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Nonassociation of Estrogen Receptor Genotypes with Bone Mineral Density and Estrogen Responsiveness to Hormone Replacement Therapy in Korean Postmenopausal Women

Department of Internal Medicine (K.O.H., H.Y.C., H.K.M., I.K.H.) and Endocrinology Research Laboratory (I.G.M., Y.S.K.), Samsung Cheil Women’s Healthcare Center, Seoul, Korea

Address all correspondence and requests for reprints to: Dr. In Kwon Han, Department of Internal Medicine, Samsung Cheil Women’s Healthcare Center, 1–19 Choong Gu Mukjung-Dong, 100–380 Seoul, Korea.

	Abstract

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Hormone replacement therapy (HRT) prevents bone loss in postmenopausal women, but some women are resistant to therapy. A recently reported case of severe estrogen resistance caused by a germ-line mutation at the estrogen receptor (ER) gene locus suggests the possibility that other variants of the ER gene could be responsible for resistance to HRT and could also be an answer to the heritable components of bone density. Three restriction fragment length polymorphisms (RFLPs) at the ER gene locus, represented as BstUI (or B variant), PvuII, and XbaI, and their relationship to bone mineral density (BMD) and estrogen responsiveness to HRT were examined in 248 healthy postmenopausal women, aged 41–68 yr (mean ± SD, 52.0 ± 4.6 yr) in Korea. The BstUI restriction site was not found in Korean women. The distribution of the PvuII and XbaI RFLPs was as follows: PP, 35 (14.1%); Pp, 136 (54.8%); pp, 77 (31.1%); and XX, 18 (7.3%); Xx, 72 (29.0%); and xx, 158 (63.7%), respectively (capital letters signify the absence of and lower case letters signify the presence of the restriction site of each RFLP). There was no significant relation between ER genotypes and z score values of lumbar spine BMD. Also, no significant genotypic differences were found in the change in lumbar spine BMD and those in biochemical markers before and after 1 yr of HRT. These data indicate no significant effects of ER genotypes on BMD and estrogen responsiveness after HRT.

	Introduction

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IN 1994, the case study by Smith et al. was the first to describe a man with complete estrogen deficiency caused by a germ-line mutation of estrogen receptor (ER) genomic DNA (Arg¹⁵⁷stop) (1). A 28-yr-old man with severe estrogen resistance had incomplete epiphyseal closure and severe osteoporosis with biochemical evidence of increased bone resorption. This case offers a great deal of information about estrogen’s effect on bone. Estrogen is critical for bone maturation and normal bone development even in males, in whom testosterone cannot be substituted. From this case, we could infer that any other variants of the ER gene might also have an influence on bone and cause estrogen resistance to hormone replacement therapy (HRT).

Recently, two studies have reported that the PvuII and XbaI restriction fragment length polymorphisms (RFLPs) at the ER gene locus had a significant effect on bone. The study reported by Kobayashi et al. (2) showed that the PPxx genotype of the two combined RFLPs was associated with low bone mineral density (BMD), whereas the report by Qi et al. (3) revealed that the pp genotype of the PvuII RFLP was related to low BMD. The contradictory conclusions of both groups about the association of BMD with the ER RFLPs demand further investigation.

The Christiansen group reported that about 1.2% of early healthy postmenopausal women who received HRT over 2 yr had lost more than 1% of forearm bone mineral content per yr (4). That is, they demonstrated that nonresponders to HRT existed. However, there have been no reported studies about the mechanism of estrogen resistance occurring in some women despite good drug compliance and good health.

We, therefore, hypothesize that any variants in the ER gene could have an effect on the development of peak bone mass and thus on the development of osteoporosis; these variants could also account for the lack of response to HRT in nonresponders. We examined three established RFLPs represented by BstUI (or B variant), PvuII, and XbaI at the ER gene locus (5, 6, 7) and analyzed the association of each genotype with lumbar spine BMD in healthy postmenopausal Korean women. We also analyzed differences between genotypes concerning the changes in BMD and bone markers after 1 yr of HRT.

	Subjects and Methods

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Subjects

Two hundred and forty-eight healthy postmenopausal women of ethnic Korean background were studied. Their mean age was 52 yr (range, 41–68 yr). All subjects took HRT with conjugated equine estrogen (Premarin) alone or combined with medroxyprogesterone acetate (Provera) in a cyclic or continuous regimen. Women with good drug compliance who were not taking any drugs that would affect bone turnover rate and did not switch to other drugs during 1 yr of HRT were eligible. Women with early menopause (before 40 yr of age) and those who had had an ovariectomy were excluded. None had a history of bone disease, illness, or drug use that might affect bone turnover. Women were excluded if they had a spine density less than 3 SD below an age-matched reference mean or a spinal degenerative disease detected by conventional spine radiographs.

