The endocrine role of estrogens on human male skeleton

Abstract

Before the characterization of human and animal models of estrogen deficiency, estrogen action was confined in the context of the female bone. These interesting models uncovered a wide spectrum of unexpected estrogen actions on bone in males, allowing the formulation of an estrogen-centric theory useful to explain how sex steroids act on bone in men. Most of the principal physiological events that take place in the developing and mature male bone are now considered to be under the control of estrogen. Estrogen determines the acceleration of bone elongation at puberty, epiphyseal closure, harmonic skeletal proportions, the achievement of peak bone mass, and the maintenance of bone mass. Furthermore, it seems to crosstalk with androgen even in the determination of bone size, a more androgen-dependent phenomenon. At puberty, epiphyseal closure and growth arrest occur when a critical number of estrogens is reached. The same mechanism based on a critical threshold of serum estradiol seems to operate in men during adulthood for bone mass maintenance via the modulation of bone formation and resorption in men. This threshold should be better identified in-between the ranges of 15 and 25 pg/mL. Future basic and clinical research will optimize strategies for the management of bone diseases related to estrogen deficiency in men.

Figure 1

Direct and indirect effects of increasing circulating estrogens and their depletion on the growth plate (a), and effects of estrogen deprivation on bone elongation and epiphyseal status (b). AR: androgen receptor; E1: estrone; E₂: estradiol; T: testosterone; ER-α: estrogen receptor alpha; ER-β: estrogen receptor beta; GPR30: membranous-G-protein-coupled estrogen receptor.

Figure 2

Proposed range for a critical serum estradiol threshold above which both skeletal maturation and mineralization can proceed in an optimal way. E₂: estradiol; BioE₂: Bioavailable estradiol.

Figure 3

Schematic representation of the role of estrogen and androgen bone size according to gender. The effects of sex steroids on cortical and trabecular bone are represented. Bone size is reached in late puberty and early adulthood as depicted at the left of the panel where the effect of each sex steroid and their sum are shown according to gender. In men, the combined action of both T and E₂ led to greater bone size and cortical thickness than in women. The prevailing effect of E₂ is consistent with higher endosteal bone formation in women. Bone loss during aging occurs in a different fashion between man and women and is subordinate to the baseline conditions. Women lose more bone on the endosteal surface and in the trabecular portion of bone, while men lose mainly bone mass in the cortical bone (right side of the panel). E₂: estradiol, T: testosterone; modified in part from figures published in [75, 77].