Review
Endocrine consequences of anorexia nervosa Madhusmita Misra, Anne Klibanski
Anorexia nervosa is prevalent in adolescents and young adults, and endocrine changes include hypothalamic amenorrhoea; a nutritionally acquired growth-hormone resistance leading to low concentrations of insulin-like growth factor-1 (IGF-1); relative hypercortisolaemia; decreases in leptin, insulin, amylin, and incretins; and increases in ghrelin, peptide YY, and adiponectin. These changes in turn have harmful effects on bone and might affect neurocognition, anxiety, depression, and the psychopathology of anorexia nervosa. Low bone-mineral density (BMD) is particularly concerning, because it is associated with changes in bone microarchitecture, strength, and clinical fractures. Recovery leads to improvements in many—but not all—hormonal changes, and deficits in bone accrual can persist. Oestrogen-replacement therapy, primarily via the transdermal route, increases BMD in adolescents, although catch-up is incomplete. In adults, oral oestrogen—combined with recombinant human IGF-1 in one study and bisphosphonates in another—increased BMD, but not to the normal range. More studies are necessary to investigate the optimum therapeutic approach in patients with, or recovering from, anorexia nervosa.
Introduction
Nutrient intake and resting energy expenditure
Anorexia nervosa is a prevalent cause of severe undernutrition in adolescent girls and young women, and affects 0·2–1·0% of these populations in developed countries.1–5 The disorder is characterised by an altered body image and very low weight, and is associated with an inability to gain or maintain weight. In girls and women amenorrhoea (for at least three cycles) was included in the diagnosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV criteria,6 but the weight criteria in DSM 5 have become less stringent, and amenorrhoea is no longer a defining criterion.7 The disorder occurs predominantly in girls and women, and most frequently begins during adolescence.8,9 Boys and young men comprise 10% of all diagnosed cases,10 although some studies suggest the prevalence could be higher.5 In response to the severe energy restriction, alterations occur in many endocrine axes—most of which are adaptive—to stimulate food intake, help maintain euglycaemia, and divert available energy for essential body functions. Hypothalamic oligoamenorrhoea in anorexia nervosa leads to infertility that typically reverses with restoration of a stable weight.11,12 Hormonal alterations contribute to low bone-mineral density (BMD), which substantially increases the risk of fractures.13 Furthermore, neuropsychiatric comorbidities, such as anxiety and depressive symptoms, might be associated with hormonal changes in anorexia nervosa.14–17 Although 50% of adults with anorexia nervosa recover after behavioural, psychiatric, and medical therapy,18 about 30% only partly recover, and the remainder are characterised by remission and relapse or chronic disease.19,20 Of major concern is the high risk of suicide, which is a common cause of death in patients with anorexia nervosa.21 Among adolescents with anorexia nervosa, relapses are seen after inpatient hospital admissions and before medical recovery in 30% of patients, although 70–75% completely recover over 5–10 years, with a low risk of relapse.22,23 About 30% of patients will develop binge-eating behaviours in the long term.22
Macronutrients Individuals with anorexia nervosa have lower total caloric intake than normal-weight controls, primarily due to substantial reductions in fat intake, but also from some decreases in protein and carbohydrate intake.24,25 Reduced fat intake is associated with reduced fat mass.24 Individuals with anorexia nervosa have lower resting energy expenditure than normal-weight controls,24 probably because of an adaptive mechanism to preserve energy for vital functions. Consistent with findings of reduced resting energy expenditure, the proportion of brown adipose tissue (a form of fat responsible for thermogenesis26) is also reduced.27 Another study showed that individuals with anorexia nervosa had lower resting metabolic rates and lower energy intake than constitutionally thin individuals and normal-weight controls.28
