Produce Weight Gain Research Articles

Atypical antipsychotic induced weight gain: pathophysiology and management.

There is compelling evidence that patients with schizophrenia are prone to gain weight. In addition, atypical antipsychotic (AAP) drugs also induce weight gain. All antipsychotic drugs produce weight gain but the potential varies. Many studies overwhelmingly confirm that AAP drugs produce substantially more weight gain in comparison to conventional antipsychotic drugs. Clozapine and olanzapine have the most weight inducing potential. Even ziprasidone, which is considered to be weight neutral, and aripiprazole a dopamine modulator produce weight gain in some. The pathophysiology of weight gain is complicated. Many neurohormones, neuropeptides, gut hormones, as well as adipose tissue and hair root derived hormones interact with environmental factors to produce weight gain. Management of weight gain is a difficult problem. Basic to treatment is an understanding of the etiology. Drug induced obesity provides a unique opportunity to psychiatrists to understand this clinically important problem. In the absence of this knowledge, prevention is the best hope. Education, diet control and simple behavioral measures may prevent excessive weight gain. In those with weight gain, treatment can be attempted with pharmacotherapy with careful monitoring of the side effects.

The 'cancer cachectic factor'.

The object of this study was to summarize information on catabolic factors produced by tumours which lead to tissue catabolism in cancer cachexia and to use this information for the development of effective therapy. The study population was made up of patients with cancer cachexia and weight loss greater than 1 kg month(-1). They had a varied range of carcinomas, particularly pancreatic, but also of the breast, ovary, lung, colon and rectum. Cachectic factors were isolated by standard biochemical methods, and the mechanism of tissue catabolism was evaluated in vitro and in vivo. We isolated a 24-kDa sulphated glycoprotein produced by cachexia-inducing murine and human tumours, which induces catabolism of myofibrillar proteins in skeletal muscle and for this reason has been named proteolysis-inducing factor (PIF). PIF was shown to be present in a diverse range of carcinomas in patients whose rate of weight loss exceeded 1.0 kg month(-1). Administration of PIF to normal mice produced a rapid decrease in body weight, which arose primarily from a loss of skeletal muscle, accompanied by increased mRNA levels for ubiquitin, the ubiquitin-carrier protein (E2(14k)), and proteasome subunits. This suggests that PIF induces protein catabolism through an increased expression of the key components of the ATP-ubiquitin-dependent proteolytic pathway. The action of PIF was attenuated both in vitro and in vivo by eicosapentaenoic acid (EPA). Oral EPA has been found to stabilize the body weight of patients with advanced pancreatic cancer and, when combined with an energy- and protein-rich nutritional supplement, to produce weight gain arising solely from an increase in lean body mass. Nutritional supplementation alone is unable to reverse the process of muscle wasting in cancer patients, since this arises from activation of the ubiquitin proteasome pathway by PIF, which is independent of nutrient intake. EPA is able to down-regulate the increased expression of this pathway and prevents muscle wasting in cancer patients.

Effects of smoking status and smoking cessation on leptin levels.

Cigarette smoking is associated with lower body weight, and quitting smoking typically produces weight gain. An effect of chronic smoking on increasing leptin, a protein product associated with reducing weight, may help explain this influence of smoking on lowering body weight. We examined fasting serum leptin levels in male and female adult smokers (n = 52) and non-smokers (n = 12) as well as long-time ex-smokers (n = 13), with all groups similar in body mass index (BMI). Partial regression analyses controlling for BMI and, where relevant, age were used to relate leptin to indices of smoking exposure and dependence within the smokers, and with typical alcohol and caffeine intake in the entire sample. Furthermore, a subset of the smokers (n = 22) quit for at least 3 weeks, and changes in leptin and weight were prospectively assessed. Results showed no difference in mean leptin levels as a function of smoking status and no significant associations of leptin with smoking exposure variables after controlling for BMI and age. However, leptin was significantly correlated with alcohol intake (inversely) in women. In addition, smoking cessation increased leptin, the opposite change expected if leptin were responsible for weight gain, but again only in women and not in men. This leptin change remained significant after controlling for the increase in weight observed in both men and women. In conclusion, the influence of cigarette smoking on body weight does not appear to be due directly to changes in leptin levels, as there is no difference in leptin due to smoking status and leptin does not decline after cessation.

Gastric emptying of two whey-based formulas of different energy density and its clinical implication in children with volume intolerance.

