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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6025-6029
Copyright © 2004 by The Endocrine Society

Estrogens Are Essential for Male Pubertal Periosteal Bone Expansion

Roger Bouillon, Marie Bex, Dirk Vanderschueren1 and Steven Boonen1

Divisions of Endocrinology (R.B., M.B., D.V.) and Geriatric Medicine (S.B.), Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Roger Bouillon, M.D., Ph.D., Laboratory for Experimental Medicine and Endocrinology, Onderwijs & Navorsing, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: roger.bouillon{at}med.kuleuven.ac.be.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The skeletal response to estrogen therapy was studied in a 17-yr-old boy with congenital aromatase deficiency. As expected, estrogen therapy (1 mg estradiol valeriate/d from age 17 until 20 yr) normalized total and free testosterone and reduced the rate of bone remodeling. Dual-energy x-ray absorptiometry-assessed areal bone mineral density (BMD) of the lumbar spine and femoral neck increased significantly (by 23% and 14%, respectively), but peripheral quantitative computed tomography at the ultradistal radius revealed no gain of either trabecular or cortical volumetric BMD. The increase in areal BMD was thus driven by an increase in bone size. Indeed, longitudinal bone growth (height, +8.5%) and especially cross-sectional area of the radius (+46%) and cortical thickness (+12%), as measured by peripheral quantitative computed tomography, increased markedly during estrogen treatment. These findings demonstrate that androgens alone are insufficient, whereas estrogens are essential for the process of pubertal periosteal bone expansion typically associated with the male bone phenotype.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
OSTEOPOROSIS IN MEN is a major public health problem that is associated with significant morbidity, mortality, and economic cost (1). As in women, susceptibility to osteoporosis and osteoporotic fracture in men is determined by skeletal accrual and subsequent bone loss. In both sexes, sex steroids are known to be critically involved in the developing human skeleton, with androgens traditionally assumed to drive the acquisition of bone mass in men. More recently, observations in men with estrogen insensitivity (due to a disruptive mutation in the estrogen receptor-{alpha} gene or due to estrogen deficiency in the context of congenital aromatase deficiency) have provided evidence for a primary role of estrogens in male skeletal development (2, 3, 4, 5, 6). The affected men presented with open epiphyses and continuous growth resulting in tall stature, increased bone remodeling, and reduced bone mineral density (BMD). Administration of estrogen, started at ages 24–31 yr, induced rapid epiphyseal closure and cessation of linear growth, reduced bone turnover, and increased (areal) bone density (3, 4, 5, 6).

In all these reports, BMD was assessed by dual-energy x-ray absorptiometry (DXA), providing a two-dimensional areal view of the three-dimensional mineralized mass of bone, but these studies were not designed to address the relative contribution of bone growth vs. changes in true bone density. Moreover, during puberty in men, the impact of estrogen on epiphyseal closure, linear growth, bone size, and/or bone mass may change over time (7). In this study of a boy with congenital aromatase deficiency, we report the skeletal response to estrogen treatment at a significantly earlier stage of skeletal development. In addition to DXA measurements at the lumbar spine and femoral neck, bone size and true volumetric BMD (vBMD) were sequentially obtained at the radius, using peripheral quantitative computed tomography (pQCT).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Case reports

At the age of 16 yr and 4 months, genetic analysis confirmed the diagnosis of aromatase deficiency in our patient. The propositus was evaluated because this mutation had been suspected and subsequently confirmed in his older sister with pubertal failure. Physical examination revealed no gynecomastia or other abnormalities. He weighed 82 kg and was 172 cm tall at the time of diagnosis. Testicular volume and consistency and the degree of virilization were also normal for his age (Tanner stage V). The patient and his sister were of Moroccan descent, and their parents were first cousins. His history was unremarkable except for a congenital hearing loss of 85%, which was also present in his adult brother and a paternal cousin (also a product from a consanguineous marriage). The father of the propositus has less severe decreased hearing as well. The patient did not use any medication, alcohol, or drugs. He had a sedentary lifestyle, as his hearing impairment interfered with an active social life.

Genetic analysis and biochemical measurements

Genetic analysis of both siblings revealed homozygosity for a C-base deletion in exon 5 of the CYP19 gene, causing a frame-shift mutation that resulted in a truncated, inactive enzyme (8). Their parents and elder brother were heterozygous carriers. Serum concentrations of hormones and osteocalcin were measured by conventional RIAs. Free testosterone was computed as an estimate of biologically available testosterone from its total serum concentrations, SHBG, and albumin (9).

