Review
Recent experimental and clinical findings in the skeleton associated with loss of estrogen hormone or estrogen receptor activity☆

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Abstract

Studies on rodent models and rare human disorders of estrogen production or response have revealed an increased complexity of the actions of estrogen on bone. ERα disruption in human males results in delayed epiphyseal maturation, tall stature, trabecular thinning, marked cortical thinning, genu valgum and significantly reduced cortical vBMD, but trabecular number is preserved and there is normal to increased periosteal expansion. Aromatase deficiency results overall in a similar phenotype, although less is known about skeletal architecture. Importantly, estrogen replacement in these individuals, even if provided late in the third decade, may normalize aBMD. Less certain is whether there is complete recovery of normal skeletal architecture and strength. Rodent models, in general, are consistent with the human phenotype but are confounded by inherent differences between mouse and human physiology and issues regarding the completeness of the different knock-out lines. Both human and rodent studies suggest that residual effects of estrogen through ERβ, truncated ERα forms or nonclassical estrogen receptors might account for different phenotypes in the hERKO man, aromatase deficient subjects and rodents. Importantly, androgen, particularly by preserving trabecular number and augmenting both periosteal and epiphyseal growth, also has significant actions on bone.

Introduction

Estrogen is well known to be important in females for bone growth and metabolism. However, evidence has emerged from rodent models [1] and rare disorders of estrogen production or response in humans [2], [3] that the physiologic role for estrogen is far more complicated, involving actions in males as well as females [4]. Estrogen actions are further complicated by the presence of two distinct but related nuclear receptors, ERα [4] and ERβ [5], both with different splice variants [6] and the recent discovery of a membrane bound functional ER, the G protein-coupled receptor GPR30 [7], [8], [9]. For this review, we will describe recent experimental evidence from human and animal models that increase understanding of the role of estrogen relative to androgen in bone.

Section snippets

Production and cellular mechanism of action of estrogen

Circulating estrogens are produced from the aromatization of androgens by the cytochrome P450 enzyme, aromatase [10]. In males, unlike females in which the ovaries are the primary source of estrogen, the majority of the estrogen in the circulation is derived from extragonadal tissues [11]. The regulation of aromatase activity in different tissues such as breast, adipose and gonads is complex and it is increasingly clear that in addition to classical hormonal pathways there are important local

Control of longitudinal growth and final stature

The most visible action of estrogen on the human skeleton for both males and females is control of body proportion and determination of final stature [2], [3]. The male identified with ERα point mutation (hERKO), described throughout this review, is a unique individual and clinical case. He presented at age 28 with tall stature (204 cm), eunuchoid body proportions (0.83 (average for men, 0.96)), unfused epiphyses (bone age ∼15 years) and moderate to severe genu valgum. Unlike normal males, in

Bone mineral density and architectural integrity in human models

The next most consistent clinical phenotype of human models of estrogen deficiency and/or resistance is marked decreased areal measures of bone mineral density (aBMD). The decreased spine aBMD in the 7 reported aromatase patients improved significantly within 6 months of estrogen treatment (Table 1). The decreased aBMD is presumably a manifestation of decreased trabecular volume from increased bone resorption coupled with decreased bone formation, a predictable outcome of the severe disruption

Conclusions

Detailed analysis of homozygous-affected hERKO patient and aromatase individuals, as well as appropriate experimental animal models, suggest a complex contribution of estrogen to bone growth, aBMD, and skeletal structural integrity (Fig. 2). ERα disruption specifically results in delayed epiphyseal maturation, tall stature, trabecular thinning, marked cortical thinning, significantly reduced cortical vBMD, and normal to increased periosteal expansion. Of significant clinical relevance,

Acknowledgements

The authors thank Sarah E. Smith for providing an artist's rendition of a distal femur. This research was supported by the Clinical Research Center, CCHMC and the Division of Internal Research at the NIEHS project Z01 ES70065 to KSK.

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    ☆

    Special Issue selected article from the IX International Aromatase Conference (Aromatase 2008) held at Shanghai, China, on October 13th–16th, 2008.

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