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Department of Endocrinology (B.A.L.C., M.T.K.,), ANZAC Research Institute, and Department of Andrology (P.Y.L., D.J.H.), Institute of Rheumatology and Orthopaedics (J.F.B.), Royal Prince Alfred (B.A.L.C., M.T.K., J.F.B.), and Concord (P.Y.L., D.J.H.) Hospitals and University of Sydney, Sydney, New South Wales, Australia
Address all correspondence and requests for reprints to: Dr. Bronwyn Crawford, Endocrinology Department, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia. E-mail: brcrawfo{at}mail.usyd.edu.au.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Glucocorticoid therapy in men also may result in decreased serum testosterone levels (6, 7, 8) because of combined effects on reduced GnRH secretion and a direct effect on testosterone production from the testes (9). The resultant relative androgen deficiency may contribute to the development of sarcopenia as well as loss of bone mass. A direct interaction between glucocorticoids and testosterone is supported by molecular studies showing heterodimer formation between androgen and glucocorticoid receptors and mutual inhibition of transcriptional activity (10). We therefore aimed to test the potential of androgen therapy, with associated anabolic effects on protein synthesis, in opposing some of the catabolic glucocorticoid effects on muscle and bone and to determine whether changes in functional status (i.e. muscle strength, quality of life) could be achieved.
Androgen replacement therapy in hypogonadal men (11, 12) as well as pharmacological androgen therapy in eugonadal men (13, 14) increases muscle mass and strength. In addition, androgen treatment can restore deficits in bone mineral density (BMD) in androgen-deficient men (12, 15). In contrast, androgen therapy has minimal effects on muscle strength and bone mass in older men with minimal androgen deficiency (16, 17). A key issue in androgen action is the tissue-specific effects of the two bioactive metabolites of testosterone, namely dihydrotestosterone (DHT), produced via 5
reductase especially in the prostate (18), and estradiol, via aromatase activity particularly in bone (19). How these metabolites influence androgen action on muscle and other tissues is not clear (20). By using equivalent doses of testosterone and its minimally aromatizable analog, nandrolone (19-nortestosterone) (21, 22), the study aimed also to determine the importance of aromatization for any potential therapeutic effects of androgen therapy.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We studied men over 20 yr of age on long-term glucocorticoid therapy, defined as 5 mg or more prednisone daily for at least 6 months or 1000 µg or more of inhaled steroid plus at least one course of oral prednisone within the last 6 months. Men were excluded if they had unstable heart disease; sleep apnea; polycythemia; prostate disease within the last 5 yr; or treatment within the last 12 months with any androgen, antiandrogen, or bisphosphonate drugs. The study was approved by the institutional Human Ethics Committee, and all men provided written informed consent.
Procedures
Eligible men were randomly assigned to treatment with either testosterone 200 mg (mixed esters, Sustanon; Organon Australia Pty. Ltd.), nandrolone decanoate 200 mg (Deca-Durabolin; Organon Australia Pty. Ltd., Sydney, NSW, Australia), or a matching placebo (arachis oil vehicle) given as 2 ml im injections into the gluteal muscle every 2 wk for 12 months by study staff or the patient’s primary care physician. All patients received calcium carbonate 600 mg (Caltrate; Whitehall Consumer Healthcare Pty. Ltd., Australia) daily. Every 3 months fasting blood and urine samples were collected and questionnaires administered; every 6 months BMD, body composition, and muscle strength were measured. At each visit the average daily glucocorticoid dose over the previous 3 months was calculated and changes in other medications noted.
Bone density
Bone density at the lumbar spine (L1–L4), hip and total body was measured by dual x-ray absorptiometry at one of three sites using a DPXIQ, DPX-L, or Prodigy densitometer (Lunar Corp., Madison, WI) with all measurements for an individual conducted on the same machine. Ten serial scans of a spine phantom on the three machines were within 1.6% of each other. In vitro and in vivo coefficients of variation for lumbar spine, neck of femur, and total body BMD were less than 1.0 and less than 2.5%, respectively. Standardized BMD was determined by comparison of the individual BMD with the appropriate gender-specific North American reference data expressed as a number of SDs different from young normal controls (T-score).
Lean and fat mass
Muscle (lean) mass was calculated by subtraction of fat and bone mass from total body mass. Total body fat and bone mass was measured directly by dual x-ray absorptiometry. In addition, skinfold thickness was measured at four standard sites (biceps, triceps, subscapular, suprailiac) by Harpenden skin calipers (Holtain Ltd. Crymych, Dyfed, UK). Weight (wt) was measured to the nearest 0.1 kg on floor scales (BWB-600, Wedderburn Scales, Summer Hill, Australia) with subjects dressed in a light gown. Height was measured to the nearest 0.1 cm by a wall-mounted stadiometer (Pharmacia & Upjohn, Sydney, NSW, Australia), and waist and hip circumference were measured to the nearest 0.1 cm using a nonstretchable tape.
