Osteoporosis Associated With Megestrol Acetate
To our knowledge, this is the first report suggesting a possible association between megestrol and osteoporosis. Both of our patients were receiving high doses of megestrol, had evidence of adrenal axis suppression, and recovered fully after discontinuation of the drug. A clear relationship was seen between initiation of megestrol and the timing of vertebral compression fractures. This finding suggests that megestrol, especially at higher doses, may negatively affect bone quality and potentially be associated with bone loss and the development of fractures.
The glucocorticoidlike effect of megestrol is 1 mechanism that could lead to the development of osteoporosis. Biologically active progestins, including megestrol, have been shown to have efficient binding to the glucocorticoid receptor and to the progesterone receptor.4x4Kontula, K, Janne, O, Vihko, R, de Jager, E, de Visser, J, and Zeelen, F. Progesterone-binding proteins: in vitro binding and biological activity of different steroidal ligands. Acta Endocrinol (Copenh). 1975; 78: 574–592
PubMed | Google ScholarSee all References In fact, high-dose medroxyprogesterone acetate has been given to patients who have undergone adrenalectomy in the absence of glucocorticoids, with no reported signs of adrenal insufficiency.5x5Camanni, F, Massara, F, and Molinatti, GM. The cortisone-like effect of 6α-methyl-17α-acetoxyprogesterone in the adrenalectomized man. Acta Endocrinol (Copenh). 1963; 43: 477–483
PubMed | Google ScholarSee all References Megestrol also has been shown to have considerable affinity for the glucocorticoid receptor of human mononuclear leukocytes and has been associated with immunosuppressive activity in animals.6x6Kontula, K, Paavonen, T, Luukkainen, T, and Andersson, LC. Binding of progestins to the glucocorticoid receptor: correlation to their glucocorticoid-like effects on in vitro functions of human mononuclear leukocytes. Biochem Pharmacol. 1983; 32: 1511–1518
Crossref | PubMed | Scopus (126) | Google ScholarSee all References, 7x7Turcotte, JG, Haines, RF, Brody, GL, Meyer, TJ, and Schwartz, SA. Immunosuppression with medroxyprogesterone acetate. Transplantation. 1968; 6: 248–260
Crossref | PubMed | Scopus (40) | Google ScholarSee all References Thus, in vitro data support the concept that certain progestin compounds have an important peripheral glucocorticoidlike effect.
Several cases of Cushing syndrome due to megestrol have been reported.1x1Mann, M, Koller, E, Murgo, A, Malozowski, S, Bacsanyi, J, and Leinung, M. Glucocorticoidlike activity of megestrol: a summary of Food and Drug Administration experience and a review of the literature. Arch Intern Med. 1997; 157: 1651–1656
Crossref | PubMed | Google ScholarSee all References, 8x8Steer, KA, Kurtz, AB, and Honour, JW. Megestrol-induced Cushing’s syndrome. Clin Endocrinol (Oxf). 1995; 42: 91–93
Crossref | PubMed | Scopus (21) | Google ScholarSee all References, 9x9Siminoski, K, Goss, P, and Drucker, DJ. The Cushing syndrome induced by medroxyprogesterone acetate. Ann Intern Med. 1989; 111: 758–760
Crossref | PubMed | Scopus (25) | Google ScholarSee all References These observations are consistent with results of a prospective randomized trial that found that approximately one quarter of patients taking either progestin megestrol or medroxyprogesterone developed a cushingoid appearance after 3 months.10x10Willemse, PH, van der Ploeg, E, Sleijfer, DT, Tjabbes, T, and van Veelen, H. A randomized comparison of megestrol acetate (MA) and medroxyprogesterone acetate (MPA) in patients with advanced breast cancer. Eur J Cancer. 1990; 26: 337–343
Abstract | Full Text PDF | PubMed | Scopus (44) | Google ScholarSee all References Another prospective evaluation in 12 patients taking 800 mg of megestrol daily revealed that the weight gain associated with megestrol was due to an increase in adipose tissue and not lean tissue mass, again supporting a glucocorticoidlike effect of the drug.11x11Loprinzi, CL, Schaid, DJ, Dose, AM, Burnham, NL, and Jensen, MD. Body-composition changes in patients who gain weight while receiving megestrol acetate. J Clin Oncol. 1993; 11: 152–154
Crossref | PubMed | Scopus (182) | Google ScholarSee all References Finally, there have been reports of aseptic necrosis of the hip, presumably due to a glucocorticoidlike effect in HIV-seropositive patients taking megestrol.12x12Koller, E, Mann, M, Malozowski, S, Bacsanyi, J, and Gibert, C. Aseptic necrosis in HIV seropositive patients: a possible etiologic role for megestrol acetate. AIDS Patient Care STDS. 2000; 14: 405–410
