Mais la polymyxine n'est pas du tout absorbée dans le sang du système gastro-intestinal et n'a d'effet que dans l'intestin et est utile pour le traitement des infections intestinales metronidazole prix Internet en y faisant des achats permettant d’économiser jusqu'à soixante-dix pour cent, tout en étant sûr de la qualité des produits pharmaceutiques.
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.
Access the most recent version of this article at:
This article cites by 61 articles, 25 of which you can access for free at:
This article has been cited by 2 HighWire-hosted articles. Access the articles at:
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
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.
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
18. Ellison PT, Lager C. Moderate recreational running is associated with
lowered salivary progesterone profiles in women. Am J Obstet Gynecol1986;154:1000 – 3.
Levels of ovarian steroid hormones produced in menstrual
19. Lager C, Ellison PT. Effect of moderate weight loss on ovarian function
cycles are both important determinants of fecundity (5, 48) and
assessed by salivary progesterone measurements. Am J Hum Biol 1990;2:
are related to risk of several diseases, especially in post-
menopausal years (8). Cumulative lifetime levels of sex-steroid
20. Bullen BA, Skrinar GS, Beitins IZ, von Mering G, Turnbull BA, McArthur
JW. Induction of menstrual disorders by strenuous exercise in untrained
hormones are implicated in development of hormone-
women. N Engl J Med 1985;312:1349 – 53.
dependent cancers (1-4). Due to individual differences in
21. Pirke KM, Schweiger V, Lemmel W, Krieg JC, Berger M. The influence of
exposure to factors modifying genetic levels of E2, however,
dieting on the menstrual cycle of healthy young women. J Clin Endocrinol
a relationship between CYP17 genetic polymorphism and risk
of breast cancer may not be detectable. Several studies tested
22. De Souza MJ, Miller BE, Loucks AB, et al. High frequency of luteal phase
deficiency and anovulation in recreational women runners: blunted
the relationship between CYP17 polymorphism and risk of
elevation in follicle-stimulating hormone observed during luteal-follicular
breast cancer (23, 37, 42, 49-59), but results are conflicting.
transition. J Clin Endocrinol Metab 1998;83:4220 – 32.
The existence of genetic variation underling variation in
23. Haiman CA, Hankinson SE, Spiegelman D, et al. Relationship between a
polymorphism in CYP17 with plasma hormone levels and breast cancer.
2 does not preclude the importance of other factors.
Well documented is the influence of lifestyle on sex-steroid
24. Feigelson HS, Shames LS, Pike MC, Coetzee GA, Stanczyk FZ, Henderson
levels, especially factors related to availability of metabolic
BE. Cytochrome P450c17a gene (CYP17) polymorphism is associated with
energy during fetal and adult life (11, 12, 14-22, 60-62). Future
serum estrogen and progesterone concentrations. Cancer Res 1998;58:585 – 7.
studies should investigate a relationship between environ-
25. Small CM, Marcus M, Sherman SL, Sullivan AK, Manatunga AK, Feigelson
HS. CYP17 genotype predicts serum hormone levels among pre-menopausal
mental effects and genetic polymorphism in CYP17 from the
women. Hum Reprod 2005;20:2162 – 7.
perspective of genotype-environment interactions. In addition,
26. Sharp L, Cardy AH, Cotton SC, Little J. CYP17 gene polymorphisms:
interactive effects of other genes involved in estrogen
prevalence and associations with hormone levels and related factors. A
metabolic pathways, such as CYP19, COMT, CYP1A1,
HuGE review. Am J Epidemiol 2004;160:729 – 40.
SRD5A2, and HSD17B, should be studied to account for
27. Lurie G, Maskarinec G, Kaaks R, Stanczyk FZ, Le Marchand L. Association
of genetic polymorphisms with serum estrogens measured multiple times
potential epistatic interactions among genetic loci.
during a 2-year period in premenopausal women. Cancer EpidemiolBiomarkers Prev 2005;14:1521 – 7.
28. Tworoger SS, Chubak J, Aiello EJ, et al. Association of CYP17, CYP19,
CYP1B1, and COMT polymorphisms with serum and urinary sex hormone
We thank the women who participated in this study, Dr. Susan F.
concentrations in postmenopausal women. Cancer Epidemiol Biomarkers
Lipson who oversaw the steroid measurements, and students of the
Faculty of Public Health, Jagiellonian University who worked as
29. Brentano ST, Picadoleonard J, Mellon SH, Moore CCD, Miller WL. Tissue-
specific, cyclic adenosine 3¶,5¶-monophosphate-induced, and phorbol ester-repressed transcription from the human P450c 17 promoter in mouse cells.
Mol Endocrinol 1990;4:1972 – 9.
30. Sasano H, Okamoto M, Mason JI, et al. Immunolocalization of aromatase,
17-a-hydroxylase and side-chain-cleavage cytochromes P-450 in the humanovary. J Reprod Fertil 1989;85:163 – 9.
