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Reproductive Endocrinology |
Institute of Reproductive Medicine (H.M.B., S.K., E.L., E.N.) and Institute of Clinical Radiology (T.M.L.) of the University, Münster, Germany
Address all correspondence and requests for reprints to: Prof. Dr. E. Nieschlag, Institute of Reproductive Medicine of the University, Domagkstraße 11, D-48129 Münster, Germany. E-mail: nieschl{at}uni-muenster.de
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Large multicenter clinical trials have shown that estrogen replacement therapy prevents loss of BMD and decreases the incidence of bone fractures, which in untreated women are caused by the decrease in endogenous estrogens after menopause (9, 10, 11). As comparatively little is known about the beneficial effects of long term testosterone substitution therapy on bone in men (2), we investigated BMD changes in hypogonadal men treated with testosterone preparations for up to 16 yr. In addition, we compared the effects of standard im testosterone injection therapy to those of modern transdermal testosterone application.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Adult male hypogonadal patients, aged 18–74 yr, who received effective androgen substitution therapy and underwent serial measurements of lumbar spine BMD by quantitative computed tomography (QCT) after giving informed consent were included in the evaluation. Patients with constitutional delay of puberty, other endocrine diseases causing lowered BMD (e.g. Cushing’s disease), dietary calcium or vitamin D deficiency, or heritable disorders of connective tissue were excluded from the analysis. Thirty-seven patients with primary hypogonadism (mean ± SD age, 35.0 ± 12.5 yr; body mass index, 24.6 ± 4.5 kg/m2; 21 patients with Klinefelter’s syndrome and 16 patients with primary hypogonadism because of anorchia, previous orchitis or unknown reasons) and 35 patients with secondary hypogonadism (age, 35.4 ± 11.3 yr; body mass index, 25.3 ± 4.7 kg/m2; 14 patients with idiopathic hypogonadotropic hypogonadism or Kallmann’s syndrome and 21 patients with pituitary tumor including macroprolactinoma or panhypopituitarism with effective substitution therapy of the other endocrine axes) qualified for the study analysis. In 32 of these patients initial QCT measurement was carried out before initiation of androgen substitution therapy. The other 40 patients had received effective androgen therapy for 3.4 yr (range, 1–11 yr) when QCT was introduced into our diagnostic work-up 10 yr ago.
Androgen therapy
Hypogonadism was treated by exogenous testosterone or, in seven patients with secondary hypogonadism, with hCG or pulsatile GnRH. Testosterone preparations were administered im, transdermally, or orally. Intramuscular substitution therapy was applied to 52 patients by 250 mg testosterone enanthate (Testoviron Depot 250, Schering, Berlin, Germany), injected in most cases every 3 weeks (range, 2–4 weeks). Eleven patients were given transdermal therapy with scrotal testosterone patches (Testoderm, Alza, Palo Alto) at a daily dose of 4–6 mg/day. Two patients received oral substitution therapy with 3 doses of 40 mg testosterone undecanoate (Andriol, Organon, Oberschleißheim, Germany)/day. Patients with secondary hypogonadism desiring paternity received combined treatment with human menopausal gonadotropin (hMG; Pergonal, Serono, Unterschleißheim, Germany; 150 IU, three times per week) and hCG (Pregnesin, Serono, Unterschleisheim, Germany; 1000–2500 IU, twice per week; 6 patients) or pulsatile GnRH (Lutrelef, Ferring, Kiel, Germany; 1 patient) for a period of 12–24 months.
Hormone measurements
Morning blood samples for testosterone measurements were drawn between 0800–1200 h. To test for effective testosterone substitution, blood was taken at time points indicating average testosterone serum levels during substitution therapy (12). In patients treated with transdermal testosterone patch or oral testosterone undecanoate, blood was taken 3–6 h after administration (12, 13). In patients treated with im testosterone, blood was collected preferentially during the second week, and in hCG/hMG-treated patients, blood was obtained 2 days after injection (12). Serum testosterone levels were measured before initiation of therapy and then at yearly intervals. Testosterone levels before initiation of therapy, after 1 yr of treatment, and at the last QCT measurement of all individual patients were included in the statistical analysis. Serum testosterone levels were measured by RIA as described previously (14). The detection limit for testosterone was 0.7 nmol/L. The intra- and interassay coefficients of variation were 5.8% and 8.5%, respectively. Estradiol was measured by RIA (Sorin Biomedica, Saluggia, Italy). The detection limit for estradiol was 37 pmol/L. The intra- and interassay coefficients of variation for estradiol were 6.6% and 8.1%, respectively. The upper normal limit for estradiol is 250 pmol/L.
