Izk
Well-known Member
[Sherri-Ann M. Burnett-Bowie, Kristen C. Roupenian, Melissa E. Dere, Hang Lee and Benjamin Z. Leder,Endocrine Unit, Department of Internal Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA]
link: http://www.medscape.com/viewarticle/586804_4
In this study, we examined the effects of 12 months of daily anastrozole therapy on gonadal steroids, body composition, strength, PSA and lipids in older men with low normal serum testosterone. Aromatase inhibition increased testosterone levels by approximately 50%, resulting in levels that were generally in the mid-eugonadal range for young men. Aromatase inhibition also modestly decreased E2(approximately 20%), though the mean remained in the normal range. Additionally, anastrozole therapy increased bioavailable testosterone, DHT and LH as compared to placebo. These increases in androgen levels and the associated mild decrease in E2, however, failed to significantly improve body composition or strength. Importantly, anastrozole therapy did not alter PSA levels, urinary obstructive symptoms, or lipid profiles.
Male ageing is associated with a slow, steady decline in gonadal androgen production.[1]Circulating oestrogens also decrease as men age, though this decrease is less dramatic than the decrease in androgens.[13] These changes result in decreased testosterone : E2 ratios, likely due to increased peripheral aromatase activity with ageing.[14] The clinical significance of the decline in gonadal steroids in ageing men remains controversial. Additionally, the mechanisms underlying this decrease have not been fully defined. Possible mechanisms include decreased Leydig cell mass,[15] increased Leydig cell resistance to pituitary stimulation,[16,17] age-associated increases in the gonadotropin-suppressive activity of gonadal steroids,[17,18] or a direct consequence of the increased oestrogen : testosterone ratio.[19]
Aromatase inhibition lowers circulating E2 levels. By removing negative feedback signals, this decrease in E2 increases gonadotropin releasing hormone and gonadotropin production at the hypothalamus and pituitary, respectively, increasing circulating testosterone.[20] Possible benefits of this method of testosterone supplementation include convenience (one pill daily), and avoiding treatment-associated gynecomastia or deleterious oestrogenic effects on cognition or cardiovascular disease (as demonstrated when oestrogens are administered to postmenopausal women).[21,22] Additionally, as discussed below, aromatase inhibition may be a better alternative to standard testosterone replacement because of potentially differential effects of the two therapies on the prostate gland.
In a prior short-term double-blind placebo-controlled study of 37 elderly men with borderline hypogonadism treated with anastrozole,[6] we demonstrated similar increases in mean testosterone levels over 12 weeks. Similar results were also reported in an uncontrolled short-term study.[23] In the current study, we confirmed these initial increases but unexpectedly observed a decrease in mean androgens between months 3 and 12. The observed decrease in testosterone could reflect acquired resistance to anastrozole. Because testosterone levels waned despite sustained increases in LH, hypogonadal older men may be unable to maintain increased testosterone production for more than a transitory period despite continued pituitary stimulation. This hypothesis is consistent with the observation that Leydig cell LH receptor expression is down-regulated in the presence of increased ligand exposure.[24] Given the pill counts, medication diaries, and stable E2 levels between months 3 and 12, medication noncompliance is an unlikely explanation for the decrease in androgens.
Most previous studies of older hypogonadal men have shown that testosterone administration increases muscle and decreases fat, whereas effects on strength are equivocal.[3-5,25] In this study, however, we did not observe changes in strength, fat or muscle mass after 12 months of anastrozole. In a prior study of eugonadal older men with frailty, treatment with a different aromatase inhibitor over a shorter time similarly failed to improve strength or body composition.[26]There are several potential explanations for our findings. First, our subjects may not have been sufficiently hypogonadal to experience changes in body composition. This explanation seems unlikely, however, given that in previous studies, men with similar or less rigorously defined biochemical hypogonadism experienced testosterone-induced changes in body composition.[4,5,25] Alternatively, the lack of an effect on body composition may be related to the magnitude of the testosterone increase. Previous studies showing effects on body composition have generally used relatively high doses of testosterone.[1] Parenteral testosterone preparations, in particular, are nonphysiologic because the associated peak levels are often well above the normal range.[27] In this study, however, testosterone levels increased within the mid-physiologic range, particularly in the later months when subjects may have acquired partial drug resistance (as discussed above). Finally, the anastrozole-associated decrease in serum E2 (as compared to the increased levels seen with standard testosterone replacement) may have contributed to the unexpected result. While E2's role in regulating body composition in men is not well defined, evidence suggests that oestrogens may be important. For example, fat mass is increased in male mice with inactivation of the oestrogen receptor-α or aromatase genes[28,29]and oestrogen administration builds muscle and prevents fat accumulation in castrated rats.[30]Furthermore, men with prostate cancer gain less fat when treated with bicalutamide (an androgen blocker that increases E2) compared to a GnRH-analogue (which reduces both androgens and oestrogen).[31] Combined with the results of this study, these observations argue for further exploration of oestrogen's role in regulating body composition in men.
