06-0450 2131.2135

Estradiol Levels: A
Genotypes Differ in Salivary 17-
Study Based on Hormonal Profiles from Entire Menstrual

Grazyna Jasienska, Maria Kapiszewska, Peter T. Ellison, et al. Updated version
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To request permission to re-use all or part of this article, contact the AACR Publications CYP17 Genotypes Differ in Salivary 17-B Estradiol Levels:A Study Based on Hormonal Profiles fromEntire Menstrual Cycles Grazyna Jasienska,1,3 Maria Kapiszewska,2 Peter T. Ellison,4 Malgorzata Kalemba-Drozdz,2Ilona Nenko,1 Inger Thune,5,6 and Anna Ziomkiewicz1 1Department of Epidemiology and Population Studies, Collegium Medicum and 2Department of General Biochemistry,Faculty of Biotechnology, Jagiellonian University, Krako´w, Poland; 3Radcliffe Institute for Advanced Study and4Department of Anthropology, Harvard University, Cambridge, Massachusetts; 5Department ofCommunity Medicine, University of Tromso, Norway; and 6Ulleval University Hospital,Oslo, Norway Variation in the levels of sex-steroid hormones results from menstrual cycles and no reported fertility problems partici- differences in developmental conditions, adult lifestyle, and pated in the study. Women with A2/A2 genotype had 54% genetic polymorphism. Genes involved in sex-steroid bio- higher mean E2 levels than women with A1/A1 genotype (P = synthesis have been implicated to influence levels of 0.0001) and 37% higher than women with A1/A2 genotype hormones in premenopausal women, but the results were (P = 0.0008). Heterozygous A1/A2 women had 13 % higher E2 inconclusive. We tested variation among women in levels of levels than homozygous A1/A1 women (but this difference salivary estradiol (E2) corresponding to CYP17 genotypes.
was significant only in a nonparametric test). Levels of E2 CYP17 encodes cytochrome P450c17A, which mediates two during the day with highest E2 (day À1) were 72% higher enzymes important in E2 synthesis. In contrast to the earlier in A2/A2 compared with A1/A1 (P = 0.01) and 52 % higher studies that relied on one or a few samples for assessing compared with A1/A2 (P = 0.03). Our results suggest that the E2 levels of an individual woman, our study is based on CYP17 genotype may serve as a biomarker of endocrine daily collected saliva samples for one entire menstrual cycle.
function in women of reproductive age.
Sixty Polish women, ages 24 to 36 years, with regular Sex-steroid hormones are implicated in the development and studies suggest that no additional transcription factor binding growth of breast cancer and most of the risk factors for that activity is associated with the presence of the A2 allele (33, 34).
disease exert their effect by influencing levels of sex-steroid Studies investigating the relationship between CYP17 hormones, especially estrogens (1-4). Levels of sex-steroids are polymorphism and levels of E2 in premenopausal women also important for fecundity, risks of osteoporosis, cardiovas- (24, 25, 27, 35-37) have yielded inconsistent results. E2 levels cular health, and psychological well-being (5-9).
measured around day 11 of the menstrual cycle have been Considerable variation has been documented in the levels of reported to be 11% and 57% higher among women with geno- sex-steroid hormones among populations and among healthy, types A1/A2 and A2/A2, respectively, compared with A1/A1 premenopausal women within a population (10). Many women (24). In the same study, E2 levels during the luteal sources of this variation have been identified. Levels of phase, around day 22 of the cycle, were reported to be 7% and ovarian hormones are sensitive to factors related to fetal 28% higher for women with A1/A2 and A2/A2, respectively.
development (11, 12), childhood growth (13), and adult life Another study found that women with the A2/A2 genotype (14-22). It is also likely that variation in sex-steroid levels had 42% and heterozygotes 19% higher E2 than the A1/A1 results partly from genetic variation (i.e., polymorphism of genotype but only among women with body mass index values genes that control steroid hormone biosynthesis; refs. 23-28).
