The progestin derivatives MPA and MA have been widely used in the treatment of cancer cachexia, which shows clinical features and, probably, pathological mechanisms similar to those of AIDS wasting syndrome [73, 74]. In anorectic and cachectic AIDS patients, MPA and MA have proved to be particularly effective [65-69,75-80].
Medroxyprogesterone Acetate In two clinical studies [22, 66], we used MPA(1 g/day, os) and a hypercaloric diet to correct anorexia and cachexia occurring in HIV-infected patients. In the first study , MAP was administered to 74 AIDS patients. The control group of 96
Table 2. Drugs for the treatment of cachexia
Steroids: nandrolone decanoate, oxandrolone, dexam-ethasone, prednisone, metilprednisolone, progestin derivatives (medroxyprogesterone acetate, megestrol acetate)
Anti-cytokines Hydralazine sulfate (reduces PEP-carboxykinase) Pentoxyfylline (increases cAMP) Amrinone (reduces phosphodiesterase) Dobutamine (ß-agonist; increases cAMP) Thalidomide (reduces TNF)
FANS(indomethacin, ibuprofen, aspirin; reduce cytokines synthesis)
Antibodies against TNF, LPS, IL-1, etc. (reduce cytokine effects)
Anti-serotonin Cyproheptadine (reduces serotonin)
malnourished but not anorectic patients received only the hypercaloric diet. In all patients, nutritional status and body composition were evaluated. By means of traditional anthropometry, and a monopolar bioelectrical impedance analyser, we determined at baseline, weekly for the first month and fortnightly thereafter: actual (W) and ideal (IBW) body weight; body surface area (S); body mass index (BMI); midarm (MAC) and midarm muscle circumference (MAMC); arm muscle area (AMA); triceps (TSF), biceps (BSF), subscapular (SSF), and iliac (ISF) skinfold thickness; lean(LBM) and fat (FBM) body mass; total body water (TBW), and body impedance (BIA). Basal energy expenditure (BEE) for each patient was calculated with an adapted Harris-Benedict formula. Food intake (Kcal/day), appetite(scale: 0 = very poor to 3 = very good), sense of well-being (Karnofsky scale), muscle power and endurance (Cyclette); and routine clinical and laboratory data. TNF levels were measured before and after MPA treatment. Any specific and necessary therapy was prescribed. At the end of the study, there were 50 patients (67.6%) in the MPA group and 80 (83.3%) in the diet-only group. At the beginning of the study, median weight loss was 11.3 kg (= at least 10% of IBW) in the first group and 5.1 kg (= at least 10 % of baseline weight) in the second. In a mean time of 52.3 days, MPA-treated patients had increased caloric intake (+1322 kcal), W (+6.2 kg), %IBW (+9.2), increases in four skinfold thicknesses (+10.8 mm) [TSF (+3 mm), BSF (+1 mm), SSF ( + 2.7 mm), ISF(+4.1 mm)], MAC ( + 2.1 cm), MAMC (+1.1 cm), AMA (+4.1 cm2), S (+0.9 m2), BMI (+2.1), LBM (+2.6 kg), FBM (+3.6 kg), % body fat (+5), %TBW (+0.1)]. Patients treated only with diet had increased daily caloric intake (+900 kcal), gaining W (+2.4 kg), increases in four skinfold thicknesses (+5.8 mm) [TSF (+1.1 mm), BSF (+1.4 mm), SSF (+1.2 mm), ISF (+2.1 mm), MAC (+0.7 cm), MAMC (+0.3 cm), AMA (+1.1 cm2), S(+0.02 m2), BMI (+0.51), LBM (+0.9 kg), FBM (+1.1 kg), % body fat (+0.7), % TBW(+0.6), in a mean time of 100.1 days. Thus, 93% of patients responded to MPA and 73% to diet. Weight gain in MPA patients was significantly greater and obtained more quickly than in diet patients; it was also prevalently associated with increases in fat and lean tissue. TBW remained constant during treatment, as confirmed by anthropometry and a mild reduction of BIA (-31.3 ohm), compared with the value of the patient's diet (-13.5 ohm). Appetite, muscle power and endurance, and sense of well-being significantly improved in the MPA group. No adverse changes in routine haematological or biochemical profiles attributable to MPA were reported. We also were able to demonstrate a reduction of high initial levels (> 100 pg/ml) of TNF-a after MPA treatment. In conclusion, our experience provides evidence that MPA improves appetite, nutritional status, and quality of life in AIDS anorectic and cachectic patients, counteracting disturbances of fat and protein metabolism induced by high levels of cytokines produced during chronic infection.
