The American Journal of Geriatric Pharmacotherapy D L Bodeuuer et al

Effects of on Pituitary Function and End-Organ Hormone Secretion: A Post Hoc Analysis of Serum Samples from a 12-Week Study in Healthy Older Men

Donald L. Bodenner, MD, PhD; Monisha Medhi, MD;William J. Evans, PhD; Dennis H. Sullivan, MD; Hui Liu, MS; and Charles R Lambert, PhD

Department of Geriatrics, Donald W Reynolds Center on Agmg, The University of Arkansas for Medical Sciences and the Geriatric Research, Education and Chnlcal Center, Central Arkansas Veterans Healthcare System, Little Roc£ Arkansas

ABSTRACT Background: Mcgestrol acetate (MA) is a synthetic progestln commonly used to promote weight gain in mal- nourished older individuals. In small studies, MA administration has been associated with reduced serum cortlsol con- centratlons in patients with cancer or AIDS. The impact of MA on the pituitary secretion of adrenocortlcotroplc hormone (ACTH) and other hormones is unclear, and the prevalence and extent of hypocortlsolemla in older indi- viduals after MA treatment is unknown. A randomized, placebo-controlled study of the effects of (T) and resistance training (RT) on body composition after MA administration in older men has been reported previously. Objective: The purpose of this post hoc analysis was to examine the effect of 12 weeks of MA on pituitary func- tion and end-organ hormone secretion in healthy older individuals using frozen serum samples from that study. Methods: The previous study was conducted at the Department of Geriatrics, Donald W. Reynolds Center on Aging and the General Clinical Research Center at The University of Arkansas for Medical Sciences, Little Rock, Arkansas. Healthy male volunteers aged 60 to 85 years were recruited from the center and were randomly assigned to 1 of 4 study groups: RT + T, T, RT + placebo (P), or P. Subjects enrolled in the RT groups underwent supervised upper- and lower-body strength-training exercises 3 d/wk at 80% of I repetition maximum. Subjects in the groups to receive T received injections of 100 mg IM QW for 12 weeks. Subjects receiving P were given 1-mL saline injections IM QW for 12 weeks. All subjects received MA 800 mg PO QD concurrently for 12 weeks. For the present analysis, serum concentrations of the pituitary hormones follicle-stimulating hormone (FSH), thyroid- stimulating hormone (TSH), ACTH, prolactln (PRL), and lutelnlzlng hormone (LH), as well as the end-organ hormoncs cstradlol (E2), cortlsol, frcc T4, and T, wcrc mcasurcd in samplcs obtained at baseline (week 0) and after 12 wccks of/VIA trcatmcnt. Results: Scrum samplcs from 21 mcn (mcan [SD] agc, 67.0 [7.3] ycars; mcan [SD] body mass lndcx, 23.1 [10.4] kg/m2; mcan [SD] pcrccntagc of body fat, 22.5% [8.8%]; RT + T, T, RT + P, and P groups, n = 4, 5, 6, and 6 subjccts, rcspcctlvcly) wcrc avallablc from thc original study. Thc mcan pcrccntagc changcs from baschnc an scrum pitu- itary hormonc conccntratlons aftcr 12 wccks of MA administration wcrc as follows: TSH, -14.7%; ACTH, -89.5%; PRL, 162.2%; and LH, 49.0%; (P = 0.03, <0.001, <0.001, and <0.001, rcspcctlvcly). Thc mcan (SD) pcrccntagc changcs from bascllnc an scrum cnd-organ hormonc conccntratlons with MA at 12 wccks wcrc as follows: E 2, 181.6%; and cor- tlsol, -90.8% (both, P < 0.001). In thc P and RT + P groups, thc mcan pcrccntagc changcs from bascllnc an T wcrc -84% and -85%, rcspcctlvcly (both, P < 0.001). FSH and frcc T4 conccntratlons wcrc not significantly changcd. Conclusions: This analysis ofscrum samplcs from hcalthy oldcr mcn suggcsts that MA administration significantly affcctcd thc sccrctlon of scvcral pituitary hormoncs and cnd-organ hormonc synthcsls. Most notably, ACTH sccrc- tlon and scrum cortlsol lcvcls wcrc statistically significantly supprcsscd an 20 of 21 subjccts, without thc dcvclop-

