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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.
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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.
Cancer Epidemiol Biomarkers Prev 2006;15(11). November 2006
2134 CYP17 Polymorphism and Entire Cycle Estradiol Profiles
had maintained regular menstrual cycles for at least 6 months
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Cancer Epidemiol Biomarkers Prev 2006;15(11). November 2006
1 0 2 2 3 S a w m i l l P k w y P o w e l l O H 4 3 0 6 5 We have reached October, our tenth month of our 12 month program of fitness. Our goal this month is to buy a new pair of shoes. A tennis shoe lasts 300-500 miles or at least twice a year get them re-placed. We have had many patients be more fit and reports of 18-32 lbs. lost, by participating in one of the many forms of lifestyle
A sampling of targeted integrative therapies By Aoife Earls MSc, ND I nflammatory Bowel Diseases (IBD) such as Crohn’s of energy for colonocytes and can regenerate mucosa, as well as disease (CD) and ulcerative colitis (UC) are chronic, having the capacity to reduce inflammation through enhancement relapsing-remitting inflammatory diseases with several of anti-inflammatory cytokines such