Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1766
The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 2 378-382
Copyright © 2006 by The Endocrine Society
Sex Steroids and the Periosteum—Reconsidering the Roles of Androgens and Estrogens in Periosteal Expansion
Dirk Vanderschueren,
Katrien Venken,
Jill Ophoff,
Roger Bouillon and
Steven Boonen
Laboratory for Experimental Medicine and Endocrinology (D.V., K.V., J.O., R.B., S.B.), Leuven University Center for Metabolic Bone Diseases (D.V., R.B., S.B.), and Division of Geriatric Medicine (S.B.), Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Address all correspondence and requests for reprints to: Dirk Vanderschueren, Laboratory for Experimental Medicine and Endocrinology, Gasthuisberg, Onderwijs and Navorsing, Herestraat 49, B-3000 Leuven, Belgium. E-mail: dirk.vanderschueren{at}uz.kuleuven.ac.be.
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Abstract
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Context: Traditionally, differences in periosteal bone formation between men and women have been assumed to reflect two diverging endocrine effects: stimulatory effects of androgens in men and inhibitory effects of estrogens in women. In line with this concept, it is tempting to speculate that men experience more periosteal bone expansion than women because they are exposed to more endogenous androgens and less estradiol. However, recent data challenge this traditional concept.
Evidence Acquisition: A PubMed search was conducted for relevant most recent findings in both humans and animals in the context of an intriguing observation of ongoing periosteal expansion after estrogen treatment in an aromatase-deficient boy.
Evidence Synthesis: Human experiments of nature have provided evidence that androgens and estrogens are both required for the process of pubertal periosteal bone expansion typically associated with the male bone phenotype. Androgens alone appear insufficient to drive male periosteal bone formation. In both sexes, androgens may stimulate periosteal bone formation, but low levels of estrogen may increase the mechanical sensitivity of the periosteum. Higher concentrations of endogenous estrogen, however, inhibit periosteal bone apposition and/or its interaction with mechanical loading. This biphasic action of estrogen on the periosteum may result from a direct effect on its receptor, either 
or ß, but may also depend on changes in serum IGF-I.
Conclusions: Simple concepts of the roles of sex steroids in periosteal apposition have to be reconsidered in the context of these recent findings.
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Introduction
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MALE OSTEOPOROSIS REPRESENTS an important public health problem, but the overall incidence of the disease in men is considerably less than that in women. Lifetime risk of any fragility fracture in men has been estimated to be about 15%, compared with 40% in women. Of all nonvertebral fractures, less than one third occur in men (1). Among other factors, differences in skeletal fragility play a major role in the observed differences in fracture occurrence between men and women (2). Compared with women, men have increased bone strength, not because of increased bone mineral density (BMD), but because of increased bone size, resulting from bone acquired at the periosteal surface during male puberty (2, 3).
Traditionally, differences in periosteal bone formation between men and women have been assumed to reflect two diverging endocrine effects: androgen-mediated stimulatory effects on periosteal bone formation in men and estrogen-induced inhibitory effects on periosteal expansion in women. This assumption is based on experimental animal data obtained in orchidectomized and ovariectomized rodents, respectively (4, 5, 6). In line with this concept, it is tempting to speculate that men experience more periosteal bone expansion than women because they are exposed to more endogenous androgens and less estradiol. However, compelling evidence from human studies to support that assumption is lacking. No studies have as yet assessed changes in periosteal expansion in sex steroid-deficient men or in women receiving sex steroid replacement, to give just two examples.
Recently, we observed a failure of bone expansion in an estrogen-deficient young man suffering from aromatase deficiency despite supranormal testosterone concentrations (7). Treatment with estradiol substantially increased axial and peripheral BMD, and this estrogen-induced gain in BMD was primarily driven by an increase in bone size. This finding challenges the traditional concept of high exposure to androgens and low exposure to estrogens as the main determinants of male periosteal expansion. In this paper we have critically analyzed published data about the interaction between sex steroids and the periosteum and suggest that it may be time to reconsider the roles of androgens and estrogens in periosteal expansion.
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Periosteal Bone Apposition Drives Bone Acquisition during Male Puberty
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Men gain more bone than women during puberty (1, 8), and in this process of bone acquisition, the periosteum appears to be the major site (9, 10, 11). However, our understanding of the regulation of periosteal bone apposition is hampered by the fact that most studies of pubertal bone acquisition have used dual-energy x-ray absorptiometry (DXA). Because DXA is a projectional method, its ability to distinguish between changes in bone size and changes in true, volumetric BMD is limited (2, 12). Because periosteal expansion is primarily reflected by changes in bone size, this limitation of DXA is particularly relevant, and alternative approaches have been explored. These include peripheral quantitative computed tomography (pQCT), a technique that allows assessment of bone size and true density and, thus, evaluation of bone expansion. Using pQCT, a number of studies have measured changes in cross-sectional area in male and female adolescents during normal puberty (13, 14, 15). The effects of sex steroid deficiency on adolescent bone size have not been reported, but the pQCT data in normal adolescents provide compelling evidence that, at least in the appendicular skeleton, periosteal expansion accounts for most differences between men and women in bone mass and density acquisition as observed in DXA-based measurements.