Bone density measurements

Areal BMD (aBMD) of the lumbar spine, femoral neck, and radius (g/cm2) was measured using the DXA QDR 4500a fan beam system (Hologic Inc., Waltham, MA) with a precision error of less than 1%. To account for changes in bone size, vBMD was also estimated by calculation of the bone mineral apparent density (BMAD; g/cm3) as previously described (10). Spine BMAD was derived from the following equation: bone mineral content (BMC) ÷ Ap3/2; and BMAD of the femoral neck and radius was determined using the following equation: BMC ÷ Ap2 (BMC is the quantity of bone mineral within the scan area, and Ap is the projected area).

pQCT was performed at the ultradistal radius using Stratec XCT-960 equipment (Stratec GmbH, Pforzheim, Germany). Measurements of vBMD were taken at the 4% point (4% of ulna length proximal to the most proximal site of the radial articular surface). Image processing and the calculation of numerical values were performed using the manufacturer’s software. The cross-sectional area (CSA) of the radius was determined after detecting the outer bone contour at a threshold of 280 mg/cm3. Total vBMD was defined as the mean density of the total cross-section. Trabecular vBMD was determined as the mean density of the 45% central area of the bone’s cross-section. The pQCT system also yields a parameter called cortical + subcortical vBMD, which is usually referred to as cortical vBMD. This represents the mean density in the 55% peripheral bone area. To include a measure of true cortical vBMD, an additional calculation was performed using a cortical threshold of 650 mg/cm3. Cortical thickness was calculated using a formula assuming a circular ring model for the radius (11). Reproducibility was 1.28% for CSA, 1.72% for total vBMD, 1.02% for trabecular vBMD, and 1.14% for cortical vBMD.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
At the time of diagnosis, serum levels of testosterone (1305 ng/dl; reference range, 300-1000 ng/dl) (45 nmol/liter; range, 10–35 nmol/liter) and free testosterone (42 ng/dl; reference range, 5–20 ng/dl) (1.46 nmol/liter; range, 0.17–0.69 nmol/liter) were elevated. FSH (8 mU/ml; reference range, 2–10 mU/ml) and LH (8 mU/ml; reference range, 2–10 mU/ml) were in the upper normal range. Serum concentrations of estrone were below the lower normal limit (23 pg/ml; reference range, 25–65 pg/ml) (84 pmol/liter; range, 92–238 pmol/liter), and serum estradiol was undetectable (<5 pg/ml; reference range, 0–30 pg/ml) (<18 pmol/liter; range, 0–110 pmol/liter); serum osteocalcin (132 ng/dl; reference range, 10–40 ng/dl) (244 pmol/liter; range, 17–68 pmol/liter) provided evidence for an increased rate of bone remodeling.

Despite full pubertal development and supraphysiological levels of total and free testosterone, x-rays of the left wrist and hand revealed open epiphyses and a bone age of only 12 yr (as assessed by roentgenographic standards for bone development by Gruelich and Pyle).

At the age of 17 yr, treatment with estradiol valeriate at a daily oral dose of 1 mg was initiated, after obtaining informed consent. Administration of estrogen increased serum estradiol (16 pg/ml) (59 pmol/liter) and normalized total and free testosterone (468 ng/dl and 16 ng/dl, respectively) (16 nmol/liter and 0.55 nmol/liter, respectively), FSH (4.7 mU/ml), and LH (4.4 mU/ml). Serum osteocalcin (88 ng/ml) was significantly reduced as well (values were at 3 yr of estrogen therapy and representative of values obtained during active treatment). During treatment, body height increased by 8.5%, from 176 to 191 cm, and bone age matured from 12 yr and 5 months to 16 yr and 8 months, with near closure of the epiphyses only observed at 20 yr and 5 months of age (Figs. 1Go and 2Go).



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  		FIG. 1. Growth curve and bone age before and during estrogen administration.

 


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  		FIG. 2. Changes from baseline in body height, bone size (cross-sectional area), cortical thickness, and total volumetric density (as assessed by pQCT at the ultradistal radius) during estrogen administration. The change in total vBMD (–4.3%) was below the least significant change (LSC).