Measurements of BMD and bone markers

BMD and bone markers were measured before and after 1 yr of HRT. BMD at the lumbar spine was measured by dual energy x-ray absorptiometry using a QDR-2000 (Hologic, Waltham, MA) or a DPX-L (Lunar Co., Madison, WI). The precision errors (coefficient of variation of repeated measurements on individuals) were 0.65% and 1.2%, respectively. At the time of follow-up, we used the same densitometer as that used at baseline. The scores measured by the DPX-L were converted to those of the QDR-2000 by the conversion equation: QDR-2000 = (0.847 x DPX-L) + 0.019 (8). The z score (the value of the SD obtained when the average of the data was adjusted to 0) was calculated by using the data of BMD obtained from up to 2000 Korean women. Plasma osteocalcin (OC) was determined by RIA using an Incstar Osteocalcin ¹²⁵I RIA kit (Stillwater, MN). The intra- and interassay variations were 4.8% and 9.8%, respectively. Carboxy-terminal propeptide of type I collagen (PICP) was measured by the enzyme-linked immunosorbent assay method using a prolagen-C kit from Metra Biosystems (Winooski, VE). The intra- and interassay variations were 2.8% and 7.2%, respectively. Urine deoxypyridinoline (DPD) was assayed by the enzyme-linked immunosorbent assay method using a Pyrilinks-D kit and corrected for creatinine. The intra- and interassay variations were 5.7% and 3.5%, respectively. Spot urine specimens were collected between 0800–1000 h. Serum alkaline phosphatase (ALP) and urinary creatinine were measured by automatized routine procedures. Data for PICP and DPD were obtained from only 67 and 87 women, respectively, because of a delayed test start.

DNA analysis

DNA was isolated from peripheral blood leukocytes using conventional methods. The 143-bp fragment of genomic DNA containing the polymorphic portion of exon 1 (GCG to GCC; codon 87) described by Garcia et al. as the ER B variant was amplified by PCR using previously described oligonucleotide primers (5). The PCR fragments were digested with the BstUI restriction endonuclease and separated on a 7.5% polyacrylamide gel. In every case of enzyme digestion, the PCR product with the restriction site (87, 54, and 2 base pair), provided by Dr. Schatchter, was used as a control (Fig. 1). To analyze the PvuII and XbaI RFLPs in intron 1, approximately 1.3-kilobase (kb) fragments were amplified by PCR using the same oligonucleotide primers and PCR reaction steps originally described by Yaich et al. (2, 6, 7). The PCR products were digested by the PvuII or XbaI restriction endonuclease and separated on a 4% agarose gel. PP and XX, signifying the absence of restriction sites, gave one 1.3-kb fragment, and pp, signifying the presence of restriction sites on both alleles, was digested into two fragments (0.85 and 0.45 kb). The cutting fragment of the XbaI polymorphism near the PvuII RFLP site (50 bp apart) revealed two fragments (0.9 and 0.4 kb) and was labeled as xx (Fig. 1) (2). To identify the XbaI polymorphic site, the PCR product was cloned by TA cloning kit (Invitrogen, San Diego, CA) and sequenced using a U.S. Biochemical Corp. sequencing kit (Cleveland, OH).

View larger version (66K): [in this window] [in a new window]   Figure 1. Genotype analysis of the B variant in exon 1 of the ER gene. Genomic leukocyte DNA from the control with the BstUI restriction site (lane 2) and from three study subjects (lanes 3–5) was PCR amplified, digested with BstUI, and separated on a 7.5% polyacrylamide gel. The restriction site of BstUI was not found in our samples (top). Genotype analysis of the PvuII (lane 2, PP; lane 3, Pp; lane 4, pp) and XbaI (lane 5, XX; lane 6, Xx; lane 7, xx) RFLP sites in intron 1 of the ER gene was performed. Genomic leukocyte DNA was PCR amplified using the same primers, digested with PvuII or XbaI, and separated on a 4% agarose gel (bottom). The fragment sizes are indicated in base pairs.

