Prof. Kang Chen
The First Medical Center of the General Hospital of the Chinese People's Liberation Army
Anorexia nervosa can actually be classified as a disorder in the psychological domain, but there may be a substantial hormone-related pathophysiological basis. Case studies of patients with anorexia nervosa have shown psychological improvements after treatment with recombinant human leptin, including a reduction in the constraints of this eating disorder. Hypoleptinomia due to loss of adipose tissue mass may trigger the psychological changes observed during starvation. Thus, leptin analogues may prove beneficial in the treatment of anorexia nervosa.
Leptin replacement therapy –
Can the predicament of anorexia nervosa be ended?
Starvation leads to a decrease in the synthesis and secretion of the leptin hormone. Hypoleptinemia subsequently serves as the main signal of hormonal adaptation at starvation, including well-known alterations in the hypothalamic-pituitary-endocrine organ axis. This neuroendocrine adaptation can be attenuated if exogenous leptin is administered to food-restricted animals. In human studies, treatment with recombinant human leptin (metreleptin/metreplatin) for 36 weeks improved reproductive function in women with hypothalamic amenorrhea secondary to underweight or strenuous exercise.
Leptin receptors (LEPR-202), which are essential for intracellular signaling, are found in a variety of peripheral tissues, such as hair follicles, skin, endothelial cells, bone, bone marrow, liver, gastrointestinal tract, and autonomic nervous system. Thus, hypoleptinogenemia may directly trigger many starvation-induced adaptations and may represent a potential mechanism to explain the various somatic symptoms of anorexia nervosa. Similarly, leptin receptors in various brain regions, including the hypothalamus, amygdala, hippocampus, and cerebellum, may modulate complex neuronal adaptations to hunger, leading to emotional, cognitive, and behavioral changes. Hunger situations require a visible response from all tissues to reduce energy expenditure in order to increase the likelihood of survival. However, foraging behavior in some species suggests that locomotor activity may increase intermittently during periods of starvation. Notably, in a rat model of anorexia nervosa, starvation-induced hypoleptinemia triggered an increase in running wheel activity, thereby confirming the critical role of leptin in behavioral adaptation to food restriction.
Anorexia nervosa usually begins during adolescence with a lifetime prevalence of 1.0% in women and <0.5% in men, and is associated with weight loss, to the point that starvation symptoms follow. In fact, anorexia nervosa has the highest mortality rate of all mental illnesses, with starvation and suicide being the leading causes of death. The patient seems to be in a predicament from which he cannot extricate himself: despite being focused on food, a deep fear of weight gain causes the patient to eat too little to normalize the quality of his adipose tissue. Habitual behaviors mediated by the dorsal frontostriatum nervous system may play a role in the persistence of anorexia nervosa, particularly maladaptive eating behaviors.
The endocrine disruption of anorexia nervosa adapts to the low-energy state of chronic starvation and is reversed with treatment-induced weight regain. Hypoleptinomia due to low quality of adipose tissue is a core endocrine feature of anorexia nervosa. Based on the hypothesis that addressing hypoleptinemia, i.e., leptin replacement (Figure 1) improves clinical symptoms, data have been published to date on five patients with anorexia treated with metreplastine off-label (non-indicated). Psychological improvement begins within 2-5 days. Improvement in sleep, mood, and concentration compared to baseline; Irritability, rigid thinking, and an important focus on food and weight are all reduced. In addition, an increase in white and red blood cell counts, improved wound healing, increased skin elasticity, and relief of constipation were observed. Patients describe the "comfort period" experience they have from eating disorders, allowing them to assess their own situation outside the "cage" imposed by anorexia nervosa (i.e.: patients with anorexia being treated are able to temporarily recover from their eating disorder through leptin replacement therapy; This temporary relief gives them the opportunity to objectively assess their condition without being affected by anorexia. The "cage" here is a metaphor that refers to the restrictions and constraints that anorexia places on the patient's life. With treatment, patients are able to break this restriction and become more aware of their problems, thus helping them recover). Some patients experience appetite and hunger again during dosing. One male patient described recurrence. Metriprine appears to rapidly improve several symptoms of anorexia nervosa through specific central and peripheral pathways downstream of leptin receptors.
Figure 1: A hypothetical model of hypoleptinemia in anorexia nervosa
Hypothesis: A hypothetical model and possible treatment of hunger symptoms caused by hypoleptinogenemia in anorexia nervosa.
What is the etiological and clinical significance of the observed improvement in patients with anorexia nervosa after treatment with metreplatin?
Some experts in the field have proposed that anorexia nervosa can be conceptualized to some extent as a hormone deficiency. The intense focus on food caused by hypoleptinemia will represent an adaptive strategy to increase the likelihood of energy intake. Other symptoms, especially fatigue and depression, may require reduced energy expenditure. Hypoleptinemia may also be the basis for this characteristic of eating disorder (or "addiction" to hunger).
