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Department of Internal Medicine (L.G., L.M., L.P., A.F., A.T., C.M., F.D.M., M.L.B.), University of Florence, 50139 Florence, Italy; and Institute of Internal Medicine (D.M., S.G., B.L., C.G.), University of Siena, 53100 Siena, Italy
Address all correspondence and requests for reprints to: Maria Luisa Brandi, M.D., Ph.D., Department of Internal Medicine, University of Florence, Viale Pieraccini 18, 50139 Florence, Italy. E-mail: m.brandi{at}dmi.unifi.it.
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Abstract |
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Introduction |
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Sex steroid hormones are important regulators of bone physiology in both sexes, and reduction in their circulating levels represents a major factor in the pathogenesis of osteoporosis (4). However, although the importance of estrogen in maintaining bone mass in women is well recognized (5), the relative contribution of estrogen and androgens in regulating male skeletal homeostasis remains unclear. Androgens are the dominant sex steroids secreted in males and have long been assumed to be critical for skeletal maintenance in men because hypogonadism and castration are associated with increased bone turnover and osteoporosis (6). However, in the past few years, several clinical and experimental observations indicated a dominant role of estrogen in the regulation of bone growth and mineralization in males, suggesting that the skeletal effects of androgens are partly mediated by their aromatization into estrogen. Unfused epiphyses, increased bone turnover, and severe osteoporosis were described in males with homozygous mutations in the aromatase gene (7, 8, 9) who showed lack of response to intramuscular testosterone (T) treatment but increased bone mass after administration of transdermal estrogen (8, 9). In addition, several epidemiological studies showed that in elderly males circulating estradiol (E2) levels or bioavailable estrogen levels were correlated with bone mineral density (BMD) more strongly than T concentrations, suggesting a key role of estrogen not only for skeletal maturation but also for the maintenance of bone mass (10, 11, 12, 13, 14). This latter hypothesis has been clearly addressed by a recent interventional study that investigated the relative contributions of estrogens vs. androgens in preventing the increase in bone resorption after the induction of hypogonadism and aromatase inhibition in normal men (15). In this study, E2 replacement played the major role in preventing the increase in bone resorption markers, whereas T had no significant effect (15). Moreover, in three recent longitudinal studies on elderly men (16, 17, 18), bioavailable estrogen concentrations appeared as the most consistent predictor of bone turnover and bone loss, and interestingly, a lower E2 to T ratio was observed in osteoporotic than in nonosteoporotic subjects (18). Thus, evidence is accumulating that peripheral conversion of testicular androgens into estrogen plays an important role in the maintenance of normal bone mass in aging males.
Expression and activity of aromatase, the enzyme that catalyzes the conversion of androgens into estrogen, have been shown to vary widely among subjects (19, 20). This variation could be genetically determined. Several polymorphic regions have been detected in the human CYP19 aromatase gene, and these could be responsible for qualitative and/or quantitative differences in gene expression or aromatase activity (21, 22, 23). In a recent study, we demonstrated that a tetranucleotide TTTAn repeat polymorphism in intron 4 of the CYP19 gene, previously associated with breast cancer risk (24), correlated with bone mass and vertebral fracture risk in postmenopausal women (25). In a previous study in community-dwelling elderly men, the same CYP19 polymorphism was significantly associated with BMD changes at the distal forearm and with self-reported clinical fracture risk (17). To date, the functional mechanisms underlying the TTTA repeat effect on bone remains unknown.
The present study was designed to longitudinally evaluate the effect of the CYP19 TTTA repeat polymorphism on sex steroid levels, bone turnover, and rates of BMD change in a cohort of elderly Italian men. To uncover possible mechanisms through which this polymorphism influences aromatase activity, a functional in vitro study on fibroblasts from patients with different CYP19 TTTA genotypes was also performed.
