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Jean D Wilson - One of the best experts on this subject based on the ideXlab platform.
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formation of 5α reduced androgens in the testes and urogenital tract of the grey short tailed opossum monodelphis domestica
Reproduction Fertility and Development, 2009Co-Authors: Jean D Wilson, Marilyn B Renfree, Richard J Auchus, Andrew J Pask, Geoffrey ShawAbstract:Testicular 5alpha-reduced androgens, largely 5alpha-androstane-3alpha,17beta-diol (androstanediol), are responsible for virilisation of pouch young in one marsupial (the tammar wallaby), but are not formed until later in development in another marsupial (the brushtail possum) and in rodents. Because the mechanism of virilisation of the urogenital tract in the grey short-tailed opossum Monodelphis domestica has never been defined, androgen formation and metabolism were investigated in this species. Testis fragments from grey short-tailed opossums of a wide range of ages were incubated with [3H]-progesterone and the metabolites were separated by high-performance liquid chromatography (HPLC). The only 19-carbon metabolites identified in the youngest ages (5-26 days) and the major metabolites in adult testes were testosterone and androstenedione. At 30, 42 and 49 days of age, Dihydrotestosterone and small amounts of androstanediol were present. Time-sequence studies indicated that Dihydrotestosterone and androstanediol were formed from the 5alpha-reduction (and 3-keto reduction) of testosterone. In a second series of experiments, tissue fragments of a variety of urogenital tract tissues were incubated with [3H]-testosterone and the metabolites separated by HPLC. During the interval in which male urogenital tract differentiation takes place in this species (between Days 15 and 28), the major metabolite identified was Dihydrotestosterone. We conclude that the timing of 5alpha-reductase expression in the testes of the grey short-tailed possum resembles that of rodents and the brushtail possum rather than that of the tammar wallaby and that Dihydrotestosterone is probably the intracellular androgen responsible for virilisation of the urogenital tract in this species.
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formation of 5α reduced androgens in the testes and urogenital tract of the grey short tailed opossum monodelphis domestica
Reproduction Fertility and Development, 2009Co-Authors: Jean D Wilson, Marilyn B Renfree, Richard J Auchus, Andrew J Pask, Geoffrey ShawAbstract:Testicular 5α-reduced androgens, largely 5α-androstane-3α,17β-diol (androstanediol), are responsible for virilisation of pouch young in one marsupial (the tammar wallaby), but are not formed until later in development in another marsupial (the brushtail possum) and in rodents. Because the mechanism of virilisation of the urogenital tract in the grey short-tailed opossum Monodelphis domestica has never been defined, androgen formation and metabolism were investigated in this species. Testis fragments from grey short-tailed opossums of a wide range of ages were incubated with ( 3 H)-progesterone and the metabolites were separated by high-performance liquid chromatography (HPLC). The only 19-carbon metabolites identified in the youngest ages (5-26 days) and the major metabolites in adult testes were testosterone and androstenedione. At 30, 42 and 49 days of age, Dihydrotestosterone and small amounts of androstanediol were present. Time-sequence studies indicated that Dihydrotestosterone and androstanediol were formed from the 5α-reduction (and 3-keto reduction) of testosterone. In a second series of experiments, tissue fragments of a variety of urogenital tract tissues were incubated with ( 3 H)-testosterone and the metabolites separated by HPLC. During the interval in which male urogenital tract differentiation takes place in this species (between Days 15 and 28), the major metabolite identified was Dihydrotestosterone. We conclude that the timing of 5α-reductase expression in the testes of the grey short-tailed possum resembles that of rodents and the brushtail possum rather than that of the tammar wallaby and that Dihydrotestosterone is probably the intracellular androgen responsible for virilisation of the urogenital tract in this species.