To determine whether the proportions observed in our data were those to be expected in a random mating equilibrium population, they were explored using the ² method under the Hardy-Weinberg law. Distribution of characteristics among each genotype was evaluated with one-way ANOVA or the Kruskal-Wallis H test. Comparisons of z score values of BMD, percent change in BMD, and percent change in bone markers in each genotype were examined using the Kruskal-Wallis H test. Rates of change in BMD and those in each bone marker were expressed as the percent change from initial levels. Pearson’s ² test was used for evaluation of the association between genotypes and responsiveness to HRT (i.e. responder or nonresponder). Independent Student’s t test and logistic regression were used to evaluate the independency between genotypes and responsiveness to HRT after adjusting possible confounding biases. Responder or nonresponder was set as a dependent variable in logistic regression.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The B variant could not be found in our samples even though we used the control DNA containing the BstUI restriction site. The distribution of the PvuII and XbaI RFLPs was as follows: PP, 35 (14.1%); Pp, 136 (54.8%); pp, 77 (31.1%); and XX, 18 (7.3%); Xx, 72 (29.0%); and xx, 158 (63.7%), respectively. The genotype distribution of these RFLPs was compatible with the populations in the Hardy-Weinberg equilibrium. Sequencing of the XbaI PCR product revealed the putative site, approximately 0.35 kb upstream from exon 2, which differed by only 1 base from the XbaI recognition sequence (TCTAGA to TCTGGA; Fig. 2).

View larger version (16K): [in this window] [in a new window]   Figure 2. Sequence analysis of the XbaI RFLP site in intron 1 of the ER gene. The XbaI RFLP is located approximately 50 bp apart from the PvuII RFLP site and is approximately 400 bp upstream from exon 2 (top), with a point mutation (AG) that differed by one base pair from the Xba I recognition site (TCTAGA) to TCTGGA for the XbaI allele (bottom). The fragment sizes are indicated in base pairs.

View larger version (26K): [in this window] [in a new window]   Figure 3. The z score values of the lumbar spine BMD of the PvuII (top left) and XbaI (top right) RFLP genotypes and the combined genotypes of the PvuII and XbaI RFLPs (bottom). Values are expressed as medians. No significant difference between the groups was found by the Kruskal-Wallis H test.

View larger version (31K): [in this window] [in a new window]   Figure 4. Adjusted rates of bone loss by the PvuII (top left) and XbaI (top right) RFLP genotypes, and the combined genotypes of the PvuII and XbaI RFLPs (bottom) before and after 1 yr of HRT. Values are expressed as medians. No significant difference between the groups was found by the Kruskal-Wallis H test.

View larger version (32K): [in this window] [in a new window]   Figure 5. Percent change in each bone marker before and after HRT in the PvuII (top) and XbaI (bottom) RFLP genotypes. The black bar represents the PP or XX genotype, the gray bar the Pp or Xx genotype, and the white bar the pp or xx genotype. Values are expressed as medians. n, Number of subjects. No significant difference between groups was found by Kruskal-Wallis H test.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The ER gene on chromosome 6q25.1 is comprised of more than 140 kb and has eight exons and five functional domains, designated A/B–F (9). All three RFLPs we examined are located in the A/B domain, which is called transactivating factor 1. It is an important site for stimulating transcription from certain estrogen-responsive promoters. The B variant in the exon 1 site is a silent mutation that changes codon 87 from GCG to GCC of alanine (5, 10). Several reports have shown that the frequency of BB' heterozygotes is about 12% in Caucasians (5, 7, 11) and approximately the same in African-Americans (Schachter, B., personal communication), but there have been no reported data about the distribution of this RFLP among Asians. In our study, the B variant could not be found even though we used the control DNA containing the BstUI restriction site. This finding might be explained by ethnic differences in the B variant; the BstUI RFLP may be rare or absent in ethnic Koreans. The PvuII RFLP site was sequenced in the first intron, 0.4 kb upstream from exon 2, with a point mutation (TC) in the recognition sequence CAGCTG responsible for the P allele (6). The XbaI RFLP site has not been sequenced yet, but it has been studied by Southern blot analysis using an M72 probe that is a 1.6-kb EcoRI fragment containing exon 2 with flanking intron sequences (7). We sequenced the putative XbaI site in intron 1, approximately 50 bp apart from the known PvuII site. The distribution of these two RFLPs was similar to that of RFLPs demonstrated in other studies of Caucasians and Japanese women (2, 3, 7), and it did not deviate significantly from the Hardy-Weinberg equilibrium.