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Subjects and Methods |
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Patients eligible for the study were 500 Caucasian elderly men more than 55 yr old who were contacted by direct mailing. This sample was obtained by the population register of the city of Siena. The study was designed to investigate the role of sex hormones and of genetic polymorphisms on bone metabolism and the ageing process in the male. Detailed exclusion criteria have been previously described in an earlier article focusing on sex hormone levels and bone loss (18). Briefly, 364 subjects (age range, 55–85 yr) agreed to participate and were followed longitudinally. From this total cohort of 364 men, 64 subjects were excluded because of past or current history of diseases or treatments affecting bone metabolism or because they did not complete the first follow-up examination. The longitudinal study cohort consisted of 300 men (mean ± SEM age, 66.2 ± 0.8 yr) who completed the 2-yr follow-up. Of these men, 200 (mean ± SEM age, 64.8 ± 0.8 yr) completed the 4-yr follow-up. For all subjects, a detailed medical history was obtained, and dietary calcium intake was assessed by a sequential self-questionnaire including foods that account for the majority of calcium in the diet (26). Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters. Informed written consent was obtained from all participants, and the study was approved by the Institutional Review Board of Siena Medical Center.
Clinical analysis
Areal BMD (g/cm2) was determined for lumbar spine (L2–L4), and proximal femur was determined by dual-energy x-ray absorptiometry (DXA) using the Hologic 4500 instrument (Hologic, Waltham, MA), with short-term in vivo CV of 0.9 and 1.9%, respectively. Calcaneal (Achilles; Lunar, Madison, WI) and phalangeal bone ultrasound (DBM Sonic 1200; IGEA, Carpi, Italy) were also evaluated for each subject. The in vivo CV were 2.5% for broadband ultrasound attenuation (BUA) and 0.5% for speed of sound (SOS) at the calcaneous and 0.6% for amplitude-dependent SOS at the phalanxes. Baseline DXA at the proximal femur and ultrasound (os calcis) were repeated after 2 and 4 yr, and a new lumbar BMD examination was repeated in the 200 men who completed the 4-yr follow-up.
After recruitment, 130 of the 300 men agreed to undergo a spinal x-ray examination. The documentation of vertebral fractures was based entirely on spine radiographs, following the method of McCloskey et al. (27), with a 3-SD cutoff value for each vertebral level. Radiographs of the lumbar spine were further evaluated for the presence of osteophytosis and facet joint osteoarthritis according to the methods of Orwoll et al. (28) and Masud et al. (29), respectively.
Serum concentrations of calcium, phosphate, bone alkaline phosphatase (Tandem-R Ostase; Beckman Coulter Inc, Fullerton CA; interassay CV < 8.1%), urinary type I collagen C-telopeptides (
-CrossLaps RIA; Osteometer Biotech, Herlev, Denmark; interassay CV < 6.5%), E2 (RIA; Diasorin Diagnostics, Saluggia, Italy; interassay CV < 7.9%), total T (RIA; Diasorin Diagnostics; interassay CV < 10.3%), (SHBG RIA; BIOCODE S.A., Liege, Belgium; interassay CV < 8.0%), dehydroepiandrosterone sulfate (R-DHEA-S CTK RIA; Diasorin Diagnostics; interassay CV < 8.5%), parathyroid hormone (N-tact PTH SP, IRMA Kit; Diasorin Diagnostics; interassay CV < 4.9%), and 25-hydroxyvitamin D (25-Hydroxyvitamin D 125I RIA Kit; Diasorin Diagnostics; interassay CV < 11%) were evaluated at baseline. Free androgen index (FAI) and free estrogen index (FEI) were calculated as the percent ratios between total hormone levels and SHBG. As adjunctive measures of biologically active sex hormone values, non-SHBG-bound T [calculated bioavailable T (c-bioT)], and non-SHBG-bound E2 [calculated bioavailable E2 (c-bioE2)] were calculated according to the method described by Vermeulen et al. (30) and Van den Beld et al. (31), taking the concentration of T, E2, and SHBG into account and assuming a fixed albumin concentration of 45 g/liter.
Circulating E2 and T levels were reevaluated after 2 and 4 yr.