Lancet Diabetes Endocrinol 2014 Published Online April 2, 2014 http://dx.doi.org/10.1016/ S2213-8587(13)70180-3 Neuroendocrine Unit and Pediatric Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA (M Misra MD, Prof A Klibanski MD) Correspondence to: Dr Madhusmita Misra, BUL 457, Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA [email protected]
Micronutrients Intake of saturated and unsaturated fat is lower in individuals with anorexia nervosa than in controls; whereas intake is higher for soluble and insoluble fibre, oxalates, and phytates,24 which could potentially reduce absorption of other nutrients. Thus, attention to diet composition is important. Vitamin intake from diet and supplements, including of vitamin D, is typically higher in individuals with anorexia nervosa than in controls, mostly because of greater use of supplements. In a study of teenagers with anorexia nervosa, 76% of girls, compared with 50% of controls, achieved recommended dietary intake of vitamin D.24 Another study found a lower prevalence of vitamin D deficiency in adolescents with anorexia nervosa than in controls (2% vs 24%).29 Similarly, intakes of calcium, magnesium, and zinc are generally higher in individuals with anorexia nervosa than in controls, and about 59% of girls with anorexia nervosa compared with 30% of controls achieve the recommended dietary intake for calcium.24
www.thelancet.com/diabetes-endocrinology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(13)70180-3
1
Review
A
B Anorexia nervosa
Normal-weight control
7
*
6
30 Mean GH (μg/L)
25 20 15 10
5 4 3 2
5
1
0
0
3·5
104·8
3·0 78·6
2·5
IGF-1 (nmol/L)
Hormone secretion (μg L–1 min –1)
Hormone concentration (μg/L)
35
2·0 1·5 1·0
* 52·4 26·2
0·5 0
0 0
100
200
300 400 500 Time (min)
600 700
800
0
100
200
300 400 500 Time (min)
600 700
800
Anorexia nervosa
Controls
Figure 1: Effects of anorexia nervosa on concentrations of growth hormone and IGF-1 (A) Representative overnight growth-hormone secretory characteristics: secretion is greater in a teenage girl with anorexia nervosa than in a normal-weight control. (B) Mean overnight growth-hormone concentrations and fasting IGF-1 concentrations in 22 adolescent girls with anorexia nervosa and 20 normal-weight controls: the girls with anorexia nervosa have lower IGF-1 levels than controls despite higher growth-hormone concentrations. IFG-1=insulin-like growth factor 1. *p
Endocrine consequences of anorexia nervosa Madhusmita Misra, Anne Klibanski
Anorexia nervosa is prevalent in adolescents and young adults, and endocrine changes include hypothalamic amenorrhoea; a nutritionally acquired growth-hormone resistance leading to low concentrations of insulin-like growth factor-1 (IGF-1); relative hypercortisolaemia; decreases in leptin, insulin, amylin, and incretins; and increases in ghrelin, peptide YY, and adiponectin. These changes in turn have harmful effects on bone and might affect neurocognition, anxiety, depression, and the psychopathology of anorexia nervosa. Low bone-mineral density (BMD) is particularly concerning, because it is associated with changes in bone microarchitecture, strength, and clinical fractures. Recovery leads to improvements in many—but not all—hormonal changes, and deficits in bone accrual can persist. Oestrogen-replacement therapy, primarily via the transdermal route, increases BMD in adolescents, although catch-up is incomplete. In adults, oral oestrogen—combined with recombinant human IGF-1 in one study and bisphosphonates in another—increased BMD, but not to the normal range. More studies are necessary to investigate the optimum therapeutic approach in patients with, or recovering from, anorexia nervosa.