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role of the alternate pathway of Dihydrotestosterone formation in virilization of the wolffian ducts of the tammar wallaby macropus eugenii
Endocrinology, 2006Co-Authors: Geoffrey Shaw, Jean D Wilson, Richard J Auchus, Jane C Fenelon, Michelle Sichlau, Marilyn B RenfreeAbstract:Dihydrotestosterone in androgen target tissues is formed under most circumstances by the 5alpha-reduction of testosterone, but an alternate pathway involves the oxidation of androstanediol to Dihydrotestosterone. To investigate the mechanism by which androgens virilize the Wolffian ducts in the tammar wallaby, [(3)H]progesterone was incubated with testes from d 10 and 19 pouch young, and radioactivity was recovered in testosterone and androstanediol at both ages. Analysis of the intermediates indicates that androstanediol was formed both from testosterone via 5alpha-reduction and 3alpha-keto reduction and directly from 5alpha-reduced progestogens. 5alpha-Reductase activity was high in minces of mesonephros/epididymis from d 6-21 pouch young. When minces of urogenital tract tissues from d 19 pouch young were incubated with [(3)H]testosterone, [(3)H]Dihydrotestosterone, and [(3)H]androstanediol, Dihydrotestosterone was the principal androgen formed in the mesonephros/epididymis, urogenital sinus, and urogenital tubercle, whereas androstanediol was the principal androgen formed by the testis. In intact pouch young studied between d 10 and 34, administration of the 5alpha-reductase inhibitor, 17beta-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5alpha-androstan-3-one, blocked virilization of the Wolffian ducts in males, and administration of androstanediol caused virilization of the Wolffian ducts in females. We conclude that Dihydrotestosterone, largely formed in the tissue by the oxidation of androstanediol derived from the testes and also the 5alpha-reduction of testosterone, is responsible for Wolffian duct virilization in this species.
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virilization of the urogenital sinus of the tammar wallaby is not unique to 5α androstane 3α 17β diol
Molecular and Cellular Endocrinology, 2001Co-Authors: Michael W Leihy, Jean D Wilson, Geoffrey Shaw, Marilyn B RenfreeAbstract:The androgen 5alpha-androstane-3alpha,17beta-diol (5alpha-adiol) is synthesized in testes and secreted into plasma of male tammar wallaby pouch young and appears to virilize the urogenital sinus. To provide insight into its mechanism of action, a dose response study showed that administration of 1 microg 5alpha-adiol monoenanthate per g body wt. per week for 3 weeks to 24-day-old female pouch young induced prostate bud formation equivalent to that of males of the same age. Administration of this same dose of the enanthates of testosterone, Dihydrotestosterone, and 5alpha-adiol to female pouch young caused equivalent virilization of the urogenital sinus. The fact that 5alpha-adiol does not exert a unique effect, together with our earlier findings in this species that 5alpha-adiol and testosterone are converted to Dihydrotestosterone in the urogenital sinus and that virilization of the urogenital sinus is prevented by the androgen receptor antagonist flutamide, suggest that 5alpha-adiol is a circulating precursor for Dihydrotestosterone formation in this tissue.
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virilization of the male pouch young of the tammar wallaby does not appear to be mediated by plasma testosterone or Dihydrotestosterone
Biology of Reproduction, 1999Co-Authors: Jean D Wilson, Fredrick W George, Geoffrey Shaw, Marilyn B RenfreeAbstract:Virilization of the male urogenital tract of all mammals, including marsupials, is mediated by androgenic hormones secreted by the testes. We have previously demonstrated profound sexual dimorphism in the concentrations of gonadal androgens in pouch young of the tammar wallaby Macropus eugenii during the interval when the urogenital sinus virilizes. To provide insight into the mechanisms by which androgens are transported from the testes to the target tissues, we measured testosterone and Dihydrotestosterone in plasma pools from tammar pouch young from the day of birth to Day 150. Plasma testosterone levels were measurable (0.5-2 ng/ml) at all times studied, but there were no differences between males and females. These low concentrations of plasma testosterone appear to be derived from the adrenal glands and not the testes. Plasma Dihydrotestosterone levels in plasma pools from these animals were also low and not sexually dimorphic. We conclude that virilization of the male urogenital tract cannot be explained by the usual transport of testosterone or Dihydrotestosterone in plasma but may be mediated by the direct delivery of androgens to the urogenital tract via the Wolffian ducts. Alternatively, circulating prohormones may be converted to androgens in target tissues.
Geoffrey Shaw - One of the best experts on this subject based on the ideXlab platform.