25 kg/m2 and under (25). Among women with higher body The gene CYP17 encodes cytochrome P450c17a, which mass indexes, the genotypes did not differ in E2 levels. Both of mediates the activity of 17a-hydroxylase and 17,20-lyase, both these studies are based on only one or two E2 values per woman.
involved in the biosynthesis of estradiol (E2; ref. 29). In women, A third study of 173 premenopausal women did not find CYP17 is expressed in the ovarian theca cells, the corpus any differences in E2 levels among CYP17 genotypes but luteum, adrenals, and adipose tissue (30-32). A single documented significant differences in the levels of steroid nucleotide polymorphism in the 5¶-untranslated region of hormone dehydroepiandrosterone, a precursor for E2 synthesis CYP17 is relatively common and the presence of the A2 allele (37). E2 levels were measured in a single blood sample is thought to increase transcription rates (26), although other presumably collected in the luteal phase of the cycle, betweenday 20 and 24 from the beginning of the cycle. Two otherstudies that did not find statistically significant differences inE2 levels among CYP17 genotypes also used a single blood Received 5/30/06; revised 8/28/06; accepted 9/13/06.
sample for hormonal measurements (35, 36). Only one study Grant support: State Committee for Scientific Research, Poland and Radcliffe Institute for attempted to control the within-cycle variability in E2 levels by Advanced Study at Harvard University.
sampling, on the average, 4.4 days per woman over a 2-year The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
period, but did not find significant differences in relation to Section 1734 solely to indicate this fact.
Requests for reprints: Grazyna Jasienska, Department of Epidemiology and Population We document, for the first time, a relationship between Studies, Collegium Medicum, Jagiellonian University, Grzego´rzecka 20, 31-531 Krako´w,Poland. Phone: 48-12-424-1380. E-mail: [email protected] polymorphism in CYP17 and full cycle profiles of 17-h E2 Copyright D 2006 American Association for Cancer Research.
among healthy, regularly menstruating women in midrepro- ductive years. In contrast to the earlier studies that relied on Cancer Epidemiol Biomarkers Prev 2006;15(11). November 2006 2132 CYP17 Polymorphism and Entire Cycle Estradiol Profiles one or a few samples for assessing the E2 levels of anindividual woman, our study is based on daily collected salivasamples for one entire menstrual cycle.
Study Group. The subjects were 60 urban (n = 22) and rural (n = 38) women from Poland recruited for the study byadvertisements. Women were selected for participation if theymet the following criteria: age between 24 and 36 years, regularmenstrual cycles and no fertility problems, no gynecologicand/or chronic disorders (i.e., diabetes and hypothyroidism/hyperthyroidism), not taking any hormonal medication orusing hormonal contraception during the 6 months beforerecruitment, and not being pregnant or lactating during the6 months before recruitment. The recruited women signed aconsent form after being informed about the aims andrequirements of the study, which had been approved by theJagiellonian University Research Ethics Committee.
Figure 1. Mean E2 profiles for CYP17 genotypes. Mean E2 for A2/A2 Anthropometric Measurements, General Questionnaire, genotype is 54% higher than for A1/A1 genotype and 37% higher than and Birth Characteristics. Subjects’ body weight, height, and for A1/A2 genotype. A1/A2 heterozygote has 13% higher E2 than percentage body fat (by bioimpedance) were measured by a A1/A1 homozygote (but this difference is significant only in a trained anthropologist. A general questionnaire (one part nonparametric test). 95% Confidence intervals are omitted for clarity.
completed by interview and one part self-administered) wasused to collect information on education, reproductive history,and past use of hormonal medication, tobacco, and alcohol.
identified by gel electrophoresis were assigned as homozy- Data on birth weight and birth length were recorded at birth gous wild-type (A1/A1) 145-bp band, heterozygous variant by a nurse and obtained from subjects’ personal ‘‘health (A1/A2) 145-, 75-, and 70-bp bands, and homozygous variant books’’ issued by hospitals following birth. Detailed descrip- tion of the methods was published elsewhere (11, 17).
The protocol was run twice for each DNA sample.