The genetic influence on bone density has been confirmed by a number of family and twin studies. An estimated 46–80% of the total variance in adult bone mass is attributed to genetic determinants (12, 13, 14, 15). Recently, great interest has been generated by a report from Morrison et al. (16), who investigated this genetic mechanism at the molecular basis. They claimed that a natural polymorphism within the VDR gene was responsible for as much as 75% of the total genetic effect on bone density (16). However, the consistency of this effect has not been established, and controversy over the reported relationship between the BsmI genotype and BMD demands further investigation (17). There are fewer studies about the relationship between the genotypes of the ER gene and BMD. Kobayashi et al. (2) showed that the PPxx genotype of combined PvuII and XbaI RFLPs was associated with low lumbar spine BMD in 238 Japanese healthy volunteer postmenopausal women, but in a population-based study by Qi et al. (3), the pp genotype of the PvuII RFLP was significantly related to lower lumbar spine BMD in women and lower femoral neck BMD in men. However, we could not find any significant associations between the ER genotypes and lumbar spine BMD in postmenopausal women. As in the case of VDR polymorphisms, the effect of ER polymorphisms on bone mass may need further study and evaluation.

After 12 months, about 11% of the treated women had lost more than 1% of their bone density in our study. In some studies in which the raw data are provided, spinal BMD diminished in 3–30% of the women who took accepted bone-sparing doses of estrogen (18, 19, 20, 21). The Christiansen group reported that if a nonresponder to HRT was defined as a woman who had lost more than 1% bone/yr, then about 0–5% of healthy early postmenopausal women were classified as nonresponders. However, no studies on the mechanism of occurrence of estrogen resistance have been reported. In other steroid receptors, such as the glucocorticoid, androgen, and vitamin D₃ receptors, hormone resistance has clearly been linked to deletions and point mutations of the respective genes (22, 23, 24). As the steroid hormone receptors are closely related in their domain structure and function as ligand-inducible transcriptional regulators, one would expect the type of ER defects associated with estrogen resistance to be analogous to those described for other steroid receptors. In the ER, it has been thought that mutation would be lethal in the embryo stage (25). However, recently, a case report of a man with complete estrogen deficiency was revealed to be caused by a cystine to thymine transition at codon 157 of both alleles, resulting in a premature stop codon and a severely truncated nonfunctioning protein (1). From this case, one would predict the possibility that any other variants at the ER gene locus could cause estrogen resistance. We examined three ER variants, but there were no significant genotypic differences concerning the changes in BMD and bone markers after 1 yr of HRT. Because no other data about the effect of ER variants on estrogen resistance have been reported, further studies must be conducted to find other sites of the ER gene.

In conclusion, BMD in Koreans could not be associated with three ER genotypes: the B variant, PvuII, and XbaI RFLPs. After 1 yr of HRT, the changes in bone density are not associated with any of these ER genotypes.

	Acknowledgments

 
The authors are grateful to Dr. Beth Schachter, Mount Sinai Hospital (New York, NY), for providing the control DNA of the B variant and technical assistance. Dr. Tone Ikdahl Anderson (Department of Genetics Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway) kindly provided the control DNA of the PvuII RFLP. We also owe many thanks to Mr. Phillip Cheung for proofreading our manuscript.

Received September 2, 1996.

Revised November 12, 1996.

