| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Special Features |
Endocrine Research Unit (S.K., B.L.R.) and Department of Health Sciences Research (L.J.M.), Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Sundeep Khosla, M.D., Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905. E-mail: . khosla.sundeep{at}mayo.edu
Abstract
Because estrogen (E) and T are the major sex steroids in women and men, respectively, the traditional view had been that E primarily regulated bone turnover in women and T played the analogous role in men. The description of ER- deficient and aromatase-deficient males, however, initiated a major shift in our thinking on the relative roles of T and E in regulating the male skeleton, because these individuals all had unfused epiphyses, high bone turnover, and osteopenia. Similar, albeit less striking, findings were noted in mouse models with knock-out of either the ER-
or the aromatase genes. Although these human experiments of nature and mouse knock-out models clearly demonstrated an important role for E in the growth and maturation of the male skeleton, they did not define the role of E vs. T in regulating the adult male skeleton. The past several years have witnessed an accumulation of evidence from observational as well as direct interventional studies that now clearly indicates that E plays a major, and likely dominant, role in bone metabolism in men. These data also suggest that a threshold level of bioavailable (or non-SHBG bound) E is needed for skeletal E sufficiency in the male, and that with aging, an increasing percentage of elderly men begin to fall below this level. It is this subset of men who may be at greatest risk for the development of age-related bone loss and osteoporosis. Moreover, these men may also be the ones most likely to respond favorably to treatment with selective E receptor modulators, or perhaps even to T replacement, because the skeletal effects of the latter may be mediated largely via aromatization to E.
ESTROGEN (E) DEFICIENCY has a dramatic, and sometimes devastating, effect on the female skeleton. Indeed, loss of E after natural or surgical menopause is the single most important factor in the development of postmenopausal bone loss and osteoporosis ( 1). Consequently, there has been an enormous amount of research performed over the past decade on E regulation of the female skeleton. By contrast, other than under the circumstances of medical or surgical castration, men do not have the equivalent of a menopause and thus do not manifest a rapid phase of bone loss, although they clearly do undergo age-related bone loss ( 2 3 4 5). Because serum total T levels decline only marginally with age in men ( 6), it was assumed that men remain gonadally competent throughout their lives. Moreover, because T is the major circulating sex steroid in men, it was also assumed that the loss of T caused the increased bone resorption and bone loss in castrated men. Although T had long been known to be aromatized to E in men by both the testes and peripheral tissues ( 7), the skeletal effects of E in men were largely ignored.
This traditional view of the role of T and E in bone metabolism in men has undergone a fairly dramatic paradigm shift since 1994, when the sentinel case of the ER-negative male was described ( 8). This led to a radical change in our thinking about sex steroid regulation of the male skeleton, which was fueled further by the description of two aromatase-deficient males ( 9 10 11), mouse knock-out models and studies in rats using an aromatase inhibitor ( 12 13 14 15 16 17 18 19 20 21 22), observational and interventional human studies ( 6 23 24 25 26 27 28 29 30 31), and a provocative new idea about gender-neutral effects of sex steroids on bone ( 32). Thus, several independent lines of investigation have significantly altered our understanding of the role of sex steroids in regulating bone metabolism in males ( 33 34). This review summarizes the key studies that led to this paradigm shift in our thinking, as well as some recent evidence suggesting that the male skeleton may require a threshold level of E for preventing increased bone resorption and bone loss.
Human experiments of nature
During the course of evaluating a tall man aged 28 yr for genu valgum, Smith et al. ( 8) noted that the patient had unfused epiphyses and, on further evaluation, E levels that were well into the premenopausal female range despite no evidence of feminization. This constellation of findings correctly suggested a heretofore undescribed syndrome of E resistance, which was confirmed by direct sequence analysis of his ER gene [which we now know as ER-, as opposed to the more recently described ER-ß ( 35)]. Thus, he had homozygous cytosine to thymine substitutions at codon 157, resulting in a premature stop codon. Although this sentinel case has provided important insights into a number of aspects of E action in males, perhaps none has been as dramatic as the impact this patient had on our understanding of E regulation of bone metabolism in men.
