Glucocorticoid-associated central obesity: pathophysiological mechanisms and prevention of iatrogenic Cushing's syndrome

Glucocorticoids (GCs), named for their secretion by the adrenal cortex and regulation of glucose metabolism, play a crucial regulatory role in the body's development, growth, metabolism, and immune function. They are the most important regulatory hormones for the body's stress response and are among the most widely used and effective anti-inflammatory, anti-shock, and immunosuppressant drugs in clinical practice. GC toxicity is one of the most common causes of iatrogenic diseases associated with chronic inflammatory diseases. GCs can cause adverse reactions in multiple organ systems, such as Cushing's syndrome (iatrogenic hyperadrenocorticism), weight gain, accelerated bone density loss, premature cataracts, and in severe cases, life-threatening conditions like severe infections. I. The Relationship Between GCs and Weight Gain: While highly effective, GCs have many side effects, such as causing abnormal accumulation of adipose tissue. Patients taking these drugs long-term often exhibit central obesity. Several observational studies have assessed the incidence of Cushing's syndrome and weight gain. Cushing's syndrome and weight gain are dose- and duration-related and can occur within two months of treatment. Oral and topical GCs are the most common causes of Cushing's syndrome. Other methods, such as inhalation, topical administration, ocular, and nasal drops, can also lead to hyperadrenocorticism. A Cushing-like appearance can be very distressing and can occur even with low doses of GCs, though it is less common below the physiological replacement dose range. The most common feature is progressive central obesity, often affecting the face, neck, trunk, and abdomen; fat accumulation in the cheeks can cause a "moon face," and enlarged fat pads filling the supraclavicular fossa and obscuring the clavicle are one of the most specific signs of Cushing's syndrome. Prominent supraclavicular fat pads make the neck appear short and thick. "Buffalo hump" (cervical back fat pads) is common and often consistent with the overall degree of obesity. The limbs are usually unaffected and may be relatively thin. However, symptoms of iatrogenic hyperadrenocorticism usually resolve spontaneously after discontinuation of GCs. An observational study of 779 patients with rheumatoid arthritis (RA) showed that patients treated with at least 5 mg/day of prednisone or an equivalent dose of another drug for at least 6 months were more likely to experience weight gain compared to patients who did not receive any GCs for at least 12 months (22.4% vs 9.5%). However, a threshold effect was observed; the incidence of weight gain was not increased in patients using GCs less than 5 mg/day (8.7%), nor was it further increased in patients using doses greater than 7.5 mg/day (21.3%). In contrast, the incidence of Cushing's syndrome increased linearly with dose without a threshold effect. Another survey of 2167 long-term GC users found that weight gain was the most common adverse reaction (70% of patients). Wung et al. observed the effect of GCs on the weight of patients with Wegener's granulomatosis, and found that 35 out of 157 patients (22.3%) who received prednisone for 1 year experienced a weight gain ≥10 kg. During a two-year follow-up, patients who had gained weight did not experience a weight loss after discontinuing prednisone due to stabilization of their condition. II. Mechanisms of Weight Gain Promoted by GCs Iatrogenic hyperadrenocorticism is a result of excessive hormones causing disturbances in lipid and water-electrolyte metabolism. Abdominal fat accumulation may be due to the downregulation of cortisol-induced adenosine monophosphate activated protein kinase (AMPK), an enzyme that regulates lipid and carbohydrate metabolism. The conversion of cortisol to cortisol also promotes fat accumulation. Patients with Cushing's syndrome have higher serum leptin concentrations compared to obese individuals with similar BMIs. Factors that may contribute to weight gain from GCs include increased appetite (a common side effect of GC treatment) and increased food intake in patients with gastritis or peptic ulcers to relieve symptoms. The hypothalamus is the center for regulating visceral and endocrine activity. The arcuate nucleus (ARC) of the hypothalamus contains pro-aporhein (POMC) neurons that suppress appetite and regulate energy metabolism. Guo Feifan's research group discovered in animal experiments that dexamethasone can reduce the expression of POMCs in the hypothalamus and the content of α-MSH by regulating the kinase 1 (SGK1)/FOXO3 signaling pathway through GCs, which is related to the occurrence of obesity. III. Interventions for GC-Induced Weight Gain 1. Choosing an appropriate GC treatment regimen: The adverse reactions of GCs are related to both dosage and duration of use. Therefore, the GC drug treatment regimen should be formulated comprehensively based on the patient's condition and the characteristics of the drug. To reduce the occurrence of iatrogenic hyperadrenocorticism, local medication (such as aerosol inhalation for patients with bronchial asthma) can be used to reduce systemic side effects. For systemic use, an alternate-day dosing regimen is recommended. 2. Close monitoring of various indicators during GC use: Patients should be fully informed when using GCs, and various indicators such as electrolytes, blood glucose, blood lipids, weight, blood pressure, and bone mineral density should be closely monitored. 3. Lifestyle Prevention: Genetic Glutamates (GCs) have physiological effects such as raising blood glucose, promoting protein breakdown and inhibiting protein synthesis leading to negative nitrogen balance, causing central obesity, and retaining sodium while excreting potassium and inhibiting calcium absorption. Therefore, it is recommended to adopt a low-sodium, high-potassium, and high-protein diet, limit high-fat and high-sugar diets, supplement with calcium and vitamin D, and engage in appropriate exercise while using GCs. 4. Adding Metformin: The potential of metformin to reverse the adverse effects of GC overdose while preserving the anti-inflammatory effects of GCs was evaluated. Results showed that compared with the placebo group, the metformin group showed improvements in carbohydrate, lipid, liver, and bone metabolism indicators. Furthermore, metformin improved fibrinolysis, inflammatory parameters, and clinical disease activity markers. The frequency of pneumonia, the overall incidence of moderate to severe infections, and the rate of all-cause hospitalizations were all lower in the metformin group than in the placebo group.