Whey-based formulas have faster gastric emptying than casein-based formulas. Isoenergetic, isovolumic, whey-based formulas of different osmolarity and fat content empty in a similar manner. Will the gastric emptying of high and low energy density whey-based formulas be similar? We studied the gastric emptying rate of equal volumes of two whey-based formulas of different energy density (4.18 kJ/ml and 6.27 kJ/ml) and osmolality (270 and 450 mOsm/kg, respectively) in 10 children (4.5-12 y) with volume intolerance and resultant inability to gain weight. The two formulas had comparable gastric emptying rates at 30, 60, 90 and 120 min. Over a one month clinical trial, substitution of the lower energy density whey-based formula (no weight gain over 2 months) with an equal volume of the high energy density formula produced a mean weight gain of 1.17+/-0.5 kg per patient without change in tolerance. The higher density whey-based formula can safely substitute an equal volume of a lower energy density formula to produce weight gain without affecting tolerance. This provides an important intervention for increasing energy intake in children with volume intolerance or fluid restriction.

Low-fat diets and energy balance: how does the evidence stand in 2002?

The role of high-fat diets in weight gain and obesity is assessed by evidence-based principles. Four meta-analyses of weight change occurring on ad libitum low-fat diets in intervention trials consistently demonstrate a highly significant weight loss of 3-4 kg in normal-weight and overweight subjects (P < 0.001). The analyses also find a dose-response relationship, i.e. the reduction in percentage energy as fat is positively associated with weight loss. Weight loss is also positively related to initial weight; a 10 % reduction in dietary fat is predicted to produce a 4-5 kg weight loss in an individual with a BMI of 30 kg/m2. The non-fat macronutrient composition of the diet is also important. Whereas the glycaemic index of the carbohydrate may play a role for cardiovascular risk factors, there is so far no evidence that low-glycaemic index foods facilitate weight control. In contrast, intervention studies show that sugar in drinks is more likely to produce weight gain than solid sugar in foods. Although the evidence is weak, alcoholic beverages promote a positive energy balance, and wine may be more obesity-promoting than beer. Protein is more satiating and thermogenic than carbohydrates, and one intervention study has shown that an ad libitum low-fat diet where carbohydrate was replaced by protein produced more weight loss after 6 months (8.1 v. 5.9 kg). The evidence linking particular fatty acids to body fatness is weak. If anything, monounsaturated fat may be more fattening than polyunsaturated and saturated fats, and no ad libitum dietary intervention study has shown that a normal-fat high-monounsaturated fatty acid diet is equivalent or superior to a low-fat diet in the prevention of weight gain and obesity. The evidence strongly supports the low-fat diet as the optimal choice for the prevention of weight gain and obesity, while the use of a normal-fat high-monounsaturated fatty acid diet is unsubstantiated.

Phase III, Multicenter, Double-Blind, Randomized Study of Letrozole, an Aromatase Inhibitor, for Advanced Breast Cancer Versus Megestrol Acetate

To compare two doses of letrozole (0.5 mg and 2.5 mg every day) and megestrol acetate (40 mg qid) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. This double-blind, randomized, multicenter, multinational study enrolled 602 patients, all of whom were included in the primary analysis in the protocol. Patients had advanced or metastatic breast cancer with evidence of disease progression while receiving continuous adjuvant antiestrogen therapy, had experienced relapse within 12 months of stopping adjuvant antiestrogen therapy given for at least 6 months, or had experienced disease progression while receiving antiestrogen therapy for advanced disease. Tumors were required to be estrogen receptor- and/or progesterone receptor-positive or of unknown status. Confirmed objective response rate was the primary efficacy variable. Karnofsky Performance Status and European Organization for Research and Treatment of Cancer quality-of-life assessments were collected for 1 year. There were no statistically significant differences among the three treatment groups for overall objective tumor response. Patients treated with letrozole 0.5 mg had improvements in disease progression (P =.044) and a decreased risk of treatment failure (P =.018), compared with patients treated with megestrol acetate. Letrozole 0.5 mg showed a trend (P =.053) for survival benefit when compared with megestrol acetate. Megestrol acetate was more likely to produce weight gain, dyspnea, and vaginal bleeding, and the letrozole groups were more likely to experience headache, hair thinning, and diarrhea. Given a favorable tolerability profile, once-daily dosing, and evidence of clinically relevant benefit, letrozole is equivalent to megestrol acetate and should be considered for use as an alternative treatment of advanced breast cancer in postmenopausal women after treatment failure with antiestrogens.