Genetic analysis
Genomic DNA was extracted from EDTA blood samples by a standard phenol/chloroform extraction procedure. The DNA region containing the polymorphic TTTAn repeat at 1174-bp at the human CYP19 gene was amplified by PCR as previously described (25). Briefly, the reaction was carried out in 10-µl volumes containing 100 ng of genomic DNA, buffer solution (10 mM Tris HCl, pH 9; 50 mM KCl, 5 mM MgCl2, and 1% Triton X-100), 200 µM each of deoxy (d)TTP, dGTP, and dATP, and 10 µM dCTP plus 1.0 µCi of [-32P]-dCTP, one unit of Taq polymerase, and 0.4 µM of oligonucleotide primers (forward, 5'-GCAGGACTTAGCTAC-3'; reverse, 5'-TTACAGTGAGCCAAGGTGGT-3'). PCR was performed through 30 cycles with 30 sec at 94 C, 45 sec at 58 C, and 1 min at 72 C. Products were electrophoresed in 6% denaturing polyacrylamide gel, and genotypes were detected by autoradiography. In addition, PCR products from the DNA of six cases (two homozygous subjects each for 7–3 bp, 7, and 11 TTTA repeat alleles) were cloned and sequenced using the ABI Prism 310 (Perkin-Elmer, Monza, Italy).
Functional analysis on fibroblasts
Fibroblasts were obtained from skin biopsies at the nondominant arm of both seven subjects from the 300 men and 10 subjects from a cohort of postmenopausal women selected for different CYP19 genotypes (five homozygotes with 
11 TTTA repeats, four heterozygotes, and eight homozygotes with seven TTTA repeats). Skin explants were cultured in Coon’s modified Ham’s F12 medium containing 10% fetal calf serum. At the first passage, fibroblasts derived from each patient were incubated in duplicate with 2 nM [3H]-androstenedione (42 Ci/mmol; 1 Ci = 12 GBq; NEN Life Science Products, Milan, Italy) for 24 h, and conditioned media were then extracted and stored at –20 C. The extracted steroids were separated from the frozen aqueous layer, evaporated, and applied to thin-layer chromatography plates, as previously described (32).
Statistical analysis
Data were evaluated by ANOVA and analysis of covariance (ANCOVA), with Fisher’s protected least significant difference post hoc test, and presented as means ± SEM. P < 0.05 was accepted as the value of significance. The following covariates were considered for the ANCOVA analysis: age, weight, calcium intake, smoking status, and alcohol use. Standard 
2 tests or Fisher’s exact test were used to compare observed genotype frequencies with those expected under Hardy-Weinberg equilibrium and to test the distribution of genotypes in men with and without vertebral fractures. Odds ratios [with 95% confidence intervals (CI)] were calculated by logistic regression analysis to estimate the relative risk of vertebral fractures. All statistical tests were two-sided and were performed by using Statistica 5.1 (Statsoft Inc., Tulsa, OK).
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Results |
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In the total population, circulating T and dehydroepiandrosterone sulfate levels decreased linearly with age (r = –0.27, P < 0.001; and r = –0.40, P < 0.001, respectively), whereas SHBG increased significantly (r = 0.45; P < 0.001). Circulating E2 levels did not significantly vary with age. By contrast, the FAI and the FEI significantly decreased with age (r = –0.43, P < 0.001; and r = –0.24, P < 0.01, respectively), as did c-bioE2 (r = –0.25, P < 0.001) and c-bioT (r = –0.45, P < 0.001) levels. Circulating E2 positively correlated with BMI (r = 0.20, P < 0.01) and total T (r = 0.32, P < 0.001). Consistent with a 4-yr longitudinal observation in 200 of the 300 studied subjects (18), baseline BMD and SOS at the calcaneous were positively correlated with FEI and c-bioE2 levels, with correlation coefficients (r) ranging between 0.15 and 0.27. Conversely, no significant association was observed between densitometric measurements and T or c-bioT concentrations.