 
Table 1Go and Fig. 2Go show the effect of estrogen therapy on aBMD and vBMD. At baseline, lumbar spine and femoral neck BMD were remarkably low. From age 17 yr and 1 month to 20 yr and 5 months, during 41 months of estrogen treatment, aBMD improved by 23% at the lumbar spine and by 14% at the femoral neck, as assessed by DXA. When these results were expressed as improvements in T scores (SDs from the mean in normal young men), lumbar spine aBMD increased from –2.31 to –0.55, and femoral neck aBMD increased from –0.46 to +0.44. An increase of BMAD was only observed at the spine (from 0.120 to 0.136 g/cm3 at the spine vs. 0.156 to 0.147 g/cm3 at the femoral neck) At one third of the distance from the wrist to the elbow (one third radius site), aBMD increased by 15%, and at the ultradistal radius, aBMD increased by 18%. In contrast, BMAD at the radius (one third radius site) did not increase (0.255 vs. 0.247 g/cm3). In line with the BMAD data, total vBMD, as assessed by pQCT at the ultradistal radius, did not change either (–4.3%; from 282 to 270 mg/cm3 during treatment, below the least significant change of ±4.8%; Table 1Go and Fig. 2Go). Similarly, no significant changes were observed in trabecular or cortical vBMD (Table 1Go). Bone size (as determined by the CSA of the radius) increased dramatically by 46%, from 247 to 360 mm2; cortical and trabecular area increased by 34 and 64%, respectively. The increase in cortical thickness was 12%.


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  		TABLE 1. Effect of estrogen therapy on areal and volumetric bone density

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Androgens alone are not sufficient for normal skeletal pubertal maturation, as demonstrated by several case reports of men with estrogen insensitivity or deficiency (2, 3, 4, 6). In the patient affected by congenital aromatase deficiency presented in this article, we confirm improvements in (DXA-assessed) axial and peripheral BMD during treatment with estrogen (3, 4, 5, 6). Between the ages of 17 yr and 1 month and 20 yr and 5 months, daily administration of 1 mg of estradiol was associated with an increase in lumbar spine and femoral neck BMD of 23 and 14%, respectively. This estrogen dose normalized testosterone, FSH, and LH values and thus represents a physiological replacement dose, which is equivalent to the 0.625 mg of conjugated estrogens (4) or 50 µg of transdermal estrogen (3, 12) used in previous case reports. In osteoporotic women, similar doses of oral and transdermal estrogen have comparable effects on bone density as well (13).

In men with aromatase deficiency, estrogen treatment has been associated with rapid closure (within 3–6 months) of the initially unfused epiphyses (3, 4, 12), providing compelling evidence that estrogen fuses the epiphyses and terminates male linear growth. Our patient, however, continued linear growth during several years of estrogen therapy, with delayed closure of the epiphyses. This difference probably reflects the significantly younger bone age at which estrogen was initiated (12 yr and 5 months vs. 14 yr and 5 months to 16 yr and 5 months in previously reported cases). Earlier studies in patients with idiopathic delay of puberty already suggested a growth-promoting effect of low-dose estradiol (14), whereas administration of an aromatase inhibitor to patients with familial precocious puberty, a rare disorder associated with a mutation of the LH receptor resulting in adult levels of serum testosterone by the age of 2 yr, decreased growth rate (15). Overall, these findings support the concept that estrogens accelerate pubertal skeletal growth, followed by an estrogen-induced growth-limiting effect through epiphyseal maturation and closure.

During treatment with estradiol, bone age increased from 12 yr and 5 months to 16 yr and 8 months after 41 months of estradiol treatment. Along with the maturation of the skeleton, axial and peripheral BMD increased substantially. However, aBMD, as assessed by DXA, is a function of both the size of the bone and the true amount of bone within its periosteal envelope (vBMD). In the patient presented here, peripheral vBMD (whether estimated from DXA or directly measured by pQCT) did not change significantly during treatment with estradiol. However, bone size (as determined by the CSA of the radius) increased dramatically by approximately 45%, with a concomitant increase in cortical thickness of 12%. The changes observed in our propositus are similar to those associated with normal pubertal growth and support the notion that, in growing bones, except for the spine, true density does not increase (7, 16). As the bone grows in length and diameter, the mass of bone inside the periosteum increases in proportion to the enlarging volume of the whole bone, including the marrow space. During normal growth, vBMD remains constant, but aBMD increases due to an increase in external bone size. This increase is a particularly important contributor to bone strength because the resistance of bone to bending or torsional forces is related exponentially to its diameter (17).