Despite having elevated E levels (for a male) and normal T levels, this individual had unfused epiphyses, elevated markers of bone remodeling, and marked skeletal osteopenia (Table 1
) ( 8). As would be expected with complete E resistance, E treatment had no effect on any of these parameters. Soon after the description of this case, two cases of complete aromatase deficiency were described ( 9 10 11), with virtually identical skeletal phenotypes. These men had normal or elevated T levels but low E levels, and E treatment resulted in epiphyseal closure, suppression of bone resorption, and marked increases in bone mass (Fig. 1) ( 10 11). These human experiments of nature taught us, therefore, that inability either to respond to or to produce E resulted in dramatic skeletal consequences in males, despite the presence of normal, or even supranormal, T levels. E was clearly important, indeed critical, for development of the male skeleton. Even in retrospect, this was not what most of us would have predicted.
|
|
Mouse knock-out models and studies in rats using an aromatase inhibitor
Studies using knock-out mice, along with data from rats treated with an aromatase inhibitor and the testicular feminization rat, have also provided useful information on the role of E and T, at least in the male rodent skeleton. However, for reasons that remain unclear, the mouse knock-out models have generally shown much less dramatic phenotypes than the corresponding human mutations. Thus, ER- knock-out (ERKO) and ER-/ß double knock-out (DERKO) mice have shortened femoral length ( 12 13) and decreased appendicular bone growth that is greater in females than in males ( 12 14). However, ERKO males have cortical osteopenia and increased bone turnover that is greater in the male than in the female ( 12). In contrast, the ER-ß knock-out (ßERKO) males have a skeletal phenotype that is indistinguishable from that of the wild-type ( 13), whereas the ßERKO females have an increase in cortical bone that is associated with increased periosteal apposition ( 15 16). ßERKO females also do not appear to have the age-related reductions in cancellous bone that are present in wild-type mice ( 15 16), suggesting that either ER-ß may be permissive for age-related bone loss in female mice or deletion of ER-ß may lead to enhanced sensitivity of bone to ER-, and hence to an increase in E action despite age-related decreases in serum E levels. Finally, ovariectomy results in the same degree of bone loss in adult DERKO mice as in wild-type females, and the bone loss can be prevented by E treatment, although 5-fold higher doses of E are needed in the DERKO compared with the wild-type mice ( 17). Whether this is due to sex-nonspecific, nongenomic mechanisms involving E action via the androgen receptor ( 32) or to the presence of ER- splice variants in the DERKO mice that allow partial sensitivity to E is at present unclear. Indeed, a recent study has found that osteoblasts do express a shorter form of ER- (of 
46 kDa, in contrast to the full-length form of 66 kDa) that arises through alternate splicing ( 37). This short form does possess at least partial transcriptional activity and is, in fact, present in the bones of ERKO mice ( 37). These caveats notwithstanding, the mouse knock-out models do indicate that E plays an important role in the male skeleton and that ER- is the primary receptor mediating E actions on bone, with ER-ß playing a more limited role and perhaps, in fact, repressing E action.
The aromatase gene has also been knocked out (ARKO) and, similar to the humans with aromatase deficiency, ARKO male mice have osteopenia ( 18 19). However, whereas one report found that bone turnover was reduced in these mice ( 18), a second report noted increased bone turnover in the male ARKO mice ( 19), similar to the human males with aromatase deficiency. The findings in the ARKO mice essentially confirm previous studies in which treatment with an aromatase inhibitor decreased BMD and bone size in growing rats ( 21). In addition, aged male rats treated with an aromatase inhibitor were found to have reductions in BMD and increased indices of bone resorption ( 20 22) Finally, testicular feminized rats lacking the androgen receptor have a female skeletal phenotype, but are not osteopenic ( 38). Indeed, the major defect in these animals appears to be a reduction in bone size, rather than deficits in bone density.
Thus, deletion of ER- or aromatase in the male mouse results in osteopenia, although the findings in the mouse knock-out models have generally not been as striking as in the human ER-mutant or aromatase-deficient males. In addition, studies using an aromatase inhibitor clearly demonstrate that E regulates bone metabolism in both the growing and mature male rat.
Studies in adult men
As important as the human ER- mutant, the aromatase-deficient, and the testicular feminization males were in enhancing our understanding of E and T regulation of bone metabolism in males, what was being observed were E and T effects on the growing, immature skeleton. Thus, the severe deficits in bone mass in the ER- mutant and aromatase-deficient males clearly reflect the importance of E in the acquisition of peak bone mass. These effects of E on the growing skeleton cannot, however, be directly extrapolated to men with mature, adult skeletons. As such, the human experiments of nature left unresolved the question of what role E played in regulating bone metabolism in adult men, as well as whether E (or E deficiency) had any role in mediating age-related bone loss in men. Answers to these questions required extensive clinical studies in adult and aging men.