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Megestrol use has been associated with suppression of serum cortisol levels in humans.3x3Alexieva-Figusch, J, Blankenstein, MA, Hop, WC et al. Treatment of metastatic breast cancer patients with different dosages of megestrol acetate: dose relations, metabolic and endocrine effects. Eur J Cancer Clin Oncol. 1984; 20: 33–40
Abstract | Full Text PDF | PubMed | Scopus (66) | Google ScholarSee all References, 13x13Willemse, PH, Dikkeschei, LD, Tjabbes, T, van Veelen, H, and Sleijfer, DT. Adrenal steroids as parameters of the bioavailability of MA and MPA. Eur J Cancer. 1990; 26: 359–362
Abstract | Full Text PDF | PubMed | Scopus (14) | Google ScholarSee all References, 14x14Briggs, MH and Briggs, M. Glucocorticoid properties of progestogens. Steroids. 1973; 22: 555–559
Crossref | PubMed | Scopus (39) | Google ScholarSee all References Loprinzi et al15x15Loprinzi, CL, Jensen, MD, Jiang, NS, and Schaid, DJ. Effect of megestrol acetate on the human pituitary-adrenal axis. Mayo Clin Proc. 1992; 67: 1160–1162
Abstract | Full Text | Full Text PDF | PubMed | Scopus (64) | Google ScholarSee all References evaluated the effects of megestrol on the adrenal axis in a prospectively followed cohort of 66 patients. Serum cortisol levels were decreased in all patients receiving 800 mg of megestrol daily. Furthermore, serum cortisol levels normalized in 3 patients who discontinued use of megestrol. In 5 patients, corticotropin levels were inappropriately decreased, suggesting suppressed hypothalamic-pituitary function. Hypothalamic-pituitary dysfunction was documented in 2 patients who had no response to metyrapone testing. Clinically, Cushing syndrome was not apparent in any patient in that study. Our patient in case 1 had nausea and emesis when megestrol was discontinued, suggestive of possible adrenal insufficiency. However, this may have simply represented the known benefit of megestrol in improving cancer-related nausea and vomiting.16x16Loprinzi, CL, Ellison, NM, Schaid, DJ et al. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst. 1990; 82: 1127–1132
Crossref | PubMed | Scopus (259) | Google ScholarSee all References, 17x17Rowland, KM Jr, Loprinzi, CL, Shaw, EG et al. Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/placebo in extensive-stage small-cell lung cancer: a North Central Cancer Treatment Group study. J Clin Oncol. 1996; 14: 135–141
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Corticosteroids have several well-known adverse effects on bone metabolism including direct inhibition of osteoblast function, direct enhancement of bone resorption, inhibition of gastrointestinal calcium absorption, increased urinary calcium loss, and inhibition of gonadal hormones.18x18Canalis, E and Giustina, A. Glucocorticoid-induced osteoporosis: summary of a workshop. J Clin Endocrinol Metab. 2001; 86: 5681–5685
Crossref | PubMed | Scopus (99) | Google ScholarSee all References Although traditionally the effect of megestrol on peripheral endocrine activity (eg, glucose and bone metabolism) was believed to be minimal, the reported cases of Cushing syndrome associated with megestrol show the potential for a peripheral glucocorticoidlike effect. Furthermore, there is a suggested dose effect of megestrol because Cushing syndrome appears to develop during higher-dose therapy.1x1Mann, M, Koller, E, Murgo, A, Malozowski, S, Bacsanyi, J, and Leinung, M. Glucocorticoidlike activity of megestrol: a summary of Food and Drug Administration experience and a review of the literature. Arch Intern Med. 1997; 157: 1651–1656
Crossref | PubMed | Google ScholarSee all References The development of multiple spontaneous vertebral compression fractures as seen in our patients would be typical of what often occurs in glucocorticoid-induced osteoporosis. Even more compelling are the reports of adverse skeletal effects from low-dose glucocorticoids that have few clinical features of corticosteroid excess. Clinical examples include reduced BMD in patients using inhaled glucocorticoids19x19Israel, E, Banerjee, TR, Fitzmaurice, GM, Kotlov, TV, LaHive, K, and LeBoff, MS. Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med. 2001; 345: 941–947
Crossref | PubMed | Scopus (263) | Google ScholarSee all References and in patients with Addison disease receiving replacement glucocorticoid therapy.20x20Zelissen, PM, Croughs, RJ, van Rijk, PP, and Raymakers, JA. Effect of glucocorticoid replacement therapy on bone mineral density in patients with Addison disease. Ann Intern Med. 1994; 120: 207–210
Crossref | PubMed | Scopus (171) | Google ScholarSee all References Also, Van Staa et al21x21Van Staa, TP, Leufkens, HG, Abenhaim, L, Zhang, B, and Cooper, C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res. 2000; 15: 993–1000
Crossref | PubMed | Scopus (985) | Google ScholarSee all References have shown that oral prednisone doses as low as 2.5 to 7.5 mg daily are associated with excess fracture risk.