In another study , 151 subjects, 74 in the placebo and 77 in the MPA group, were enrolled at ten teaching and general Departments of Infectious Diseases to evaluate the efficacy of MPA (flavoured granules formulation 1 g/day) in promoting weight gain in AIDS cachectic patients. The study was a 12-week randomised, double blind, placebo-controlled, multicentre clinical study. The eligibility excluded pregnancy, steroid contraindications, renal and liver diseases, and intractable diarrhoea. The 151 patients (109 men and 42 women), who ranged in age from 22 to 61 years (mean 33.6 ± 7.4) and had lost > 10% of their usual body weight, were randomly assigned to orally receive either 1 g MPA or placebo once daily for 12 weeks. Baseline and monthly, appetite, caloric intake, body weight, body composition, and quality of life (Karnofsky scale) were assessed.
Adequate nutritional support was personalised for each patient according to a Harris-Benedict modified equation.
Of the 77 patients receiving MPA and of the 74 placebo recipients 52 and 49, respectively, could be evaluated at the end of the study.
Most patients receiving MPA had increased caloric intake, resulting in a mean weight gain of 5.5 kg, compared with 1.9 kg for the placebo group (p < 0.05). From baseline to week 12, patients in the MPA group significantly increased their daily caloric intake.
Significantly (p < 0.001) more MPA subjects than placebo gained > 10% of baseline body weight. The mean difference in percentage from baseline to 12 weeks between the two groups for skinfold thickness of the triceps and iliac, and lean and body fat was statistically significant (p < 0.05). The values of appetite scale and Karnofsky scores increased. No serious adverse effects were observed. The study therefore shows that 1 g of MPA, given orally once a day, is safe, well-tolerated, and effective in controlling AIDS cachexia during a period of 12 weeks.
The progestogenic synthesised derivative MA has been successfully used in the treatment of neoplas-tic cachexia, anorexia, and in AIDS patients [24,56, 81-83], but the optimal dosage of the drug remains to be defined. Also, the mechanism of action of MA is many-sided and not yet completely understood. It is thought that the stimulation of appetite by progestogens takes place at the hypo-thalamic level [84-86]. A second effect of MA, which has been demonstrated in vitro, is the promotion of fibroblast transformation into adipocyte. Finally, evidence has emerged showing anti-TNF and anti-IL-1 action .
A dose-response and cost-benefit compromise may be achieved with a dose of 320 mg/day. We designed a controlled study to evaluate the safety and efficacy of MA at this dosage in the treatment of anorexia and cachexia in AIDS patients . The trial had a total duration of 60 days divided into two 30-day periods: the first was a double-blind randomised versus placebo study; while in the second all patients received MA. Inclusion criteria were AIDS and body weight loss > 10% of usual weight.
Patients. Of the 56 AIDS patients (45 men and 11 women) enrolled in the study, 12 were assigned to subgroup 4A (MA: 7; placebo: 5), 39 into subgroup 4C1 (MA: 19; placebo: 20), and five into subgroup 4C2 (MA: 2; placebo: 3). The 82.1% of the patients who were drug addicts were divided equally into the MA group (n = 23) and the placebo group (n = 23). The average age (± SD) of the patients was 32.68 ± 5.21 years and was comparable between men and women and in the two groups: MA men 32.17 ± 4.88 years, MA women 33.20 ± 5.36 years; placebo men 33.36 ± 5.93 years, placebo women 31.67 ± 4.32 years. The average height for the entire sample was 171.23 ± 7.82 cm. The average current weight was 55.22 ± 8.35 kg (MA men 59.04 ± 5.84 kg, MA women 44.30 ± 5.29 kg; placebo men 56.82 ± 8.64 kg, placebo women 47.67 ± 6.74 kg). The usual weight was 67.26 ± 9.97 kg (MA men 70.17 ± 6.34 kg, MA women 51.70 ± 7.41 kg; placebo men 70.50 ± 9.31 kg; placebo women 56.17 ± 7.60 kg). The difference compared to the actual weight of 12.04 kg was equal to a weight loss of 18%. The ideal weight was 64.21 ± 6.25 kg (MA men 66.38 ± 4.80 kg, MA women 54.88 ± 3.87 kg; placebo men 65.57 ± 5.78; placebo women 58.65 ± 4.79 kg). The difference compared to the actual weight of 8.99 kg was equal to 11.62%.