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formation of 5α reduced androgens in the testes and urogenital tract of the grey short tailed opossum monodelphis domestica
Reproduction Fertility and Development, 2009Co-Authors: Jean D Wilson, Marilyn B Renfree, Richard J Auchus, Andrew J Pask, Geoffrey ShawAbstract:Testicular 5α-reduced androgens, largely 5α-androstane-3α,17β-diol (androstanediol), are responsible for virilisation of pouch young in one marsupial (the tammar wallaby), but are not formed until later in development in another marsupial (the brushtail possum) and in rodents. Because the mechanism of virilisation of the urogenital tract in the grey short-tailed opossum Monodelphis domestica has never been defined, androgen formation and metabolism were investigated in this species. Testis fragments from grey short-tailed opossums of a wide range of ages were incubated with ( 3 H)-progesterone and the metabolites were separated by high-performance liquid chromatography (HPLC). The only 19-carbon metabolites identified in the youngest ages (5-26 days) and the major metabolites in adult testes were testosterone and androstenedione. At 30, 42 and 49 days of age, Dihydrotestosterone and small amounts of androstanediol were present. Time-sequence studies indicated that Dihydrotestosterone and androstanediol were formed from the 5α-reduction (and 3-keto reduction) of testosterone. In a second series of experiments, tissue fragments of a variety of urogenital tract tissues were incubated with ( 3 H)-testosterone and the metabolites separated by HPLC. During the interval in which male urogenital tract differentiation takes place in this species (between Days 15 and 28), the major metabolite identified was Dihydrotestosterone. We conclude that the timing of 5α-reductase expression in the testes of the grey short-tailed possum resembles that of rodents and the brushtail possum rather than that of the tammar wallaby and that Dihydrotestosterone is probably the intracellular androgen responsible for virilisation of the urogenital tract in this species.
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formation of 5α reduced androgens in the testes and urogenital tract of the grey short tailed opossum monodelphis domestica
Reproduction Fertility and Development, 2009Co-Authors: Jean D Wilson, Marilyn B Renfree, Richard J Auchus, Andrew J Pask, Geoffrey ShawAbstract:Testicular 5alpha-reduced androgens, largely 5alpha-androstane-3alpha,17beta-diol (androstanediol), are responsible for virilisation of pouch young in one marsupial (the tammar wallaby), but are not formed until later in development in another marsupial (the brushtail possum) and in rodents. Because the mechanism of virilisation of the urogenital tract in the grey short-tailed opossum Monodelphis domestica has never been defined, androgen formation and metabolism were investigated in this species. Testis fragments from grey short-tailed opossums of a wide range of ages were incubated with [3H]-progesterone and the metabolites were separated by high-performance liquid chromatography (HPLC). The only 19-carbon metabolites identified in the youngest ages (5-26 days) and the major metabolites in adult testes were testosterone and androstenedione. At 30, 42 and 49 days of age, Dihydrotestosterone and small amounts of androstanediol were present. Time-sequence studies indicated that Dihydrotestosterone and androstanediol were formed from the 5alpha-reduction (and 3-keto reduction) of testosterone. In a second series of experiments, tissue fragments of a variety of urogenital tract tissues were incubated with [3H]-testosterone and the metabolites separated by HPLC. During the interval in which male urogenital tract differentiation takes place in this species (between Days 15 and 28), the major metabolite identified was Dihydrotestosterone. We conclude that the timing of 5alpha-reductase expression in the testes of the grey short-tailed possum resembles that of rodents and the brushtail possum rather than that of the tammar wallaby and that Dihydrotestosterone is probably the intracellular androgen responsible for virilisation of the urogenital tract in this species.
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role of the alternate pathway of Dihydrotestosterone formation in virilization of the wolffian ducts of the tammar wallaby macropus eugenii
Endocrinology, 2006Co-Authors: Geoffrey Shaw, Jean D Wilson, Richard J Auchus, Jane C Fenelon, Michelle Sichlau, Marilyn B RenfreeAbstract:Dihydrotestosterone in androgen target tissues is formed under most circumstances by the 5alpha-reduction of testosterone, but an alternate pathway involves the oxidation of androstanediol to Dihydrotestosterone. To investigate the mechanism by which androgens virilize the Wolffian ducts in the tammar wallaby, [(3)H]progesterone was incubated with testes from d 10 and 19 pouch young, and radioactivity was recovered in testosterone and androstanediol at both ages. Analysis of the intermediates indicates that androstanediol was formed both from testosterone via 5alpha-reduction and 3alpha-keto reduction and directly from 5alpha-reduced progestogens. 5alpha-Reductase activity was high in minces of mesonephros/epididymis from d 6-21 pouch young. When minces of urogenital tract tissues from d 19 pouch young were incubated with [(3)H]testosterone, [(3)H]Dihydrotestosterone, and [(3)H]androstanediol, Dihydrotestosterone was the principal androgen formed in the mesonephros/epididymis, urogenital sinus, and urogenital tubercle, whereas androstanediol was the principal androgen formed by the testis. In intact pouch young studied between d 10 and 34, administration of the 5alpha-reductase inhibitor, 17beta-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5alpha-androstan-3-one, blocked virilization of the Wolffian ducts in males, and administration of androstanediol caused virilization of the Wolffian ducts in females. We conclude that Dihydrotestosterone, largely formed in the tissue by the oxidation of androstanediol derived from the testes and also the 5alpha-reduction of testosterone, is responsible for Wolffian duct virilization in this species.