Another reported effect of megestrol that could lead to osteoporosis is the profound suppression of estradiol production. One group of investigators reported suppression of follicle-stimulating hormone and luteinizing hormone in a group of women with metastatic breast cancer who were taking megestrol.3x3Alexieva-Figusch, J, Blankenstein, MA, Hop, WC et al. Treatment of metastatic breast cancer patients with different dosages of megestrol acetate: dose relations, metabolic and endocrine effects. Eur J Cancer Clin Oncol. 1984; 20: 33–40
Abstract | Full Text PDF | PubMed | Scopus (66) | Google ScholarSee all References These changes were associated with a reduction in serum levels of estradiol and sex hormone-binding globulin. A more recent prospective study involving 12 postmenopausal women with advanced breast cancer who took low-dose megestrol (oral doses escalating from 40 to 160 mg daily) for 1 month revealed a reduction in serum levels of testosterone, estradiol, estrone, and estrone sulfate to 18% to 29% of pretreatment values.2x2Lundgren, S, Helle, SI, and Lonning, PE. Profound suppression of plasma estrogens by megestrol acetate in postmenopausal breast cancer patients. Clin Cancer Res. 1996; 2: 1515–1521
PubMed | Google ScholarSee all References The reduction in serum estradiol concentration was similar to that reported with use of the aromatase inhibitor aminoglutethimide and was a secondary phenomenon based on a 35% to 52% reduction of serum gonadotropins (luteinizing hormone and follicle-stimulating hormone). In that study, the decrease in serum estradiol and testosterone levels was dose dependent, although gonadotropins were suppressed maximally at a dose of 80 mg of megestrol. Low levels of endogenous estrogen in postmenopausal women have been associated with increased bone turnover, reduced bone density, and increased fracture risk.22x22Heshmati, HM, Khosla, S, Robins, SP, O’Fallon, WM, Melton, LJ III, and Riggs, BL. Role of low levels of endogenous estrogen in regulation of bone resorption in late postmenopausal women. J Bone Miner Res. 2002; 17: 172–178
Crossref | PubMed | Scopus (162) | Google ScholarSee all References, 23x23Ettinger, B, Pressman, A, Sklarin, P, Bauer, DC, Cauley, JA, and Cummings, SR. Associations between low levels of serum estradiol, bone density, and fractures among elderly women: the study of osteoporotic fractures. J Clin Endocrinol Metab. 1998; 83: 2239–2243
Crossref | PubMed | Scopus (234) | Google ScholarSee all References, 24x24Cummings, SR, Browner, WS, Bauer, D…, and Study of Osteoporotic Fractures Research Group. Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med. 1998; 339: 733–738
Crossref | PubMed | Scopus (543) | Google ScholarSee all References, 25x25Melton, LJ III, Khosla, S, Malkasian, GD, Achenbach, SJ, Oberg, AL, and Riggs, BL. Fracture risk after bilateral oophorectomy in elderly women. J Bone Miner Res. 2003; 18: 900–905
Crossref | PubMed | Scopus (89) | Google ScholarSee all References Thus, reduced serum estrogen concentrations associated with megestrol use are not inconsequential and could lead to increased bone loss and skeletal fracture.
