- Email: [email protected]
An estrogen metabolism-related polymorphism of the 17-α HSD gene is associated with perimenopausal body mass index
An estrogen metabolism-related polymorphism of the 17-␣ HSD gene is associated with perimenopausal body mass index In a cross-sectional study of 2,802 perimenopausal caucasian women, carriage of at least one mutated allele of the 17-␣-hydroxysteroid dehydrogenase type 1 (17-␣ HSD) vlV A¡C single nucleotide polymorphism (SNP) was associated with a significantly increased body mass index (mean 24.3 ⫾ 4.4 kg/m2 vs. 23.5 ⫾ 4.2 kg/m2; P⬍.001), and obesity was more frequent among mutant allele carriers (P⫽.06; odds ratio 1.38; 95% confidence interval 0.97–1.95), providing evidence of 17-␣ HSD as a candidate gene of perimenopausal obesity. (Fertil Steril威 2007;87:1494 – 6. ©2007 by American Society for Reproductive Medicine.)
Menopause is associated with an increased risk of obesity and a shift to an abdominal fat distribution with associated increases in health risks. In a study of 1,303 women, postmenopausal or hysterectomized women had significantly higher levels of metabolic risk factors, such as body mass index (BMI), waist circumference, total and lowdensity lipoprotein cholesterol, and glycosylated hemoglobin (HbA1c), than premenopausal women of the same age (1). The menopausal transition is associated with an increased waist-hip ratio (2). It has been speculated that perimenopausal weight and body composition changes are, at least in part, dependent on estrogen metabolism. Obesity also has a genetic component. For example, the incidence of obesity is significantly increased in first-degree relatives compared with controls. In a series of 1,102 healthy adults in 67 Utah pedigrees, a heritability estimate of 21% has been calculated for the BMI (3). Concordance in twins has also been demonstrated for obesity (4), and single nucleotide polymorphisms (SNPs) are associated with the clinical course of and the susceptibility to obesity, e.g., the PTPN1 rs914458 SNP (5) and the Peroxisome Proliferator– Activated Receptor ␥ 2 (PPAR-␥ 2) Pro12Ala SNP (6). The CYP17 A2 T¡C SNP is associated with elevated serum and plasma levels of estradiol (E2), progesterone (P), and testosterone (T) (7). The 17-␣-hydroxysteroid dehydrogenase type 1 (17-␣ HSD) vlV A¡C SNP has been associated with changes in E2 serum concentrations and the development of osteoporosis (8). We assessed the genotype frequencies of the CYP17 A2 T¡C and the 17-␣ HSD vlV A¡C SNPs in a large series of perimenopausal caucasian women. We hypothesized that the CYP17 A2 T¡C and the Received May 21, 2006; revised July 9, 2006; accepted November 10, 2006. Supported by Ludwig Boltzmann Institute of Gynecology and Gynecologic Oncology, Vienna, Austria. Reprint requests: Clemens Tempfer, M.D., Department of Gynecologic Endocrinology and Infertility Treatment, Medical University Vienna, Waehringer Guertel 18 –20, A-1090 Vienna/Austria (FAX: ⫹43 1 40400 2911; E-mail: [email protected]).