Weight. In the double-blind phase, the initial weight of subjects in the two groups was comparable: MA 55.24 ± 8.32 kg; placebo 55.65 ± 9.21 kg. However, after 30 days of treatment, the increase for the MA subgroup was +3.87 ± 2.24 kg vs a decrease of -0.32 ± 2.36 kg for the placebo subgroup.
The differences between usual weight and actual weight at the start and after 30 days decreased in subjects treated with MA, from -11.37 ± 4.72 kg to -7.50 ± 4.60 kg, while they remained unchanged in the placebo group, from 10.06 ± 2.86 kg to 10.38 ± 4.30 kg. In the 'open' phase, the patients who were already receiving MA showed a modest weight gain, from 59.10 ± 8.61 kg to 59.11 ±9.1 kg, while those who went from placebo to MA had a more significant increase in weight, from 55.32 ± 9.26 kg to 58.47 ± 9.69 kg. These data show that, 30 days after the start of MA administration, a peak is reached that remains mostly stable during the following 30 days of treatment.
Body Mass Index. A BMI index < 20 kg/m2 is significant when evaluating weight loss: all patients enrolled in our trial had baseline values < 20 (MA 18.82 ± 2.09 kg/m2, placebo 18.70 ± 1.84 kg/m2), but after 30 days of treatment the MA group re-entered the normal range (20.06 ± 2.00 kg/m2) whereas in the placebo group the BMI value fell further (18.48 ± 2.03 kg/m2).
Circumference of the wrist: MA, from 15.70 ± 1.22 cm to 15.70 ± 1.22 cm; placebo, from 15.50 ± 0.95 cm to 15.33 ± 0.93 cm.
Circumference of the arm: MA, from 23.72 ±3.13 cm to 24.63 ± 3.12 cm; placebo, from 23.29 ± 2.57 cm to 23.21 ± 2.88 cm.
Circumference of the waist: MA, from 73.70 ± 7.49 cm to 76.48 ± 7.65 cm; placebo, from 73.41 ± 6.36 cm to 73.29 ± 6.06 cm.
Circumference of the buttocks: MA, from 84.26 ± 4.48 cm to 86.61 ± 4.95 cm; placebo, from 83.47 ± 4.64 cm to 82.71 ± 4.82 cm.
Circumference of the thigh: MA, from 44.43 ±4.13 cm to 46.57 ± 4.57 cm; placebo, from 44.18 ± 3.32 cm to 43.47 ± 3.56 cm.
Circumference of the arm muscles (MAMC): The measurements were significantly different in the two groups. In subjects treated with MA, MAMC increased from 204.40 ± 65.22 mm to 213.52 ± 50.61 mm, while in subjects receiving placebo MAMC decreased from 215.26 ± 29.58 mm to 202.78 ± 56.41 mm.
Skinfolds. Skinfolds are a measure of subcutaneous fat, which represents about half of all body fat. In those MA-treated patients, skinfold thickness increased significantly, while there was a modest increase in placebo-treated subjects that was a result of the hypercaloric-hyperproteic diet. TSF: MA, from 5.15 ±1.63 mm to 7.23 ±2.11 mm; placebo, from 5.95 ± 2.76 mm to 6.00 ± 2.54 mm. SSF: MA, from 8.70 ± 2.95 mm to 11.00 ± 3.85 mm; placebo, from 10.50 ± 4.29 mm to 10.65 ± 4.54 mm. ISF: MA, from 5.33 ± 2.54 mm to 8.03 ± 3.67 mm; placebo, from 7.29 ± 6.93 mm to 7.35 ± 6.86 mm.
Body Impedance. Cutaneous BIA values decreased in both groups, dropping in the MA group from 497.57 ± 83.40 ohms to 456.17 ± 90.75 ohms, and in the placebo group from 507.47 ± 91.97 ohms to 505.35 ± 98.45 ohms.