Henderson BE, Feigelson HS. Hormonal carcinogenesis. Carcinogenesis
31. Hanukoglu I. Steroidogenic enzymes—structure, function, and role in
regulation of steroid-hormone biosynthesis. J Steroid Biochem Mol Biol
Pike MC, Spicer DV, Dahmoush L, Press MF. Estrogens, progestogens,
normal breast cell proliferation, and breast cancer risk. Epidemiol Rev 1993;
32. Puche C, Jose M, Cabero A, Meseguer A. Expression and enzymatic activity
of the P450c17 gene in human adipose tissue. Eur J Endocrinol 2002;146:
Jasienska G, Thune I, Ellison PT. Energetic factors, ovarian steroids and the
risk of breast cancer. Eur J Cancer Prev 2000;9:231 – 9.
33. Kristensen VN, Haraldsen EK, Anderson KB, et al. CYP17 and breast cancer
Ellison PT. Reproductive ecology and reproductive cancers. In: Panter-Brick
risk: the polymorphism in the 5¶ flanking area of the gene does not influence
C, Worthman CM, editors. Hormones, Health, and Behavior A socio-
binding to Sp-1. Cancer Res 1999;59:2825 – 8.
ecological and lifespan perspective. Cambridge: Cambridge University
34. Lin CJ, Martens JWM, Miller WL. NF-1C, Sp1, and Sp3 are essential for
transcription of the human gene for P450c17 (steroid 17 a-hydroxylase/17,20
Lipson SF, Ellison PT. Comparison of salivary steroid profiles in naturally
lyase) in human adrenal NCI-H295A cells. Mol Endocrinol 2001;15:1277 – 93.
occurring conception and non-conception cycles. Hum Reprod 1996;11:
35. Garcia-Closas M, Herbstman J, Schiffman M, Glass A, Dorgan JF. Relation-
ship between serum hormone concentrations, reproductive history, alcohol
Jasienska G, Ziomkiewicz A, Gorkiewicz M, Pajak A. Body mass, depressive
consumption, and genetic polymorphisms in pre-menopausal women. Int J
symptoms, and menopausal status: an examination of the ‘‘jolly fat’’
hypothesis. Womens Health Issues 2005;15:145 – 51.
36. Travis RC, Churchman M, Edwards SA, et al. No association of
Solomon CG, Hu FB, Dunaif A, et al. Menstrual cycle irregularity and
polymorphisms in CYP17, CYP19, and HSD17 – 1 with plasma estradiol
risk for future cardiovascular disease. J Clin Endocrinol Metab 2002;87:
concentrations in 1,090 British women. Cancer Epidemiol Biomarkers Prev
Barrett-Conor E, Bush TL. Estrogen and coronary heart disease in women.
37. Hong CC, Thompson HJ, Jiang C, et al. Association between the T27C
polymorphism in the cytochrome P450 c17 a (CYP17) gene and risk factors
Riggs BL, Khosla S, Melton LJ. Sex steroids and the construction and
for breast cancer. Breast Cancer Res Treat 2004;88:217 – 30.
conservation of the adult skeleton. Endocr Rev 2002;23:279 – 302.
38. Berstein LM, Imyanitov EN, Kovalevskij AJ, et al. CYP17 and CYP19 genetic
10. Ellison PT, Lipson SF, O’Rourke MT, et al. Population variation in ovarian
polymorphisms in endometrial cancer: association with intratumoral
function. Lancet 1993;342:433 – 4.
aromatase activity. Cancer Lett 2004;207:191 – 6.
11. Jasienska G, Ziomkiewcz A, Lipson SF, Thune I, Ellison PT. High ponderal
39. Lai J, Vesprini D, Chu W, Jernstrom H, Narod SA. CYP gene polymorphisms
index at birth predicts high estradiol levels in adult women. Am J Hum Biol
and early menarche. Mol Genet Metab 2001;74:449 – 57.
40. Carey AH, Chan KL, Short F, White D, Williamson R, Franks S. Evidence for
12. Jasienska G, Lipson S, Ellison P, Thune I, Ziomkiewicz A. Symmetrical
a single gene effect causing polycystic ovaries and male pattern baldness.
women have higher potential fertility. Evol Hum Behav 2006;27:390 – 400.
Clin Endocrinol (Oxf) 1993;38:653 – 8.
13. Nunez-De-la Mora A, Chatterton RT, Choudhury O, Napolitano D,
41. Kadonaga JT, Carner KR, Masiarz FR, Tijian R. Isolation of CDNA-encoding
Hochman J, Bentley GR. Developmental effects on salivary progesterone
transcription factor Sp1 and functional-analysis of the DNA-binding
levels in migrant Bangladeshi women. Am J Hum Biol 2003;15:277 – 7.
