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In 1993, megestrol acetate (MA) was approved by the US Food and Drug Administration for the treatment of anorexia, cachexia, or unexplained weight loss in patients with acquired immunodeficiency syndrome. The mechanism by which MA increases appetite is unknown, and its effectiveness for anorexia and cachexia in neoplastic, elderly, and acquired immunodeficiency syndrome patients is under investigation. This is an updated version of a Cochrane systematic review first published in 2005 and later updated in 2013 entitled 'Megestrol acetate for the treatment of anorexia-cachexia syndrome'. MA vs. placebo: in studies where MA was compared with placebo, the overall results showed that MA patients gained weight (mean difference, MD 2.25 kg, 95% CI [1.19, 3.3]) but did not gain quality of life (QOL) (standarized mean difference, SMD 0.5, 95% CI [-0.13, 1.13]), with more adverse events (relative risk, RR 1.46, 95% CI [1.05, 2.04]), but no difference in deaths (RR 1.26, 95% CI [0.70, 2.27]). MA vs. no treatment: MA patients gained weight (MD 1.45 kg, 95% CI [0.15, 2.75]) but did not gain QOL (standardized mean difference 3.89 95% CI [-14, 6.28]). There was no increase in adverse events (RR 0.90, 95% CI [0.39, 2.08]) or deaths (RR 1.01, 95% CI [0.42, 2.45]). MA vs. active drugs: MA patients gained weight (MD 2.5 kg, 95% CI [0.37, 4.64]) but did not gain QOL (MD 0.20 95% CI [-0.02, 0.43]) and did not report an increase in adverse events (RR 1.05 95% CI [0.95, 1.16]) or in deaths (RR 1.53, 95% CI [1.02, 2.29]) Different doses of MA: in studies where lower doses of MA were compared with higher doses of MA, we did not find differences either in weight gain (MD -0.94 kg, 95% CI [-3.33, 1.45]), QOL (MD 0.31 95% CI [-0.19, 0.81]), or adverse events (RR 1.34, 95% CI [0.65, 2.76]). Thus, we cannot reach a conclusion for an optimal dose of MA., (© 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

Objective: Malnutrition is a common problem in dialysis patients, and may affect up to one third of patients. It is associated with high mortality and morbidity. Although a number of studies were performed to determine effective treatment, there is no proven medication for this condition. This study aimed to evaluate the effect of megestrol acetate (MA) on serum albumin levels in malnourished dialysis patients., Design: This was a randomized, controlled clinical trial., Setting: The setting, a dialysis center at Razi Hospital, Rasht, Iran, provides services to dialysis patients., Patients: Twenty-two malnourished dialysis patients with persistent hypoalbuminemia (albumin, <3.5 g/dL for 2 months) participated, and were randomly assigned to either an experimental group or a control group., Intervention: The experimental group was treated with MA, 40 mg twice daily, over 2 months, and was compared with the control group. The collected data were analyzed using SPSS (version 10; Chicago, IL)., Results: After 2 months, the mean (+/-SD) serum albumin level in the experimental group rose from 3.31 +/- 0.31 g/dL to 4.41 +/- 0.31 g/dL, but in the control group, it declined, from 3.35 +/- 0.21 to 3.02 +/- 0.48 g/dL. The difference between the two groups was significant (P = .002)., Conclusion: At a dose of 40 mg twice a day, MA safely increased serum albumin in malnourished dialysis patients.

Background: Cancer-associated anorexia/cachexia syndrome (CACS) is common in advanced gastrointestinal malignancies and felt to be due primarily to cytokine-induced appetite suppression. Therapy with an appetite stimulant (megesterol acetate) is commonly employed, but results are sometimes disappointing. We hypothesize that CACS not only suppresses appetite but also interferes with gastrointestinal function., Methods: We conducted a prospective study in which 21 subjects with advanced gastrointestinal cancer and weight loss had digestive function. Patients were assessed using an indirect stable isotope method, and nutritional parameters were determined following which patients were treated with megesterol acetate for 4 weeks. Nutritional parameters were then reassessed, weight change determined, and the results were correlated with digestive function results obtained at the initiation of the study., Results: Abnormal gastrointestinal function based on the stable isotope test was common (86% of patients). The majority of the abnormal function appeared to be due to abnormal pancreatic function testing, in which 17/21 subjects recorded low results. Initial albumin, prealbumin, and carotene values were also frequently abnormal (55-65% of patients). Megesterol acetate therapy resulted in a weight gain in most (75%) patients, although serum albumin fell modestly in the group (average decrease of 0.2 mg/dl). However, prealbumin levels rose in 70% and carotene levels rose in 55%. The degree of weight gain was negatively correlated with previous self-reported weight loss ( r=-0.53, p<0.05), and positively correlated ( p<0.05) with pretherapy carotene ( r=0.58), prealbumin ( r=0.61) and the pancreatic function (digestive) phase of the digestive function test ( r=0.41)., Conclusion: These data suggest that abnormal digestive function is commonly seen in subjects with CACS and advanced gastrointestinal cancer, and that both pretherapy digestive function and nutritional status can predict or possibly influence the outcome of hormonal appetite stimulation therapy.