Importantly, this study suggests that anastrozole has little effect on the prostate gland. Specifically, anastrozole therapy did not increase PSA or obstructive urinary symptoms. It is possible that inhibiting the conversion of testosterone to E2prevented the increase in PSA that is often reported with standard testosterone replacement.[32] In fact, the relationship between oestrogen and the prostate deserves special mention. Aromatase is expressed in the prostate, and both age and BPH are associated with increased intraprostatic oestrogen levels.[33,34] Furthermore, in animal models, oestrogen administration increases PSA and stimulates prostatic epithelial and stromal cell proliferation, which predispose to BPH and prostate cancer, respectively; while aromatase inhibition reverses these effects.[35-37] Finally, E2levels are independently associated with prostate size.[38]
Anastrozole therapy did not cause polycythemia or worsen lipid profiles. The effect of testosterone on lipid profiles, and cardiovascular risk generally, is an area of great current interest. Epidemiologic studies suggest that higher androgen levels are associated with beneficial lipid profiles and reduced cardiac mortality.[39,40] Some androgen administration studies, however, demonstrate deleterious effects of testosterone on lipids, particularly with pharmacologic dosing.[1]Conversely, oral oestrogens raise serum HDL and lower LDL levels in older men and women[41,42]while transdermal oestrogens cause few, if any, alterations in lipoprotein levels.[43] Because the generally favourable lipid effects of oestrogen replacement in postmenopausal women are unaccompanied by cardiovascular benefits,[44] it is clear that hormonal influences on cardiovascular risk are complicated and may be mediated through mechanisms independent of effects on lipids. These mechanisms may include effects on the inflammatory component of cardiovascular disease, insulin resistance, coagulation or endothelial function.[45]
A limitation of this study deserves mention. Currently, there is no universally accepted definition of hypogonadism in older men, an issue that complicates the interpretation of clinical trials in this area. For entry into the present study, a testosterone level that many physicians use to initiate therapy was chosen. Nonetheless, some investigators have proposed a more stringent biochemical definition of hypogonadism (i.e. < 6·9 nmol/l). While using this definition may have increased the likelihood of finding an effect on body composition, it would have severely limited the generalizability of these findings as very few men in this age group would be expected to have testosterone levels in this range.[46]
In summary, anastrozole therapy, given over 12 months, significantly increased serum testosterone and modestly reduced E2 levels in men aged 60 and older with mild-to-moderate hypogonadism. While this intervention resulted in the restoration of testosterone levels into the mid-normal range for healthy young men, it did not alter body composition or strength. This lack of an effect may have been secondary to acquired resistance to aromatase inhibition or to the influence of reduced oestrogen production. Further study should focus on other important end-points such as skeletal health, insulin sensitivity, cognition, quality of life, and sexual function. In doing so, these investigations will increase our understanding of the role of oestrogen in male health.
link: http://www.medscape.com/viewarticle/586804_4
In this study, we examined the effects of 12 months of daily anastrozole therapy on gonadal steroids, body composition, strength, PSA and lipids in older men with low normal serum testosterone. Aromatase inhibition increased testosterone levels by approximately 50%, resulting in levels that were generally in the mid-eugonadal range for young men. Aromatase inhibition also modestly decreased E2(approximately 20%), though the mean remained in the normal range. Additionally, anastrozole therapy increased bioavailable testosterone, DHT and LH as compared to placebo. These increases in androgen levels and the associated mild decrease in E2, however, failed to significantly improve body composition or strength. Importantly, anastrozole therapy did not alter PSA levels, urinary obstructive symptoms, or lipid profiles.
Male ageing is associated with a slow, steady decline in gonadal androgen production.[1]Circulating oestrogens also decrease as men age, though this decrease is less dramatic than the decrease in androgens.[13] These changes result in decreased testosterone : E2 ratios, likely due to increased peripheral aromatase activity with ageing.[14] The clinical significance of the decline in gonadal steroids in ageing men remains controversial. Additionally, the mechanisms underlying this decrease have not been fully defined. Possible mechanisms include decreased Leydig cell mass,[15] increased Leydig cell resistance to pituitary stimulation,[16,17] age-associated increases in the gonadotropin-suppressive activity of gonadal steroids,[17,18] or a direct consequence of the increased oestrogen : testosterone ratio.[19]
Aromatase inhibition lowers circulating E2 levels. By removing negative feedback signals, this decrease in E2 increases gonadotropin releasing hormone and gonadotropin production at the hypothalamus and pituitary, respectively, increasing circulating testosterone.[20] Possible benefits of this method of testosterone supplementation include convenience (one pill daily), and avoiding treatment-associated gynecomastia or deleterious oestrogenic effects on cognition or cardiovascular disease (as demonstrated when oestrogens are administered to postmenopausal women).[21,22] Additionally, as discussed below, aromatase inhibition may be a better alternative to standard testosterone replacement because of potentially differential effects of the two therapies on the prostate gland.