Amygdala-lesion obesity: what is the role of the various amygdaloid nuclei?

Anatomic descriptions of amygdaloid lesions resulting in hyperphagia and obesity in rats, cats, and dogs have been inconsistent and often contradictory, frequently resulting in failures to replicate. The present study attempted to reconcile these differences by examining common areas of overlap among differently placed lesions in female rats. Small bilateral lesions of the most posterodorsal aspects of the amygdala resulted in substantial weight gains (mean = 45.4 g/10 days). The smallest lesions caused damage limited to the posterodorsal medial amygdaloid nucleus and the bed nucleus of the stria terminalis and were directly in the area where axons are collecting to form the stria terminalis. Larger lesions that extensively damaged the central and/or anterodorsal medial amygdaloid nuclei sometimes resulted in excess weight gains, as did very large lesions of the basolateral nuclei, but substantial weight gains occurred only when the lesions extended (unilaterally or bilaterally) into the posterodorsal amygdala. Examination of previously published brain sections indicated that the hyperphagia and obesity that have been observed after widely differing lesion placements in cats and dogs were also the result of damage to a common area of overlap (i.e., the bed nucleus and/or stria terminalis). In rats, the critical area producing weight gain has extensive reciprocal relations with the medial hypothalamus.

Clinical evaluation of the overweight patient.

Evaluation of an overweight patient is the first step in any therapeutic program. The syndromes of obesity can be classified in several ways. The first is an anatomic classification based on the size, number, and distribution of fat cells and fat tissue. The second is an etiologic classification based on identification of specific diseases and settings that produce obesity. Hypothalamic injury and endocrine disease such as Cushing's disease and the polycystic ovary syndrome are three identifiable causes of obesity. In this medicated society drugs are always candidates to produce weight gain. The most common causes, however, are stopping smoking, overconsumption of high-fat foods, a decrease in the level of activity, and aging. The natural history of obesity provides a useful framework in which to view both preventive and therapeutic strategies. Some individuals will never become overweight, but of those who do, about one-third will do so during the first two decades, and the remaining two-thirds will become overweight after age 20. A number of epidemiological and metabolic factors can serve as a guide to those individuals who are at high risk. Having overweight parents tops the list, but multiple births, cessation of smoking, and a sedentary lifestyle are additional factors. Therapeutic decisions should be based on risk-benefit decisions. The risk can be assessed from the body mass index, the distribution of fat in upper or lower body obesity, the rate of weight gain, and the degree of physical inactivity. After assessing risk, the therapeutic choices can be selected from the age category of the patient. With any therapeutic activity, involvement of the patient in a realistic approach to the treatment process is essential.

Nutrition intervention for weight gain in cystic fibrosis: A meta analysis

Objective: A meta analysis of the literature on treatment approaches to malnutrition in cystic fibrosis (CF) was conducted to evaluate the effectiveness of oral supplementation, enteral nutrition, parenteral nutrition, and behavioral intervention on weight gain before and after treatment. Study design: Eighteen studies were reviewed: four behavioral, six supplement, five enteral nutrition, and three parenteral nutrition. Results: The weighted effect size for weight gain was large for each intervention: 1.51 behavioral, 1.62 oral, 1.78 enteral, and 2.20 parenteral intervention. All interventions produced a large effect for weight gain in patients with CF. A univariate analysis of variance indicated no significant difference among the four interventions, F(3, 17) = 0.87, p > 0.05. Effect size for calorie intake was also evaluated when data were available ( N = 7 studies), yielding a sample size of three behavioral, two enteral, and two oral supplement studies. Analysis of variance indicated a significant effect for treatment, F(2,4) = 13.34, p < 0.05, with post hoc analysis indicating that the behavioral intervention had a greater effect size for calorie intake than oral supplement. Conclusions: All interventions were effective in producing weight gain in patients with CF. Behavioral intervention appeared to be as effective in improving weight gain in patients with CF as more invasive medical procedures. These findings support continued research on nutrition intervention with patients with CF including controlled clinical trials of the interventions and long-term follow-up on the impact of nutrition on disease progression. (J Pediatr 1998;132:486-92)