Clinical data suggest increased bone turnover and potential bone loss with megestrol use. In a randomized study of postmenopausal women with breast cancer, megestrol was associated with increased biochemical markers of bone resorption compared with placebo.26x26Martinetti, A, Zilembo, N, Ferrari, L et al. Bone turnover markers and insulin-like growth factor components in metastatic breast cancer: results from a randomised trial of exemestane vs megestrol acetate. Anticancer Res. 2003; 23: 3485–3491
PubMed | Google ScholarSee all References Likewise, men receiving androgen deprivation therapy (megestrol included) for prostate cancer have been reported to have increased bone loss.27x27Higano, CS. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology. 2003; 61: 32–38
Abstract | Full Text | Full Text PDF | PubMed | Scopus (179) | Google ScholarSee all References Finally, most prospective studies of depot medroxyprogesterone in premenopausal women suggest a modest decline in BMD.28x28Westhoff, C. Bone mineral density and DMPA. J Reprod Med. 2002; 47: 795–799
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Although our report focuses on the possible adverse skeletal effect of progestational agents, there are data to suggest beneficial skeletal effects. For example, medroxyprogesterone has been shown to have a positive effect on calcium homeostasis when given to premenopausal women receiving gonadotropin-releasing hormone agonist therapy.29x29Carr, BR, Breslau, NA, Peng, N, Adams-Huet, B, Bradshaw, KD, and Stein-kampf, MP. Effect of gonadotropin-releasing hormone agonist and medroxyprogesterone acetate on calcium metabolism: a prospective, randomized, double-blind, placebo-controlled, crossover trial. Fertil Steril. 2003; 80: 1216–1223
Abstract | Full Text | Full Text PDF | PubMed | Scopus (9) | Google ScholarSee all References Also, progesterone receptors are present on human osteoblasts, and progesterone may activate bone formation.30x30Prior, JC. Progesterone as a bone-trophic hormone. Endocr Rev. 1990; 11: 386–398
Crossref | PubMed | Scopus (218) | Google ScholarSee all References, 31x31Tremollieres, FA, Strong, DD, Baylink, DJ, and Mohan, S. Progesterone and promegestone stimulate human bone cell proliferation and insulin-like growth factor-2 production. Acta Endocrinol (Copenh). 1992; 126: 329–337
PubMed | Google ScholarSee all References Progesterone has been shown to stimulate proliferation and differentiation of osteoprogenitor cells in bone cells derived from adult female rats.32x32MacNamara, P, O’Shaughnessy, C, Manduca, P, and Loughrey, HC. Progesterone receptors are expressed in human osteoblast-like cell lines and in primary human osteoblast cultures. Calcif Tissue Int. 1995; 57: 436–441
Crossref | PubMed | Scopus (48) | Google ScholarSee all References, 33x33Ishida, Y and Heersche, JN. Progesterone stimulates proliferation and differentiation of osteoprogenitor cells in bone cell populations derived from adult female but not from adult male rats. Bone. 1997; 20: 17–25
Abstract | Full Text PDF | PubMed | Scopus (64) | Google ScholarSee all References Although progestins have been reported to prevent bone loss in postmenopausal women, other studies have been unable to show this benefit.34x34Horowitz, M, Wishart, JM, Need, AG, Morris, HA, and Nordin, BE. Effects of norethisterone on bone related biochemical variables and forearm bone mineral in post-menopausal osteoporosis. Clin Endocrinol (Oxf). 1993; 39: 649–655
Crossref | PubMed | Scopus (58) | Google ScholarSee all References, 35x35Lobo, RA, McCormick, W, Singer, F, and Roy, S. Depo-medroxyprogesterone acetate compared with conjugated estrogens for the treatment of postmenopausal women. Obstet Gynecol. 1984; 63: 1–5
PubMed | Google ScholarSee all References, 36x36Gallagher, JC, Kable, WT, and Goldgar, D. Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. Am J Med. 1991; 90: 171–178
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The potential association of megestrol and osteoporosis is important to recognize because patients given megestrol likely will have other risk factors associated with the development of osteoporosis (as were present in our patients). Women with breast cancer appear to be at increased risk of osteoporosis because of multiple factors, including premature ovarian failure (a direct effect of chemotherapy) and perhaps breast cancer itself.37x37Mincey, BA, Moraghan, TJ, and Perez, EA. Prevention and treatment of osteoporosis in women with breast cancer . Mayo Clin Proc. 2000; 75: 821–829
Abstract | Full Text | Full Text PDF | PubMed | Scopus (31) | Google ScholarSee all References Subjects in the Women’s Health Initiative Observational Study with a history of breast cancer had more than a 28% increased risk of all types of fractures except hip fractures. This fracture risk was present after adjustment for other risk factors during a mean follow-up of 5.1 years.38x38Chen, Z, Maricic, M, Bassford, TL et al. Increased fracture risk among breast cancer survivors: results from the Women’s Health Initiative . J Bone Miner Res. 2003; 18: S22 (Abstract 1077.)