Introduction
Nutrient intake and resting energy expenditure
Anorexia nervosa is a prevalent cause of severe undernutrition in adolescent girls and young women, and affects 0·2–1·0% of these populations in developed countries.1–5 The disorder is characterised by an altered body image and very low weight, and is associated with an inability to gain or maintain weight. In girls and women amenorrhoea (for at least three cycles) was included in the diagnosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV criteria,6 but the weight criteria in DSM 5 have become less stringent, and amenorrhoea is no longer a defining criterion.7 The disorder occurs predominantly in girls and women, and most frequently begins during adolescence.8,9 Boys and young men comprise 10% of all diagnosed cases,10 although some studies suggest the prevalence could be higher.5 In response to the severe energy restriction, alterations occur in many endocrine axes—most of which are adaptive—to stimulate food intake, help maintain euglycaemia, and divert available energy for essential body functions. Hypothalamic oligoamenorrhoea in anorexia nervosa leads to infertility that typically reverses with restoration of a stable weight.11,12 Hormonal alterations contribute to low bone-mineral density (BMD), which substantially increases the risk of fractures.13 Furthermore, neuropsychiatric comorbidities, such as anxiety and depressive symptoms, might be associated with hormonal changes in anorexia nervosa.14–17 Although 50% of adults with anorexia nervosa recover after behavioural, psychiatric, and medical therapy,18 about 30% only partly recover, and the remainder are characterised by remission and relapse or chronic disease.19,20 Of major concern is the high risk of suicide, which is a common cause of death in patients with anorexia nervosa.21 Among adolescents with anorexia nervosa, relapses are seen after inpatient hospital admissions and before medical recovery in 30% of patients, although 70–75% completely recover over 5–10 years, with a low risk of relapse.22,23 About 30% of patients will develop binge-eating behaviours in the long term.22
Macronutrients Individuals with anorexia nervosa have lower total caloric intake than normal-weight controls, primarily due to substantial reductions in fat intake, but also from some decreases in protein and carbohydrate intake.24,25 Reduced fat intake is associated with reduced fat mass.24 Individuals with anorexia nervosa have lower resting energy expenditure than normal-weight controls,24 probably because of an adaptive mechanism to preserve energy for vital functions. Consistent with findings of reduced resting energy expenditure, the proportion of brown adipose tissue (a form of fat responsible for thermogenesis26) is also reduced.27 Another study showed that individuals with anorexia nervosa had lower resting metabolic rates and lower energy intake than constitutionally thin individuals and normal-weight controls.28
Lancet Diabetes Endocrinol 2014 Published Online April 2, 2014 http://dx.doi.org/10.1016/ S2213-8587(13)70180-3 Neuroendocrine Unit and Pediatric Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA (M Misra MD, Prof A Klibanski MD) Correspondence to: Dr Madhusmita Misra, BUL 457, Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA [email protected]
Micronutrients Intake of saturated and unsaturated fat is lower in individuals with anorexia nervosa than in controls; whereas intake is higher for soluble and insoluble fibre, oxalates, and phytates,24 which could potentially reduce absorption of other nutrients. Thus, attention to diet composition is important. Vitamin intake from diet and supplements, including of vitamin D, is typically higher in individuals with anorexia nervosa than in controls, mostly because of greater use of supplements. In a study of teenagers with anorexia nervosa, 76% of girls, compared with 50% of controls, achieved recommended dietary intake of vitamin D.24 Another study found a lower prevalence of vitamin D deficiency in adolescents with anorexia nervosa than in controls (2% vs 24%).29 Similarly, intakes of calcium, magnesium, and zinc are generally higher in individuals with anorexia nervosa than in controls, and about 59% of girls with anorexia nervosa compared with 30% of controls achieve the recommended dietary intake for calcium.24
www.thelancet.com/diabetes-endocrinology Published online April 2, 2014 http://dx.doi.org/10.1016/S2213-8587(13)70180-3
1
Review
A
B Anorexia nervosa
Normal-weight control
7
*
6
30 Mean GH (μg/L)
25 20 15 10
5 4 3 2
5
1
0
0
3·5
104·8
3·0 78·6
2·5
IGF-1 (nmol/L)
Hormone secretion (μg L–1 min –1)
Hormone concentration (μg/L)
35
2·0 1·5 1·0
* 52·4 26·2
0·5 0
0 0
100
200
300 400 500 Time (min)
600 700
800
0
100
200
300 400 500 Time (min)
600 700
800
Anorexia nervosa
Controls
Figure 1: Effects of anorexia nervosa on concentrations of growth hormone and IGF-1 (A) Representative overnight growth-hormone secretory characteristics: secretion is greater in a teenage girl with anorexia nervosa than in a normal-weight control. (B) Mean overnight growth-hormone concentrations and fasting IGF-1 concentrations in 22 adolescent girls with anorexia nervosa and 20 normal-weight controls: the girls with anorexia nervosa have lower IGF-1 levels than controls despite higher growth-hormone concentrations. IFG-1=insulin-like growth factor 1. *p