Hormone therapy in women in the menopause transition: Randomised, double‐blind, placebo‐controlled trial of effects on body weight, blood pressure, lipoprotein levels, antithrombin Ill activity, and the endometrium

To determine whether hormone treatment of women during the menopause transition induces changes in body weight, blood pressure, lipoprotein levels, antithrombin III activity, and the endometrium. Prospective, randomised, placebo-controlled, double-blind, 12-month study, with crossover at 6 months. Outpatient clinic of a city hospital. 105 apparently healthy women in the menopause transition (40-52 years), with menstrual function, who were experiencing minor menopausal symptoms, were selected from the general population by advertising. Active arm--oral conjugated oestrogens (0.625 mg daily) and cyclic medroxyprogesterone acetate (10 mg daily) on Day 14-27 of each menstrual cycle; placebo arm--placebos of both medications. Excess change from baseline associated with active compared with placebo treatment for all variables; effect of order of treatment. Baseline biochemical values were similar for both treatment-order groups, but baseline blood pressures and body weights were higher in the group receiving placebo first. With treatment, there were no differences in overall values for body weight and blood pressure (P > 0.4), and order of treatment had no significant influence (P > 0.3). There were no differences in total and low density lipoprotein cholesterol levels, overall or with order of treatment. Active treatment increased high density lipoprotein (HDL) cholesterol levels (overall and when placebo was given first; P = 0.001), and triglyceride levels (when active treatment was given first; P = 0.03). There was no overall treatment effect, but a significant order-of-treatment effect, on antithrombin III activity (mean levels were decreased by active treatment to a greater extent when it was given first; P = 0.02). The endometrium showed only physiological changes regardless of treatment. The lack of significant excess change in anthropometry, lipoprotein levels, antithrombin III activity, and endometrial histology in women given hormone treatment compared with placebo is reassuring. The increase in HDL cholesterol level is an extra benefit. Our study provides conclusive evidence that hormone treatment does not produce weight gain in women during the menopause transition.

Modern approach to corticosteroid replacement therapy

The therapeutic index of corticosteroids for adrenal insufficiency is narrowing with recognition of the adverse consequences from even minor overtreatment. As in endogenous Cushing syndrome, chronically excessive glucocorticoid dosage can produce weight gain, hypertension, hypercholesterolemia, glucose intolerance, and bone demineralization. By contrast, deficient replacement leads to the constitutional and other symptoms of adrenal insufficiency and can induce lifethreatening shock, particularly during major stress. Optimum therapy depends on the cause of adrenal insufficiency. Primary and secondary adrenal insufficiency, congenital adrenal hyperplasia, and Nelson syndrome each present unique problems that require specific approaches to treatment. The clinician's major challenge is to adjust mineralocorticoid and glucocorticoid doses so as to meet physiologic requirements without inducing corticosteroid excess. Herein, we review the patho-physiology of adrenal insufficiency, outline a stepwise approach to adrenal hormone replacement, and discuss literature relevant to current issues of corticosteroid replacement therapy.

The role of megestrol acetate in neoplastic anorexia and cachexia

Anorexia and cachexia, major problems in patients with advanced cancer, lead to decreased caloric intake and weight loss. Successful treatment of these conditions has a positive effect on patients' quality of life. Megestrol acetate therapy has been shown to stimulate appetite and nonfluid weight gain in patients with cancer. We explored the effect of oral megestrol acetate, 160 mg twice daily (total daily dose 320 mg) for 3 weeks in 24 patients with advanced bladder or colorectal carcinoma. After treatment, 15 patients (63%) significantly increased their food intake ( P < 0.05); 20 patients (83%) gained weight ( P < 0.05), and 16 patients (67%) showed improvement in performance status. No patient reported negative effects of therapy such as nausea, emesis, edema, hypertension, or thromboembolic events. No signs of hepatic, renal, metabolic, or cardiac toxicity were seen. Although the mechanism by which megestrol acetate produces weight gain and subsequently improves the quality of life of cancer patients is not fully understood, our data show that it is safe, well tolerated, and, above all, capable of containing anorexia and cachexia in patients with advanced cancer.

Weight gain associated with neuroleptic medication: a review.