1494
17-␣ HSD vlV A¡C SNPs are associated with the perimenopausal BMI and would be overrepresented in women with perimenopausal obesity. MATERIALS AND METHODS Approval for this study was obtained by the Institutional Review Board at the Medical University of Vienna, Austria. From May 2001 to December 2005 we enrolled 2,802 consecutive caucasian women seeking counseling for perimenopausal disorders in university hospitals, primary and secondary care facilities, and private offices nationwide in Germany and Austria. Women with a history of malignant disease and those using hormone therapy were excluded. Signed written consent was obtained from all participating women. To avoid confounding by ethnicity, only women of Austrian and German ethnic background were included. Obesity was defined as BMI ⬎30 for the purpose of this study. Natural menopause was defined as age at the last menstrual period (years) without having menstrual periods for at least 12 consecutive months. Categorization of menopausal status was by interview, no serum concentrations of E2 or FSH were determined. Time since natural menopause was not quantified. In all, 884 women were premenopausal, 411 women had a personal history of hysterectomy, and 1,507 women had experienced natural menopause. Surgically menopausal women were included, but they were excluded in the subgroup analysis comparing pre- and postmenopausal women. DNA was extracted from patients’ blood or buccal swabs, and genotyping was performed as previously described (9). The 17-␣ HSD vlV A¡C genotypes were assessed in 2,802 women, whereas the CYP17 A2 allele T¡C genotypes were assessed in only 2,492 women owing to limited DNA availability and DNA degradation. Values are given as mean (SD). Student t-test, one-way analysis of variance (ANOVA), and 2 test with Bonferroni correction were used. Allele frequencies were estimated by
Fertility and Sterility姞 Vol. 87, No. 6, June 2007 Copyright ©2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.11.055
the gene-counting method. P⬍.05 was considered statistically significant. Smoking information was available for only 572 women. We performed a multivariate linear regression model with BMI as dependent variable and age, a personal history of hysterectomy, and carriage of the 17-␣ HSD vlV A¡C SNP as independent variables.
1.09; 95% confidence interval [CI] 0.79 –1.50). Obesity was more frequent among mutant allele carriers of the 17-␣ HSD vlV A¡C SNP compared with noncarriers, but this difference was not statistically significant (44 out of 533 [8%] vs. 214 out of 1,869 [11%]; P⫽.06; OR 1.38; 95% CI 0.97–1.95).
Based on the genotype distributions of the 17-␣ HSD vlV A¡C SNP published in the literature, we performed a power analysis. With the given sample size of 2,802 probands, we achieved a power of 91.9% with an ␣ of .05. We used the statistical software SAS System for Windows V8.2 (SAS Institute, Cary, NC).
In a univariate model, age, a personal history of hysterectomy, and carriage of the 17-␣ HSD vlV A¡C SNP, but not the CYP17 A2 allele T¡C SNP, were positively associated with an increased BMI. In a multivariate model, both age (P⫽.04; regression coefficient 0.03 [standard error 0.01]) and a personal history of hysterectomy (P⬍.001; regression coefficient 1.0 [standard error 0.2]), as well as the 17-␣ HSD vlV A¡C SNP (P⫽.002; regression coefficient ⫺0.8 [standard error 0.3]) were significantly associated with BMI.
RESULTS The mean age of the women was 54.2 (⫾10.0) years. The CYP17 A2 allele T¡C T/T, T/C, and C/C genotypes were present in 885 (36%), 1,160 (46%), and 447 (18%) women, respectively. The 17-␣ HSD vlV A¡C A/A, A/C, and C/C genotypes were present in 2,196 (78%), 416 (15%), and 190 (7%) women, respectively. The genotype distributions were in Hardy-Weinberg equilibrium. Table 1 shows personal history parameters broken down by the presence or absence of the CYP17 A2 allele T¡C and 17-␣ HSD vlV A¡C SNPs. Using a dominant genotype model, carriage of at least one mutated allele of the 17-␣ HSD vlV A¡C SNP was associated with a significantly increased BMI (mean 24.3 ⫾ 4.4 kg/m2 [A/A] vs. 23.5 ⫾ 4.2 kg/m2 [A/C⫹C/C]; P⬍.001). Excluding women with a personal history of hysterectomy did not affect this association (data not shown). Recessive and gene-dosage genetic models showed no statistically significant effects for both SNPs (data not shown). There was no statistically significant difference in the frequency of obesity between mutant allele carriers of the CYP17 A2 allele T¡C SNP and noncarriers (135 out of 1,299 [10%] vs. 69 out of 729 [9%]; P⫽.6; odds ratio [OR]