Although it is now well established that during puberty, men have more periosteal bone apposition than women, and although this observation is consistent with the traditional concept of stimulatory vs. inhibitory effects of androgens vs. estrogens, it does not prove that concept. In fact, the endocrine mechanisms accounting for sex-related differences in periosteal expansion may be more complex.
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Hormonal Regulation of Periosteal Bone Gain in Men: What Have We Learned from Human Experiments of Nature?
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As indicated, greater periosteal bone expansion in men has traditionally been assumed to result from exposure to higher levels of androgens and/or lower levels of estrogens, an assumption largely based on data obtained in gonadectomized rodents (4, 5, 6). It would seem that this concept is also supported by human data obtained in individuals with the testicular feminization syndrome (Tfm). Subjects suffering from this syndrome have an XY genotype, but, because of an inactive androgen receptor (AR), they have a female phenotype, with a typical decline in bone mass and density as assessed by DXA (16), again consistent with the concept that bone size is stimulated primarily by androgens. However, the data should be interpreted with caution, because it is unclear to what extent the lower values of areal bone density in Tfm subjects reflect reduced bone size or, alternatively, a reduction in true, volumetric density. Moreover, Tfm subjects respond to estrogen treatment with an increase in areal bone density, making it very difficult, if not impossible, to draw any firm conclusions with regard to the effects of androgen and estrogen on radial bone expansion from this model.
More recently, both animal and human data have challenged the traditional concept of stimulatory vs. inhibitory effects of androgens vs. estrogens. Transgenic male mice, with inactivation of either estrogen receptor (ER) or the aromatase enzyme, were found to have thinner bones as a result of reduced radial bone growth (17, 18), suggesting that, at least in mice, not only androgens, but also estrogens, may stimulate male radial growth. Even more importantly, the role of androgens as the main determinant of male bone acquisition has been challenged by observations in men with aromatase deficiency (7, 19, 20, 21, 22). These men, who have normal androgen concentrations, but undetectable levels of endogenous estrogen, have surprisingly low bone mass and areal density and respond very well to estrogen therapy, with significant and even dramatic increases in DXA-assessed BMD. Unfortunately, most of these reports did not include pQCT measurements and could not address the relative contributions of increases in bone size vs. increases in volumetric density.
This changed after a recent report of a young male suffering from aromatase deficiency, adding a new dimension to our current understanding of estrogen and androgen actions in men (7). In this estrogen-deficient patient, pQCT showed that reduced bone mass in the context of aromatase deficiency is not due to reduced volumetric bone density, but reflects a deficit in bone size (Fig. 1
). Similarly, the increase in bone mass during estrogen therapy was found to be driven primarily by an increase in bone size (+46% in cross-sectional area), without evidence of a treatment effect on volumetric density (Fig. 1). The enlargement of cortical bone in the patient could not be explained by estrogen-stimulated endosteal apposition and, therefore, reflected periosteal apposition.
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FIG. 1. Changes from baseline in longitudinal and radial skeletal growth during estrogen therapy in a 16-yr-old boy with aromatase deficiency (7 ). The increase in radial growth occurred within the first 2 yr of treatment and represented an increase in cross-sectional area (CSA) and cortical thickness, whereas volumetric BMD (vBMD) remained unchanged. LSC, Least significant change.
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The involvement of sex steroids in periosteal expansion is clearly more complex than originally anticipated. As evidenced in the aromatase-deficient adolescent (who had androgen concentrations at the upper end of the normal range), androgens alone may not be sufficient to drive periosteal expansion. Moreover, the periosteal expansion observed in response to estrogen therapy demonstrates that in growing men, estrogens stimulate, rather than inhibit, periosteal apposition. Taken together, these findings, in line with data recently obtained in transgenic mice (17, 18, 23), lend support to the hypothesis that exposure to estrogens is essential for the process of pubertal periosteal bone expansion typically associated with the male bone phenotype (Fig. 2).
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FIG. 2. A, The traditional concept that testosterone stimulates periosteal expansion in men, and estrogen inhibits periosteal apposition in women. B, Hypothetical unisex model in which testosterone stimulates periosteal expansion through the AR, whereas estradiol has a double action on periosteal bone apposition in both sexes: stimulatory effects of estradiol are mediated via ER, whereas ERß may limit periosteal expansion. However, estrogen action on the periosteum may be affected indirectly by changes in IGF-I and/or mechanical sensitivity.