In this article we review the empirical literature on weight gain associated with neuroleptic drug use. Weight gain, which appears to be associated with an increase in appetite, is variable but likely to be larger initially and then plateau. Clozapine and low-potency phenothiazines are associated with the largest gains and molindone with weight loss, but the mechanism is not known. Amantadine and fenfluramine may reverse weight gain to some degree. Dietary fat seems to play an important role in obesity, and research is needed to increase the data base and elucidate possible mechanisms. Studies are also needed to evaluate preventive strategies and to determine which drugs are least likely to produce weight gain as well as which drugs could be added to a neuroleptic regimen to control weight.

Segmental vascular pressures in lung embolism.

Average microvascular filtration pressure and vascular permeability measures were obtained in 100-microns glass bead-embolized dog lung lobes randomly assigned to groups in which isolated perfusion was designed to produce weight gain (edema groups) or no weight gain (isogravimetric groups). The solvent drag reflection coefficient (sigma), an index of vascular permeability, was obtained during edema formation, whereas isogravimetric capillary pressure was obtained during isogravimetry. Vascular permeability increased in response to embolism, because sigma was 0.53 +/- 0.03 vs. 0.80 +/- 0.05 (P < 0.005) in embolized and control lobes, respectively. Vascular occlusion methods indicated the greatest resistance increase in response to embolism in the vascular segment represented by Pao--Pdo (arterial occlusion pressure--double occlusion pressure). Because papaverine vasodilation reduced total vascular resistance (RT; P < 0.05) by decreasing Pao (P < 0.01) without altering Pdo, the RT increase in response to embolism was likely due to both vasoconstriction and obstruction. Because Pdo approximated capillary pressure at isogravimetry, Pdo appears to estimate average filtration pressure in both embolized (n = 6) and control lungs (n = 6). Arterial pressure was 56.2 +/- 13.6 vs. 17.6 +/- 1.5 cmH2O (P < 0.01) in embolized (n = 5) and control lobes (n = 6), respectively, whereas Pdo values of 16.1 +/- 1.5 vs. 12.4 +/- 0.8 (P < 0.05) suggested relatively little increase in filtration pressure in response to embolism. If the beads obstructed 100-microns vessels, the vascular segment represented by Pao--Pdo, the major site of vasoconstriction as well as mechanical obstruction, likely includes 100-microns arteries.

The induction of amenorrhoea.

A survey has shown that many women favour eliminating menstruation and it has been suggested that therapeutic induction of amenorrhoea might be an advantage in female personnel mobilised for war. The traditional method has been to take the oral contraceptive pill continuously. This produces weight gain and other side-effects; spotting and breakthrough bleeding can be a problem initially. The method is however cheap. The Gonadotrophin Releasing Hormone (GnRH) analogue, goserelin, is extremely effective, produces less side-effects, but it is very expensive. Two synthetic steroids, danazol and gestrinone, are moderately effective, have a variety of prominent side-effects and are also quite expensive. With all these drugs normal menstruation resumes in the cycle after they are discontinued. Although goserelin has many advantages over the continuously taken contraceptive pill, its cost precludes it from consideration as a means of eliminating menstruation.

The Antidepressant Effects of 5-HT Uptake Inhibitors

The functional roles of monaminergic transmitters in depression have been widely studied during the past decade. Data from that research suggest that lower levels of the 5-HT metabolite, 5-HIAA, in the cerebrospinal fluid; 5-HT uptake in human platelets; and platelets [3H]-imipramine binding sites occur in depressed patients. In recent years several potent and selective 5-HT uptake inhibitors have become available for clinical studies. The first shown to have antidepressant effects, zimelidine, was followed by similar compounds such as femoxetine, fluvoxamine, citalopram, indalpine, fluoxetine, paroxetine, and sertraline. The effectiveness of serotonin inhibitors in treating other disorders, such as obsessive-compulsive disorder, anxiety, and panic disorder, has also been demonstrated. This review reports the data from clinical studies with these agents. The 5-HT uptake inhibitors are devoid of anticholinergic properties and have not produced weight gain or sedative side-effects, but may have another profile of side-effects. Headache, nausea, and vomiting have been reported, however.

Monoamine oxidase inhibitors and weight gain.

Weight gain associated with antidepressant therapy is a common problem that often results in noncompliance. Some authors suggest that monoamine oxidase inhibitors (MAOI) are less likely to produce weight gain than tricyclic antidepressants. This paper addresses the relative potential for weight gain with the MAOI. Assessing the potential for antidepressant-induced weight gain necessitates separating the weight changes associated with alterations in mood disorders from those due to drug-induced alterations in appetite control. The mechanisms of appetite control are reviewed briefly followed by proposed mechanisms by which the MAOI may alter this control. A literature review suggests that phenelzine is the MAOI most likely to induce weight gain; reports of isocarboxazid-induced weight gain are less common. There are no cases of tranylcypromine-induced weight gain in the literature that are clearly associated with the drug. The MAOI probably have different effects on the mechanisms of appetite control.