DISCUSSION Perimenopausal weight gain is a clinical phenomenon observed in about 40% of women. It is distressing for affected women and a frequent cause of complaint in clinical practice. In addition, perimenopausal BMI is a significant predictor of disease, e.g., type 2 diabetes and breast cancer (10). Individual genetic variation based on SNPs has been strongly implicated in E2 metabolism, body weight homeostasis, and the development of obesity (5, 6). In the present study, we found that the 17-␣ HSD vlV A¡C SNP was associated with a higher perimenopausal BMI. Obesity was also more common among carriers of the mutated 17-␣ HSD vlV A¡C allele, but this association was of only borderline significance. This finding is in accordance with the hypothesis that a proestrogenic metabolic state influences perimenopausal obesity. Furthermore, we ascertained various parameters of the womens’ personal history, such as age at menopause and a personal history of hysterectomy. In a univariate analysis,
TABLE 1 Womens’ personal characteristics broken down by presence or absence of polymorphic alleles. SNP CYP17 wt/wt wt/mt, mt/mt 17- HSD wt/wt wt/mt, mt/mt
Age at menarche
P
Age at menopause
P
No. of pregnancies
P
No. of women with hysterectomy
P
13.4 (1.6) 13.3 (1.6)
.4
47.6 (5.7) 47.9 (5.7)
.2
1.7 (1.3) 1.7 (1.5)
.9
196 176
.9
13.4 (1.6) 13.2 (1.5)
.5
47.7 (5.8) 48.3 (5.1)
.6
1.6 (0.9) 1.7 (1.5)
.6
199 212
.9
Note. wt ⫽ wild-type; mt ⫽ mutant; values are given as mean (standard deviation) or absolute number (%). Tempfer. 17-␣ HSD polymorphism and perimenopausal BMI. Fertil Steril 2007.
Fertility and Sterility姞
1495
both of these parameters were significantly associated with the perimenopausal BMI. Because age at menopause and a personal history of hysterectomy are surrogate parameters of lifetime estrogen exposure, these data support the assumption that longer lifetime estrogen exposure is responsible for an increased perimenopausal BMI. This is biologically plausible, because sex steroids regulate adipocytes in abdominal fat depots in men and women and E2 induces the proliferation of preadipocytes and affects fat cell number in human abdominal subcutaneous and omental adipose tissues (11, 12). Dominant, recessive, and gene-dosage genetic models were performed. Within the two investigated loci, the presence of at least one mutant allele of 17-␣ HSD vlV A¡C, but not of CYP17 A2 allele T¡C, was found to be significantly associated with perimenopausal BMI in a dominant manner. We found no recessive effect for the 17-␣ HSD vlV A¡C SNP. The present study has limitations. Selection bias has to be acknowledged when interpreting the results of this study. We had to exclude women with a history of malignant disease. We also excluded women using perimenopausal hormone therapy, because these women have no clear time point of menopause. Also, we consecutively recruited women seeking advice due to perimenopausal symptoms, so we can not rule out bias by self-selection of women participating in the study. Also, associations between the investigated genotypes and diseases such as fibroids and menorrhagia in women with a history of hysterectomy may affect the results of this study. Excluding women with hysterectomy from the analysis, however, did not change the results. Furthermore, we have no longitudinal data on body weight, BMI, and obesity, and therefore cause-effect relationships cannot be fully appreciated in this cross-sectional study. In summary, we present the largest cross-sectional series of caucasian women investigating estrogen-metabolizing gene polymorphisms and perimenopausal BMI to date. In this series, the presence of the 17-␣ HSD vlV A¡C SNP was a significant predictor of perimenopausal BMI. Clemens B. Tempfer, M.D.a Claudia Huber, M.D.a Johannes C. Huber, M.D., Ph.D.a Christian Schneeberger, Ph.D.a Eva-Katrin Bentz, M.D.a
1496
Tempfer et al.
