The endocrine manifestations of anorexia nervosa: mechanisms and management

Abstract

Anorexia nervosa is a psychiatric disorder characterized by altered body image, persistent food restriction and low body weight, and is associated with global endocrine dysregulation in both adolescent girls and women. Dysfunction of the hypothalamic-pituitary axis includes hypogonadotropic hypogonadism with relative oestrogen and androgen deficiency, growth hormone resistance, hypercortisolaemia, non-thyroidal illness syndrome, hyponatraemia and hypooxytocinaemia. Serum levels of leptin, an anorexigenic adipokine, are suppressed and levels of ghrelin, an orexigenic gut peptide, are elevated in women with anorexia nervosa; however, levels of peptide YY, an anorexigenic gut peptide, are paradoxically elevated. Although most, but not all, of these endocrine disturbances are adaptive to the low energy state of chronic starvation and reverse with treatment of the eating disorder, many contribute to impaired skeletal integrity, as well as neuropsychiatric comorbidities, in individuals with anorexia nervosa. Although 5-15% of patients with anorexia nervosa are men, only limited data exist regarding the endocrine impact of the disease in adolescent boys and men. Further research is needed to understand the endocrine determinants of bone loss and neuropsychiatric comorbidities in anorexia nervosa in both women and men, as well as to formulate optimal treatment strategies.

Figure 1. Endocrine dysregulation in anorexia nervosa

Endocrine abnormalities in anorexia nervosa are likely adaptive to the state of chronic starvation except for elevated levels of peptide YY (PYY). Anorexia nervosa commonly results in hypothalamic amenorrhea, with reduced gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) pulsatility and resultant low estradiol and testosterone levels. Anorexia nervosa is a state of acquired growth hormone (GH) resistance, characterized by increased GH secretion and decreased systemic insulin-like growth factor 1 (IGF1) levels. The hypothalamic-pituitary-adrenal axis may be in a chronically stimulated state, with elevated levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol. Nonthyroidal illness syndrome, characterized by low levels of T₃ levels, might be present. Anti-diuretic hormone (ADH) might be inappropriately secreted, resulting in free water retention in the kidneys and hyponatremia. The adipokine, leptin, is low in anorexia nervosa due to reduced fat mass, whereas adiponectin levels have been variably reported to be unchanged, increased or reduced. The orexigenic hormone, ghrelin, is elevated, but the anorexigenic hormone PYY is paradoxically also elevated. * factors whose levels are variably reported to be unchanged, elevated or reduced. DHEAS, dehydroepiandrosterone sulphate.

Figure 2. The effect of endocrine dysregulation on the bone microenvironment

Bone marrow adipose tissue is paradoxically elevated in anorexia nervosa despite reduced total body fat. Elevated levels of Pref1, which are an important regulator of mesenchymal stem cell differentiation, may be one of the mechanisms underlying the increase in bone marrow adipose tissue. Overall, a decrease in osteoblast differentiation, proliferation and activity with a concomitant increase in osteoblast apoptosis is seen, in addition to an increase in osteoclast differentiation, proliferation and activity with a concomitant decrease in osteoclast apoptosis. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) stimulate osteoblast differentiation while inhibiting osteoclast differentiation, and GH independently stimulates osteoblast proliferation. In contrast, cortisol decreases bone formation and increases bone resorption. Both oestrogen and testosterone stimulate bone formation and inhibit bone resorption. Alterations in adipokines, such as leptin and adipokine, and appetite-regulating hormones, such as peptide YY (PYY), might also contribute to impaired bone microarchitecture in anorexia nervosa but are not well understood. * Hormone effect for which there are limited data. +, positive effect; -, negative effect.