Although several studies had measured T and E levels in men and related these to BMD with somewhat inconclusive results ( 39 40), more recent studies using newer, more sensitive assays, particularly assays for E2 capable of accurately assessing the relatively low circulating E2 levels present in men, have found fairly consistent results. Thus, virtually all of the recent cross-sectional observational studies done in men have found that E2, and particularly the non-SHBG bound (or bioavailable) E2 levels, correlated better with BMD at multiple sites than either total or bioavailable T levels ( 6 23 24 25 26 27 28, 29, 30). Moreover, even in a group of T-deficient men, selected specifically to have T levels below 10.4 nmol/liter (300 ng/dl), Amin et al. (29) found that serum E2 levels were much more robust predictors of BMD than serum T levels. Consequently, there is now little doubt that E is a better predictor of BMD in men than T, at least as judged from cross-sectional data. Moreover, although total T and E2 levels change little over life in men, the bioavailable fractions of both T and E2 decline markedly (by 70 and 50%, respectively), due principally to a marked age-related increase in serum SHBG levels in men (6, 23). This further raises the possibility that these declining sex steroid (and particularly declining bioavailable E2) levels may contribute to bone loss in aging men.
Cross-sectional observational studies, however, clearly have limitations, because they cannot fully dissociate possible E effects on bone mass acquisition early in life (which we know is E-dependent from the human experiments of nature) from its effects on bone loss in senescence. To address this issue, we recently reported results from a prospective study in which the gain in BMD in young (age, 20–40 yr) men vs. the loss in BMD in elderly (age, 60–90 yr) men was related to sex steroid levels (23). The findings in this study were also fairly unequivocal: both the increase in BMD in the young men and the decline in BMD in the elderly men were most closely associated with serum E2 levels, particularly the bioavailable E2 levels in the elderly men (Table 2). These longitudinal data thus indicate not only that E is important for optimal bone mass acquisition in young adulthood, but also that declining levels of bioavailable E2 may contribute substantially to age-related bone loss in men.
|
Figure 2A shows the impact of these interventions of the bone resorption markers, which increased significantly in group A (-T, -E), but remained unchanged in group D (+T, +E). E alone (group B) was almost completely able to prevent the increase in bone resorption markers, whereas T alone (group C) was much less effective. In fact, using a two-factor ANOVA model, the E effect on urine deoxypyridinoline (Dpd) and N-telopeptide of type I collagen (NTx) excretion was highly significant (P = 0.005 and 0.0002, respectively) with at best a borderline T effect on NTx excretion (P = 0.232 and 0.085 for Dpd and NTx, respectively). On the basis of these data, we estimated that, in normal elderly men, E accounted for approximately 70% of the total effect of sex steroids on bone resorption, with T contributing (in the absence of aromatization to E) at most 30% of the effect. In a subsequent study, Leder et al. (41) have been able to demonstrate an independent effect of T on bone resorption, but because that study lacked an E-alone group, the relative contributions of T vs. E toward the regulation of bone resorption could not be quantified.
|
shows the changes in the bone formation markers in the four groups. Both serum osteocalcin and N-terminal extension peptide of type I collagen (PINP) levels decreased significantly in group A (-T, -E), indicating an important effect of sex steroids in maintaining bone formation. These findings are consistent with the induction of osteoblast apoptosis that has been observed in the setting of sex steroid withdrawal both in vivo and in vitro (42, 43). Interestingly, the decrease in serum osteocalcin, which is a marker of function of mature osteoblasts and osteocytes (44), was prevented equally well by either T or E (ANOVA P values of 0.013 and 0.002, respectively). This may represent the in vivo correlate of the recent provocative in vitro demonstration by Kousteni et al. (32) of sex nonspecific, nongenomic actions of T and E on preventing apoptosis. By contrast, PINP, which is produced not only by mature osteoblasts, but also by cells in the entire osteoblast lineage (from the immature marrow stromal cell to the osteocyte) (44) was modulated primarily by E and not T (ANOVA P values, 0.0001 and 0.452, respectively), suggesting that it is principally E that regulates osteoblast differentiation in vivo. This direct interventional study thus provided unequivocal evidence for an important, and likely dominant, role for E in bone metabolism in normal elderly men. Subsequently, similar findings were reported by Taxel et al. (45), who demonstrated that treatment of elderly men with an aromatase inhibitor for 9 wk resulted in significant increases in bone resorption and decreases in bone formation markers. Combined with the now overwhelming observational data, these direct interventional studies leave little doubt that E is critical not only for the growing, but also for the adult and aging skeleton. The major question left unresolved at this point is not whether E regulates bone metabolism in the adult male, but how much E is enough?