Muscle strength
Muscle strength (peak torque) was measured at the knee in flexion and extension at rotational speeds of 75, 85, and 95 degrees/sec (in triplicate) by isokinetic dynamometry every 6 months using a Cybex NORM dynamometer (Cybex, Ronkonoma, NY) as described previously (23).
Questionnaires
Quality of life was measured every 3 months by the Qualeffo-41 questionnaire (24). This questionnaire specifically evaluates quality of life in patients with osteoporosis and covers five main domains: pain, physical function (activities of daily living, jobs around the house, general mobility), social function, general health perception, and mental function. Domain scores and the total Qualeffo score were assessed following linear transformation as described (24, 25). Lower urinary tract symptoms were measured every 3 months by the International Prostate Symptom Score (26).
Laboratory testing
Fasting morning blood samples and second void urine samples were collected every 3 months. For 90% of subjects, blood samples were drawn at the time that the next injection was due (i.e. reflecting trough hormone levels); for the remainder, blood samples were at variable times from the last injection. Serum total testosterone, LH, FSH, SHBG, PTH, osteocalcin, and urinary free deoxypyridinoline were measured on the Immulite 2000 autoanalyzer (Diagnostic Products, Los Angeles, CA). Serum-free testosterone was measured by an in-house centrifugal ultrafiltration assay (detection limit 4 pmol/liter) as described previously (27). Estradiol was measured by direct time-resolved fluoroimmunoassay with a detection limit of 12 pmol/liter (Delfia, Perkin-Elmer Pty. Ltd., NSW, Sydney, Australia). Both 25 and 1,25 hydroxyvitamin D were measured by RIA (DiaSorin, Inc. Stillwater, MN) following an initial extraction from serum with acetonitrile and a second solvent column extraction step for 1, 25 hydroxyvitamin D. Serum IGF-I was measured by a double-antibody RIA following acid-ethanol extraction (Bioclone, Sydney, Australia). Hematology (full blood count) and routine biochemistry (electrolytes, urea, creatinine, liver function, cholesterol, triglycerides, high-density lipoprotein) were measured by standard autoanalyzer methodologies. Prostate-specific antigen (PSA) was measured by the Delfia Prostatus kit (Wallac, Inc., Turku, Finland).
Data analysis
Treatment and time effects were estimated by repeated-measures ANOVA using standard and generalized estimating equation approaches (28). Effect modification by key a priori baseline variables (testosterone, BMD, prednisone dose) was evaluated by using the baseline value as a covariate in a repeated measures analysis of covariance. Bone density data were analyzed using raw data expressed as gram per square centimeter. Data were analyzed using StatXact (version 4; SPSS, Inc., Chicago, IL), version 10 NCSS 2001 (Number Cruncher Statistical Systems, Kaysville, UT), and ToxTools, version 1.0 (Cytel Software Corp., Cambridge, MA). A value of less than 0.05 (two-tailed) was considered statistically significant. Results are presented as mean ± SEM.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Fifty-one men (age, 60.3 ± 1.9 yr) were recruited, with 43 men completing 6 months and 37 men completing the full 12 months of the study. The number of men discontinuing from the testosterone, nandrolone, and placebo groups, respectively, were 3, 4, and 1 before 6 months and similarly, 1, 3, and 2 men between 6 and 12 months. In the remainder, attendance at scheduled visits was greater than 95%. Baseline demographic, clinical, and laboratory features of the three groups were well matched (Table 1
) apart from an unexpectedly lower lumbar spine BMD in the group destined to receive testosterone (P < 0.01). The baseline T scores (SD) for testosterone, nandrolone, and placebo groups, respectively, were -1.9 ± 0.08, -0.7 ± 0.06, and -1.0 ± 0.08 for lumbar spine and -1.6 ± 0.06, -0.9 ± 0.07, and -1.4 ± 0.08 for neck of femur. Prednisone dose both at entry and completion of the study was not significantly different among groups (final prednisone dose: 14.8 ± 5.4 mg, testosterone; 10.5 ± 3.8 mg, nandrolone; 14.0 ± 5.2 mg, placebo). Similarly, inhaled steroids were used by eight men in both the testosterone and placebo groups and nine men in the nandrolone group.