Fat-free mass: BIA measurements confirmed those obtained from body circumference measurements, with an increase in the MA group from 52.94 ± 8.29 kg to 56.50 ± 8.61 kg and a reduction in the placebo group from 53.41 ± 7.89 Kg to 52.64 ± 7.96 Kg. Fat mass: In the MA group, there was an increase from 2.30 ± 2.43 kg to 2.39 ± 3.01 kg and in the placebo group from 2.24 ± 3.42 kg to 2.65 ± 4.48 kg. TBW: TBW determination is important in a study involving progestogenic derivatives, which are believed to cause water retention. Our data exclude significant action of this type, in that the values for MA subjects went from 73.44 ± 2.00% to 73.51 ± 2.45%, and for the placebo from 72.83 ± 2.20% to 73.26 ± 2.15%.
Basal metabolism (REE): The caloric consumption necessary for maintaining vital functions and thermoregulation with respect to sex, age, weight, and body surface comprise the REE. For MA subjects, this increased from 1594.75 ± 167.41 Kcal to 1674.67 ± 183.99 Kcal and for subjects receiving placebo dropped from 1606.93 ± 201.31 Kcal to 1601.52 ± 201.06 Kcal.
In the open phase of the study, a slight further increase for MA subjects during the second month of treatment and a significant increase in patients who went onto MA after placebo period were observed.
Caloric Intake. MA patients had an actual basal caloric intake of 1415.49 ± 435.30 Kcal and a theoretical intake of 2096.52 ± 476/68 Kcal, with a difference of 681.03 Kcal. After 30 days of therapy, the actual intake increased to 2872.43 ± 539.84 Kcal as opposed to a theoretical intake of 2268.70 ± 468.45 Kcal, with a positive difference of + 603.73 Kcal. Patients in the placebo group showed an actual basal intake of 1390.12 ± 423.27 Kcal as opposed to a theoretical intake of 2000 ± 525.36 Kcal, with a difference of -609.99 Kcal. After 30 days of placebo and dietetic counselling the actual intake increased to 1850 ± 815.13 Kcal as opposed to a theoretical intake of 2015.29 ± 513.88 Kcal, with a difference of -165.29 Kcal. It should be noted that, under basal conditions, all patients consumed fewer calories than were necessary to maintain weight, whereas after 30 days both the MA and the placebo group increased their caloric intake albeit differently. In the open phase of the study, the actual caloric intake increased further, from 2872.43 ± 539.84 Kcal to 3158.93 ± 464.55 Kcal, with a difference of +908.93 Kcal after 60 days of MA, and from 2015.29 ± 513.88 Kcal to 2557 ± 756.84 Kcal, with a difference of +418.33 Kcal after 30 days of MA following placebo. The difference between the final and basal intake was 1456.95 ± 565.96 Kcal for MA and 459.88 ± 820.26 Kcal for placebo, with high statistical significance (p < 0.0001).
Appetite. At the time of enrolment the amount of appetite as measured with the visual analogue scale (VAS) was very poor in ten patients (4 MA, 6 placebo) and poor in 30 (19 MA, 11 placebo). At the second and third examination, only two placebo patients had a very poor appetite, eight placebo patients had a poor appetite; in 11 (7 MA, 4 placebo) appetite was fair, in 15 (13 MA, 2 placebo) good, and in 4 (3 MA, 1 placebo) very good. Clinically and statistically, the results were highly significant (p < 0.0001). In the open phase, appetite stabilised in the MA group (2 fair, 8 good, 4 very good) and there was clear improvement in patients who went onto MA after placebo, with none having a very poor appetite, 3 with poor appetite, 3 fair, 7 good, and 2 very good.
Performance Status. The Karnofsky index showed that MA improved the score by 66.52 ± 8.85 to 70.43 ± 9.28, whereas placebo failed to modify these values, 64.71 ± 8.74 to 64.71 ± 10.07. In the open phase, the scores of the MA group increased further (from 70.43 ± 9.28 to 75.00 ± 6.50) and those of the placebo group who switched to MA also increased (from 64.71 ± 10.07 to 68.67 ± 10.60).
Tumour Necrosis Factor. The TNF levels of the MA group decreased by 302.90 ± 355.44 pg/ml to 107.57 ± 166.28 pg/ml. In the placebo group, they increased from 243.52 ± 288.55 pg/ml to 364.65 ± 380.01 pg/ml.