During normal male puberty, the enlargement of the bone diameter is associated with cortical thickening as a result of accelerated periosteal apposition (with less endocortical expansion). In this process, both the stimulatory effects of androgens and the lack of exposure to the inhibitory effects of estrogen on periosteal apposition are considered to be critical (7, 18, 19). During prepubertal growth, periosteal apposition increases bone width in both sexes. In pubertal males, periosteal diameter continues to expand; however, when females enter puberty, periosteal apposition is inhibited (20). These gender-specific patterns are considered to reflect differences in exposure to endogenous estrogens. However, in our patient, periosteal diameter did not cease to expand in response to estrogen therapy. In fact, CSA of the radius continued to increase during administration of estradiol. In other recent reports of affected men, increases in aBMD were reported, but vBMD and bone size were not assessed. The periosteal expansion observed in our patient, without concomitant changes in vBMD, suggests that the estrogen-induced gain in aBMD in the context of aromatase deficiency may be primarily driven by an increase in bone size. The enlargement of cortical bone in our patient cannot be explained by estrogen-stimulated endosteal apposition and demonstrates that, in growing men, estrogens stimulate rather than inhibit periosteal apposition.

Although the stimulation of linear growth in our patient was generally modest (8.5% during the 41-month treatment period), his increase in bone size was substantial. At cortical sites, such as radius and femoral neck, DXA-assessed total area increased by 18 and 21%, respectively, without a significant change in BMAD. Direct measurements of vBMD using pQCT at the radius confirmed that volumetric density was largely unaffected by estrogen treatment. Our observations challenge the traditional view that periosteal expansion of male pubertal bone results only from stimulation of the androgen receptor and lack of inhibitory signals from the estrogen receptor. The present data demonstrate the essential contribution of low-dose estrogen to periosteal pubertal growth, although we acknowledge that an individual case study, by design, does not allow us to elucidate the exact molecular or cellular mechanisms. Androgen action alone, without estrogen receptor activation, appears to be insufficient. Of course, it is possible and might even be likely that combined androgen receptor and estrogen receptor-{alpha} activation are needed for male pubertal bone expansion.

How can these findings be reconciled with the well-established gender differences in bone size? A unifying hypothesis could be that estrogens, rather than androgens, are driving periosteal bone apposition, with a biphasic, dose-dependent effect of estrogen. Assuming a dose-response relationship between estradiol levels and bone expansion in both sexes, stimulation would occur at low levels, as is the case in males and in early pubertal girls, whereas increasing exposure to higher concentrations of estrogen (as found in late puberty and adulthood in females) would inhibit periosteal growth. This assumption is consistent with both the lifelong slow periosteal bone expansion in males and the resumption of bone expansion after menopause (21, 22). Estrogen may induce periosteal bone formation in both sexes through estrogen receptor-{alpha}, whereas inhibition of periosteal expansion may be primarily an estrogen receptor-ß effect. Observations of increased periosteal expansion in female estrogen receptor-ß knockout mice are consistent with this hypothesis (23, 24). Because of the biomechanical importance of the deposition of bone on the periosteal surface, identifying the molecular basis of estrogen actions on periosteal apposition and their potential interaction with local and systemic factors, such as androgens, GH, IGF-I, and PTH, could have major implications for bone physiology and therapy.

Estrogens are critically involved in male linear growth, ultimately leading to growth plate closure. From our findings of low-dose estrogen treatment of an adolescent male with congenital aromatase deficiency, we conclude that exposure to estrogens is also essential for the process of pubertal periosteal bone expansion typically associated with the male bone phenotype. Androgens alone are insufficient to drive periosteal bone formation.


   Footnotes
 
1 D.V. and S.B. contributed equally to this work. Back

Abbreviations: ABMD, Areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; CSA, cross-sectional area; DXA, dual-energy x-ray absorptiometry; pQCT, peripheral quantitative computed tomography; vBMD, volumetric bone mineral density.

Received March 30, 2004.

Accepted September 9, 2004.


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 Introduction
 Materials and Methods
 Results
 Discussion
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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals