Elsevier

The Lancet

Volume 366, Issue 9479, 2–8 July 2005, Pages 74-85
The Lancet

Review
Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa

https://doi.org/10.1016/S0140-6736(05)66830-4Get rights and content

Summary

Leptin is an adipocyte-secreted hormone that plays a key part in energy homoeostasis. Advances in leptin physiology have established that the main role of this hormone is to signal energy availability in energy-deficient states. Studies in animals and human beings have shown that low concentrations of leptin are fully or partly responsible for starvation-induced changes in neuroendocrine axes, including low reproductive, thyroid, and insulin-like growth factor (IGF) hormones. Disease states such as exercise-induced hypothalamic amenorrhoea and anorexia nervosa are also associated with low concentrations of leptin and a similar spectrum of neuroendocrine abnormalities. We have recently shown in an interventional, proof-of-concept study that leptin can restore ovulatory menstrual cycles and improve reproductive, thyroid, and IGF hormones and bone markers in hypothalamic amenorrhoea. Further studies are warranted to establish the safety and effectiveness of leptin for the infertility and osteoporosis associated with hypothalamic amenorrhoea, and to clarify its role in anorexia nervosa.

Introduction

In 1994, the discovery of leptin fundamentally changed our perspective of adipose tissue from that of an inert energy store to a true endocrine organ that secretes metabolically active hormones. Leptin was identified as the hormone whose absence resulted in morbid obesity in the ob/ob mouse,1 thus acquiring its name from the Greek word “leptos” (thin). Although initially hopes were high that leptin would prove important in the pathophysiology and thus treatment of human obesity, early studies quickly showed that human obesity is generally not associated with leptin deficiency due to a leptin gene defect,2 a finding not altogether surprising in view of the complex, multifactorial nature of obesity. It was also soon realised, however, that leptin might be more important at the other end of the energy homoeostasis spectrum—ie, energy deprivation rather than obesity. In this context, studies in mice3 and also in people4 have shown that leptin has a role in the neuroendocrine adaptation to starvation, which includes changes in hormone concentrations that probably have a protective effect. These findings are clinically relevant for common disease states associated with low leptin concentrations and neuroendocrine abnormalities—ie, energy-deficient states such as exercise-induced amenorrhoea, non-athletic forms of hypothalamic amenorrhoea, and anorexia nervosa. We review the role of leptin in neuroendocrine function, the reproductive and other neuroendocrine abnormalities associated with these energy-deficient conditions, and the evidence that low leptin concentrations could play a part in their pathophysiology and potentially their treatment. We also discuss the clinical relevance of these syndromes with respect to effect on fertility and skeletal health.

Section snippets

Leptin physiology

Leptin is a 167 aminoacid protein product of the ob gene that was discovered in 1994 through positional cloning in the ob/ob obese mouse, a model of morbid obesity resulting from absence of leptin due to a gene mutation.1 The tertiary structure of leptin suggests that it belongs to the cytokine family. Leptin is expressed mainly in white adipose tissue, but also in stomach, placenta, and the mammary gland.5 Leptin circulates in the serum in a free form or bound to leptin-binding proteins, and

Obesity: a high-leptin state

Leptin acts as a signal from the periphery to the brain, conveying information about the amount of energy available in adipose tissue or acute changes in energy availability (or both). Although leptin was originally discovered as an anti-obesity hormone, because congenital absence of leptin causes morbid obesity, the hope that leptin deficiency would play a part in the cause of common obesity in people has not been borne out. Rare cases of functional leptin deficiency due to mutations in the

Hypothalamic-pituitary-gonadal axis

Leptin acts by binding to specific leptin receptor isoforms (one long and several short), which are widely distributed in many tissues.5 The long isoform is expressed abundantly in the hypothalamus and activates mainly the Janus kinase signal transducer and activator of transcription system to change the expression of hypothalamic neuropeptides and thus regulate energy homoeostasis.19, 20 Leptin receptors have also been identified at all levels of this axis, including anterior pituitary,21

Exercise-induced amenorrhoea and other neuroendocrine abnormalities

Menstrual abnormalities arise commonly in association with intensive exercise and athletic sports. The reported frequency of amenorrhoea in female athletes varies widely from a few percent up to 50%, with a positive correlation with training intensity.48, 49, 50 Additionally, independent of training intensity, the type of activity is important with long-distance runners, gymnasts, and ballet dancers (sports that favour a leaner physique) having a particularly high rate of amenorrhoea (40–50%)

Clinical relevance: infertility and osteoporosis

Hypothalamic amenorrhoea is associated with substantial morbidity in terms of fertility and skeletal health. In developed countries, infertility affects 10–20% of couples.115 Infertility is attributable to the female partner in 37% of couples and to both partners in 35%.52 Ovulatory disorders account for 25% of the disease states causing infertility in women, with the most common cause of anovulation being hypothalamic dysfunction (38%).52 At the moment, treatment with injectable gonadotropins

Conclusion and future directions

Much research on leptin, stimulated by intense interest since its discovery in 1994, has transformed and refined our understanding of this molecule. From the initial simplistic view of leptin as an adipocyte-derived hormone that acts in a negative feedback loop with the brain to decrease appetite, we now have a far greater although still incomplete understanding of the pleiotropic nature of this hormone, which affects physiological processes as diverse as neuroendocrine, metabolic, immune, and

Search strategy and selection criteria

We searched MEDLINE for articles relating “leptin” to “hypothalamic-pituitary-peripheral axes”, “neuroendocrine function”, “hypothalamic amenorrhea”, “exercise-induced amenorrhea”, and “anorexia nervosa”, with emphasis on articles on human beings.

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