Additionally, 20% of templates were rerun according to an E2 Indices and Assay Procedure. Women collected daily alternative method (39). A control sample which did not morning saliva samples for one entire menstrual cycle. Saliva contain DNA was run in every reaction to confirm the absence samples from 20 days (reverse cycle days À5 to À24, where the of contamination. The quality of the PCR product was checked last day of each cycle was marked as day À1) of each cycle by running 4 mL of each sample on 1% agarose gel.
were analyzed for the concentration of E2 using an I-125 basedRIA kit (Diagnostic Systems Laboratories, Webster, TX) with Statistical Analysis. Differences among the three genotypes published (16) modifications to the manufacturer’s protocol.
in mean E2 were tested in two-way repeated measure The sensitivity of the E2 assay is 4 pmol/L. Average intra-assay univariate and multivariate ANOVAs. Mean values of E2 were variability was 9%, and inter-assay variability ranged from calculated for each woman for each 3 consecutive days of the 23% for lower (15 pmol/L) to 13% for higher (50 pmol/L) menstrual cycle (i.e., the first arithmetic mean was calculated values. Before other statistical analyses, cycles were aligned from untransformed values for cycle days À9, À8, and À7; the based on identification of the day of the midcycle E2 drop second mean from cycle days À6, À4, and À5, etc.), obtaining a (day 0; Fig. 1), which provides a reasonable estimate of the day six-level hormonal profile for each woman. The profile was of ovulation (5). E2 values from 18 consecutive days of each analyzed as the repeated measure variable and the genotypes cycle aligned on day 0 were used in analyses. Reliable were the between-group factor (A1/A1, A1/A2, and A2/A2).
identification of the day of the midcycle E2 drop could not The ANOVA was followed by contrast analyses; an a level of be made for two subjects. Therefore, we used data from 58 0.0167 (with the Bonferroni correction) was used to indicate statistical significance. Differences among genotypes in log-transformed E Genotype Determination. Genotyping was done according 2 levels during the cycle day À1 (preovulatory day; Fig. 1) were tested in a one-way ANOVA.
to published methods (38). Genomic DNA was extracted Differences among the genotypes in age, reproductive from 0.2 mL peripheral blood using extraction kit (Qiagen characteristics, length of menstrual cycle, size at birth, GmbH, Hilden, Germany). PCR was done using primers that anthropometrics and body composition, tobacco smoking, amplify restriction sites for Msp A1 I (A2 polymorphism- alcohol consumption, and mean 24-hour physical activity were CYP17): 5¶-CAAGGTGAAGATCAGGGTAG-3¶ (forward) and tested in factorial, fixed-model, one-way ANOVA analyses 5¶-GCTAGGGTAAGCAGCAAGAG-3¶ (reverse). A 145-bp followed by Tukey-Kramer post-hoc tests.
fragment encompassing biallelic single gene polymorphism(T!C) in the untranslated 5¶ region of CYP17 was amplified.
For the PCR, 25 AL final volume of reaction mixture contained the following: 200 pg of genomic DNA, 0.45 Amol/L of eachprimer, 2 mmol/L MgSO4, 200 Amol/L of each deoxynucleo- Table 1 shows the characteristics of the study group stratified tide triphosphate, and 1 unit plaque-forming unit polymerase.
by genotype. Genotypes did not show statistically significant PCR cycling conditions were 94jC for 45 seconds, 57jC for 60 differences in age, reproductive characteristics, size at birth, seconds, and 72jC for 60 seconds for a total of 35 cycles. PCR anthropometrics and body composition, tobacco smoking, product was digested by restriction enzyme Msp A1 I for 3 alcohol consumption, and physical activity. The length of the hours at 37jC, separated on 4% agarose, and visualized by menstrual cycle during which samples were collected did not ethidium bromide fluorescence under UV light. The polymor- phism was identified by digestion of the PCR fragment, There was significant variation among genotypes in mean resulting in 70- and 75-bp DNA fragments. Genotypes salivary E2 levels (F2,54 = 3.535; P = 0.036; see Table 2). The Cancer Epidemiol Biomarkers Prev 2006;15(11). November 2006 Cancer Epidemiology, Biomarkers & Prevention 2133 Table 1. Characteristics of study subjects according to CYP17 genotype Self-reported usual length of a cycle (d) NOTE: Ps derived from factorial, fixed-model, one-way ANOVA analyses.
overall interaction between the genotypes and the six-level enzyme expression (33, 34, 40-44). Apparently, transcriptional hormonal profile was significant in the univariate repeated efficacy is affected by other, still unknown factor(s).