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virilization of the urogenital sinus of the tammar wallaby is not unique to 5α androstane 3α 17β diol
Molecular and Cellular Endocrinology, 2001Co-Authors: Michael W Leihy, Jean D Wilson, Geoffrey Shaw, Marilyn B RenfreeAbstract:The androgen 5alpha-androstane-3alpha,17beta-diol (5alpha-adiol) is synthesized in testes and secreted into plasma of male tammar wallaby pouch young and appears to virilize the urogenital sinus. To provide insight into its mechanism of action, a dose response study showed that administration of 1 microg 5alpha-adiol monoenanthate per g body wt. per week for 3 weeks to 24-day-old female pouch young induced prostate bud formation equivalent to that of males of the same age. Administration of this same dose of the enanthates of testosterone, Dihydrotestosterone, and 5alpha-adiol to female pouch young caused equivalent virilization of the urogenital sinus. The fact that 5alpha-adiol does not exert a unique effect, together with our earlier findings in this species that 5alpha-adiol and testosterone are converted to Dihydrotestosterone in the urogenital sinus and that virilization of the urogenital sinus is prevented by the androgen receptor antagonist flutamide, suggest that 5alpha-adiol is a circulating precursor for Dihydrotestosterone formation in this tissue.
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virilization of the male pouch young of the tammar wallaby does not appear to be mediated by plasma testosterone or Dihydrotestosterone
Biology of Reproduction, 1999Co-Authors: Jean D Wilson, Fredrick W George, Geoffrey Shaw, Marilyn B RenfreeAbstract:Virilization of the male urogenital tract of all mammals, including marsupials, is mediated by androgenic hormones secreted by the testes. We have previously demonstrated profound sexual dimorphism in the concentrations of gonadal androgens in pouch young of the tammar wallaby Macropus eugenii during the interval when the urogenital sinus virilizes. To provide insight into the mechanisms by which androgens are transported from the testes to the target tissues, we measured testosterone and Dihydrotestosterone in plasma pools from tammar pouch young from the day of birth to Day 150. Plasma testosterone levels were measurable (0.5-2 ng/ml) at all times studied, but there were no differences between males and females. These low concentrations of plasma testosterone appear to be derived from the adrenal glands and not the testes. Plasma Dihydrotestosterone levels in plasma pools from these animals were also low and not sexually dimorphic. We conclude that virilization of the male urogenital tract cannot be explained by the usual transport of testosterone or Dihydrotestosterone in plasma but may be mediated by the direct delivery of androgens to the urogenital tract via the Wolffian ducts. Alternatively, circulating prohormones may be converted to androgens in target tissues.
Marilyn B Renfree - One of the best experts on this subject based on the ideXlab platform.
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formation of 5α reduced androgens in the testes and urogenital tract of the grey short tailed opossum monodelphis domestica
Reproduction Fertility and Development, 2009Co-Authors: Jean D Wilson, Marilyn B Renfree, Richard J Auchus, Andrew J Pask, Geoffrey ShawAbstract:Testicular 5α-reduced androgens, largely 5α-androstane-3α,17β-diol (androstanediol), are responsible for virilisation of pouch young in one marsupial (the tammar wallaby), but are not formed until later in development in another marsupial (the brushtail possum) and in rodents. Because the mechanism of virilisation of the urogenital tract in the grey short-tailed opossum Monodelphis domestica has never been defined, androgen formation and metabolism were investigated in this species. Testis fragments from grey short-tailed opossums of a wide range of ages were incubated with ( 3 H)-progesterone and the metabolites were separated by high-performance liquid chromatography (HPLC). The only 19-carbon metabolites identified in the youngest ages (5-26 days) and the major metabolites in adult testes were testosterone and androstenedione. At 30, 42 and 49 days of age, Dihydrotestosterone and small amounts of androstanediol were present. Time-sequence studies indicated that Dihydrotestosterone and androstanediol were formed from the 5α-reduction (and 3-keto reduction) of testosterone. In a second series of experiments, tissue fragments of a variety of urogenital tract tissues were incubated with ( 3 H)-testosterone and the metabolites separated by HPLC. During the interval in which male urogenital tract differentiation takes place in this species (between Days 15 and 28), the major metabolite identified was Dihydrotestosterone. We conclude that the timing of 5α-reductase expression in the testes of the grey short-tailed possum resembles that of rodents and the brushtail possum rather than that of the tammar wallaby and that Dihydrotestosterone is probably the intracellular androgen responsible for virilisation of the urogenital tract in this species.