Correspondence
Lukas A. Hefler, M.D.b a Department of Gynecologic Endocrinology and Infertility Treatment and b Department of Obstetrics and Gynecology, Medical University Vienna, Vienna, Austria REFERENCES 1. Langenberg C, Hardy R, Kok H, Cooper R, Butterworth S, Wadsworth ME. Cardiovascular risk at age 53 years in relation to the menopause transition and use of hormone replacement therapy: a prospective British birth cohort study. BJOG 2005;112:476 – 85. 2. Gaspard UJ, Gottal JM, van den Brule FA. Postmenopausal changes of lipid and glucose metabolism: a review of their main aspects. Maturitas 1995;21:171– 8. 3. Hunt SC, Hasstedt SJ, Kuida H, Stults BM, Hopkins PN, Williams RR. Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in Utah pedigrees and twins. Am J Epidemiol 1989;129:625–38. 4. Poulsen P, Vaag A, Kyvik K, Beck-Nielsen H. Genetic versus environmental aetiology of the metabolic syndrome among male and female twins. Diabetologia 2001;44:537– 43. 5. Cheyssac C, Lecoeur C, Dechaume A, Bibi A, Charpentier G, Balkau B, et al. Analysis of common PTPN1 gene variants in type 2 diabetes, obesity, and associated phenotypes in the French population. BMC Med Genet 2006;5:44. 6. Ghoussaini M, Meyre D, Lobbens S, Charpentier G, Clement K, Charles MA, et al. Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population. BMC Med Genet 2005;22:6 –11. 7. Feigelson S, Shames LS, Pike MC, Coetzee GA, Stanczyk FZ, Henderson BE. Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res 1998;58:585–7. 8. Cheng ZN, Zhou HH. Contribution of genetic variations in estradiol biosynthesis and metabolism enzymes to osteoporosis. Acta Pharmacol Sin 2000;21:587–90. 9. Huber M, Mundlein A, Dornstauder E, Schneeberger C, Tempfer CB, Mueller MW, Schmidt WM. Accessing single nucleotide polymorphisms in genomic DNA by direct multiplex polymerase chain reaction amplification on oligonucleotide microarrays. Anal Biochem 2002;303:25–33. 10. Di Donato P, Giulini NA, Bacchi Modena A, Cicchetti G, Comitini G, Gentile G; Gruppo di Studio Progetto Menopausa Italia. Risk factors for type 2 diabetes in women attending menopause clinics in Italy: a cross-sectional study. Climacteric 2005;8:287–93. 11. Dieudonne MN, Sammari A, Dos Santos E, Leneveu MC, Giudicelli Y, Pecquery R. Sex steroids and leptin regulate 11betahydroxysteroid dehydrogenase I and P450 aromatase expressions in human preadipocytes: Sex specificities. J Steroid Biochem Mol Biol 2006 [Epub ahead of print]. 12. Anderson LA, McTernan PG, Barnett AH, Kumar S. The effects of androgens and estrogens on preadipocyte proliferation in human adipose tissue: influence of gender and site. J Clin Endocrinol Metab 2001;86:5045–51.
Vol. 87, No. 6, June 2007
Menopause is associated with an increased risk of obesity and a shift to an abdominal fat distribution with associated increases in health risks. In a study of 1,303 women, postmenopausal or hysterectomized women had significantly higher levels of metabolic risk factors, such as body mass index (BMI), waist circumference, total and lowdensity lipoprotein cholesterol, and glycosylated hemoglobin (HbA1c), than premenopausal women of the same age (1). The menopausal transition is associated with an increased waist-hip ratio (2). It has been speculated that perimenopausal weight and body composition changes are, at least in part, dependent on estrogen metabolism. Obesity also has a genetic component. For example, the incidence of obesity is significantly increased in first-degree relatives compared with controls. In a series of 1,102 healthy adults in 67 Utah pedigrees, a heritability estimate of 21% has been calculated for the BMI (3). Concordance in twins has also been demonstrated for obesity (4), and single nucleotide polymorphisms (SNPs) are associated with the clinical course of and the susceptibility to obesity, e.g., the PTPN1 rs914458 SNP (5) and the Peroxisome Proliferator– Activated Receptor ␥ 2 (PPAR-␥ 2) Pro12Ala SNP (6). The CYP17 A2 T¡C SNP is associated with elevated serum and plasma levels of estradiol (E2), progesterone (P), and testosterone (T) (7). The 17-␣-hydroxysteroid dehydrogenase type 1 (17-␣ HSD) vlV A¡C SNP has been associated with changes in E2 serum concentrations and the development of osteoporosis (8). We assessed the genotype frequencies of the CYP17 A2 T¡C and the 17-␣ HSD vlV A¡C SNPs in a large series of perimenopausal caucasian women. We hypothesized that the CYP17 A2 T¡C and the Received May 21, 2006; revised July 9, 2006; accepted November 10, 2006. Supported by Ludwig Boltzmann Institute of Gynecology and Gynecologic Oncology, Vienna, Austria. Reprint requests: Clemens Tempfer, M.D., Department of Gynecologic Endocrinology and Infertility Treatment, Medical University Vienna, Waehringer Guertel 18 –20, A-1090 Vienna/Austria (FAX: ⫹43 1 40400 2911; E-mail: [email protected]).