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At entry into the study, 18 men (six in each treatment group) had a testosterone level below the lower limit of the eugonadal reference range (<11 nmol/liter) and another 16 (seven, five, and four men in testosterone, nandrolone, and placebo groups, respectively) had a testosterone level in the low-normal range (11–15 nmol/liter). With nandrolone treatment, plasma total and free testosterone concentrations were markedly suppressed (P < 0.001), but there was no change with time in the placebo group (Fig. 1). Mean plasma total testosterone remained within the eugonadal reference range for both the testosterone and placebo treatment groups. Plasma estradiol was also suppressed in the nandrolone group (P < 0.001) but was maintained at consistent levels in placebo group, but the testosterone group had higher levels (P = 0.02) (Fig. 1). Serum levels of LH and FSH were significantly suppressed with both androgen treatments but were unchanged with placebo (Fig. 1). SHBG (Fig. 1) and IGF-I levels (data not shown) did not significantly change with time or treatment.
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Lean mass was increased at 6 and 12 months by both androgen treatments but did not change with placebo (P < 0.0001) (Fig. 2). There was no significant difference between testosterone and nandrolone in the magnitude of increase in lean muscle. At 12 months, the average change in lean mass was +1.8 kg, +2.8 kg, and -0.5 kg in the testosterone, nandrolone, and placebo groups, respectively. Conversely, total body fat was decreased by testosterone and nandrolone at 6 and 12 months, compared with an increase with placebo (P < 0.0001) (Fig. 2), representing an average change in fat mass at 12 months of -2.3 kg, -3.0 kg, and +0.7 kg in the testosterone, nandrolone, and placebo groups, respectively. There were no significant changes with time or treatment in body weight, body mass index, waist circumference, waist:hip ratio, or skin fold thickness (data not shown). Muscle strength (Fig. 3) was increased by both nandrolone and testosterone treatment for 11 of 12 movement and speed combinations (P < 0.0001 for left knee flexion at 75 degrees/sec; P < 0.01 for left knee flexion at 85 and 95 degrees/sec, and right knee extension at 75 degrees/sec; P < 0.05 for left knee extension at 75 and 95 degrees/sec, right knee flexion and extension at 85 and 95 degrees/sec, and right knee flexion at 75 degrees/sec).
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Lumbar spine BMD increased progressively with testosterone treatment (+2.9% at 6 months; 4.7% at 12 months (P < 0.01), but there was no significant change in BMD in the nandrolone- or placebo-treated groups (+1.4%, -1.1% at 6 months; -0.7%, +0.7% at 12 months, respectively) (Fig. 4). There was no significant change in BMD in the neck of femur in any group (+2.2%, -0.2%, -2.5% at 12 months in testosterone, nandrolone, and placebo groups, respectively) or total body BMD (Fig. 4). Similarly, no significant change was seen in BMD of the trochanter or Ward’s triangle (data not shown). To correct for the baseline difference in lumbar BMD, which occurred despite randomization, reanalysis of BMD for each site using the baseline BMD as covariate did not change the significant difference among treatment groups. Inclusion of other key a priori potential effect modifiers (baseline testosterone levels, prednisone dose) in the final model also did not alter the findings.
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Testosterone, but not nandrolone, improved the total Qualeffo-41 score, compared with placebo (P < 0.001) (Fig. 6), but there was no difference for any of the five individual domains. There were no consistent time (learning) effects.
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No men developed polycythemia, sleep apnea, lower urinary tract symptoms, prostate cancer, mood/behavioral disturbance, acne, or edema. Plasma PSA concentrations were not significantly altered and all PSA values remained within the normal range apart from a transient elevation in one man, possibly related to an episode of prostatitis. The total International Prostate Symptom Score score did not significantly change with time or treatment; however, one of eight scores (Q1) decreased significantly with testosterone treatment, indicating more frequent sensation of incomplete bladder emptying.