Accepted November 13, 1996.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Smith EP, Boyd J, Frank GR, et al. 1994 Estrogen resistance caused by a mutation in the estrogen receptor gene in a man. N Engl J Med. 331:1056–1061.[Abstract/Free Full Text]
2. Kobayashi S, Inoue S, Hosoi T, Ouchi Y, Shiraki M, Orimo H. 1996 Association of bone mineral density with polymorphism of the estrogen receptor gene. J Bone Miner Res. 11:306–311.[Medline]
3. Qi JC, Morrison NA, Nguyen TV, et al. 1995 Estrogen receptor genotypes and bone mineral density in women and men. J Bone Miner Res. 10:S170.
4. Hassager C, Jensen SB, Christiansen C. 1994 Non-responders to hormone replacement therapy for the prevention of postmenopausal bone loss: do they exist? Osteoporosis Int. 4:36–41.[CrossRef][Medline]
5. Garcia T, Lehrer S, Bloomer WD, Schachter B. 1988 A variant estrogen receptor messenger ribonucleic acid is associated with reduced level of estrogen binding in human mammary tumors. Mol Endocrinol. 2:785–791.[CrossRef][Medline]
6. Yaich L, Dupont WD, Cavener DR, Parl FE. 1992 Analysis of the PvuII restriction fragment-length polymorphism and exon structure of the estrogen receptor gene in breast cancer and peripheral blood. Cancer Res. 52:77–83.[Abstract/Free Full Text]
7. Andersen TI, Heimdal KR, Skrede M, Tveit K, Berg K, Borresen A-L. 1994 Oestrogen receptor (ESR) polymorphisms and breast cancer susceptibility. Hum Genet. 94:665–670.[Medline]
8. Kim SW, Lim CH, Han KO, Jung HY, Min HK, Han IK. Standardization of dual energy X-ray absorptiometry (DXA) in spinal BMD of Korean women and phantom. Proc of the 10th Int Congr of Endocrinol. 1996; 372.
9. Ponglikitmongkol M, Green S, Chambon P. 1988 Genomic organization of the human oestrogen receptor gene. EMBO J. 7:3385–3388.[Medline]
10. Macri P, Khoriaty G, Lehrer S, Karurunaratne A, Milne C, Schachter BS. 1992 Corrigendum: sequence of a human estrogen receptor variant allele. Nucleic Acids Res. 20:2008.[Free Full Text]
11. Lehrer S, Sanchez M, Song HK, et al. 1990 Oestrogen receptor B-region polymorphism and spontaneous abortion in women with breast cancer. Lancet. 335:622–624.[CrossRef][Medline]
12. Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S. 1987 Genetic determinants of bone mass in adults. A twin study. J Clin Invest. 80:706–710.
13. Dequeker J, Nijs J, Verstraeten A, Geusens P, Gevers G. 1987 Genetic determinants of bone mineral content at the spine and radius: a twin study. Bone. 8:207–209.[Medline]
14. Kelly PJ, Eisman JA, Sambrook PN. 1990 Interaction of genetic and environmental influences on peak bone density. Osteoporosis Int. 1:56–60.[CrossRef][Medline]
15. Krall EA, Dawson-Hughes B. 1993 Heritable and lifestyle determinants of bone mineral density. J Bone Miner Res. 8:1–9.[Medline]
16. Morrison NA, Qi JC, Tokita A, et al. 1994 Prediction of bone density from vitamin D receptor alleles. Nature. 367:284–287.[CrossRef][Medline]
17. Peacock M. 1995 Vitamin D receptor alleles and osteoporosis: a contrasting view. J Bone Miner Res. 10:1294–1297.[Medline]
18. Genant HK, Cann CE, Ettinger B, Gordan GS. 1982 Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophrectomy. Arch Intern Med. 97:699–705.
19. Riis BJ, Thomsen K, Strom V, Christiansen C. 1987 The effect of percutaneous estradiol and natural progesterone on postmenopausal bone loss. Am J Obstet Gynecol. 156:61–65.[Medline]
20. Hodgkinson A, Thompson T. 1982 Measurement of the fasting urinary hydroxyproline: creatinine ratio in normal adults and its variation with age and sex. J Clin Pathol. 35:807–11.[Abstract/Free Full Text]
21. Stevenson JC, Cust MP, Gangar KF, Hillard TC, Lees B, Whitehead MI. 1990 Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet. 336:265–269.[CrossRef][Medline]
22. Harmon JM, Elsasser MS, Eisen LP, Urda LA, Ashraf J, Thompson EB. 1989 Glucocorticoid receptor expression in receptorless mutants isolated from the human leukemic cell line CEM-C7. Mol Endocrinol. 3:734–743.[CrossRef][Medline]
23. Brown TR, Lubahn DB, Wilson EM, Joseph DR, French FS, Migeon CJ. 1988 Deletion of the steroid-binding domain of the human androgen receptor gene in one family with complete androgen insensitivity syndrome: evidence for further genetic heterogeneity in this syndrome. Proc Natl Acad Sci USA. 85:8151–8155.[Abstract/Free Full Text]
24. Ritchie HH, Hughes MR, Thompson ET, et al. 1989 An ochre mutation in the vitamin D receptor gene causes hereditary 1,25-dihydroxyvitamin D₃-resistant rickets in three families. Proc Natl Acad Sci USA. 86:9783–9787.[Abstract/Free Full Text]
25. George FW, Wilson JD. 1988 Sex determination and differentiation. In: Knobil E, Neill JD, eds. The physiology of reproduction. New York: Raven Press;3–26.

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