1494
17-␣ HSD vlV A¡C SNPs are associated with the perimenopausal BMI and would be overrepresented in women with perimenopausal obesity. MATERIALS AND METHODS Approval for this study was obtained by the Institutional Review Board at the Medical University of Vienna, Austria. From May 2001 to December 2005 we enrolled 2,802 consecutive caucasian women seeking counseling for perimenopausal disorders in university hospitals, primary and secondary care facilities, and private offices nationwide in Germany and Austria. Women with a history of malignant disease and those using hormone therapy were excluded. Signed written consent was obtained from all participating women. To avoid confounding by ethnicity, only women of Austrian and German ethnic background were included. Obesity was defined as BMI ⬎30 for the purpose of this study. Natural menopause was defined as age at the last menstrual period (years) without having menstrual periods for at least 12 consecutive months. Categorization of menopausal status was by interview, no serum concentrations of E2 or FSH were determined. Time since natural menopause was not quantified. In all, 884 women were premenopausal, 411 women had a personal history of hysterectomy, and 1,507 women had experienced natural menopause. Surgically menopausal women were included, but they were excluded in the subgroup analysis comparing pre- and postmenopausal women. DNA was extracted from patients’ blood or buccal swabs, and genotyping was performed as previously described (9). The 17-␣ HSD vlV A¡C genotypes were assessed in 2,802 women, whereas the CYP17 A2 allele T¡C genotypes were assessed in only 2,492 women owing to limited DNA availability and DNA degradation. Values are given as mean (SD). Student t-test, one-way analysis of variance (ANOVA), and 2 test with Bonferroni correction were used. Allele frequencies were estimated by
Fertility and Sterility姞 Vol. 87, No. 6, June 2007 Copyright ©2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.11.055
the gene-counting method. P⬍.05 was considered statistically significant. Smoking information was available for only 572 women. We performed a multivariate linear regression model with BMI as dependent variable and age, a personal history of hysterectomy, and carriage of the 17-␣ HSD vlV A¡C SNP as independent variables.
1.09; 95% confidence interval [CI] 0.79 –1.50). Obesity was more frequent among mutant allele carriers of the 17-␣ HSD vlV A¡C SNP compared with noncarriers, but this difference was not statistically significant (44 out of 533 [8%] vs. 214 out of 1,869 [11%]; P⫽.06; OR 1.38; 95% CI 0.97–1.95).
Based on the genotype distributions of the 17-␣ HSD vlV A¡C SNP published in the literature, we performed a power analysis. With the given sample size of 2,802 probands, we achieved a power of 91.9% with an ␣ of .05. We used the statistical software SAS System for Windows V8.2 (SAS Institute, Cary, NC).
In a univariate model, age, a personal history of hysterectomy, and carriage of the 17-␣ HSD vlV A¡C SNP, but not the CYP17 A2 allele T¡C SNP, were positively associated with an increased BMI. In a multivariate model, both age (P⫽.04; regression coefficient 0.03 [standard error 0.01]) and a personal history of hysterectomy (P⬍.001; regression coefficient 1.0 [standard error 0.2]), as well as the 17-␣ HSD vlV A¡C SNP (P⫽.002; regression coefficient ⫺0.8 [standard error 0.3]) were significantly associated with BMI.