Google ScholarSee all References Similarly, many patients receiving megestrol are postmenopausal and predisposed to bone loss. Vitamin D deficiency and reduced calcium intake in anorexic or cachectic patients may contribute to secondary hyperparathyroidism and further reduce bone density. Thus, because of the potential adverse skeletal effects of megestrol, its use is of concern and warrants further investigation in a population already predisposed to the development of osteoporosis.
We describe 2 cases that suggest megestrol may have been an important factor in the development of osteoporotic fractures. Clearly, further study is needed to clarify the relationship between megestrol and metabolic bone disease because case reports do not prove causality. Because of the retrospective nature of these case reports, baseline BMD tests and radiography of the spine were not performed before initiation of megestrol. Also, we recognize that our patients had several other risk factors for osteoporosis. However, considering the associated evidence of a glucocorticoidlike effect in our patients’ clinical presentations, together with the known endocrine effects of megestrol on adrenal and ovarian function, we believe that megestrol likely contributed to the development of osteoporosis and subsequent fractures in our patients.
Anorexia, defined as a lack of desire to eat, is a frequent disorder among patients treated with periodic haemodialysis. A loss in appetite was noted by 33% of the patients in the HEMO1 study, by 24% of those in the DOPPS2 study, and in up to 38% in other series.3
Anorexia is one of the factors that contribute to malnutrition among patients undergoing dialysis.4,5 Insufficient food intake is the main cause of type 1 uraemic malnutrition, which is characterised by weight and muscle mass loss with a modest impact on albumin concentrations, in contrast to type 2, which is more related to concurrent inflammatory processes.6,7 Apart from its impact on nutrition, anorexia is itself an independent risk factor for morbidity and mortality.1,2 Its pathogenesis is unknown. Inflammatory cytokines, deregulation of hormones and neuropeptides that control appetite, retention of medium molecular weight molecules, and alterations in amino acid concentrations seem involved.4,8,9
The control of anorexia is important for the prevention and treatment of malnutrition associated with renal failure; however, few studies have focused on appetite and specific measures to stimulate it. In the HEMO study, it was found that neither the administration of a greater dose of haemodialysis than that currently considered adequate nor the use of high-flux dialysers resulted in an improvement in appetite.10 Appetite is lower on the day of haemodialysis,11 but an increase has been reported as the number of sessions increases.12
Steroids, progestogens, and serotonin agonists have been used to stimulate appetite in various clinical situations.13 Of all substances with orexigenic effects, the best known is megestrol acetate. It is a synthetic progestin that is used to increase appetite and weight in cancer patients or those infected with the HIV virus.14,15 Two systematic reviews concluded that treatment with megestrol acetate is effective in those cases.16,17 Its tolerance is considered to be good, with a rate of side effects no higher than those observed in placebo groups,17 but adverse effects have been reported such as gastrointestinal intolerance, hyperglycaemia, and inhibition of secretion of pituitary hormones such as corticotropin (ACTH) and the gonadotropins.14 The use of megestrol acetate in patients undergoing dialysis has limited experience; the doses used have varied, as have the results.18-23
In January 2009 we began a protocol of treatment of anorexia in dialysis patients with megestrol acetate. In this paper we describe our experience with the patients that began treatment during its first year of use.