Adverse Events. No adverse events occurred that were serious enough to lead to a suspension in drug administration or to a change in treatment. Minor intolerances were, however, reported by 40 patients, 25/27 (92.59%) in the MA group and 15/20 (75%) in the placebo group, with a difference in the incidence of 17.59%; this is a very low percentage and indicative of the good tolerability of the drug. For MA subjects, a reduction in libido was recorded (40% vs placebo 5%), gastrointestinal discomfort (29.63% vs placebo 15%), pruritus (22.22% vs placebo 10%), amenorrhoea (11.11% vs placebo 0%), sleep disorders (14.81% vs placebo 35%), and nausea and vomiting (0% vs placebo 10%).
Biochemical Parameters. No significant changes were observed in the biochemical or virological parameters in the two groups of patients.
Compliance. The degree of compliance was calculated only for the double-blind phase as the ratio between the difference in tablets given to the patient and those returned and the number of days of treatment. Overall, compliance for all the patients (ITT) was 94.67% ± 5.78 (MA) and 92.16% ± 10.44 (placebo); for patients evaluated for the efficacy of the drug, the percentage was 95.43% ± 4.49 (MA) and 94.88% ± 6.68 (placebo).
Completion of the Study. Of the 56 patients enrolled, 43 (76.8%) completed the double-blind phase: 24/28 (85.7%) in the MA group and 19/28 (67.9%) in the placebo group. The difference emphasises the subjective perception of the efficacy of the placebo.
Conclusions. The results obtained in this randomised study demonstrate the efficacy of MA treatment in rectifying loss of weight and appetite in AIDS patients.
The main variable studied was A-weight, in which, after 30 days of therapy, there was a significant, important difference between the MA (+3.87 ± 2.24 kg) and the placebo (-0.2 ± 2.36 kg) groups. The statistical significance of these values is evident both in terms of analysis for protocol (t = 5.7161, d.o.f. = 38, p < 0.00001) and for analysis of intention to treat (t = 5.5234, d.o.f.=45, p < 0.00001). The positive data for weight are also strengthened by results obtained for caloric intake and appetite - variables closely connected with body weight increase - since these were also significantly modified by MA. In fact, the increase in caloric intake was 1456.94 Kcal compared to 459.88 Kcal in the placebo group (t = 4.5532, d.o.f.+38,p < 0.0001). At the third examination, in the MA group, appetite was fair in 7 patients, good in 13, and very good in 3, as opposed to the placebo group in which appetite was very poor in 2 patients, poor in 8, good in 2 and very good in 1; the degree of significance was high (p < 0.0001).
Data relating to the open phase of the study, when all patients were taking MA, irrefutably confirms the efficacy of this drug; in fact, patients who were already under this treatment further increased their weight by 0.01 kg and their caloric intake by 908.93 Kcal. Appetite improved to fair in 2 patients, good in 8, and very good in 8. Subjects who were initially in the placebo group increased their weight by 3.15 kg, their caloric intake by 418.33 Kcal, and their appetite, which improved to poor in 3 patients, fair in 3, good in 7, and very good in 2. Only a few undesirable effects were recorded, by two out of 27 patients in the MA
group and 5 out of 20 in the placebo group, with no requests to stop treatment. Unwanted side effects consisted of a reduction in libido, amenor-rhoea, intestinal discomfort, and pruritus. No negative effects on the CD4+/CD4+ lymphocyte population or on |32-microglobulin were recorded, while a reduction in TNF levels was noted.
In conclusion, it can be stated that, at a dose of 320 mg/day, MA is an effective and safe drug in the treatment of AIDS cachexia.
Megestrol Acetate and rhGH The metabolic effects of growth hormone (GH) and progestin derivatives, i.e. MPA and MA, are well-documented in humans. GH predominantly promotes positive nitrogen balance, increasing lean body mass (LBM) but simultaneously reducing fat body mass (FBM) [87-89]; MA prevalently increases FBM, body water, and appetite [90, 91]. In AIDS-cachexia syndrome, there are important losses in LBM, FBM, and appetite [92-95], but the administration of GH alone may be insufficient to correct metabolism disturbances that lead to this condition. We therefore tested whether improved results could be obtained with the combined use of GH and MA .