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Does Periosteal Bone Apposition in Men Require a Threshold of Estrogen?
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Can these findings be reconciled with the traditional concept of a stimulatory effect of androgen action on the periosteum and an inhibitory effect of estrogen? Animal data in gonadectomized male rodents (5) and in male mice with disrupted AR (24, 25, 26) provide convincing evidence that after activation of the AR, androgens stimulate male periosteal expansion, but none of these animal models is completely estrogen deficient, and it is possible that some exposure to estrogen is required to facilitate or at least allow androgen action on the periosteum. As recently reviewed by Khosla et al. (27), more and more data support the concept of a threshold concentration of estrogens to maintain skeletal integrity in aging men. It is tempting to speculate that a similar estrogen threshold may also be required for periosteal pubertal growth. As discussed, this assumption is consistent with recent animal data (17, 18, 23) and clinical evidence (7).
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Sex Steroid Action beyond Activation of Sex Steroid Receptors in Bone: Sex Steroids and Their Interaction with Mechanical Sensitivity and GH/IGF-I
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The interaction of estrogen with the periosteum has been extensively reviewed, providing evidence for both stimulatory and inhibitory effects on periosteal bone apposition, with conflicting conclusions. In a recent overview, Lanyon et al. (28) highlighted the positive effects of estrogen on bone formation. Animal data suggest that estrogens may decrease the set point of the mechanostat and thereby increase the sensitivity of bone for mechanical stimuli (29). This may indirectly impact on the response of the bone to androgens, because androgens increase lean body mass and the mechanical loading of the male skeleton, and this mechanical loading constitutes one of the main triggers for androgen-induced periosteal apposition (30, 31, 32). Androgens indirectly induce mechanical loading through their anabolic action on muscle (32, 33, 34, 35), and there is growing evidence that estrogens interact with this process, although both inhibitory (36) and stimulatory (28) effects have been reported; estrogen does not directly affect the mechanical loading per se, but may affect the sensitivity of the growing skeleton to loading. Exposure to estrogen may be critical to allow the increased loading to be translated into periosteal bone formation and radial expansion.
The concept that estrogen induces periosteal bone apposition has, however, been challenged in other reviews (36, 37). The point made in these analyses is that estrogen has been shown to be anabolic on endosteal and trabecular bone, but not on periosteal bone, and that estrogen does not enhance, but inhibits, the anabolic action of mechanical stimuli on the periosteum. Support for this concept comes mainly from exercise studies, suggesting that estrogen-replete women may be less sensitive to loading-induced bone formation than prepubertal girls or men (38, 39). Similarly, the mechanical sensitivity of the aging skeleton appears to be affected by exposure to estrogen, as suggested by increased periosteal expansion after menopause (40), presumably as a result of estrogen deficiency. Whether androgens affect the mechanical sensitivity of the bone is not known.
In addition to potentially affecting the skeletal response to loading, estrogen action on bone may reflect an interaction with GH and/or IGF-I, two other main determinants of cortical bone growth (41). Estrogens are known to have a biphasic effect on pubertal skeletal growth. During early puberty, low estrogen concentrations increase the secretion of GH and subsequent IGF-I synthesis in boys and girls (42). As a consequence, estrogens initiate the pubertal growth spurt and stimulate skeletal growth. Hence, sex steroid-related changes in GH and IGF-I secretion may impact on bone size and cross-sectional area. By the end of puberty, elevated concentrations of estrogen limit skeletal longitudinal growth through a direct effect on growth plate closure (42). Recent data suggest that by the end of puberty, estrogens may inhibit radial growth not only in women but also in men. In a large cohort of young Swedish men, free estradiol appeared to be a negative predictor of cortical bone size (43).
The cortical phenotypes of ER and ERß knockout (KO) mice are likely to be confounded by changes in IGF-I levels as well. ERKO and ERßKO have lower (18) and higher (44) serum IGF-I levels, respectively, which correlate well with their respective cortical phenotypes. It is therefore tempting to speculate that estrogen-related changes in serum IGF-I may be more important than direct estrogen-mediated stimulation of the periosteal surfaces. In line with this concept, our group recently demonstrated that estradiol stimulates radial bone growth in male GH receptor KO mice as a result of an up-regulation of hepatic IGF-I synthesis and secretion (45). Interestingly, only ER, not AR, activation results in changes in serum IGF-I, indicating that AR-mediated androgen action, in contrast with the effects of estrogen, is independent of GH and/or IGF-I (46).
