J Clin Endocrinol Metab 2004; 89:4434.
- Castro J, Toro J, Lazaro L, et al. Bone mineral density in male adolescents with anorexia nervosa. J Am Acad Child Adolesc Psychiatry 2002; 41:613.
- Mehler PS, Sabel AL, Watson T, Andersen AE. High risk of osteoporosis in male patients with eating disorders. Int J Eat Disord 2008; 41:666.
- Misra M, Katzman DK, Cord J, et al. Bone metabolism in adolescent boys with anorexia nervosa. J Clin Endocrinol Metab 2008; 93:3029.
- Misra M, Katzman DK, Clarke H, et al. Hip structural analysis in adolescent boys with anorexia nervosa and controls. J Clin Endocrinol Metab 2013; 98:2952.
- Gaudiani JL, Sabel AL, Mascolo M, Mehler PS. Severe anorexia nervosa: outcomes from a medical stabilization unit. Int J Eat Disord 2012; 45:85.
- Kohn MR, Madden S, Clarke SD. Refeeding in anorexia nervosa: increased safety and efficiency through understanding the pathophysiology of protein calorie malnutrition. Curr Opin Pediatr 2011; 23:390.
- Díaz M, Becker DE. Thermoregulation: physiological and clinical considerations during sedation and general anesthesia. Anesth Prog 2010; 57:25.
- Miller KK, Grinspoon SK, Ciampa J, et al. Medical findings in outpatients with anorexia nervosa. Arch Intern Med 2005; 165:561.
- Miller KK, Lee EE, Lawson EA, et al. Determinants of skeletal loss and recovery in anorexia nervosa. J Clin Endocrinol Metab 2006; 91:2931.
- Pitts S, Blood E, Divasta A, Gordon CM. Percentage body fat by dual-energy X-ray absorptiometry is associated with menstrual recovery in adolescents with anorexia nervosa. J Adolesc Health 2014; 54:739.
- Eagles JM, Lee AJ, Raja EA, et al. Pregnancy outcomes of women with and without a history of anorexia nervosa. Psychol Med 2012; 42:2651.
- Bansil P, Kuklina EV, Whiteman MK, et al. Eating disorders among delivery hospitalizations: prevalence and outcomes. J Womens Health (Larchmt) 2008; 17:1523.
- Waugh EJ, Woodside DB, Beaton DE, et al. Effects of exercise on bone mass in young women with anorexia nervosa. Med Sci Sports Exerc 2011; 43:755.
- Dominguez J, Goodman L, Sen Gupta S, et al. Treatment of anorexia nervosa is associated with increases in bone mineral density, and recovery is a biphasic process involving both nutrition and return of menses. Am J Clin Nutr 2007; 86:92.
- Herzog W, Minne H, Deter C, et al. Outcome of bone mineral density in anorexia nervosa patients 11.7 years after first admission. J Bone Miner Res 1993; 8:597.
- Muñoz MT, Morandé G, García-Centenera JA, et al. The effects of estrogen administration on bone mineral density in adolescents with anorexia nervosa. Eur J Endocrinol 2002; 146:45.
- Golden NH, Lanzkowsky L, Schebendach J, et al. The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa. J Pediatr Adolesc Gynecol 2002; 15:135.
- Strokosch GR, Friedman AJ, Wu SC, Kamin M. Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study. J Adolesc Health 2006; 39:819.
- 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; 26:2430.
- Grinspoon S, Thomas L, Miller K, et al. Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa. J Clin Endocrinol Metab 2002; 87:2883.
- Miller KK, Meenaghan E, Lawson EA, et al. Effects of risedronate and low-dose transdermal testosterone on bone mineral density in women with anorexia nervosa: a randomized, placebo-controlled study. J Clin Endocrinol Metab 2011; 96:2081.
- Golden NH, Iglesias EA, Jacobson MS, et al. Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2005; 90:3179.
- Fazeli PK, Wang IS, Miller KK, et al. Teriparatide increases bone formation and bone mineral density in adult women with anorexia nervosa. J Clin Endocrinol Metab 2014; 99:1322.
- Hypothalamic-pituitary abnormalities
- - Reproductive
- - Adrenal
- - Growth hormone
- - Thyroid
- - Posterior pituitary
- Appetite-regulating hormones
- Males with AN
- CLINICAL MANIFESTATIONS
- Physical findings
- Laboratory and imaging data
- SUGGESTED EVALUATION
- Biochemical and bone density testing
- Reproductive dysfunction
- "Euthyroid-sick" syndrome
- Bone loss
- - Estrogen therapy
- - rhIGF-1
- - Bisphosphonates
- - Teriparatide
- Water balance
- SUMMARY AND RECOMMENDATIONS