Analysis of CYP19 polymorphism evidenced six different alleles, containing respectively seven, eight, nine, 10, 11, and 12 TTTA repeats (Fig. 1
). The frequency distribution of TTTA repeat alleles followed the Hardy-Weinberg equilibrium and did not differ from that previously reported in other populations (23, 24, 25). Sequence analysis confirmed the presence of a 3-bp deletion in 70% of seven-repeat alleles but not in the other alleles. The deletion was in the 5' flanking region of the tetranucleotide repeat, just 50 nucleotides upstream. Given the bimodal distribution of the TTTA repeat alleles, showing two major peaks at seven and 11 repeats and a very low distribution of the nine-repeat allele, genotypes were grouped within genotype 1, which included alleles with a high number of repeats (> nine repeats), and genotype 2, which included low TTTA repeat alleles (< nine repeats). General characteristics of study subjects according to CYP19 genotype are shown in Table 1. The genotype groups did not differ significantly in age, dietary calcium intake, smoking habits, alcohol intake, or height. There was a significant gene-dose effect on weight and BMI, which was lower in the 1–2 than 2–2 genotype groups and higher in the 1–1 genotype group (P < 0.01).
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The three genotype groups differed significantly for baseline lumbar BMD but not for baseline femoral BMD and calcaneal or phalangeal ultrasound parameters (Table 2). Subjects homozygous for a high number of TTTA repeat alleles (genotype 1–1) showed 5.7% and 7.5% higher lumbar BMD values than subjects heterozygous (genotype 1–2) and homozygous for a low number of TTTA repeats (genotype 2–2), respectively (P < 0.05). At the hip, Ward’s triangle and femoral neck BMD values in genotype 1–1 were 4.3% and 0.9% higher, respectively, than in genotype 2–2, but these differences did not reach statistical significance. When the bone density values were adjusted for BMI, the differences between genotype groups were moderately reduced, but they were still statistically significant at the lumbar spine (P = 0.05, ANCOVA). Figure 2 shows lumbar BMD values according to CYP19 genotype in subjects divided by BMI categories of normal (BMI 
25), overweight (25 < BMI < 30), and obese (BMI 30). Differences in BMD were greater in men with a normal BMI (n = 145) and lower in the overweight and obese groups (n = 155). In the group of subjects with normal BMI, lumbar spine BMD was 12.5% higher in genotype 1–1 than in genotype 2–2 (P < 0.01), whereas BMD of the femoral neck and Ward’s triangle were 4.5% (P = 0.09) and 10% (P < 0.05) higher, respectively, in genotype 1–1 than in genotype 2–2. As shown in Table 3, baseline bone-specific alkaline phosphatase and urinary type I collagen C-telopeptide levels were significantly lower in genotype 1–1 than in genotypes 1–2 and 2–2 (P < 0.05). By contrast, serum calcium, phosphate, parathyroid hormone, and 25-hydroxyvitamin D levels did not significantly differ among genotype groups.
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The relationships between sex hormones and CYP19 polymorphism are shown in Table 3
. Men with a high number of TTTA repeats (genotype 1–1) showed higher baseline serum E2 levels than those with genotypes 1–2 and 2–2 (P < 0.01). A similar relationship was observed between CYP19 genotype and E2 levels measured after 2 yr (P < 0.01). Adjustments of E2 levels for age, BMI, total T, or SHBG did not change the results. Conversely, total T and SHBG did not significantly differ among men grouped according to the three CYP19 genotype groups. Serum c-bioE2 and FEI were significantly higher in subjects with 1–1 genotype than in those with 1–2 and 2–2 genotypes (P < 0.01). No significant differences in the FAI were observed among the three genotype groups. The ratio between E2 and T, an indirect measure for aromatase activity, increased significantly with age (r = 0.19, P < 0.01) and, as shown in Fig. 3, was higher in genotype 1–1 than in genotypes 1–2 and 2–2 both at baseline and after 2 yr (P < 0.01).
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The recruited subjects showed a slight increase in BMD at the total hip over 2 yr (yearly rate of change: +0.45%; 95% CI, +0.17 to +0.77). The relative site-specific annualized BMD changes were +0.21% (95% CI, –0.27 to +0.69) at the femoral neck and –1.58% (95% CI, –2.84 to +0.77) at the Ward’s triangle. At the calcaneous, a +0.78% (95% CI, +0.28 to +1.28) annual increase in BUA and a –0.10% (95% CI, –0.14 to –0.04) annual decrease in SOS were observed.