Anorexia and weight loss represent a major cause of morbidity and mortality. At present in the United States two effective anorectic agents are commonly used, namely, megestrol acetate and dronabinol. These two agents are compared in Table 1. In persons with a large excess cytokine production. megestrol acetate should be tried at a does of 800 mg per day for no longer than 3 months. Megestrol acetate should be administered with testosterone in men. It should be avoided in persons who are bed-bound because of the risk of deep vein thrombosis. Dronabinol should be used for most anorectic patients. Dronabinol should initially be given in a low dose (2.5 mg) in the evening. The dose should be increased to 5 mg per day if no improvement in appetite is seen after 2 to 4 weeks. Dronabinol can be continued indefinitely. It seems to have a particularly good profile for persons with anorexia who are at the end of life. In persons with depression and anorexia. mirtazapine seems to be the antidepressant of choice. In addition, the use of taste enhancers can be considered in persons who complain that the food does not taste good. The appropriate use of anabolic agents in older persons with weight loss is controversial. Certainly all older men who are losing weight should have bioavailable testosterone measured and, if the testosterone level is low, should receive testosterone replacement therapy. Women who are losing weight may benefit from the use of low-dose testosterone (eg, Estratest). Anabolic agents, such as oxandrolone, should be reserved for those who have profound cachexia. An approach to the management of anorexia and weight loss in older persons is given in Fig. 1. Thomas et al have provided a more complex algorithm the management of weight loss in nursing home residents.

Rats offered a zinc-deficient (-Zn) diet voluntarily reduce their food intake within 3-4 days. Megestrol acetate (MA) is an appetite-stimulating drug used to treat cachexia of chronic diseases. In previous work, we found MA administration to male rats increased consumption of a -Zn diet. This approach would provide a useful tool for nutritional studies in which nutrient intake, except for zinc, would be maintained. The present study further examined the use of MA to increase consumption of a -Zn diet over a longer time period in both male and female rats. Rats were fed either a -Zn or a zinc-adequate (+Zn) diet. In Experiment 1, rats were treated orally with 0, 20, 50 or 100 mg MA/kg BW in corn oil for 21 days. MA stimulated intake of the -Zn diet in a linear manner. In Experiments 2 and 3, male and female rats, respectively, were fed the -Zn or +Zn diets and treated with 100 mg MA/kg BW for 21 days. In both experiments, MA administration increased intake of the -Zn diet to levels similar to the +Zn diet through Day 14. MA increased the hypothalamic neuropeptide Y (NPY) concentration in male rats, but did not affect serum IGF-I. MA administration improved growth of female but not male rats fed the -Zn diet. In females, serum IGF-I was not lower in zinc-deficient rats, which may have allowed the improved growth response with MA. Hence, MA administration may be a useful tool to increase consumption of a -Zn diet in short-term studies.