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Dual Mode of Estrogen on the Periosteum: A Tale of Two ERs?
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Assuming that the effects of estrogen on periosteal bone are dose dependent, contrasting views on the role of estrogen in periosteal expansion may reflect exposure to different levels of endogenous estradiol. Low levels of estrogen might increase the mechanical sensitivity of the periosteum and/or affect circulating IGF-I levels. In the context of the aromatase-deficient boy (7), this would explain why the anabolic action of androgens requires exposure to estrogens. Alternatively, higher concentrations of estrogen might inhibit periosteal bone apposition and its interaction with mechanical loading, possibly through an ERß effect (36, 47, 48, 49). In line with this concept, the inhibitory effect of estrogen is not or hardly observed in men, because men are exposed to relatively low endogenous estrogen concentrations. The concept is also consistent with animal data showing that disruption of ERß does not affect the male cortical phenotype (50).
The idea that estrogen may have inhibitory or stimulatory effects on the periosteum according to concentrations and receptor subtype fits with the observed differences in bone size between men and women. Compared with women, men exhibit more periosteal expansion because they are more exposed to the stimulatory effects of androgens and less exposed to the inhibitory effects of estrogens. Androgens may primarily affect lean body mass and the loading of the male skeleton; exposure to low-dose estrogen may allow this loading to induce bone expansion.
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Sex Steroid Action in Women: More than Just Inhibitory Effects of Estrogen?
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In the traditional concept, the differences in bone size between men and women have been attributed primarily to the inhibitory effects of estrogen on the periosteum, but the effects of estrogen in women may be dose dependent and more complex than in men, with stimulation of periosteal bone apposition during early puberty. Failure to expand long bones, as observed in aromatase-deficient female mice, is consistent with the concept that exposure to estrogen contributes to the process of periosteal apposition in early puberty (17). Female ERßKO mice, in contrast, have increased bone diameters (44, 48), suggesting that ERß could potentially mediate the inhibitory action of estrogen on the periosteum in women. However, direct ERß-mediated effects on the periosteum are less likely, given that human and rodent cortical bones contain mainly ER (51, 52, 53).
In contrast with ERß, AR is present in human periosteal osteoblasts (54). Therefore, periosteal expansion in women may be enhanced by androgens, as it is in men. In line with this assumption, hirsute women have increased bone size and bone mass, even after adjusting for body mass index (55).
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Conclusion: Moving away from the Traditional Concept of Skeletal Sexual Dimorphism
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The traditional endocrine model (Fig. 2A
), with stimulatory effects of androgens in men and inhibitory effects of estrogens in women, should be reconsidered in the context of recent findings. Men gain more bone than women during puberty, and in this process of bone acquisition, the periosteum is the major site. Human experiments of nature suggest that androgens and estrogens are both required for the process of pubertal periosteal bone expansion typically associated with the male bone phenotype. Androgens alone are insufficient to drive male periosteal bone formation (Fig. 2B). In both sexes, androgens may stimulate periosteal bone formation, and low levels of estrogen may affect the mechanical sensitivity of the periosteum, either directly or, more likely, via up-regulation of IGF-I. Higher concentrations of endogenous estrogen may inhibit periosteal bone apposition through interaction with mechanical loading or IGF-I secretion. We conclude that the involvement of sex steroids in periosteal expansion is more complex than originally anticipated.
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Footnotes
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This work was supported by Grants G.0171.03N and G.0417.03 from the Fund for Scientific Research-Flanders, Belgium and Grant OT/01/39 from the Katholieke Universiteit Leuven. D.V. and S.B. are senior clinical investigators with the Fund for Scientific Research-Flanders, Belgium.
First Published Online November 22, 2005
Abbreviations: AR, Androgen receptor; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; ER, estrogen receptor ; KO, knockout; pQCT, peripheral quantitative computed tomography; Tfm, testicular feminization syndrome.
Received August 4, 2005.
Accepted November 15, 2005.
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Bone Mineral Density Deficits in Survivors of Childhood Cancer: Long-term Follow-up Guidelines and Review of the Literature
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S. H. Windahl, M. K. Lagerquist, N. Andersson, C. Jochems, A. Kallkopf, C. Hakansson, J. Inzunza, J.-A. Gustafsson, P. T. van der Saag, H. Carlsten, et al.
Identification of Target Cells for the Genomic Effects of Estrogens in Bone
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J. Leger, I. Mercat, C. Alberti, D. Chevenne, P. Armoogum, J. Tichet, and P. Czernichow
The relationship between the GH/IGF-I axis and serum markers of bone turnover metabolism in healthy children
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November 1, 2007;
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685 - 692.
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Abstract
Introduction