The annual BMD and quantitative ultrasound changes according to CYP19 genotypes in the 300 men who completed the 2-yr follow-up is depicted in Table 4. Men with genotype 2–2 showed higher rates of bone loss at the Ward’s triangle (P < 0.01) and higher SOS loss (P < 0.05) than those with the 1–2 and 1–1 genotypes. The annual increase of total hip BMD was higher in the 1–1 genotype than in the 1–2 and 2–2 genotypes (P < 0.01), whereas the annual increase in femoral neck BMD and BUA did not significantly differ among genotype groups. Similar but not significant trends were observed in the 200 subjects who completed the 4-yr follow-up, with men carrying genotype 2–2 showing higher rates of hip BMD change compared with men with genotype 1–1. Interestingly, among the 130 men who underwent a spinal x-ray examination, the 4-yr decline in spinal BMD after exclusion of 34 subjects with severe lumbar osteoarthritis appeared higher in subjects carrying genotype 2–2 compared with noncarriers (P < 0.05, ANOVA). Similar results were observed when these analyses were repeated adjusting for age and weight or BMI at baseline.
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). Only one of the 25 men with a vertebral fracture had CYP19 genotype 1–1. This was equivalent to an odds ratio of 0.19 (95% CI, 0.02–1.39).
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The fractionation of [3H]-androstenedione into the putative aromatase and 17ß-hydroxysteroid dehydrogenase products is shown in Table 6. Fibroblasts from patients homozygous for the high TTTA repeat allele showed a greater aromatase activity than fibroblasts obtained from homozygotes for the low TTTA repeat genotype. After 24 h of incubation with [3H]-androstenedione, estrogen production reached 80–90% in fibroblasts with genotype 1–1, whereas estrogen production was less than 10% in fibroblasts with genotype 2–2 (P < 0.05). In fibroblasts obtained from heterozygotes, estrogen production ranged from 30–37%. Similar results have been obtained in skin fibroblasts obtained from 10 postmenopausal women (Table 6).
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Discussion |
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1, and the IGF-I genes (33, 34, 35, 36, 37). In view of the recognized role that estrogen plays in bone metabolism in men (7, 8, 9, 12, 15, 16, 17, 18), the CYP19 gene encoding aromatase represents an important candidate to be evaluated in attempt to elucidate the genetic background of male osteoporosis. Indeed, two recent studies suggested an association between a TTTA repeat polymorphism in the CYP19 gene and bone parameters both in postmenopausal women (25) and elderly men (17). The data presented here confirm and extend previous findings indicating that the TTTA repeat polymorphism at the CYP19 gene exerts a significant role in regulating bone turnover in elderly males (17), with consistent segregation with estrogen levels, bone density, and rates of BMD change. Homozygotes for a high number of repeats showed higher circulating E2, higher lumbar BMD, and lower rates of BMD change than heterozygotes and homozygotes for a low number of repeats. These differences in bone density were accompanied by differences in weight and BMI and were reduced in magnitude after correction for BMI. This is not unexpected in view of the close association between BMI and bone density (38, 39, 40) and suggests that the association between CYP19 genotype and bone density may be, at least in part, mediated by an effect on body size. It is also likely that variation in BMI and, consequently, in fat mass may modulate the effect of CYP19 genotypes on bone. In fact, when analysis was restricted to subjects with a normal BMI, the differences between CYP19 genotypes increased in magnitude, whereas they progressively decreased in magnitude when overweight and obese men were considered. Thus, the effect seems greatest in nonobese men, and it progressively decreased by the increase in BMI, probably due to higher aromatization of androgens into estrogen by adipose tissue. This latter observation is in keeping with a previous study on community-dwelling elderly men that demonstrated a significant association between the CYP19 genotype and BMD only after excluding subjects below the 25th percentile and above the 75th percentile for total fat mass (17). Moreover, the observed interactions between the TTTA repeat polymorphism and BMI are also consistent with the hypothesis of a threshold level of non-SHBG-bound E2 for skeletal sufficiency in the elderly male, as previously suggested by two longitudinal studies (16, 18). In fact, either the absence of CYP19 alleles with less than nine TTTA repeats (less efficient) or the abundance of adipose tissue (with increased source for aromatization) could be able to maintain an amount of circulating E2 that is necessary to prevent bone loss. Importantly, in the present study, c-bioE2 and FEI levels were above the reported threshold (equivalent to total E2 concentrations of 90–115 pmol/liter) in all the subjects within the overweight group, whereas only the 1–1 genotype in the nonobese group exhibited circulating E2 levels above that threshold.