RESULTS The mean age of the women was 54.2 (⫾10.0) years. The CYP17 A2 allele T¡C T/T, T/C, and C/C genotypes were present in 885 (36%), 1,160 (46%), and 447 (18%) women, respectively. The 17-␣ HSD vlV A¡C A/A, A/C, and C/C genotypes were present in 2,196 (78%), 416 (15%), and 190 (7%) women, respectively. The genotype distributions were in Hardy-Weinberg equilibrium. Table 1 shows personal history parameters broken down by the presence or absence of the CYP17 A2 allele T¡C and 17-␣ HSD vlV A¡C SNPs. Using a dominant genotype model, carriage of at least one mutated allele of the 17-␣ HSD vlV A¡C SNP was associated with a significantly increased BMI (mean 24.3 ⫾ 4.4 kg/m2 [A/A] vs. 23.5 ⫾ 4.2 kg/m2 [A/C⫹C/C]; P⬍.001). Excluding women with a personal history of hysterectomy did not affect this association (data not shown). Recessive and gene-dosage genetic models showed no statistically significant effects for both SNPs (data not shown). There was no statistically significant difference in the frequency of obesity between mutant allele carriers of the CYP17 A2 allele T¡C SNP and noncarriers (135 out of 1,299 [10%] vs. 69 out of 729 [9%]; P⫽.6; odds ratio [OR]
DISCUSSION Perimenopausal weight gain is a clinical phenomenon observed in about 40% of women. It is distressing for affected women and a frequent cause of complaint in clinical practice. In addition, perimenopausal BMI is a significant predictor of disease, e.g., type 2 diabetes and breast cancer (10). Individual genetic variation based on SNPs has been strongly implicated in E2 metabolism, body weight homeostasis, and the development of obesity (5, 6). In the present study, we found that the 17-␣ HSD vlV A¡C SNP was associated with a higher perimenopausal BMI. Obesity was also more common among carriers of the mutated 17-␣ HSD vlV A¡C allele, but this association was of only borderline significance. This finding is in accordance with the hypothesis that a proestrogenic metabolic state influences perimenopausal obesity. Furthermore, we ascertained various parameters of the womens’ personal history, such as age at menopause and a personal history of hysterectomy. In a univariate analysis,
TABLE 1 Womens’ personal characteristics broken down by presence or absence of polymorphic alleles. SNP CYP17 wt/wt wt/mt, mt/mt 17- HSD wt/wt wt/mt, mt/mt
Age at menarche
P
Age at menopause
P
No. of pregnancies
P
No. of women with hysterectomy
P
13.4 (1.6) 13.3 (1.6)
.4
47.6 (5.7) 47.9 (5.7)
.2
1.7 (1.3) 1.7 (1.5)
.9
196 176
.9
13.4 (1.6) 13.2 (1.5)
.5
47.7 (5.8) 48.3 (5.1)
.6
1.6 (0.9) 1.7 (1.5)
.6
199 212
.9
Note. wt ⫽ wild-type; mt ⫽ mutant; values are given as mean (standard deviation) or absolute number (%). Tempfer. 17-␣ HSD polymorphism and perimenopausal BMI. Fertil Steril 2007.
Fertility and Sterility姞
1495
both of these parameters were significantly associated with the perimenopausal BMI. Because age at menopause and a personal history of hysterectomy are surrogate parameters of lifetime estrogen exposure, these data support the assumption that longer lifetime estrogen exposure is responsible for an increased perimenopausal BMI. This is biologically plausible, because sex steroids regulate adipocytes in abdominal fat depots in men and women and E2 induces the proliferation of preadipocytes and affects fat cell number in human abdominal subcutaneous and omental adipose tissues (11, 12). Dominant, recessive, and gene-dosage genetic models were performed. Within the two investigated loci, the presence of at least one mutant allele of 17-␣ HSD vlV A¡C, but not of CYP17 A2 allele T¡C, was found to be significantly associated with perimenopausal BMI in a dominant manner. We found no recessive effect for the 17-␣ HSD vlV A¡C SNP. The present study has limitations. Selection bias has to be acknowledged when interpreting the results of this study. We had to exclude women with a history of malignant disease. We also excluded women using perimenopausal hormone therapy, because these women have no clear time point of menopause. Also, we consecutively recruited women seeking advice due to perimenopausal symptoms, so we can not rule out bias by self-selection of women participating in the study. Also, associations between the investigated genotypes and diseases such as fibroids and menorrhagia in women with a history of hysterectomy may affect the results of this study. Excluding women with hysterectomy from the analysis, however, did not change the results. Furthermore, we have no longitudinal data on body weight, BMI, and obesity, and therefore cause-effect relationships cannot be fully appreciated in this cross-sectional study. In summary, we present the largest cross-sectional series of caucasian women investigating estrogen-metabolizing gene polymorphisms and perimenopausal BMI to date. In this series, the presence of the 17-␣ HSD vlV A¡C SNP was a significant predictor of perimenopausal BMI. Clemens B. Tempfer, M.D.a Claudia Huber, M.D.a Johannes C. Huber, M.D., Ph.D.a Christian Schneeberger, Ph.D.a Eva-Katrin Bentz, M.D.a
1496
Tempfer et al.