Is there a threshold for skeletal E sufficiency in men?
Although this question cannot be answered directly at present, considerable indirect evidence suggests that the male skeleton does indeed require a threshold level to suppress bone resorption and bone loss. This evidence comes again from both observational and interventional studies.
In their cross-sectional analysis of 596 men aged 51–85 yr, Szulc et al. (30) found that men in the lowest quartile for bioavailable E2 levels [<53 pmol/liter (14 pg/ml)] had significantly lower BMD at multiple sites compared with men in the upper three quartiles (Fig. 3). Moreover, it was this group that also had the most significant increases in bone turnover markers. Similarly, we have found that bone resorption markers were unrelated to circulating E2 levels in elderly men with bioavailable E2 levels above 40 pmol/liter (11 pg/ml), whereas there was a clear inverse association between these markers and serum bioavailable E2 levels in the men with bioavailable E2 levels below this value (Fig. 4A) (23). The value of 40 pmol/liter for bioavailable E2 is also the median bioavailable E2 level in this population of elderly men, and more than 90% of postmenopausal women have bioavailable E2 levels below this value (23). In addition, the rate of bone loss at the radius in these men was unrelated to serum bioavialable E2 levels when the latter were above 40 pmol/liter, but clearly related to bioavailable E2 levels when these levels were below this value (Fig. 4B). Furthermore, even young men with bioavailable E2 levels below this value were either losing, or at least not gaining, bone mass (23). On the basis of these data, we proposed that men with bioavialable E2 levels less than 40 pmol/liter [which correspond in elderly men to total E2 levels of 114 pmol/liter (31 pg/ml) and in young men, because of their lower SHBG levels, to total E2 levels of 73 pmol/liter (20 pg/ml)] were at greatest risk for increases in bone resorption and bone loss (23).
|
|
), suggesting that there was a potential threshold level (at least in young men) for skeletal E sufficiency somewhere between 55 and 88 pmol/liter (15–24 pg/ml). This is remarkably similar to our independent estimate from observational data for approximately 73 pmol/liter (20 pg/ml) being necessary for skeletal E sufficiency in young men (23).
|
). This analysis indicated that men with serum E2 levels below 96 pmol/liter (26 pg/ml) responded to raloxifene with a decrease in NTx excretion, whereas men with serum E2 levels above this value actually had an increase in NTx excretion after raloxifene therapy. Consistent with this, the men in whom urinary NTx excretion decreased after raloxifene therapy had significantly lower baseline serum E2 levels than the men in whom urinary NTx excretion didn’t change or increased after raloxifene therapy (22 ± 2 pg/ml vs. 30 ± 3 pg/ml; P = 0.03). By contrast, no such difference was present in the placebo-treated men (28 ± 3 pg/ml vs. 28 ± 3 pg/ml; P = 0.832, for the corresponding analysis in the placebo group). One interpretation of these findings is that below 96 pmol/liter (26 pg/ml), the male skeleton is relatively E deficient, and raloxifene reduces bone resorption. By contrast, above this value the skeleton is relatively E sufficient, and raloxifene competes with the more potent endogenous E, E2, causing a net increase in bone resorption. Indeed, similar to these findings, the selective ER modulator, tamoxifen, prevents bone loss in E-deficient postmenopausal women (48, 49, 50, 51), but actually causes bone loss in E-sufficient premenopausal women (49, 50).
|
Finally, Fig. 7 places these findings in perhaps a more global framework that includes pre- and postmenopausal women. As evident, virtually all postmenopausal women have bioavailable E2 levels below 40 pmol/liter and are thus at risk for bone loss. By contrast, premenopausal women and young men are generally above this level and are consequently protected against bone loss. A subset of middle-aged men and an even larger proportion (perhaps as much as 50%) of elderly men fall below this level, and these may well be the men most likely to develop age-related increases in bone resorption and bone loss.
|
The paradigm shift in our thinking that began with the description of the human experiments of nature has now brought us to more clearly appreciate the role of E in the male skeleton. The evidence from multiple lines of investigation is now overwhelming that E plays a major, and likely dominant, role in regulating bone metabolism in men. T is not unimportant, however, and contributes in several ways: it likely has some effect on bone resorption, clearly helps maintain bone formation, and perhaps most importantly, provides the necessary substrate for aromatization to E in the testes and in peripheral tissues, including locally in bone (52). Moreover, T also has independent effects on bone size, largely by enhancing periosteal bone apposition (53).