Mean hemoglobin levels rose in both androgen treatment groups (P < 0.001) to a similar extent (
10%) resulting in a mean hemoglobin concentration of 160 ± 3 g/liter (testosterone) and 162 ± 6 g/liter (nandrolone), compared with 151 ± 4 g/liter with placebo. There was no significant change in serum creatinine levels. There were no changes in lipid levels with time or treatment. At entry, 12 men were using lipid-lowering drugs, and during the study four increased and four decreased antilipid agents, Similarly, there were no significant changes in biochemical tests of liver or kidney function. During the study, 15 serious adverse events (SAEs) were reported in 13 men, causing discontinuation of eight participants. The SAEs included myocardial ischemia (four), lung cancer (two), pulmonary embolism (two), ruptured aortic aneurysm (two), carotid artery thrombosis (one), cardiomyopathy (two), spinal stenosis (one), and avascular necrosis of head of femur (one). There was no significant difference among treatment groups in distribution of SAEs or all adverse events or discontinuations. Other discontinuations were due to loss to follow-up (three), ankle fracture (one), and injection discomfort (two).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Muscle is highly susceptible to the catabolic effects of pharmacological glucocorticoid therapy (29) as well as the anabolic effects of androgens (14) such as nandrolone and testosterone (30, 31). The striking effects on muscle mass and strength seen with both androgens in this study appear even greater than androgen therapy in hypogonadal (11, 12), eugonadal (13, 14), and male aging (32). This points to specific antiglucocorticoid effects of androgens presumably manifested as steroid receptor interactions rather than just counteraction of general catabolic effects (10). The potential detrimental consequence of such an interaction might be androgen interference with therapeutic glucocorticoid action; however, our data showing no increased requirement for prednisone suggest this is not the case.
Benefits in terms of body composition have also been seen with pharmacological androgen therapy in patients with other chronic, catabolic states such as pulmonary disease (33, 34), burns (35), renal disease (36, 37), and HIV (14); however, there has been a variable effect on functional capacity. In contrast to testosterone administration in older men (16) and androgens in HIV infection (14), a low pretreatment testosterone level in the current study was not a predictor of any efficacy outcomes. The majority of men in this study, however, had testosterone levels in the low or low-normal range, and the positive response to androgen therapy may reflect their state of partial or subclinical androgen deficiency, precipitated by the effects of glucocorticoid therapy and chronic illness superimposed on normal aging. These findings suggest that in men on long-term glucocorticoid treatment, adjuvant testosterone therapy may be useful, regardless of prior androgen status.
The positive effect of testosterone on lumbar spine but not hip BMD is consistent with a previous randomized, cross-over study using a small, subreplacement dose of testosterone in 15 men taking glucocorticoid medication for chronic asthma (38). The similar findings in these studies despite a 2-fold difference in androgen dosage suggests that the differences according to bone site may be more related to predominant bone type (trabecular in spine, cortical in femoral neck) rather than testosterone dose. Changes in BMD in the lumbar spine usually herald similar but later effects at other bone sites, and the 12-month duration of both these studies may not have been sufficient for demonstration of improved bone mass in cortical bone with a slower metabolic rate, compared with cancellous bone. Because of an imbalance in lumbar spine BMD at baseline among groups, covariate analysis was used; however, the strength of the effect of testosterone treatment on lumbar spine BMD was not altered. An unusual finding in our study was the decrease in bone turnover markers in both androgen-treated groups as well as placebo. We attribute this to the addition of calcium supplementation (600 mg daily) to a population of men with probable low dietary calcium intake, which has been shown previously (39, 40). Alternative treatments in glucocorticoid-induced osteoporosis include bisphosphonates (41, 42, 43), but they are expensive and cannot offer concurrent benefits for muscle or quality of life.
Recent studies have highlighted the importance of enzymatic activation of androgens for tissue-specific effects. The present study compared two androgens at equivalent milligram doses that differed in their susceptibility to aromatization and their conversion to DHT. Although testosterone is aromatized to a quantitatively small extent (0.5%), the high (100-fold) molar potency of estradiol means that aromatization is an important facet of testosterone action in some tissues, notably in which aromatase is highly expressed. By contrast, nandrolone has higher molar potency at the androgen receptor but is inactivated by 5 reduction and is minimally aromatizable (44, 45, 46, 47), making it a prototype pure androgen (i.e. nonamplifiable, nonaromatizable). The minimal effect of nandrolone on the prostate, which contains high levels of 5 reductase, confirms a previous study of nandrolone in dialysis patients (48) and resembles that of its 7 methyl derivative 7-methyl-19-nortestosterone, which has been shown to have striking prostate-sparing effects in rodents and humans (49, 50). By contrast, muscle and bone have minimal expression of 5 reductase and there is little DHT present in muscle tissue (51). The striking similarity of the effects of nandrolone and testosterone on muscle mass and strength are most consistent with direct androgen effects on muscle via the androgen receptor and not via the active enzymatic metabolites of testosterone.