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formation of 5α reduced androgens in the testes and urogenital tract of the grey short tailed opossum monodelphis domestica
Reproduction Fertility and Development, 2009Co-Authors: Jean D Wilson, Marilyn B Renfree, Richard J Auchus, Andrew J Pask, Geoffrey ShawAbstract:Testicular 5alpha-reduced androgens, largely 5alpha-androstane-3alpha,17beta-diol (androstanediol), are responsible for virilisation of pouch young in one marsupial (the tammar wallaby), but are not formed until later in development in another marsupial (the brushtail possum) and in rodents. Because the mechanism of virilisation of the urogenital tract in the grey short-tailed opossum Monodelphis domestica has never been defined, androgen formation and metabolism were investigated in this species. Testis fragments from grey short-tailed opossums of a wide range of ages were incubated with [3H]-progesterone and the metabolites were separated by high-performance liquid chromatography (HPLC). The only 19-carbon metabolites identified in the youngest ages (5-26 days) and the major metabolites in adult testes were testosterone and androstenedione. At 30, 42 and 49 days of age, Dihydrotestosterone and small amounts of androstanediol were present. Time-sequence studies indicated that Dihydrotestosterone and androstanediol were formed from the 5alpha-reduction (and 3-keto reduction) of testosterone. In a second series of experiments, tissue fragments of a variety of urogenital tract tissues were incubated with [3H]-testosterone and the metabolites separated by HPLC. During the interval in which male urogenital tract differentiation takes place in this species (between Days 15 and 28), the major metabolite identified was Dihydrotestosterone. We conclude that the timing of 5alpha-reductase expression in the testes of the grey short-tailed possum resembles that of rodents and the brushtail possum rather than that of the tammar wallaby and that Dihydrotestosterone is probably the intracellular androgen responsible for virilisation of the urogenital tract in this species.
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role of the alternate pathway of Dihydrotestosterone formation in virilization of the wolffian ducts of the tammar wallaby macropus eugenii
Endocrinology, 2006Co-Authors: Geoffrey Shaw, Jean D Wilson, Richard J Auchus, Jane C Fenelon, Michelle Sichlau, Marilyn B RenfreeAbstract:Dihydrotestosterone in androgen target tissues is formed under most circumstances by the 5alpha-reduction of testosterone, but an alternate pathway involves the oxidation of androstanediol to Dihydrotestosterone. To investigate the mechanism by which androgens virilize the Wolffian ducts in the tammar wallaby, [(3)H]progesterone was incubated with testes from d 10 and 19 pouch young, and radioactivity was recovered in testosterone and androstanediol at both ages. Analysis of the intermediates indicates that androstanediol was formed both from testosterone via 5alpha-reduction and 3alpha-keto reduction and directly from 5alpha-reduced progestogens. 5alpha-Reductase activity was high in minces of mesonephros/epididymis from d 6-21 pouch young. When minces of urogenital tract tissues from d 19 pouch young were incubated with [(3)H]testosterone, [(3)H]Dihydrotestosterone, and [(3)H]androstanediol, Dihydrotestosterone was the principal androgen formed in the mesonephros/epididymis, urogenital sinus, and urogenital tubercle, whereas androstanediol was the principal androgen formed by the testis. In intact pouch young studied between d 10 and 34, administration of the 5alpha-reductase inhibitor, 17beta-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5alpha-androstan-3-one, blocked virilization of the Wolffian ducts in males, and administration of androstanediol caused virilization of the Wolffian ducts in females. We conclude that Dihydrotestosterone, largely formed in the tissue by the oxidation of androstanediol derived from the testes and also the 5alpha-reduction of testosterone, is responsible for Wolffian duct virilization in this species.
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virilization of the urogenital sinus of the tammar wallaby is not unique to 5α androstane 3α 17β diol
Molecular and Cellular Endocrinology, 2001Co-Authors: Michael W Leihy, Jean D Wilson, Geoffrey Shaw, Marilyn B RenfreeAbstract:The androgen 5alpha-androstane-3alpha,17beta-diol (5alpha-adiol) is synthesized in testes and secreted into plasma of male tammar wallaby pouch young and appears to virilize the urogenital sinus. To provide insight into its mechanism of action, a dose response study showed that administration of 1 microg 5alpha-adiol monoenanthate per g body wt. per week for 3 weeks to 24-day-old female pouch young induced prostate bud formation equivalent to that of males of the same age. Administration of this same dose of the enanthates of testosterone, Dihydrotestosterone, and 5alpha-adiol to female pouch young caused equivalent virilization of the urogenital sinus. The fact that 5alpha-adiol does not exert a unique effect, together with our earlier findings in this species that 5alpha-adiol and testosterone are converted to Dihydrotestosterone in the urogenital sinus and that virilization of the urogenital sinus is prevented by the androgen receptor antagonist flutamide, suggest that 5alpha-adiol is a circulating precursor for Dihydrotestosterone formation in this tissue.