MATERIAL AND METHOD
For the definition of anorexia, we used the appetite questionnaire from the HEMO11 and DOPPS2 studies. It reflects the patient’s current appetite as they see it on a Likert scale with five possibilities: very good, good, fair, poor, or very poor. Next the patients are asked if in the last four week their appetite has improved, stayed the same, or worsened. Anorexia is diagnosed when a patient reports that their current appetite is fair, poor, or very poor, and that in the last 4 weeks it has not changed or has worsened.
In 2009, 99 patients with chronic renal failure were cared for in our haemodialysis unit. During this year, 18 patients with anorexia gave their informed consent to receive treatment with megestrol acetate. One patient was excluded who stopped the treatment one month after starting, without obvious cause, and another was diagnosed with multiple myeloma and died from his illness two months later. The 16 remaining cases were treated with megestrol acetate for 3 months and make up the object of this study.
Age, gender, time on haemodialysis, and the possible cause of anorexia are shown in Table 1. Three patients had insulin-dependent diabetes mellitus (cases 1, 2 and 16). Eight patients (cases 3, 6, 7, 8, 11, 15, and 16) had resumed haemodialysis after a failed kidney transplant; none of them received immunosupression at the time of beginning treatment with megestrol acetate. In 7 patients, an intercurrent process triggered anorexia: initiation of treatment for hepatitis C with interferon (case 6); HIV infection treated with antiretroviral drugs (case 11), and admission to hospital for various complications (cases 2, 4, 7, 13 and 16). In the 9 remaining cases, the lack of appetite could not be attributed to a specific cause. All patients started treatment as outpatients. In the cases in which anorexia was brought on by intercurrent conditions that required hospital admission, the treatment with megestrol acetate started after the patients were discharged.
The starting dose of megestrol acetate was 160 mg daily in a single dose. No calorie or protein supplements were administered orally or intravenously during haemodialysis. After 3 months of treatment, response was assessed through a survey in which patients were asked whether their appetite had improved and the evolution of dry weight and laboratory parameters were analysed. The follow-up period ended 30 June 2010.
The patients had dialysis three times per week, 3.5-4 hours per session, with high-flux dialysis and ultra-pure dialysis liquid. The dialysis dose was calculated using standard urea clearance (Kt/V) obtained using the simplified monocompartmental Daugirdas formula. The protein catabolic rate (PCR) was obtained using the Borah formula as modified by Sargent.24 Dry weight was determined using clinical criteria. Twelve patients had residual diuresis less than 150 ml/day when treatment with megestrol acetate was indicated. Blood samples for the laboratory measurements were obtained immediately before the first haemodialysis session of the week, after the long interdialytic interval.
Data are expressed as mean (SD). For the statistical analysis we used the Student’s t test for paired data. Values with P<.05 were considered statistically significant.
The loss of dry weight in the two months prior to treatment with megestrol acetate, the subjective evaluation of appetite, and the evolution of dry weight at the three-month follow-up are shown in Table 1. Thirteen patients considered that their appetite had improved. Dry weight increased in 15 patients, although in five of them the increase was less than 1 kg.
The evolution of the parameters related to nutrition analysed after the third month of treatment is shown in Table 2. Overall, the group saw a significant increase in dry weight, in concentrations of albumin and creatinine, and in the rate of protein catabolism. The last two parameters were analysed only in the 12 patients without diuresis, in order to avoid the possible influence of variations in residual renal function.
The follow-up period from the start of treatment, the time of treatment with megestrol acetate, the cause of withdrawal and weight gain are shown in Table 3. Three patients died during the follow-up period. Cases 2 and 10, with severe vascular disease, died as a consequence of this disease, and case 3, due to tuberculosis pericarditis in a patient with AIDS. The 13 remaining patients were alive when the study ended. In 5 patients the dose of megestrol acetate was increased to 320 mg/day due to a lack of response to the initial dose (cases 6, 8, and 12) or due to a later decrease of appetite (cases 9 and 14), with good appetite evolution and weight in all cases. At the time the study ended, 3 patients continued taking megestrol acetate. In two of them, attempts to withdraw the treatment were associated with loss of appetite and the need to reintroduce the treatment (cases 1 and 7).