In a prior short-term double-blind placebo-controlled study of 37 elderly men with borderline hypogonadism treated with anastrozole,[6] we demonstrated similar increases in mean testosterone levels over 12 weeks. Similar results were also reported in an uncontrolled short-term study.[23] In the current study, we confirmed these initial increases but unexpectedly observed a decrease in mean androgens between months 3 and 12. The observed decrease in testosterone could reflect acquired resistance to anastrozole. Because testosterone levels waned despite sustained increases in LH, hypogonadal older men may be unable to maintain increased testosterone production for more than a transitory period despite continued pituitary stimulation. This hypothesis is consistent with the observation that Leydig cell LH receptor expression is down-regulated in the presence of increased ligand exposure.[24] Given the pill counts, medication diaries, and stable E2 levels between months 3 and 12, medication noncompliance is an unlikely explanation for the decrease in androgens.
Most previous studies of older hypogonadal men have shown that testosterone administration increases muscle and decreases fat, whereas effects on strength are equivocal.[3-5,25] In this study, however, we did not observe changes in strength, fat or muscle mass after 12 months of anastrozole. In a prior study of eugonadal older men with frailty, treatment with a different aromatase inhibitor over a shorter time similarly failed to improve strength or body composition.[26]There are several potential explanations for our findings. First, our subjects may not have been sufficiently hypogonadal to experience changes in body composition. This explanation seems unlikely, however, given that in previous studies, men with similar or less rigorously defined biochemical hypogonadism experienced testosterone-induced changes in body composition.[4,5,25] Alternatively, the lack of an effect on body composition may be related to the magnitude of the testosterone increase. Previous studies showing effects on body composition have generally used relatively high doses of testosterone.[1] Parenteral testosterone preparations, in particular, are nonphysiologic because the associated peak levels are often well above the normal range.[27] In this study, however, testosterone levels increased within the mid-physiologic range, particularly in the later months when subjects may have acquired partial drug resistance (as discussed above). Finally, the anastrozole-associated decrease in serum E2 (as compared to the increased levels seen with standard testosterone replacement) may have contributed to the unexpected result. While E2's role in regulating body composition in men is not well defined, evidence suggests that oestrogens may be important. For example, fat mass is increased in male mice with inactivation of the oestrogen receptor-α or aromatase genes[28,29]and oestrogen administration builds muscle and prevents fat accumulation in castrated rats.[30]Furthermore, men with prostate cancer gain less fat when treated with bicalutamide (an androgen blocker that increases E2) compared to a GnRH-analogue (which reduces both androgens and oestrogen).[31] Combined with the results of this study, these observations argue for further exploration of oestrogen's role in regulating body composition in men.
Importantly, this study suggests that anastrozole has little effect on the prostate gland. Specifically, anastrozole therapy did not increase PSA or obstructive urinary symptoms. It is possible that inhibiting the conversion of testosterone to E2prevented the increase in PSA that is often reported with standard testosterone replacement.[32] In fact, the relationship between oestrogen and the prostate deserves special mention. Aromatase is expressed in the prostate, and both age and BPH are associated with increased intraprostatic oestrogen levels.[33,34] Furthermore, in animal models, oestrogen administration increases PSA and stimulates prostatic epithelial and stromal cell proliferation, which predispose to BPH and prostate cancer, respectively; while aromatase inhibition reverses these effects.[35-37] Finally, E2levels are independently associated with prostate size.[38]
Anastrozole therapy did not cause polycythemia or worsen lipid profiles. The effect of testosterone on lipid profiles, and cardiovascular risk generally, is an area of great current interest. Epidemiologic studies suggest that higher androgen levels are associated with beneficial lipid profiles and reduced cardiac mortality.[39,40] Some androgen administration studies, however, demonstrate deleterious effects of testosterone on lipids, particularly with pharmacologic dosing.[1]Conversely, oral oestrogens raise serum HDL and lower LDL levels in older men and women[41,42]while transdermal oestrogens cause few, if any, alterations in lipoprotein levels.[43] Because the generally favourable lipid effects of oestrogen replacement in postmenopausal women are unaccompanied by cardiovascular benefits,[44] it is clear that hormonal influences on cardiovascular risk are complicated and may be mediated through mechanisms independent of effects on lipids. These mechanisms may include effects on the inflammatory component of cardiovascular disease, insulin resistance, coagulation or endothelial function.[45]
A limitation of this study deserves mention. Currently, there is no universally accepted definition of hypogonadism in older men, an issue that complicates the interpretation of clinical trials in this area. For entry into the present study, a testosterone level that many physicians use to initiate therapy was chosen. Nonetheless, some investigators have proposed a more stringent biochemical definition of hypogonadism (i.e. < 6·9 nmol/l). While using this definition may have increased the likelihood of finding an effect on body composition, it would have severely limited the generalizability of these findings as very few men in this age group would be expected to have testosterone levels in this range.[46]
In summary, anastrozole therapy, given over 12 months, significantly increased serum testosterone and modestly reduced E2 levels in men aged 60 and older with mild-to-moderate hypogonadism. While this intervention resulted in the restoration of testosterone levels into the mid-normal range for healthy young men, it did not alter body composition or strength. This lack of an effect may have been secondary to acquired resistance to aromatase inhibition or to the influence of reduced oestrogen production. Further study should focus on other important end-points such as skeletal health, insulin sensitivity, cognition, quality of life, and sexual function. In doing so, these investigations will increase our understanding of the role of oestrogen in male health.