measure ANOVA (F10,270 = 3.391; P = 0.0014 with Greenhouse- Our results should be treated as preliminary due to Geisser or P = 0.0008 with Hyun-Feldt adjustments) and relatively small sample size, especially for the A2/A2 marginally significant in the multivariate test [Wilks’ k = 0.718; genotype. The frequency of the A2/A2 genotype (13%) is degrees of freedom (df) = 10,100; P = 0.071]. Contrasts showed similar to the frequency of that genotype (14%) in the pooled that the A2/A2 genotype had significantly different six-level E2 sample of populations of European descent calculated from the profile from the A1/A1 genotype (F = 6.451; df = 5; P = 0.0001) and from the A1/A2 heterozygote (F = 4.347; df = 5; P = 0.0008).
Our study is the first which measured E2 levels in daily The heterozygote A1/A2 did not differ significantly from A1/ collected saliva samples for the entire menstrual cycle.
A1 homozygote in mean E2 profiles (F = 0.990; df = 5; Previous studies addressed the question of variation in E2 in P = 0.424). However, because in the E2 profile the heterozygote menstrual cycles by measuring E2 levels in only one or two means are numerically higher than the A1/A1 homozygote serum or urine samples collected per woman (24, 25, 27, 35-37) means on 17 of 18 days, we did a nonparametric Wilcoxon and one study had, on the average, 4.4 samples per woman signed-rank test to obtain an approximate statistical assess- (27). Due to substantial intracycle variation in E2 levels, such ment of this difference. In this test, the profiles of A1/A1 and sampling is vastly insufficient and can lead to errors in A1/A2 genotypes are significantly different at P = 0.0007 level estimating mean E2 levels for individual women.7 (T = 8; N = 18), but larger sample sizes would be required to In our study, E2 was measured in saliva reflecting free, confirm this result in parametric tests.
unbound, biologically active fraction of this hormone (45).
Mean E2 on the preovulatory day À1 varied among By contrast, E2 concentrations measured in blood samples genotypes (F2,53 = 3.56; P = 0.03). The A2/A2 genotype had are influenced by levels of sex hormone-binding globulin.
significantly higher levels of E2 than the A1/A1 genotype Sex hormone-binding globulin binds estrogens and regulates (P = 0.01) and than the A1/A2 heterozygote (P = 0.03), whereas the bioavailability of sex steroids. Sex hormone-binding heterozygote A1/A2 did not differ significantly from the A1/A1 globulin has substantial interindividual variation, with addi- tive genetic factors accounting for 68% of the total pheno-typic variation (46). Urinary measurements, used in somestudies, allow only for the assessment of E of which may be influenced by the rate of metabolic clearance,as well as genetic polymorphism in CYP1B1 or COMT Our results show that variation in the levels of E2 produced involved in the 4-hydroxylation and the O-methylation of E during menstrual cycles can be partially explained by and estrone (35). Conflicting results of the previous studies polymorphism at the CYP17 locus. Women with A2/A2 may therefore result from methodologic difficulties encoun- genotypes had 54% higher mean E2 levels than women with tered by researchers in reliable characterization of individual A1/A1 genotypes and 37% higher mean E2 levels than women who had only one A2 allele. Heterozygous A1/A2 women had We accounted for a potential influence of lifestyle variation 13 % higher E2 levels than homozygous A1/A1 women. Levels 2 levels by using selection criteria for participation and by 2 during preovulatory day were 72% higher in A2/A2 controlling for factors known to influence levels of ovarian compared with A1/A1 and 52% higher compared with A1/A2.
steroid hormones. Women in our study were in peak of Polymorphism of CYP17 gene investigated by us involves a reproductive years and in the age range (24-36 years) when single bp change T!C in the 5¶-untranslated region at 27 bp relatively little age-related variation in levels of E upstream of the start of transcription. It is still controversial if (47). They did not use steroid contraception or other steroid this substitution influences the transcription of CYP17 or medication for at least 6 months before the study. Becauselactation and postpartum period are associated with changes in sex steroids, women were not recruited unless at least 6 months elapsed since these reproductive events. All women G. Jasienska, M. Jasienski. Inter-population, inter-individual, inter-cycle, and intra-cycle natural variation in progesterone levels: quantitative assessment andimplications for population studies, submitted for publication.
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Cancer Epidemiol Biomarkers Prev 2006;15(11). November 2006

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