Correspondence
Lukas A. Hefler, M.D.b a Department of Gynecologic Endocrinology and Infertility Treatment and b Department of Obstetrics and Gynecology, Medical University Vienna, Vienna, Austria REFERENCES 1. Langenberg C, Hardy R, Kok H, Cooper R, Butterworth S, Wadsworth ME. Cardiovascular risk at age 53 years in relation to the menopause transition and use of hormone replacement therapy: a prospective British birth cohort study. BJOG 2005;112:476 – 85. 2. Gaspard UJ, Gottal JM, van den Brule FA. Postmenopausal changes of lipid and glucose metabolism: a review of their main aspects. Maturitas 1995;21:171– 8. 3. Hunt SC, Hasstedt SJ, Kuida H, Stults BM, Hopkins PN, Williams RR. Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in Utah pedigrees and twins. Am J Epidemiol 1989;129:625–38. 4. Poulsen P, Vaag A, Kyvik K, Beck-Nielsen H. Genetic versus environmental aetiology of the metabolic syndrome among male and female twins. Diabetologia 2001;44:537– 43. 5. Cheyssac C, Lecoeur C, Dechaume A, Bibi A, Charpentier G, Balkau B, et al. Analysis of common PTPN1 gene variants in type 2 diabetes, obesity, and associated phenotypes in the French population. BMC Med Genet 2006;5:44. 6. Ghoussaini M, Meyre D, Lobbens S, Charpentier G, Clement K, Charles MA, et al. Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population. BMC Med Genet 2005;22:6 –11. 7. Feigelson S, Shames LS, Pike MC, Coetzee GA, Stanczyk FZ, Henderson BE. Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res 1998;58:585–7. 8. Cheng ZN, Zhou HH. Contribution of genetic variations in estradiol biosynthesis and metabolism enzymes to osteoporosis. Acta Pharmacol Sin 2000;21:587–90. 9. Huber M, Mundlein A, Dornstauder E, Schneeberger C, Tempfer CB, Mueller MW, Schmidt WM. Accessing single nucleotide polymorphisms in genomic DNA by direct multiplex polymerase chain reaction amplification on oligonucleotide microarrays. Anal Biochem 2002;303:25–33. 10. Di Donato P, Giulini NA, Bacchi Modena A, Cicchetti G, Comitini G, Gentile G; Gruppo di Studio Progetto Menopausa Italia. Risk factors for type 2 diabetes in women attending menopause clinics in Italy: a cross-sectional study. Climacteric 2005;8:287–93. 11. Dieudonne MN, Sammari A, Dos Santos E, Leneveu MC, Giudicelli Y, Pecquery R. Sex steroids and leptin regulate 11betahydroxysteroid dehydrogenase I and P450 aromatase expressions in human preadipocytes: Sex specificities. J Steroid Biochem Mol Biol 2006 [Epub ahead of print]. 12. Anderson LA, McTernan PG, Barnett AH, Kumar S. The effects of androgens and estrogens on preadipocyte proliferation in human adipose tissue: influence of gender and site. J Clin Endocrinol Metab 2001;86:5045–51.
Vol. 87, No. 6, June 2007