Five AIDS (stage IV C) cachectic and anorectic patients (4 men, 1 woman, 25-56 years, mean 35.2 ± 13 years), who lost a mean 19.4% of their IBW, were treated with rhGH (Humatrope, Lilly France SA, Fegersheim, France) 0.63 mg/m2 subcuta-neously/day for 30 days. Eight comparable patients (7 men, 1 woman, 25-56 years, mean 33.7 ±10 years), who lost a mean 23.6 % of IBW, received the same dose of rhGH for 15 days together with MA (Megestil, Boheringer Mannheim, Milan, Italy) 320 mg orally/day for 30 days.
Anthropometric [(W, IBW, body circumferences (MAC, MAMC), BMI, skinfold thickness (biceps, triceps, sub-scapular, iliac), body compartments (LBM, FBM, TBW)], biochemical, hormonal and immunological assessments were carried out at baseline and after 1, 2, and 4 weeks. Selected measurements were also made before and after the therapies. Blood samples were collected for determination of IGF-1, insulin, cortisol, GH, aldos-
terone, T3, T4, dehydroepiandrosterone sulfate (DHEA-S), insulin-like-growth-factor binding pro-tein-3 (IGFBP-3), and TNF. Body composition was determined by BIA. Individual caloric needs were calculated by means of a corrected Harris-Benedict equation, as previously described . Appetite, quality of life, and food and caloric intake were recorded at the same times by means of an appetite scale, Karnofsky index, and a dietary diary. Written informed consent was obtained from each patient. All values were expressed as mean ± SD and compared by Student's t test and analysis of variance (ANOVA). Significance was designated at the 95% confidence level.
Results. The five patients receiving rhGH completed treatment, whereas three subjects in the rhGH + MA group were excluded from the study when treatment was suspended due to opportunistic infections (1 after 3 days, 1 after 7 days, 1 after 15 days).
Patients treated with rhGH alone continued to lose weight from baseline value (55.1 kg) to 53.2 kg (-1.9 kg) after 30 days of therapy, while patients receiving combined therapy gained 0.5 kg after 15 days and 0.1 kg in the next 15 days on MA alone (Table 3). In both groups, but significantly in MA patients, there was an increase in body fat and a decrease in lean tissue after 30 days. Combined treatment of 15 days produced a gain in LBM (+ 0.1 kg) and in FBM (+ 0.7 kg). Caloric intake increased from 1848 to 3605 Kcal/day after 15 days, doubling (+ 52.6 %) the baseline value after 30 days of MA treatment (from 1848 to 3898 Kcal/day). MA alone maintained fat and food intake gains from 15th to 30th day. Caloric intake in rhGH-treated patients increased from 2194 to 2768 Kcal/day. During rhGH treatment, IGF-1, aldos-terone, and insulin levels significantly increased (p < 0. 05) in both groups but more in MA subjects; T4 and T3 increased but not statistically significantly. GH levels decreased more in rhGH- than in rhGH + MA-treated patients. Cortisol levels significantly decreased (p < 0.05) only in rhGH + MA subjects (Table 4). No significant changes were observed in DHEA-S and IGFBP-3 levels and routine haematological or biochemical parameters in either group. TNF levels decreased in patients in whom secondary infections were successfully treated.
Conclusions. This is one of the first studies investigating the effects of rhGH administered together with MA in AIDS cachectic patients who lost > 10% of their usual body weight. In contrast with previous studies [96, 97] of rhGH administered to AIDS patients, we did not document weight gain after 30 days of rhGH treatment (0.63 mg/m2, sc/day). Even when our patients had increased caloric intake, they continued to lose weight. However, rhGH + MA (320 mg, orally/day) resulted in significant increase of appetite, caloric intake, body weight, and fat.
Our data give rise to doubt about the rationale of rhGH use in treating AIDS cachexia. AIDS patients have reduced LBM, fat body mass, and cholesterol, while normal adults with GH deficiency have reduced LBM and increased body fat, cholesterol, and TGs [88, 89, 98]. Baseline GH levels in our patients were higher than normal, and exogenous rhGH may modestly contribute to reversing the metabolic alterations due to cytokines and secondary infections. Nonetheless, appetite is scarcely influenced by rhGH. There may be other reasons for rhGH treatment of AIDS patients, such as to restore a GH deficiency in children or in selected adults. Our results confirm the efficacy of MA in improving appetite, caloric intake, and weight gain but further work is necessary to define which patients might benefit from single or combined use of GH and progestin derivatives.
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