Keys et al., who conducted the Minnesota Hunger Experiment from 1944 to 1945, coined the term "semi-starvation neurosis" to describe profound psychological changes during a 24-week period of starvation. The main symptoms are persistent hunger and a high preoccupation with food. In addition, insomnia, daytime tiredness, fatigue, concentration and memory problems, depressed mood, loss, spontaneous loss, and loss of creativity follow. It will take weeks to resolve these psychological changes during weight regain.
Knowledge development
"Semi-starvation neurosis" is a technical term used to describe a psychological condition that occurs in a state of semi-starvation. The term was first coined in the Minnesota Hunger Experiment in 1944-1945 to describe the psychological and behavioral changes experienced by individuals in a state of chronic starvation or malnutrition.
"Semi-starvation neurosis"的主要症状包括：
- Constant hunger pangs and excessive attention to food
- Insomnia, daytime tiredness, fatigue
- Problems with concentration and memory
- Depressed mood and loss of libido
- Loss of spontaneity and creativity
These symptoms reflect the body's adaptive response to inadequate energy intake, as well as the impact of this state on mental health. In people with anorexia, this psychological condition may be associated with hypoleptinaemia, a hormone closely related to energy balance and hunger regulation. Leptin replacement therapy may help alleviate these symptoms and improve the mental health of patients.
Hunger and excessive attention to food are also the main symptoms of congenital leptin deficiency; Hyperphagia in infancy leads to extreme obesity. Metripstin treatment can significantly reduce hunger within a few days and weight loss over time. To date, no systematic psychological evaluation has been conducted to explore the symptoms of "hemistarvation neurosis" before and after the start of metreplatin treatment. However, the researchers reported significant changes in the patient's psyche after starting treatment. Patients with generalized lipodystrophy (another disease characterized by subphysiological levels of the leptin cycle) have also reported persistent hunger and attention to food, but not as extreme as congenital leptin deficiency. In both, these symptoms ceased after the initiation of metreplatin therapy; Preliminary evidence also suggests rapid improvement in mood.
Hunger-induced high attention to food is associated with fear of weight gain in patients with anorexia nervosa, but not in congenital leptin deficiency or lipodystrophy. This differential response to hypoleptinemia may reflect an abnormality in the starvation response. Female sex, specific developmental stage at presentation, and environmental and genetic factors increase the risk of developing the disease. There are albums that argue that anorexia nervosa's prominent fear of weight gain is driven by a constant focus on food. This reduction in attention induced by metreleptin may disrupt this connection, thereby alleviating this dilemma. Anorexia nervosa treatment guidelines emphasize weight regain as the primary goal of treatment, as leptin may be the primary mediator of health improvements associated with achieving normalized weight. Patients can benefit from a biomedical explanation of their mental health symptoms, including this sense of distress and the need for weight gain, while still needing normative psychotherapeutic strategies. Patients, caregivers, and treatment teams need to understand that the goal of intermittent metreplatin therapy is to provide an initial stimulus for subsequent weight gain.
In conclusion, hypoleptinosaemia should be considered as a contributing factor to starvation-induced somatic symptoms in anorexia nervosa and other conditions associated with hypotherminemia. Perhaps more importantly, hypoleptinomia may represent one of the overall mechanisms of mental health symptom onset and progression. The pathological mechanisms of these symptoms and their remission after treatment with leptin analogues still need to be further elucidated. Associated issues include the interdependence of these symptoms and the order in which they occur. Since the varied and significant improvements observed in case studies of anorexia nervosa patients treated with metreplatin, the hypothesis is in favor of the hypothesis that multiple mental health improvements represent the effects of re-induction of different leptinergic pathways in different brain regions. There is a future need to understand the regulatory function of leptin in relation to sex and developmental stage, which may explain the female predominance and the early age of onset of anorexia nervosa.
The high cost of metreplatin is a serious obstacle to off-label treatment for patients with such severe illnesses. Experts in the field are calling for targeted clinical studies to address the highly unmet medical needs in this situation. The involvement of the pharmaceutical industry is essential to initiate clinical trials, with the ultimate goal of value and approval as a drug for anorexia nervosa, including determining the optimal duration of this intermittent hormone replacement therapy. For this eating disorder (i.e., anorexia), if hypothesis-driven research and implementation of biomedical treatments, combined with psychotherapy, can reduce the severity and duration of anorexia, then this would represent a significant advance in treatment.
Expert presentation
Prof. Kang Chen
Chinese Deputy Chief Physician and Associate Professor, Department of Endocrinology, First Medical Center, People's Liberation Army General Hospital, Doctor of Medicine; At present, he is also the vice chairman of the Youth Committee of the Endocrinology Branch of the Chinese Medical Association, a member of the Hyperuric Acid Group, and the deputy leader of the Electrolyte Group. He is a member of the Endocrinology and Metabolism Branch of the Beijing Medical Doctor Association and a member of the Endocrinology Branch of the Beijing Medical Association
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