14. Jasienska G, Ellison PT. Energetic factors and seasonal changes in ovarian
42. Ambrosone CB, Moysich KB, Furberg H, et al. CYP17 genetic polymor-
function in women from rural Poland. Am J Hum Biol 2004;16:563 – 80.
phism, breast cancer, and breast cancer risk factors. Breast Cancer Res 2003;
15. Jasienska G, Ellison PT. Physical work causes suppression of ovarian
function in women. Proc R Soc Lond B Biol Sci 1998;265:1847 – 51.
43. Miyoshi Y, Ando A, Ooka M, et al. Association of CYP17 genetic
16. Jasienska G, Ziomkiewicz A, Ellison PT, Lipson SF, Thune I. Large breasts
polymorphism with intra-tumoral estradiol concentrations but not with
and narrow waists indicate high reproductive potential in women. Proc R
CYP17 messenger RNA levels in breast cancer tissue. Cancer Lett 2003;195:
Soc Lond B Biol Sci 2004;271:1213 – 7.
17. Jasienska G, Ziomkiewicz A, Thune I, Lipson SF, Ellison PT. Habitual
44. Hou LF, Xu JF, Gao YT, et al. CYP17 MspA1 polymorphism and risk of
physical activity and estradiol levels in women of reproductive age. Eur J
biliary tract cancers and gallstones: a population-based study in Shanghai,
China. Int J Cancer 2006;118:2847 – 53.
Cancer Epidemiol Biomarkers Prev 2006;15(11). November 2006
Cancer Epidemiology, Biomarkers & Prevention 2135
45. Riad-Fahmy D, Read GF, Walker RF, Walker SM, Griffiths K. Determination
54. Spurdle AB, Chen X, Hopper J, et al. CYP17 promoter polymorphism and
of ovarian-steroid hormone levels in saliva—an overview. J Reprod Med
breast cancer in Australian women under forty years of age. Am J Hum
46. Ring HJZ, Lessov CN, Reed T, et al. Heritability of plasma sex hormones and
55. Huang CS, Chern HD, Chang KJ, Cheng CW, Hsu SM, Shen CY. Breast
hormone binding globulin in adult male twins. J Clin Endocrinol Metab
cancer risk associated with genotype polymorphism of the estrogen-
metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on
47. Lipson SF, Ellison PT. Normative study of age variation in salivary
cancer susceptibility. Cancer Res 1999;59:4870 – 5.
progesterone profiles. J BioSoc Sci 1992;24:233 – 44.
56. Mitrunen K, Jourenkova N, Kataja V, et al. Steroid metabolism gene CYP17
48. Baird DD, Wilcox AJ, Weinberg CR, et al. Preimplantation hormonal
polymorphism and the development of breast cancer. Cancer Epidemiol
differences between the conception and non-conception menstrual cycles of
32 normal women. Hum Reprod 1997;12:2607 – 13.
57. Bergman-Jungestrom M, Gentile M, Lundin AC, Wingren S. Association
49. Wu AH, Seow A, Arakawa K, Van Den Berg D, Lee HP, Yu MC. HSD17B1
between CYP17 gene polymorphism and risk of breast cancer in young
and CYP17 polymorphisms and breast cancer risk among Chinese women in
women. Int J Cancer 1999;84:350 – 3.
Singapore. Int J Cancer 2003;104:450 – 7.
58. Dunning AM, Healey CS, Pharoah PDP, et al. No association between a
50. Feigelson HS, Coetzee GA, Kolonel LN, Ross RK, Henderson BE. A
polymorphism in the steroid metabolism gene CYP17 and risk of breast
polymorphism in the CYP17 gene increases the risk of breast cancer. Cancer
cancer. Br J Cancer 1998;77:2045 – 7.
59. Weston A, Pan CF, Bleiweiss IJ, et al. CYP17 genotype and breast cancer risk.
51. Onland-Moret NC, van Gils CH, Roest M, Grobbee DE, Peeters PHM.
Cancer Epidemiol Biomarkers Prev 1998;7:941 – 4.
Cyp17, urinary sex steroid levels and breast cancer risk in postmenopausal
60. Kapiszewska M, Miskiewicz M, Ellison PT, Thune I, Jasienska G. High tea
women. Cancer Epidemiol Biomarkers Prev 2005;14:815 – 20.
consumption diminishes salivary 17h-estradiol concentration in Polish
52. Shin MH, Lee KM, Yang JH, et al. Genetic polymorphism of CYP17 and
women. Br J Nutr 2006;95:989 – 95.
breast cancer risk in Korean women. Exp Mol Med 2005;37:11 – 7.
61. Panter-Brick C, Ellison P. Seasonality of workloads and ovarian function in
53. Miyoshi Y, Iwao K, Ikeda N, Egawa C, Noguchi S. Genetic polymorphism in
Nepali women. Ann N Y Acad Sci 1994;709:234 – 5.
CYP17 and breast cancer risk in Japanese women. Eur J Cancer 2000;36:
62. Ibanez L, Potau N, Enriquez G, De Zegher F. Reduced uterine and ovarian size
in adolescent girls born small for gestational age. Pediatr Res 2000;47:575 – 7.
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