Of the three patients with insulin-dependent diabetes mellitus (cases 1, 2, and 6), two did not need their insulin dosage to be modified after administering megestrol acetate. In case 2, the dose of Lantus insulin needed to be increased from 15 to 18 U/day. An increase in glucose concentration was found in two of the 13 remaining patients. In one patient (case 13) who had dialysis in the afternoon, the postprandial blood glucose, which had been less than 125 mg/dl, increased starting the second month of treatment (maximum concentration 156 mg/dl) and returned to normal figures one month after the end of treatment. In case 6, baseline glucose increased with the administration of interferon up to a maximum of 153 mg/dl.
One patient (case 9), who received low doses of steroids for necrotising vasculitis with leukocyte cytoplasmic antibodies, had left deep femoral vein thrombophlebitis after the sixth month of treatment and needed anticoagulation for 3 months, with complete repermeabilisation of the femoral vein.
A study of the pituitary-adrenal axis was conducted in 10 patients during the treatment with megestrol acetate. We determined baseline ACTH, baseline cortisol, and at 30 and 60 minutes after stimulation with ACTH (0.25 mg of ACTH i.v.) (Table 4). Three patients had a basal cortisol level below the normal range, associated in 2 cases with concentrations of ACTH at the lower limits of normality. Concentrations of FSH and LH gonadotropins were measured in 8 patients, which were within the normal range in all of them (data not shown).
We describe here our experience with the use of megestrol acetate in 16 patients treated with haemodialysis who reported anorexia. The diagnosis of anorexia was made using the HEMO and DOPPS questionnaire on subjective appraisal of appetite. The validity of the questionnaire was demonstrated in both studies by showing that the evaluation of appetite is a faithful reflection of the consumption of food,1,11 has a good correlation with nutritional parameters and those of quality of life,1,2 and is a predictor of morbidity and mortality.1-3
The initial dose of megestrol acetate was 160 mg/day. This is an intermediate dose among the wide range of doses used in patients on dialysis: 40 mg (18), 80 mg (22), 160 mg (21), 400 mg (20), and 800 mg daily.19,23 At 3 months, 13 of the 16 patients believed their appetite had improved. Overall, the group saw an increase in dry weight, an improvement in nutritional parameters related to protein metabolism such as albumin concentration and protein catabolic rate (a reflection of the consumption of protein) and an increase in the concentration of creatinine (an indicator of muscular mass). The effect of megestrol acetate on albumin concentration has been observed in other studies with patients on dialysis.18,20-22
Treatment with megestrol acetate is usually temporary. In our series, 87% of the cases were treated for less than one year (4-11 months), stimulating appetite itself in clinically stable patients, or helping to recover from intercurrent conditions, which are frequent in patients on dialysis.
At the dose used, clinical tolerance was good and no patient reported symptoms such as headache, diarrhoea, confusion, or dizziness, which have been reported at doses of 800 mg per day.19 However, we did observe other side effects attributable to the use of megestrol acetate. One diabetic patient needed an increase in her dose of insulin, and in 2 patients an increase in plasma glucose concentration was detected. The inhibitory effect of megestrol acetate on the pituitary-adrenal axis was a more significant revelation. In 3 of 10 patients studied, a reduction in baseline cortisol was found, with low concentrations of corticotropin in two cases. These possible effects on the endocrine system have not been analysed in other studies on dialysis patients. One patient had thrombophlebitis. Relating this with megestrol acetate is hypothetical, since the patient was receiving steroids for necrotising vasculitis. We did not observe any effect of megestrol acetate on lipid profiles or on treatment for anaemia. No inhibition of FSH or LH concentrations was found in any of the patients studied.
We can conclude that megestrol acetate stimulates appetite in patients on haemodialysis who report anorexia. The increase in appetite is accompanied by an increase in weight and an improvement in other nutritional parameters related to protein metabolism. However, induced hyperglycaemia and inhibited secretion of ACTH are possible side effects that should be taken into account when administering this drug. The dose and duration of treatment should be established in future studies.
Table 1. Baseline data on patients and progress at three months of treatment with megestrol acetate
Table 2. Changes in dry weight, albumin and creatinine concentrations, lymphocyte count and protein catabolic rate (PCR) at the third month of treatment with megestrol acetate
Table 3. Follow-up from the start of treatment until the end of the study (30 June 2010), time of treatment with megestrol acetate, cause of withdrawal and weight gain.