In this study, a possible association between CYP19 polymorphism and vertebral fracture risk was also observed, with a trend for a protective effect of the high-repeat alleles. However, the trend did not approach statistical significance, possibly due to the limited number of fractures. Consistent with the present results, in a previous study on elderly men, a low number of TTTA repeats was associated with increased self-reported fracture risk and with a positive family history of fractures (17). Similarly, we previously observed an increased incidence of radiologically assessed vertebral fractures in postmenopausal women with shorter CYP19 TTTA repeat alleles (25).
In agreement with all the above clinical findings, our preliminary in vitro analysis showed a greater aromatase activity in fibroblasts obtained from homozygous subjects with the high TTTA repeat genotype than in those from homozygous men with a low TTTA repeat genotype. In addition, these results have been confirmed in a recently carried out evaluation in skin fibroblasts obtained from 10 postmenopausal women with opposite genotypes. These data are further documented by the higher E2 to T ratio in men with the 1–1 genotype than in those with the 1–2 and 2–2 genotypes. The molecular mechanism(s) through which different CYP19 TTTAn repeat alleles affect aromatase activity and bone metabolism is still unknown. Due to its location in intron 4 of the CYP19 gene, it is unlikely that this polymorphism directly affects aromatase activity, and it is more likely that the different TTTA alleles are in linkage disequilibrium with other functional variants in the CYP19 gene or in a nearby gene. Indeed, a recent study described a strong degree of linkage disequilibrium between the TTTA repeat polymorphism in intron 4 of the CYP19 gene and a C-T substitution in exon 10, just 19 bp downstream of termination of translation (23). In that study, the T allele was associated with a higher number of TTTA repeats and showed a high-activity phenotype, with increased aromatase activity and increased aromatase mRNA levels and with a switch in promoter usage from promoter I.4 to promoter I.3 (23). The switching of alternative promoters in the CYP19 gene was proposed to result in increased aromatase expression and in overproduction of estrogen from aromatizable androgens (41).
The present study has some limitations. First, bone loss evaluation at 2 yr was limited by the ability of DXA analysis to assess BMD differences in a short period of time. The unexpected minimal increase in femoral BMD might reflect the reduced ability to detect small longitudinal changes at this site in a 2-yr follow-up period. The measurement of BMD at the Ward’s triangle does not represent the best site for longitudinal evaluation of BMD change because it is not an anatomically defined region. Moreover, the significant correlation with lumbar BMD loss over 4 yr has been observed in a limited group of subjects and needs to be confirmed in larger samples. Finally, prevalent and not incident vertebral fractures were investigated, with a low number of total fractures. Larger and prospective follow-up studies are needed to confirm the association between CYP19 polymorphism and fracture risk.
In conclusion, osteoporosis in men represents a growing health problem and certainly includes heterogeneous subsets. Studies about the genetic basis of the disease are important for a better understanding of factors that influence bone density and quality, for identifying subjects at higher osteoporotic risk, and for targeting preventive strategies. In vivo and in vitro results from the present study indicate the possibility of genetically determined differences in aromatase activity. Male subjects with a high CYP19 TTTA repeat genotype may have a more efficient aromatase activity with higher estrogen production and with more protection for bone loss.
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Acknowledgments |
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Footnotes |
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L.G. and L.M. contributed equally to this work.
Abbreviations: ANCOVA, Analysis of covariance; BMD, bone mineral density; BMI, body mass index; BUA, broadband ultrasound attenuation; c-bioE2, calculated bioavailable estradiol; c-bioT, calculated bioavailable testosterone; CI, confidence interval; CV, coefficient of variation; DXA, dual-energy x-ray absorptiometry; E2, estradiol; FAI, free androgen index; FEI, free estrogen index; SOS, speed of sound; T, testosterone.
Received August 4, 2003.
Accepted February 19, 2004.
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