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160 September2005 Volume 3 • Number 3 Copyright © 2005 Excerpta Medic& Inc D L Bodeuuer et al The American Journal of Geriatric Pharmacotherapy

ment of clinically significant adrenal suppression. (Am Thc University of Arkansas for Medical Sciences, Little J Ger~atr Pharmacother. 2005;3:160-167) Copyright Rock, Arkansas. The study protocol was approved by © 2005 Excerpta Me&ca, Inc. the Human Research Advisory Committee at the uni- Key words, megestrol acetate, adrenal insufficiency, versity. Details of the original study design wcrc cortisol, pituitary, older patients. reported previously. 22 In brief, healthy men aged 60 to 85 years and with a body mass index (BMI) <25 kg/m 2 wcrc recruited from the center. Subjects wcrc randomly assigned to INTRODUCTION 1 of 4 groups: RT + T, T, RT + placebo (P), or P. Mcgcstrol acetate (MA) is a progcstcronc-hke compound Subjects enrolled in the RT groups underwent super- used to combat malnumtion associated ~ath AIDS 1 and vised upper- and lower-body strength-training exercises cancer. 2 Long-term/VIA treatment is frequently prescribed 3 d/wk at 80% of 1 repetition maximum. Group T was to prevent or reverse weight loss in residents of long-term administered replacement with testosterone cnanthatc care facilities and in anorexic older patients. 3~5 However, 100 mg IM QW for 12 weeks; group RT + P received based on a MEDLINE search (key terms: mede~rol RT and saline injections IM QW for 12 weeks; and acetate, adrenal ~nsztffic~ency, and adrenal suppression; group P received 1-mL saline injections IM QW for years: 1965-2005), few studies have examined the efficacy 12 weeks. All subjects received/VIA 800 mg PO QD and tolcrabihty of MA in this patlcnt population. concurrently for 12 weeks. 22 /VIA, similar to progcstcronc, functions as a gluco- Venous blood was sampled from an antccubital vein cortlcold agonlst. Scvcral casc scrlcs havc shown that at 7:00 AM before the start of the study and at study /VIA significantly supprcsscs scrum cortlsol lcvcls. 7 1s cud, 8 days after the final injection, 3 days after the final Howcvcr, gcncrahzatlon ofthcsc obscrvatlons, particu- RT session, and 1 day after the last dose of/VIA. Blood larly to thc gcrlatrlc population, is hampcrcd by thc samples wcrc obtained after subjects had bccn in the small numbcrs of subjccts cnrollcd in avallablc studlcs, supine position for at least 15 minutes. 22 Serum con- thc abscncc of an untrcatcd control group, and ccntrations of the pituitary hormones FSH, thyroid- cxtrcmcly fcw oldcr subjccts cnrollcd. Morcovcr, thc stimulating hormone (TSH), adrcnocorticotropic hor- majority of thcsc rcports havc lnvolvcd chlldrcn or mone (ACTH), PRL, and LH, as well as the cud-organ patients with AIDS. 8,1°,ll,14,16 18 hormones cstradiol (E2), cortisol, frcc T4, and T, wcrc MA has been shown to markedly reduce serum estro- measured in the prctrcatmcnt (baschnc) and posttrcat- gen concentraHons in women 19 and to suppress serum mcnt (12-week) samples. The hormones wcrc assayed testosterone (T) concentrations to castrate levels in men. 2° using cnzymc-hnkcd immunosorbcnt assay kits accord- However, the mechanism of these effects and the unpact ing to manufacturer's instructions. 23 The intcrassay co- of MA on the secretion of other pituitary hormones are cfficicnts of variation for the kits wcrc as follows: FSH, poorly understood. In 1 series of patients with breast can- 4.8%; TSH, 8.9%; ACTH, 6.2%; PRL, 7.4%; LH, 8.1%; cer, MA increased basal and stimulated prolactln (PRL) E2, 3.7%; cortisol, 6.9%; frcc T4, 5.7%; and T, 7.6%. levels, decreased level, and suppressed lutelnlzlng hormone (LH) and folllcle-stunulanng hormone (FSH). 21 Statistical Analysis The purpose of this post hoc analysis was to examine Three-factor repeated measures analysis of variance the effect of MA on pituitary function and end-organ (RT x T x time [d]) was performed, followed by a hormone secretion in healthy older individuals using Tukcy post hoc analysis where appropriate. Results frozen serum samples from a previously reported inves- wcrc considered significant at P < 0.05. A power analy- tigation examining the effect of T and progressive- sis for this study was not performed. resistance muscle strength training (RT) on body com- position in healthy older men receiving MA to induce RESULTS weight gain. 22 Serum samples from 21 subjects in the original study wcrc available for analysis (RT + T, n = 4; T, n = 5; RT + MATERIALS AND METHODS P, n = 6; P, n = 6). The mean (SD) age, BMI, and per- Study Design and Population centage of body fat of the participants wcrc 67.0 (7.3) The previous study was conducted at the years, 23.1 (10.4) kg/m 2, and 22.5% (8.8%), respec- Department of Geriatrics, Donald W. Reynolds Center tively. No significant differences in age or BMI wcrc on Aging and the General Clinical Research Center at found between the 4 groups.

161 The American Journal of Geriatric Pharmacotherapy D L Bodeuuer et al

The serum concentrations of several pituitary hor- tlvcly small casc scrlcs havc shown that thc glucocortl- mones and the hormone levels associated with their cold activity of MA might induce adrenal suppres- respective target organs were significantly changed sion.8,10 12,14,16 18,25,26 However, symptomatic adrenal from baseline after 12 weeks of MA administration an insufficicncy appears to be uncommon: in a review of all 4 groups combined (Table). US Food and Drug Administration records from 1984 to 1996, 27 only 17 cascs of adrcnal insufficicncy possi- Pituitary Hormones bly associatcd with MA wcrc rcportcd. Sincc 1996, MA had httle effect on FSH levels. In contrast, the dcspitc widcsprcad MA usc an paticnts with AIDS or mean percentage decrease from baseline in LH levels canccr, few cascs of clinically significant adrcnal insuffi- was 49.0% (P < 0.001), with no significant group-by- cicncy havc bccn rcportcd. 14 Howcvcr, adrcnal insuffi- time effects. TSH was significantly decreased (by cicncy oftcn has a protcan prcscntation and frcqucntly 14.7%) after MA administration (P = 0.03), but the as underdiagnosed. 2s Thus, whether the presumed inca- changes were within the normal range. The mean per- dcncc of adrcnal insufficicncy as a rcflcction of inadc- centage decrease from baseline in ACTH was 89.5% quatc rcporting of an unrccognizcd advcrsc cffcct (from 20.9 [6.2] to 2.2 [2.3] pg/mL; P< 0.001). This rcmains unclcar. For cxamplc, an a study of 13 paticnts change is illustrated by the significant time effect as with breast cancer rccciving MA, 15 all 13 experienced shown in Figure 1. Although ACTH was significantly fatiguc and wcakncss whilc rccciving thc drug. Eight higher in the RT + T group compared with those in the paticnts wcrc hypotcnsivc, and 3 cxpcricnccd nausca other groups at baseline, there was no RT-by-time and vomiting. In another study, 29 12 of 13 children interaction, indicating diffcrcnccs bcm~ccn groups at basc- had adrcnal supprcssion whilc bcing trcatcd with MA hnc. PRL lcvcls wcrc significantly incrcascd at 12 wccks; for wcight loss from malignant discasc, with 1 paticnt the mean percentage change was 162.2% (range, 118%- cxpcricncing a circulatory collapse rcquiring inotropic 1300%; P < 0.002), v~'ith lcvcls dctcctcd outsidc thc nor- support. mal range an 19 of 21 subjects. The glucocorticoid activity of MA might be sufficicnt to providc adcquatc basal physiologic glucocorticoid End-Organ Hormones activity an most individuals, which might cxplain thc As previously reported, the percentage decreases from common finding ofadrcnal supprcssion but thc low inca- baseline in T levels at 12 weeks were 84% in the P group deuce of adrenal insufficicncy noted during treatment and 85% in the RT + P group (both, P< 0.001). 22 Con- ~ath/VIA. Similarly, an the previous study, 22 deep venous versely, E 2 levels increased from baseline by 181.6% after thrombosis was notcd an I sublcct, but no signs or symp- MA admmlstranon (from 9.7 [ 16.4] to 27.4 [24.1] pg/mL; toms consistcnt with adrcnal insufficicncy wcrc rcportcd. P < 0.001 ). The change in ACTH was reflected by a simi- In the present study, the extent of adrenal axis sup- larly significant mean percentage decrease from baseline prcssion was similar to or grcatcr than that sccn in a of 90.8% in the serum cortisol levels in all 4 groups study an 75 pancnts of similar agc (mcan, 66 ycars) combined (from 424.8 [127.2] to 38.9 [112.5] nmol/L; administcrcd glucocorticoids biocquivalcnt to at lcast P < 0.001), with no significant group-by-nine effect 25 mg/d ofprednisolone for 5 to 30 days. 3° Recovery (Figure 2). Free T4 was not significantly affected. of adrenal function after discontinuation of treatment with thcsc rclativcly high doscs of prcdnisonc occurrcd DISCUSSION within wccks an most paticnts but varicd considcrably, Hypothalamic-Pituitary-Adrenal Axis and might rcquirc >1 ycar. 3° Similarly, thc function of MA trcatment was associated with -90% dccrcascs in thc HPA axis might rccovcr ~athin wccks aftcr discon- ACTH and cortisol, representing a profound suppres- tinuation of/VIA thcrapy31; howcvcr, in cats adminis- sion of the hypothalamic-pituitary-adrenal (HPA) axis. tcrcd MA at a dosc of 5 rag/d, 32 only 3 of 7 animals had Importantly, this cxtcnt of supprcssion was almost uni- rcgaincd adrcnal function within wccks aftcr discontin- versal, with cortisol and ACTH reduced to less than the uation of the drug. Although recovery of adrenal func- lower limits of normal (LLNs) an 20 of 21 subjects, tion was not assessed an the present study, supprcssion without thc dcvclopmcnt of clinically significant adrc- was virtually universal, with ACTH and cortisol reduced nil insufficicncy. to lcss than LLN an 20 of 21 hcalthy subjccts. Evcn mild MA bands to thc glucocorticoid rcccptor, with adrcnal insufficicncy can bc harmful an critical illncss, 33 approximatcly half thc banding affinity of dcxamctha- which might cxplain thc incrcascd mortality rcportcd sone and ~UvViCC the affinity of cortisol. 24 Several rela- with MA treatment in paticnts with AIDS 34 or can-

162 D L Bodeuuer et al The American Journal of Geriatric Pharmacothera£y

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163 The Amerzcau Journal of Gerzatrzc Pharmacotherapy D L Bodeuuer et al

• RT +T (n = 4) [] T (n = 5) [] RT + P (n = 6) [] P (n = 6) 30-

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Figure I. Effect of 12 weeks of treatment w~th megestrol acetate 800 mg/d on serum adrenocort~cotrop~c hormone (ACTH) concentrations in healthy older men. RT = resistance trammg;T = testosterone; P = placebo.*P < 0.05 versus T and P groups; tp < 0.05 versus before treatment (all 4 groups).

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164 D L Bodeuuer et al The American Journal of Germtr~c Pharmacotherapy

ccr. 35'36 In the elderly, if weight gain is not observed prcss thc lcvcl of cstronc and E 2 to bcexccn 18% and after 3 months of MA treatment, the drug is often dis- 29% of prctrcatmcnt valucs. 19 The mcchanlsm bchlnd continued without taper. The development of chnlcally the highly significant, paradoxical increase in E 2 levels significant adrcnal lnsufficlcncy in frail, oldcr individuals found in men in the present study was unclear. MA after such abrupt discontinuation of MA might bc asso- administration has bccn found to decrease sex hor- ciated with similar serious outcomes. mone binding globuhn lcvcls,4s,46 which would result MA has bccn shown to affcct thc adrcnal axis at scv- in decreased, not increased, total E 2 levels. These cral levels. It has bccn found to directly inhibit cortlsol results suggest that defects in the adrenal production of production by adrenal cells in vitro by 85%. 37 However, E 2 or cnhanccd aromatization ofT might bc rcsponsl- thc rcsults of thc prcscnt study and othcrs 11,12 showcd blc. An increased E 2 level with MA treatment in males a markcd dccrcasc in ACTH affcr MA trcatmcnt, sug- might alleviate some of the concern regarding the gcstlng that thc prcdomlnant cffcct of MA on thc HPA effect of T at levels of castrate on bone mineral density axis might occur at thc hypothalamic-pituitary level. (BMD) and risk for fracture. In men, the E 2 level has a more significant role in maintaining BMD compared Gonadal Axis with the role of T. 47 In the previously reported study, 22 MA markedly reduced serum total T and frcc T to near-castrate levels Other Axes in 20 of 21 subjects studlcd. The prcclsc mechanism of In the present study, TSH levels wcrc modestly T reduction is unclear. In a study of prostate tissue decreased, but frcc T4 levels were unchanged. Simi- examined after the administration of MA 80 mg/d for larly, normal TSH and frcc T4 levels during MA trcat- up to 25 days in males with benign prostatic hyper- mcnt havc bccn rcportcd. 12 trophy, tCStlcular production of T was significantly reduced, and the conversion of T to dlhydrotcstos- Study Limitations tcronc was reduced 31% presumably by the inhibition Thc prcscnt study was limited in scvcral rcspccts. Thc of 5~-rcductasc activity. 38 MA also competes with an- analysis was pcrformcd post hoc on samplcs from a drogens for the receptor 39 and is associated study in which thc population was comprlscd only of with a decreased number of androgen receptors. 4° The hcalthy oldcr mcn, and that was not dcslgncd to asscss effect of MA on pituitary hormones might also play a thc cffccts of MA on pituitary function. As a rcsult, thc significant role in the observed reduction in serum T. changcs in hormonc lcvcls wcrc not corrclatcd with In the present study, MA was associated with 50% symptoms, and thc clinical slgnlficancc of thc changcs decreases in serum LH levels, similar to the decreases was unccrtaln. Although thc changcs from baschnc in reported during antlandrogcn therapy in patients with thc adrcnal axis and scvcral othcr pituitary hormoncs advanced prostate cancer2° and in females receiving wcrc significant, thcrc was no truc control group: all therapy for breast cancer. 41 subjccts wcrc trcatcd with MA. Hypcrprolactlncmla is also associated with lou TT lev- els. Wc observed that MA increased PRL levels by 150% CONCLUSIONS in 19 of 21 subjects. However, although the reduction In this post hoc analysis of serum samples from healthy in LH and elevation in PRL might have contributed to older men, MA significantly affected the secretion of the dcchnc in serum T levels, near-castrate levels of T several pituitary hormones and end-organ hormone with normal PRL and LH levels have bccn noted in synthesis. Significant adrenal suppression was observed patients trcatcd with lowcr doscs of MA. 17'38 Loss of in 20 of 21 subjects, without the development of clini- libido and lmpotcncc occurs in up to 18% of patlcnts cally significant adrenal insufficiency. These findings whcn MA doscs cxcccd 120 mg/d, 42,43 prcsumably suggest that the inherent glucocortlcold actlvaty of MA duc to rcduccd T lcvcls; this loss has not bccn obscrvcd was sufficient to fulfill basal glucocortlcold rcqulrc- at lowcr doscs. 44 Patlcnts should bc advlscd of thc ments. However, whether this degree of glucocortlcold possibility of loss of libido and/or impotence, and T activity is adequate in critical illness or after abrupt dis- replacement should be considered when androgen sup- continuation of MA is unknown. Even partial adrenal presslon is not a primary goal. insufficiency in malnourished, frail older patients might Based on our literature search, this is the first study have serious consequences. Until additional research of MA on E 2 levels in males. In postmenopausal establishes the adrenal status after discontinuation of women with breast cancer, MA has been found to sup- MA treatment, we recommend that oral glucocortlcold

165 The Amerzcau Journal of Gerzatrzc Pharmacotherapy D L Bodeuuer et al

administration or tapering of MA be strongly consid- 11 Meacham LR, Mazewskl C, Krawleckl N Mechanism of ered in these patients. transient adrenal insufficiency with megestrol acetate treatment of cache×la in children with cancer J Ped~atr ACKNOWLEDGMENTS Hematol Oncol 2003,25 414~H7 This study was supported by grants from Bristol-Myers 12 Nalng IZK, Dewar JA, Leese GP Megestrol acetate ther- Squibb Company, Princeton, New Jersey; General Chnlcal apy and secondary adrenal suppression Cancer 1999,86 Research Center at The University of Arkansas for Medical 1044-1049 Sciences (no. M01-RR-12488); the National Institutes of 13 Ron IG, Soyfer V, Goldray D, et al A low-dose adreno- Health, Bethesda, Maryland (nos. R01-AG-15385 cortlcotropln test reveals impaired adrenal function in [W.J.E.] and F32-AG-05873 [C.P.L.]); and the Veterans cancer patients receiving megestrol acetate therapy EurJ Health Administration (merit review grant [D.L.B.]). Cancer 2002,38 1490-1494 14 Stockhelm JA, Daaboul JJ, Yogev R, et al Adrenal sup- REFERENCES presslon in children with the human lmmunodeficlency 1 Furth PA Megestrol acetate and cachex~a associated wath virus treated with megestrol acetate J Ped~atr 1999,134 human lmmunodeficlency wrus (HIV) refection Ann 368-370 Intern Med 1989,110 667-668 15 Subramanlan S, Goker H, Kanjl A, Sweeney H Chnlcal 2 De Conno F, Marnm C, Zecca E, et al Megestrol acetate adrenal insufficiency in patients receiving megestrol ther- for anorexia ~n pataents wath far-advanced cancer A double- apy Arch Intern Med 1997,157 1008-1011 bhnd controlled chmcal trial Eur J Cancer 1998,34 16 Koch CA, Pacak K Abnormal ACTH-stlmulatlon test in 1705-1709 a patient with AIDS Adrenal insufficiency or toxoplas- 3 Yeh S, Wu SY, Lewne DM, et al Quahty of hfe and stim- mOSlS~ Endocr Regul 2001,35 91-93 ulation of weight gain after treatment wath megestrol 17 McKone EF, Tonelh MR, Altken ML Adrenal insuffi- acetate Correlataon between cytokme levels and num- ciency and testlcular failure secondary to megestrol nonal status, appetite m geriatric patients wath wasting acetate therapy in a patient with cystic fibrosis Ped~atr syndrome J Nutr Health Aging 2000,4 246-251 Pulmonol 2002,34 381-383 4 Yeh SS, Wu SY, Lee TP, et al Improvement m quahty-of- 18 Poretsky L, Maran A, Zumoff B Endocrlnologlc and hfe measures and stimulation of weight gain after treat- metabohc manifestations of the acquired lmmunodefi- ment wath megestrol acetate oral suspension m genamc clency syndrome Mt S~na~ J Med 1990,57 236- cachexla