Measurement of BMD
In most cases BMD was obtained by QCT measurements at yearly intervals. The examinations were performed with a Tomoscan 350 (Philips, Best, The Netherlands; January 1985 to March 1993) and a Tomoscan LX (Philips; since April 1993). A calibration phantom was used in all studies, initially a liquid Cann-Genant-calibration standard (15) (January 1985 to March 1993) and afterward a solid calibration standard (Image Analysis, Columbia, KS; since April 1993). To achieve comparable results, data were adjusted by cross-calibration analysis as previously described (16). Ten-millimeter thick midvertebral slices of L2, L3, and L4 were obtained with the gantry angled parallel to the vertebral end plate using a low dose technique. Trabecular BMD was measured in an oval and a round region of interest, respectively.
Single energy QCT was used to improve the long term precision of BMD measurements and to reduce total radiation exposure of the patients during longitudinal follow-up (17). The known bone marrow fat error of single energy compared to dual energy QCT has been shown to be of limited impact on follow-up BMD measurements (17, 18). A total of 249 BMD measurements (32 before testosterone therapy and 217 during therapy) were performed during the study period in 72 hypogonadal patients. Age-adjusted reference ranges for trabecular BMD (19) and reference ranges for fracture risk (20, 21) were applied for estimation of the therapeutic efficacy of testosterone substitution therapy.
Statistics
Comparisons between BMD and testosterone, respectively, at the first examination, after 1 yr of therapy, and at the last examination were performed by ANOVA for repeated measures. Multiple linear regression and partial correlation analysis were applied for evaluation of the association of testosterone, estradiol, age, and body mass index with BMD and increase in BMD after therapy, respectively. Independent data at the first QCT measurement in the individual patients were used for the analysis. Comparisons between different androgen treatment groups were made by multifactor ANOVA. To adjust for different age, etiology of hypogonadism, different androgen pretreatment, and duration of testosterone substitution therapy in the individual patients, these variables were included in the ANOVA as covariates. Because of the small group number, patients treated with oral testosterone (n = 2), hCG/hMG (n = 6), and pulsatile GnRH (n = 1) were excluded from this comparison. When necessary, analysis was performed on logarithmically or, for percentage data, arcsine-transformed data. Two-sided P < 0.05 was considered significant. Computations were performed using the statistical software package SPSS, version 6.1.3 (SPSS, Chicago, IL). Unless otherwise stated, results are given as the mean ± SE.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Effective testosterone substitution therapy resulted in a uniform
increase in BMD from 95.2 ± 5.9 to 120.0 ± 6.1
mg/cm3 after the first year and to 125.8 ± 6.0
mg/cm3 after 2.7 ± 0.3 yr of therapy (range, 1–7 yr)
in patients who were still untreated at the first QCT
(P < 0.0001; Fig. 1
). In patients who
had been effectively treated for at least 1 yr before their first QCT
measurement, BMD increased significantly from 131.6 ± 4.8 to
150.9 ± 5.4 mg/cm3 during an average treatment period
of 4.0 ± 0.4 yr (range, 1–16 yr; P < 0.001).
However, this increase of 19.3 ± 2.7 mg/cm3
(15.4 ± 2.1%) was significantly smaller than the increase in
patients untreated at the time of first BMD measurement (increase of
30.6 ± 3.1 mg/cm3 or 39.3 ± 6.0%;
P < 0.001, different duration of treatment as
covariate in the analysis). No significant association could be
detected between the age of the hypogonadal patients at initiation of
therapy and the increase in BMD during effective testosterone
substitution (P = 0.81).
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). No significant
association could be detected between duration of androgen therapy
longer than 1 yr and BMD (P = 0.54). This indicates
that, on the average, long term androgen therapy maintains the BMD
achieved during initial therapy, but does not further significantly
increase BMD.
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). The difference in BMD was still insignificant when
different age, different pretreatment at entry into the study, and
different duration of testosterone substitution therapy of the two
treatment groups were included as covariates in multifactor ANOVA
(P = 0.90).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In part, the varying effects of androgen replacement on BMD in hypogonadal men seen in previous studies can be explained by different techniques of BMD measurements, different durations of treatment, and different testosterone preparations applied. In our study we included only patients receiving long term testosterone substitution therapy for at least 1 yr who were treated effectively with established and well described androgen substitution therapies (12, 28). In addition, we applied a true volumetric method for BMD measurement at the same site in all patients and used the single energy QCT technique to improve long term precision during serial measurements (15, 16, 17).
In the present evaluation we demonstrated that decreased BMD due to hypogonadism can be restored to the age-dependent reference range by effective, long term androgen substitution therapy. The largest increase was seen in patients with initial low BMD during the first year of treatment. Our results are similar to those obtained in postmenopausal women receiving estrogen replacement therapy, where therapy is most effective during the first year of treatment, and the magnitude of the BMD increase is greatest in those women with low initial BMD (29). In our study we did not assess the incidence of fractures in hypogonadal patients. However, it was shown previously that testosterone deficiency is an important risk factor for fractures in men (3, 21, 30), and in women it has been clearly demonstrated that long term, continuous estrogen hormone replacement therapy that increases BMD reduces the individual risk of bone fractures (9).