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virilization of the male pouch young of the tammar wallaby does not appear to be mediated by plasma testosterone or Dihydrotestosterone
Biology of Reproduction, 1999Co-Authors: Jean D Wilson, Fredrick W George, Geoffrey Shaw, Marilyn B RenfreeAbstract:Virilization of the male urogenital tract of all mammals, including marsupials, is mediated by androgenic hormones secreted by the testes. We have previously demonstrated profound sexual dimorphism in the concentrations of gonadal androgens in pouch young of the tammar wallaby Macropus eugenii during the interval when the urogenital sinus virilizes. To provide insight into the mechanisms by which androgens are transported from the testes to the target tissues, we measured testosterone and Dihydrotestosterone in plasma pools from tammar pouch young from the day of birth to Day 150. Plasma testosterone levels were measurable (0.5-2 ng/ml) at all times studied, but there were no differences between males and females. These low concentrations of plasma testosterone appear to be derived from the adrenal glands and not the testes. Plasma Dihydrotestosterone levels in plasma pools from these animals were also low and not sexually dimorphic. We conclude that virilization of the male urogenital tract cannot be explained by the usual transport of testosterone or Dihydrotestosterone in plasma but may be mediated by the direct delivery of androgens to the urogenital tract via the Wolffian ducts. Alternatively, circulating prohormones may be converted to androgens in target tissues.
David J Handelsman - One of the best experts on this subject based on the ideXlab platform.
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long term effects of Dihydrotestosterone treatment on prostate growth in healthy middle aged men without prostate disease a randomized placebo controlled trial
Annals of Internal Medicine, 2010Co-Authors: Amanda Idan, Ann J Conway, Kaye A Griffiths, Tim D Harwood, Markus J Seibel, Leo Turner, David J HandelsmanAbstract:Results: Over 24 months, there was an increase in total (29% [95% CI, 23% to 34%]) and central (75% [CI, 64% to 86%]; P 0.01) prostate volume and serum prostate-specific antigen level (15% [CI, 6% to 24%]) with time on study, but DHT had no effect (P 0.2). Dihydrotestosterone treatment decreased spinal BMD (1.4% [CI, 0.6% to 2.3%]; P 0.001) at 24 months but not hip BMD (P 0.2) and increased serum aminoterminal propeptide of type I procollagen in the second year of the study compared with placebo. Dihydrotestosterone increased serum DHT levels and its metabolites (5-androstane-3,17-diol and 5-androstane3,17-diol) and suppressed serum testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone levels. Dihydrotestosterone increased hemoglobin levels (7% [CI, 5% to 9%]), serum creatinine levels (9% [CI, 5% to 11%]), and lean mass (2.4% [CI, 1.6% to 3.1%) but decreased fat mass (5.2% [CI, 2.6% to 7.7%]) (P 0.001 for all). Protocol-specific discontinuations due to DHT were asymptomatic increased hematocrit (n 8), which resolved after stopping treatment, and increased prostate-specific antigen levels (n 3; none with prostate cancer) in the DHT group. No serious adverse effects due to DHT occurred. Limitation: Negative findings on prostate growth cannot exclude adverse effects on the natural history of prostate cancer. Conclusion: Dihydrotestosterone treatment for 24 months has no beneficial or adverse effect on prostate growth but causes a decrease in spinal but not hip BMD. These findings have important implications for the wider use of nonsteroidal pure androgens in older men.