Utilization ofdl- andl-tryptophan in young pigs

ABSTRACTTwo trials involving young pigs (total numbers 288 and 400, respectively) were performed to compare the biological activity of Dl- and L-tryptophan under restricted (trial 1) andad libitum(trial 2) feeding conditions. In trial 1, three additions of Dl-tryptophan (0·3, 0·6 and 0·9 g/kg) and two additions of L-tryptophan (0·3 and 0·6 g/kg) to a basal diet containing 0·9 g natural tryptophan per kg were tested. In trial 2, the treatments were additions of 0·4, 0·8 and 1·2 g Dl- or L-tryptophan per kg to a basal diet having 1·3 g natural tryptophan per kg. Both trials were of 6 weeks duration. In trial 1, almost equal performance was achieved with both tryptophan sources at a dietary level of 0·3 g/kg, whereas at a level of 0·6 g/kg, Dl-tryptophan produced slightly better performance in weight gain, food intake and food conversion efficiency than did L-tryptophan. In trial 2, the supplemental level of 0·4 g L-tryptophan per kg produced weight gain and food intake results which were significantly superior to those of Dl-tryptophan. However, at supplemental levels of 0·8 and 1·2 g/kg, diets with Dl-tryptophan produced somewhat better performance than did L-tryptophan. Based on the results of trial 2, it was estimated that the pig's need for total tryptophan over the weight range of 10 to 35 kg is at least 2·3 g/kg in a diet having 10·3 MJ net energy per kg.

Ventromedial hypothalamic and paraventricular nucleus lesions damage a common system to produce hyperphagia

We investigated the anatomical basis of paraventricular (PVN) and ventromedial (VMH) hypothalamic hyperphagia. Asymmetrical electrolytic lesions, damaging the VMH and PVN contralaterally, produced significant hyperphagia and weight gains (mean = 257.2 g) almost three times those of controls (89.8 g) during 56 postsurgical days. Weight gain in these rats was not significantly different from that in rats with bilateral lesions of the VMH (277.2 g) or PVN (188.2 g). Combined bilateral destruction of the PVN and VMH produced weight gain (272.8 g) almost identical to that seen after bilateral VMH lesions alone. The lack of additivity of these combined lesions and the effectiveness of the asymmetrical lesions are consistent with the hypothesis that lesions of either of these two regions damage a longitudinally running system to produce elevated food intake and body weight. Cell bodies of this system may lie within the PVN and send efferent projections through the VMH. Hyperinsulinemia developed only in rats with bilateral damage in the VMH. Thus, hypothalamic hyperphagia and hyperinsulinemia appear to be dissociable, reflecting damage to separate neural systems.

Studies of high-dose megestrol acetate: potential applications in cachexia.

Cachexia can be a severe problem in the management of patients with cancer and other illnesses because it produces an ever-increasing spiral of anorexia, undernutrition, loss of tissue mass, muscle wasting, and increased susceptibility to infection and treatment toxicity. Megestrol acetate has been observed to produce weight gain in patients with hormone-sensitive tumors and has recently been noted to produce a similar degree of weight gain in those with hormone insensitive tumors. A review of our experience in a phase I-II study of escalating doses of megestrol acetate for advanced breast cancer revealed that weight gain occurred in more than 80% of all treated patients and in 90% of those patients who received treatment for 6 or more weeks. The median maximum weight gain was 5.5 kg, with a range of -5.6 to 44 kg. Subjective improvement in appetite occurred in most patients. These data provided the impetus for a series of further studies of the role of megestrol acetate in the control of cachexia, including a randomized study in cancer cachexia, AIDS cachexia, and anorexia nervosa. In addition, a number of laboratory trials seeking the mechanism of action have been initiated, as well as whole-animal studies to define the compartment of increased weight. Our data and the preliminary observation of weight gain in patients with hormone insensitive tumors suggest that megestrol acetate has a potential role in producing a possibly dose-related subjective improvement and an increase in appetite and weight. Further research is necessary to understand the mechanism of appetite stimulation and anabolic effect.