Evidence From the Aged Orchidectomized Male Rat Model That 17β‐Estradiol Is a More Effective Bone‐Sparing and Anabolic Agent Than 5α‐Dihydrotestosterone

This study was designed to evaluate the impact of estrogen versus androgen action on orchidectomy (ORX)‐induced bone loss and associated changes in body composition. During an experimental period of 4 months, aged (12‐month‐old) ORX rats were treated with 17β‐estradiol (E2; 0.75 μg/day) or different doses of the nonaromatizable androgen 5α‐dihydrotestosterone (DHT; 45, 75, and 150 μg/day, respectively), via subcutaneous (sc) silastic implants. Low doses of DHT and E2 inhibited the ORX‐induced rise of bone turnover markers (serum osteocalcin and urinary deoxypyridinoline [DPD]) to a similar extent. High‐dose DHT prevented the ORX‐induced decrease of trabecular bone density but had no significant effect on cortical thinning as assessed by peripheral quantitative computed tomography (pQCT). This bone‐sparing action of DHT occurred at the expense of hypertrophy of the ventral prostate and seminal vesicles. On the other hand, E2 restored both trabecular bone density and cortical thickness in ORX rats and even prevented age‐related bone loss. In contrast to DHT, E2 increased lean body mass and inhibited the ORX‐associated increase of fat mass, as measured by DXA. Administration of E2 was associated with increased serum concentrations of insulin‐like growth factor (IGF) I and decreased circulating levels of leptin. We conclude that, in the aged ORX rat model, E2 is more effective in preventing ORX‐induced bone loss than DHT. Additionally, E2 has anabolic effects on muscle tissue and prevents the ORX‐related increase of fat mass. Overall, these data suggest that androgen action on bone and body composition is dependent on stimulation of both androgen receptors (ARs) and estrogen receptors (ERs).

[1]  R. Jilka,et al.  Sex steroids and bone. , 2002, Recent progress in hormone research.

[2]  David Handelsman,et al.  A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency. , 2001, The Journal of clinical endocrinology and metabolism.

[3]  A. Vermeulen Androgen replacement therapy in the aging male--a critical evaluation. , 2001, The Journal of clinical endocrinology and metabolism.

[4]  H. Ke,et al.  Lasofoxifene (CP‐336,156) Protects Against the Age‐Related Changes in Bone Mass, Bone Strength, and Total Serum Cholesterol in Intact Aged Male Rats , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[5]  K. Toda,et al.  Sex- and age-related response to aromatase deficiency in bone. , 2001, Biochemical and biophysical research communications.

[6]  R. Eastell,et al.  Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. , 2000, The Journal of clinical investigation.

[7]  G. Iwamoto,et al.  Increased adipose tissue in male and female estrogen receptor-α knockout mice , 2000 .

[8]  A. Thorburn,et al.  Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[9]  S. Boonen,et al.  Skeletal effects of estrogen deficiency as induced by an aromatase inhibitor in an aged male rat model. , 2000, Bone.

[10]  H. Frost,et al.  Making Rats Rise to Erect Bipedal Stance for Feeding Partially Prevented Orchidectomy‐Induced Bone Loss and Added Bone to Intact Rats , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[11]  J. Gustafsson,et al.  Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Thompson,et al.  Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat. , 2000, Endocrinology.

[13]  Arndt F Schilling,et al.  Leptin Inhibits Bone Formation through a Hypothalamic Relay A Central Control of Bone Mass , 2000, Cell.

[14]  S. Boonen,et al.  An aged rat model of partial androgen deficiency: prevention of both loss of bone and lean body mass by low-dose androgen replacement , 1999, Endocrinology.

[15]  J. Berlin,et al.  Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. , 1999, The Journal of clinical endocrinology and metabolism.

[16]  J. Berlin,et al.  Effect of testosterone treatment on bone mineral density in men over 65 years of age. , 1999, The Journal of clinical endocrinology and metabolism.

[17]  S. Boonen,et al.  Action of androgens versus estrogens in male skeletal homeostasis. , 1998, Bone.

[18]  E. Simpson Genetic mutations resulting in estrogen insufficiency in the male , 1998, Molecular and Cellular Endocrinology.

[19]  B. L. Riggs,et al.  A Unitary Model for Involutional Osteoporosis: Estrogen Deficiency Causes Both Type I and Type II Osteoporosis in Postmenopausal Women and Contributes to Bone Loss in Aging Men , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[20]  G. Verbeke,et al.  Factors Associated with Cortical and Trabecular Bone Loss as Quantified by Peripheral Computed Tomography (pQCT) at the Ultradistal Radius in Aging Women , 1997, Calcified Tissue International.

[21]  D. Vanderschueren,et al.  Time-related increase of biochemical markers of bone turnover in androgen-deficient male rats. , 1994, Bone and mineral.

[22]  J. S. Tenover,et al.  Effects of testosterone supplementation in the aging male. , 1992, The Journal of clinical endocrinology and metabolism.

[23]  D. Vanderschueren,et al.  Bone and mineral metabolism in aged male rats: short and long term effects of androgen deficiency. , 1992, Endocrinology.

[24]  R. Turner,et al.  Androgen treatment prevents loss of cancellous bone in the orchidectomized rat , 1991, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[25]  J. Verhaeghe,et al.  Bone and Mineral Metabolism in BB Rats With Long-Term Diabetes: Decreased Bone Turnover and Osteoporosis , 1990, Diabetes.

[26]  J. Verhaeghe,et al.  Osteocalcin during the reproductive cycle in normal and diabetic rats. , 1989, The Journal of endocrinology.

[27]  Frost Hm,et al.  The mechanostat: a proposed pathogenic mechanism of osteoporoses and the bone mass effects of mechanical and nonmechanical agents. , 1987 .

[28]  H. Frost,et al.  The mechanostat: a proposed pathogenic mechanism of osteoporoses and the bone mass effects of mechanical and nonmechanical agents. , 1987, Bone and mineral.

[29]  A. Vermeulen,et al.  Radioimmunoassay of 17β-hydroxy-5α-androstan-3-one, 4-androstene-3,17-dione, dehydroepiandrosterone, 17-hydroxyprogesterone and progesterone and its application to human male plasma , 1976 .