In contrast to previous studies we demonstrated that effective androgen therapy increases BMD in hypogonadal patients independent of age. The oldest patient in our series was 74 yr old when he was first, remarkably late, diagnosed to have Klinefelter’s syndrome. His trabecular BMD increased by im testosterone injections from 36 to 87 mg/cm3 within 2 yr. Another patient with idiopathic hypogonadotropic hypogonadism was first diagnosed at the age of 61 yr. During treatment with im testosterone enanthate, his trabecular BMD increased from 49 to 85 mg/cm3 within 12 months. Statistical analysis in all 72 patients of our study revealed that testosterone therapy is an age-independent, highly significant factor influencing BMD. Hypogonadal patients with reduced BMD will benefit from long term, effective androgen substitution therapy, and thus, age per se should not preclude patients from appropriate treatment.
It might be argued that relatively high or even supraphysiological serum testosterone levels are necessary to increase BMD in hypogonadal patients. Most previous clinical studies used im testosterone preparations that result in supraphysiological testosterone levels shortly after injection, as demonstrated by detailed pharmacokinetic analysis (12). For this reason we compared the efficacy of im testosterone with transdermal scrotal testosterone systems that lead to physiological serum levels of testosterone in the lower normal range and even mimic normal diurnal variation (13). Statistical analysis revealed no significant difference between both testosterone treatments regarding the BMD achieved. Thus, as is the case for other biological effects (31, 32, 33), for treatment of reduced BMD, restoration of testosterone to the normal physiological range seems to be sufficient without the need for pharmacologically high testosterone levels.
The exact mechanism by which androgens affect BMD is not yet fully elucidated (34). In vitro studies and clinical trials have shown that nonaromatizable androgens increase bone formation (2, 35). In addition, it has been demonstrated in vitro (10) and in male patients with estrogen receptor mutations (36) or aromatase deficiency (37) that estrogens also play an important role in bone mineralization in men. Recently, it was demonstrated by histomorphometry that testosterone treatment of female to male transsexuals after bilateral ovariectomy maintains BMD (38). Available data indicate that both androgens and estrogens have important direct effects on bone. It is well accepted that testosterone substitution therapy should be performed with androgen preparations releasing natural testosterone into the general circulation, which can be converted to the active metabolites dihydrotestosterone and estradiol (28). In our evaluation we cannot discriminate between pure androgenic and estrogenic effects of testosterone therapy on BMD. However, statistical analysis revealed that serum levels of testosterone show the strongest correlation with BMD, and that serum estradiol that is converted from testosterone has no further testosterone-independent association.
In summary, our study demonstrates that long term, effective androgen therapy significantly increases BMD in hypogonadal men. Intramuscular testosterone injections and transdermal testosterone are equally effective. Independent of age, the highest increase in BMD is seen during the first year of treatment and in those patients with initial low values of BMD.
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Acknowledgments |
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Received March 17, 1997.
Revised April 28, 1997.
Accepted May 7, 1997.
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 F. Iqbal, J. Michaelson, L. Thaler, J. Rubin, J. Roman, and M. S. Nanes Declining Bone Mass in Men With Chronic Pulmonary Disease* : Contribution of Glucocorticoid Treatment, Body Mass Index, and Gonadal Function Chest, December 1, 1999; 116(6): 1616 - 1624. [Abstract] [Full Text] [PDF]
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F. Gori, L. C. Hofbauer, C. A. Conover, and S. Khosla Effects of Androgens on the Insulin-Like Growth Factor System in an Androgen-Responsive Human Osteoblastic Cell Line Endocrinology, December 1, 1999; 140(12): 5579 - 5586. [Abstract] [Full Text]
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A. Colao, C. Di Somma, R. Pivonello, S. Loche, G. Aimaretti, G. Cerbone, A. Faggiano, G. Corneli, E. Ghigo, and G. Lombardi Bone Loss Is Correlated to the Severity of Growth Hormone Deficiency in Adult Patients with Hypopituitarism J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1919 - 1924. [Abstract] [Full Text]
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 S. J. Winters Current Status of Testosterone Replacement Therapy in Men Arch Fam Med, May 1, 1999; 8(3): 257 - 263. [Abstract] [Full Text] [PDF]
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S. B. Seminara, F. J. Hayes, and W. F. Crowley Jr. Gonadotropin-Releasing Hormone Deficiency in the Human (Idiopathic Hypogonadotropic Hypogonadism and Kallmann's Syndrome): Pathophysiological and Genetic Considerations Endocr. Rev., October 1, 1998; 19(5): 521 - 539. [Abstract] [Full Text]
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E. Nieschlag VII. If Testosterone, Which Testosterone? Which Androgen Regimen Should be Used for Supplementation in Older Men? Formulation, Dosing, and Monitoring Issues J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3443 - 3445. [Full Text]
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