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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
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Mark Jimenez, Tian N Zhuang, David S Celermajer, Ann J Conway, David J HandelsmanAbstract:The efficacy and safety of androgen supplementation in older men remains controversial. Despite biochemical evidence of partial androgen deficiency in older men, controlled studies using T demonstrate equivocal benefits. Furthermore, the importance of aromatization and 5alpha reduction in androgen actions among older men remains unclear. Dihydrotestosterone is the highest potency natural androgen with the additional features that it is neither aromatizable nor susceptible to potency amplification by 5alpha reduction. Therefore, the effects of Dihydrotestosterone may differ from those of T in older men. This study evaluated the efficacy and safety of 3 months treatment with transdermal Dihydrotestosterone gel on muscle strength, mobility, and quality of life in ambulant, community-dwelling men aged 60 yr or older. Eligible men (plasma T < or =15 nmol/liter) were randomized to undergo daily dermal application of 70 mg Dihydrotestosterone gel (n = 18) or vehicle (n = 19) and were studied before, monthly during, and 1 month after treatment. Among 33 (17 Dihydrotestosterone, 16 placebo) men completing the study with a high degree of compliance, Dihydrotestosterone had significant effects on circulating hormones (increased Dihydrotestosterone; decreased total and free testosterone, LH, and FSH; unchanged SHBG and estradiol), lipid profiles (decreased total and low-density lipoprotein cholesterols; unchanged high-density lipoprotein cholesterol and triglycerides), hematopoiesis (increased hemoglobin, hematocrit, and red cell counts), and body composition (decreased skinfold thickness and fat mass; unchanged lean mass and waist to hip ratio). Muscle strength measured by isokinetic peak torque was increased in flexion of the dominant knee but not in knee extension or shoulder contraction, nor was there any significant change in gait, balance, or mobility tests, in cognitive function, or in quality of life scales. Dihydrotestosterone treatment had no adverse effects on prostate (unchanged prostate volumes and prostate-specific antigen) and cardiovascular (no adverse change in vascular reactivity or lipids) safety markers. We conclude that 3 months treatment with transdermal Dihydrotestosterone gel demonstrates expected androgenic effects, short-term safety, and limited improvement in lower limb muscle strength but no change in physical functioning or cognitive function.
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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
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Lam P Ly, Mark Jimenez, Tian N Zhuang, David S Celermajer, Ann J Conway, David J HandelsmanAbstract:The efficacy and safety of androgen supplementation in older men remains controversial. Despite biochemical evidence of partial androgen deficiency in older men, controlled studies using T demonstrate equivocal benefits. Furthermore, the importance of aromatization and 5α reduction in androgen actions among older men remains unclear. Dihydrotestosterone is the highest potency natural androgen with the additional features that it is neither aromatizable nor susceptible to potency amplification by 5α reduction. Therefore, the effects of Dihydrotestosterone may differ from those of T in older men. This study evaluated the efficacy and safety of 3 months treatment with transdermal Dihydrotestosterone gel on muscle strength, mobility, and quality of life in ambulant, community-dwelling men aged 60 yr or older. Eligible men (plasma T ≤15 nmol/liter) were randomized to undergo daily dermal application of 70 mg Dihydrotestosterone gel (n = 18) or vehicle (n = 19) and were studied before, monthly during, and 1 mon...
Richard J Auchus - One of the best experts on this subject based on the ideXlab platform.
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formation of 5α reduced androgens in the testes and urogenital tract of the grey short tailed opossum monodelphis domestica
Reproduction Fertility and Development, 2009Co-Authors: Jean D Wilson, Marilyn B Renfree, Richard J Auchus, Andrew J Pask, Geoffrey ShawAbstract:Testicular 5α-reduced androgens, largely 5α-androstane-3α,17β-diol (androstanediol), are responsible for virilisation of pouch young in one marsupial (the tammar wallaby), but are not formed until later in development in another marsupial (the brushtail possum) and in rodents. Because the mechanism of virilisation of the urogenital tract in the grey short-tailed opossum Monodelphis domestica has never been defined, androgen formation and metabolism were investigated in this species. Testis fragments from grey short-tailed opossums of a wide range of ages were incubated with ( 3 H)-progesterone and the metabolites were separated by high-performance liquid chromatography (HPLC). The only 19-carbon metabolites identified in the youngest ages (5-26 days) and the major metabolites in adult testes were testosterone and androstenedione. At 30, 42 and 49 days of age, Dihydrotestosterone and small amounts of androstanediol were present. Time-sequence studies indicated that Dihydrotestosterone and androstanediol were formed from the 5α-reduction (and 3-keto reduction) of testosterone. In a second series of experiments, tissue fragments of a variety of urogenital tract tissues were incubated with ( 3 H)-testosterone and the metabolites separated by HPLC. During the interval in which male urogenital tract differentiation takes place in this species (between Days 15 and 28), the major metabolite identified was Dihydrotestosterone. We conclude that the timing of 5α-reductase expression in the testes of the grey short-tailed possum resembles that of rodents and the brushtail possum rather than that of the tammar wallaby and that Dihydrotestosterone is probably the intracellular androgen responsible for virilisation of the urogenital tract in this species.