Results of a double-bhnd, placebo-controlled 241 study JAm Ger~atr Soc 2000,48 485492 19 Lundgren S, Helle SI, Lonnlng PE Profound suppres- 5 Yeh SS, Wu SY, Lewne DM, et al The correlation of sion of plasma by megestrol acetate in post- cytokme levels wath body weight after megestrol acetate menopausal breast cancer patients Chn Cancer Res treatment m geriatric patients J Gerontol A B~ol Sc~ Med 1996,2 1515-1521 Sc~ 2001,56 M48-M54 20 Geller J, Albert J, Yen SS, et al Medical castration of 6 ICarclc E, Phflpot C, Morley JE Treating malnutrmon males with megestrol acetate and small doses of dlethyl- wath megestrol acetate L~terature rewew and rewew of stllbestrol J Chn Endocr~nol Metab 1981,52 576-580 our experience J Nutr Health Aging 2002,6 191-200 21 Alexaeva-Flgusch J, Blankenstem MA, Hop WC, et al Treat- 7 Brolde J, Soferman R, IZwlty S, et al Low-dose adreno- ment ofmetastatac breast cancer pataents wath chfferent dos- cortlcotropm test reveals ~mpa~red adrenal functaon m ages of megestrol acetate Dose relataons, metabohc and patients taking inhaled cortlcosterolds J Chn Endocr~nol endocnne effects EurJ Cancer Chn Oncol 1984,20 3340 Metab 1995,80 1243-1246 22 Lambert CP, Sulhvan DH, Freehng SA, et al Effects of 8 Lemung MC, L~porace R, Miller CH Induction of adre- testosterone replacement and/or resistance exercise on nal suppression by megestrol acetate m pataents wath the composmon of megestrol acetate stimulated weight AIDS Ann Intern Med 1995,122 843-845 gain m elderly men A randomized controlled trial J Chn 9 Lopnnzl CL, Jensen MD, hang NS, Schald DJ Effect of Endocrlnol Metab 2002,87 2100-2106 megestrol acetate on the human pltmtary-adrenal ax~s 23 Enzyme-Linked Immunosorbent Assay Kit [product Mayo Chn Proc 1992,67 1160-1162 information] Wlndham, NH American Laboratory 10 Marchand V, Baker SS, Stark TJ, Baker RD Random- Products Company, 2000 lzed, double-bhnd, placebo-controlled pilot trial of 24 Kontula K, Paavonen T, Luukkalnen T, Andersson LC megestrol acetate m malnourished children wath cystic Binding of progestlns to the glucocortlcold receptor fibrosis J Ped~atr Gastroenterol Nutr 2000,31 264-269 Correlation to their glucocortlcold-hke effects on in vitro

166 D L Bodeuuer et al The Ameracau Journal of Geraatrac Pharmacotherapy

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Address correspondence to: Donald L. Bodcnncr, MD, PhD, Dcpartmcnt of Geriatrics, Thc University of Arkansas for Medical Sciences, Box 806, 4301 West Markham Street, Little Rock, AR 72205. E-marl: [email protected]

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