The characteristic clinical picture of anorexia, tissue wasting, loss of body weight accompanied by a decrease in muscle mass and adipose tissue, and poor performance status that often precedes death has been named the cancer-related anorexia/cachexia syndrome (CACS). Chronic administration of pro-inflammatory cytokines, including interleukin-I (IL-I), IL-6, and tumor necrosis factor (TNF), either alone or in combination, is capable of reproducing the different features of CACS. High serum levels of these cytokines have been found in cancer patients, which seem to correlate with progression of the tumor. This article describes a series of experimental and clinical studies demonstrating that: (1) high serum levels of some cytokines, including IL-I, IL-6, and TNF, are present in advanced-stage cancer patients, particularly those with CACS; (2) megestrol acetate (MA) has a beneficial therapeutic effect on CACS symptoms, such as appetite, body weight, and quality of life; (3) MA downregulates the synthesis and release of cytokines and relieves the symptoms of CACS; (4) cytokines play a key role in the onset of CACS; (5) medroxyprogesterone acetate (MPA) reduces the in vitro production of cytokines and serotonin (5-hydroxytryptamine, 5-HT) by peripheral blood mononuclear cells (PBMC) of cancer patients; and (6) MA and MPA reduce the cisplatin-induced 5-HT release in vitro from PBMC of cancer patients. Based on these results, a clinical study incorporating MA/MPA in combination with chemotherapy or chemoimmunotherapy may be warranted. In addition, it has been recently shown that "oxidative stress" resulting from reactive oxygen species, which can be induced by pro-inflammatory cytokines, is involved in tissue wasting and CACS. These results suggest promising approaches for the prevention and treatment of cytokine-induced CACS based on MA, MPA, and metabolic antioxidants.

The hypothalamus plays an essential role in the regulation of the body weight of all living creatures. In it there is a convergence of signals from the nervous system and signals from the peripheral tissues, through a complex system of neurotransmitters and neuropeptides. The ever increasing understanding of this field, opens up new therapeutic possibilities, both current and future, in the treatment of eating disorders.

The characteristic clinical picture of anorexia, tissue wasting, loss of body weight accompanied by a decrease in muscle mass and adipose tissue, and poor performance status that often precedes death has been named the cancer-related anorexia/cachexia syndrome (CACS). Chronic administration of pro-inflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) either alone or in combination, is capable of reproducing the different features of CACS. High serum levels of these cytokines have been found in cancer patients, which seem to correlate with progression of the tumor. This paper describes a series of experimental and clinical studies demonstrating that: (1) high serum levels of some cytokines, including IL-1, IL-6, and TNF, are present in advanced-stage cancer patients, particularly those with CACS; (2) megestrol acetate (MA) has a beneficial therapeutic effect on CACS symptoms, such as appetite, body weight, and quality-of-life; (3) MA downregulates the synthesis and release of cytokines and relieves the symptoms of CACS; (4) cytokines play a key role in the onset of CACS; (5) medroxyprogesterone acetate (MPA) reduces the in vitro production of cytokines and serotonin (5-hydroxytryptamine, 5-HT) by peripheral blood mononuclear cells (PBMC) of cancer patients; and (6) MA and MPA reduce the cisplatin-induced 5-HT release in vitro from PBMC of cancer patients. Based on these results, a clinical study incorporating MA/MPA in combination with chemotherapy or chemoimmunotherapy may be warranted.

Zinc deficiency in rats results in impaired growth accompanied by decreased and cyclic food intake. These signs are associated with decreased plasma insulin-like growth factor-I (IGF-I), a major mediator of growth. The purpose of this study was to determine the relationship between decreased plasma IGF-I and the impairment of appetite and growth in zinc deficiency. Immature male rats were fed free choice a low zinc (<1 mg/kg) diet (-Zn) or a zinc adequate (100 mg/kg) control diet (+Zn). Plasma IGF-I concentrations were normalized in zinc-deficient rats by the following two methods: osmotic pump infusion of IGF-I (2.4 mg/kg body weight daily) and oral administration (50 mg/kg body weight twice daily) of the synthetic progestin, megestrol acetate (MA). Infusion of IGF-I for 8 d sustained plasma IGF-I concentrations in zinc-deficient rats at control levels but had no effect on either food intake or growth rate. MA administration for 8 d maintained the plasma IGF-I of deficient rats and significantly increased food intake. The early aspects of cyclic food intake were eliminated, and, after a few days, food intake of deficient rats given MA was not different than that of controls. MA increased food intake and fat deposition regardless of zinc status, but it had no effect on the growth rate of deficient rats. MA significantly decreased body weight of controls, uncoupling energy intake and gain. The results suggest that reduced food intake precedes the decreased plasma IGF-I concentration and that IGF-I is not responsible for the decreased growth and food intake of zinc-deficient rats. The appetite and growth impairment of zinc-deficient rats may arise from disrupted function of IGF-I receptors in the brain and peripheral tissues, but not from low circulating levels of IGF-I.