Similarly, 5 reduction probably plays little part in androgen action in bone, although direct androgen effects on bone cells are likely (52). Recent studies of genetic models of congenital complete estrogen blockade by inactivation of the aromatase enzyme or estrogen receptor in man (53, 54, 55) and mouse (56, 57, 58) have shown consistently that bone development and morphology is markedly impaired, suggesting that aromatization and local estrogen action may be important components of testosterone effects on bone. Nevertheless, the gender differences in bone structure that also persist in genetic models of complete androgen receptor inactivation (59), the presence of androgen receptors on bone cells (52), the low circulating estradiol levels in men, and the known bone anabolic effects of minimally aromatizable androgens (60, 61, 62) suggest that local aromatization may be responsible for only part of testosterone’s effect on bone. The differences between testosterone and nandrolone in effects on lumbar spine BMD are most consistent with the concept that aromatization is important for maintenance of BMD, at least for trabecular bone. Differences in molar potency between nandrolone and testosterone cannot explain this difference in efficacy on spine BMD because nandrolone is more potent than testosterone; however, the dose or kinetics of nandrolone decanoate may not have been ideal in men on glucocorticoid treatment. The present study cannot further differentiate between these possibilities. The effect of nandrolone therapy on BMD in men previously has been studied only at a lower dose in which positive effects were transient (63); however, in postmenopausal women nandrolone consistently increases BMD (60, 61, 62), although these small studies were not rigorously controlled and efficacy was limited because of virilization. The lack of requirement for aromatization in androgen action on muscle, in contrast to bone (19), highlights the need to understand the variation in tissue-specific effects of androgens, particularly for the development of more metabolically and organ selective designer androgens (20).
The marked decrease in body fat seen in the androgen-treated men may help reverse some of the adverse effects of glucocorticoids on body composition and insulin resistance and the concomitant implications for cardiovascular disease. Measurement of insulin resistance was not an end point in this study; however, previous studies have shown testosterone to be an important determinant of regional fat distribution and metabolism in men (64). Percent body fat is increased in hypogonadal men, and epidemiological studies have reported an inverse correlation of endogenous testosterone levels with abdominal obesity in middle-aged men (11). Testosterone replacement in these men improved insulin sensitivity and decreased blood glucose and blood pressure (64, 65).
The improvement in testosterone-treated men in the total score for the Qualeffo-41 questionnaire is consistent with an improved general sense of well-being that is commonly associated with androgen replacement in hypogonadal men and has also been reported in HIV-treated patients (66). The positive effects of testosterone treatment on quality of life, combined with improvements in muscle strength and mass, has important implications for the function of glucocorticoid-dependent men with chronic illness in whom comorbidity and restrictions in activity levels are common. Other potential benefits of androgen treatment not studied here include improvements in skin fragility, libido, and cognition. In addition, androgen treatment may have effects on the natural history of underlying diseases because of potential modulation of immune function (67, 68) or as a direct result of improved muscle strength.
The power of this study was limited by the number of discontinuations, most of which were due to adverse events occurring in men with concurrent chronic illnesses and significant comorbidity. The safety of androgen administration in older men raises concerns in three main areas: acceleration of cardiovascular or prostate disease and idiosyncratic effects of androgens such as polycythemia, sleep apnea, and mood or behavioral disturbances. There is at present little direct evidence to evaluate these risks. The adverse cardiovascular events observed in the present study did not differ among treatments and reflected the comorbidities of the participants with significant underlying primary diseases. The absence of lipid changes is reassuring, although the significance of lipid changes in a population of men with other life-threatening chronic disease remains unclear. The effects of androgen administration on the prostate and its risk of disease remains unclear. Clearly androgens are contraindicated in men with known or undiagnosed prostate cancer, but the risks of androgen administration in others without prostate cancer remain unclear. Conclusive data of safety of androgen administration to men with chronic nongonadal disease will require larger and more powerful studies with a focus on objective disease end points rather than surrogate variables alone.
Larger studies of longer duration will also be required to determine the effect of androgen therapy on fractures and, in particular, confirm a reduction in vertebral fractures that are the most common fractures associated with long-term glucocorticoid therapy. The importance of this study is the demonstration of benefits of testosterone treatment in glucocorticoid-treated men across a wide range of clinical areas and extending into functional improvement. In men with glucocorticoid-dependent chronic disease treated with androgens, increased strength of muscles and improved exercise tolerance may delay disease progression, and, combined with an improved sense of well-being, would enhance the response to rehabilitation therapy and improve quality of life. The potential for reduction in public health costs may have additional positive implications for the wider community.
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Footnotes |
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Abbreviations: BMD, Bone mineral density; DHT, dihydrotestosterone; DPD, deoxypyridinoline; PSA, prostate-specific antigen; SAE, serious adverse event.
Received November 21, 2002.
Accepted March 17, 2003.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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-methyl-19-nortestosterone is not amplified in male reproductive tract as is that of testosterone. Endocrinology 130:3677–3683[Abstract]
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), or placebo (
). The normal ranges for adult men are represented by dashed bars.
), or placebo (
). (P < 0.0001 between groups).