The evidence that elderly men with low bioavailable E2 levels [below 40 pmol/liter (11 pg/ml)] are the ones that have the greatest increases in bone resorption markers and in rates of bone loss also suggests that age-related bone loss in men may, at least in part, be due to relative E deficiency in these men. Also, there likely is a sex steroid-independent, age-related decrease in osteoblast function (54), although given the evidence that both E and T are important for maintaining bone formation (31, 32), it is possible that even this defect is, in part, due to E and T deficiency in elderly men. Finally, these findings suggest that not all men are likely to respond to treatment with selective ER modulators or possibly even T replacement, because the effects of the latter on the skeleton are likely mediated in large part by aromatization to E. Rather, future studies using these agents should target men with low bioavailable E2 levels, because these are the individuals who are E deficient and likely to have a favorable skeletal response to hormonal therapy. As clinicians, we already knew this to be true in the case of pre- vs. postmenopausal women, who are either E sufficient or deficient. Although this distinction may be more subtle in men, it does now appear that the same may apply to men with relative E sufficiency or deficiency.
Acknowledgments
Footnotes
This work was supported by Grants PO1 AG-04875 from the National Institute on Aging and R01 AR-27065 from the National Institute of Arthritis, Musculoskeletal and Skin Diseases.
Abbreviations: ARKO, Aromatase knock-out; BMD, Bone mineral density; E, estrogen; ERKO, ER- knock-out; ßERKO, ER-ß knock-out; DERKO, ER-/ß double knock-out; Dpd, deoxypyridinoline; NTx, N-telopeptide of type I collagen; PINP, N-terminal extension peptide of type I collagen.
Received December 13, 2001.
Accepted January 17, 2002.
References
-inactive mice. Biochem Biophys Res Commun 265:569–571[CrossRef][Medline]
and ß) knockout mice. J Bone Miner Res 16(Suppl 1):S146
gene expression in human primary osteoblasts: evidence for the expression of two receptor proteins. Mol Endocrinol 15:2064–2077This article has been cited by other articles:
 |
|
 |
|
  S. Khosla, S. Amin, and E. Orwoll Osteoporosis in Men Endocr. Rev., June 1, 2008; 29(4): 441 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Grundberg, K. Akesson, A. Kindmark, P. Gerdhem, A. Holmberg, D. Mellstrom, O. Ljunggren, E. Orwoll, H. Mallmin, C. Ohlsson, et al. The Impact of Estradiol on Bone Mineral Density Is Modulated by the Specific Estrogen Receptor-{alpha} Cofactor Retinoblastoma-Interacting Zinc Finger Protein-1 Insertion/Deletion Polymorphism J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2300 - 2306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Perrien, N. S. Akel, P. K. Edwards, A. A. Carver, M. S. Bendre, F. L. Swain, R. A. Skinner, W. R. Hogue, K. M. Nicks, T. M. Pierson, et al. Inhibin A Is an Endocrine Stimulator of Bone Mass and Strength Endocrinology, April 1, 2007; 148(4): 1654 - 1665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Khosla Sex Hormone Binding Globulin: Inhibitor or Facilitator (or Both) of Sex Steroid Action? J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 4764 - 4766. [Full Text] [PDF]
|
|
|
|
|
|
H. A. Fink, S. K. Ewing, K. E. Ensrud, E. Barrett-Connor, B. C. Taylor, J. A. Cauley, E. S. Orwoll, and for the Osteoporotic Fractures in Men Study Group Association of Testosterone and Estradiol Deficiency with Osteoporosis and Rapid Bone Loss in Older Men J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3908 - 3915. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Bauman, A. M. Spungen, J. Wang, R. N. Pierson Jr., and E. Schwartz Relationship of fat mass and serum estradiol with lower extremity bone in persons with chronic spinal cord injury Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1098 - E1103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Bilezikian What's Good for the Goose's Skeleton is Good for the Gander's Skeleton. J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1223 - 1225. [Full Text] [PDF]
|
|
|
|
|
|