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formation of 5α reduced androgens in the testes and urogenital tract of the grey short tailed opossum monodelphis domestica
Reproduction Fertility and Development, 2009Co-Authors: Jean D Wilson, Marilyn B Renfree, Richard J Auchus, Andrew J Pask, Geoffrey ShawAbstract:Testicular 5alpha-reduced androgens, largely 5alpha-androstane-3alpha,17beta-diol (androstanediol), are responsible for virilisation of pouch young in one marsupial (the tammar wallaby), but are not formed until later in development in another marsupial (the brushtail possum) and in rodents. Because the mechanism of virilisation of the urogenital tract in the grey short-tailed opossum Monodelphis domestica has never been defined, androgen formation and metabolism were investigated in this species. Testis fragments from grey short-tailed opossums of a wide range of ages were incubated with [3H]-progesterone and the metabolites were separated by high-performance liquid chromatography (HPLC). The only 19-carbon metabolites identified in the youngest ages (5-26 days) and the major metabolites in adult testes were testosterone and androstenedione. At 30, 42 and 49 days of age, Dihydrotestosterone and small amounts of androstanediol were present. Time-sequence studies indicated that Dihydrotestosterone and androstanediol were formed from the 5alpha-reduction (and 3-keto reduction) of testosterone. In a second series of experiments, tissue fragments of a variety of urogenital tract tissues were incubated with [3H]-testosterone and the metabolites separated by HPLC. During the interval in which male urogenital tract differentiation takes place in this species (between Days 15 and 28), the major metabolite identified was Dihydrotestosterone. We conclude that the timing of 5alpha-reductase expression in the testes of the grey short-tailed possum resembles that of rodents and the brushtail possum rather than that of the tammar wallaby and that Dihydrotestosterone is probably the intracellular androgen responsible for virilisation of the urogenital tract in this species.
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role of the alternate pathway of Dihydrotestosterone formation in virilization of the wolffian ducts of the tammar wallaby macropus eugenii
Endocrinology, 2006Co-Authors: Geoffrey Shaw, Jean D Wilson, Richard J Auchus, Jane C Fenelon, Michelle Sichlau, Marilyn B RenfreeAbstract:Dihydrotestosterone in androgen target tissues is formed under most circumstances by the 5alpha-reduction of testosterone, but an alternate pathway involves the oxidation of androstanediol to Dihydrotestosterone. To investigate the mechanism by which androgens virilize the Wolffian ducts in the tammar wallaby, [(3)H]progesterone was incubated with testes from d 10 and 19 pouch young, and radioactivity was recovered in testosterone and androstanediol at both ages. Analysis of the intermediates indicates that androstanediol was formed both from testosterone via 5alpha-reduction and 3alpha-keto reduction and directly from 5alpha-reduced progestogens. 5alpha-Reductase activity was high in minces of mesonephros/epididymis from d 6-21 pouch young. When minces of urogenital tract tissues from d 19 pouch young were incubated with [(3)H]testosterone, [(3)H]Dihydrotestosterone, and [(3)H]androstanediol, Dihydrotestosterone was the principal androgen formed in the mesonephros/epididymis, urogenital sinus, and urogenital tubercle, whereas androstanediol was the principal androgen formed by the testis. In intact pouch young studied between d 10 and 34, administration of the 5alpha-reductase inhibitor, 17beta-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5alpha-androstan-3-one, blocked virilization of the Wolffian ducts in males, and administration of androstanediol caused virilization of the Wolffian ducts in females. We conclude that Dihydrotestosterone, largely formed in the tissue by the oxidation of androstanediol derived from the testes and also the 5alpha-reduction of testosterone, is responsible for Wolffian duct virilization in this species.
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the backdoor pathway to Dihydrotestosterone
Trends in Endocrinology and Metabolism, 2004Co-Authors: Richard J AuchusAbstract:Dihydrotestosterone (DHT) is the androgen responsible for formation of the male external genitalia during embryogenesis and for most androgen-mediated events at male puberty. In most circumstances, testosterone (T) derived from the testis is converted to DHT by 5α-reductase type 2 in genital skin and prostate. By contrast, the testes of pouch young of the tammar wallaby and immature postnatal testes of several species synthesize 5α-androstane-3α,17β-diol, which is the proximal precursor of DHT in androgen-target tissues. Human steroidogenic enzymes efficiently catalyze all the required steps in a route to DHT that does not involve the T intermediate, called the ‘backdoor pathway'. This alternative pathway of DHT production appears to explain how potent androgens are produced in some normal and pathological conditions when the conventional androgen-biosynthetic pathways fail to account completely for the of patterns androgen synthesis that are observed.