E. Orwoll, L. C. Lambert, L. M. Marshall, K. Phipps, J. Blank, E. Barrett-Connor, J. Cauley, K. Ensrud, S. Cummings, and for the Osteoporotic Fractures in Men Study Group Testosterone and Estradiol among Older Men J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1336 - 1344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Lee, J. S. Finkelstein, M. Miller, S. J. Comeaux, R. I. Cohen, and B. Z. Leder Effects of Selective Testosterone and Estradiol Withdrawal on Skeletal Sensitivity to Parathyroid Hormone in Men J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1069 - 1075. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Vanderschueren, K. Venken, J. Ophoff, R. Bouillon, and S. Boonen Sex Steroids and the Periosteum--Reconsidering the Roles of Androgens and Estrogens in Periosteal Expansion J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 378 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Greenspan, P. Coates, S. M. Sereika, J. B. Nelson, D. L. Trump, and N. M. Resnick Bone Loss after Initiation of Androgen Deprivation Therapy in Patients with Prostate Cancer J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6410 - 6417. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Kaufman and A. Vermeulen The Decline of Androgen Levels in Elderly Men and Its Clinical and Therapeutic Implications Endocr. Rev., October 1, 2005; 26(6): 833 - 876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Khosla, B. L. Riggs, R. A. Robb, J. J. Camp, S. J. Achenbach, A. L. Oberg, P. A. Rouleau, and L. J. Melton III Relationship of Volumetric Bone Density and Structural Parameters at Different Skeletal Sites to Sex Steroid Levels in Women J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5096 - 5103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-M. Yu, K. Fukamachi, K. W. Krausz, C. Cheung, and F. J. Gonzalez Potential Role for Human Cytochrome P450 3A4 in Estradiol Homeostasis Endocrinology, July 1, 2005; 146(7): 2911 - 2919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Aminorroaya, S. Kelleher, A. J Conway, L. P Ly, and D. J Handelsman Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men Eur. J. Endocrinol., June 1, 2005; 152(6): 881 - 886. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Gennari, D. Merlotti, V. De Paola, A. Calabro, L. Becherini, G. Martini, and R. Nuti Estrogen Receptor Gene Polymorphisms and the Genetics of Osteoporosis: A HuGE Review Am. J. Epidemiol., February 15, 2005; 161(4): 307 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gennari, R. Nuti, and J. P. Bilezikian Aromatase Activity and Bone Homeostasis in Men J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 5898 - 5907. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Van Pottelbergh, S. Goemaere, H. Zmierczak, and J. M. Kaufman Perturbed Sex Steroid Status in Men with Idiopathic Osteoporosis and Their Sons J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4949 - 4953. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Vanderschueren, L. Vandenput, S. Boonen, M. K. Lindberg, R. Bouillon, and C. Ohlsson Androgens and Bone Endocr. Rev., June 1, 2004; 25(3): 389 - 425. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Meier, P. Y. Liu, L. P. Ly, J. de Winter-Modzelewski, M. Jimenez, D. J. Handelsman, and M. J. Seibel Recombinant Human Chorionic Gonadotropin But Not Dihydrotestosterone Alone Stimulates Osteoblastic Collagen Synthesis in Older Men with Partial Age-Related Androgen Deficiency J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 3033 - 3041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Wang, G. Cunningham, A. Dobs, A. Iranmanesh, A. M. Matsumoto, P. J. Snyder, T. Weber, N. Berman, L. Hull, and R. S. Swerdloff Long-Term Testosterone Gel (AndroGel) Treatment Maintains Beneficial Effects on Sexual Function and Mood, Lean and Fat Mass, and Bone Mineral Density in Hypogonadal Men |
, those with values above 40 pmol/liter. r and P values indicate separate correlation coefficients for those individuals either below or above bioavailable E2 levels of 40 pmol/liter. [Adapted with permission from S. Khosla et al.: J Clin Endocrinol Metab 86:3555–3561, 2001 (
NTx = 0) is at approximately 26 pg/ml. [Reproduced with permission from P. M. Doran et al.: J Bone Miner Res 16:2118–2125, 2001 (