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Endogenous hormones in the etiology of ovarian and endometrial cancers
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The main purpose of this thesis was to examine the relationship of pre-diagnostic circulating levels of sex-steroids (androgens and estrogens), sex hormone binding globuline (SHBG), insulin-like growth factor-I (IGF-I), IGF binding proteins (BP) and C-peptide (as a marker of pancreatic insulin secretion) with risk of ovarian and endometrial cancer. Additionally, the interrelationships of body mass index (BMI), sex-steroids, IGF-I and IGFBP-3 were examined. Two case-control studies were nested within 3 prospective cohort studies centered in New York (USA), Umeå (Sweden) and Milan (Italy). The ovarian study included 132 cancer cases. The endometrial study included 166 cancer cases in the IGF-I and C-peptide component and 124 postmenopausal cases in the sex-steroids component. For each case, two controls matching the case for cohort, age, menopausal status and date at recruitment were selected. In total 286 and 315 controls were included in the ovarian and endometrial cancer studies, respectively. Odds ratios (OR) and their 95% confidence intervals (CI) for cancer risk associated with increasing hormone concentrations were estimated by conditional logistic regression. The cross-sectional analysis was based on anthropometric and hormonal data from 620 controls selected for the two nested case-control studies. There was no association of prediagnostic androstenedione, testosterone, DHEAS, SHBG or estrone with ovarian cancer risk in the whole study population or in women who were pre- or postmenopausal at blood donation. In the premenopausal group, risk appeared to increase with increasing androstenedione (OR (95% CI) for the highest tertile: 2.35 (0.81-6.82), p=0.12). There was no association of IGF-I, IGFBP-1, 2, 3 or C-peptide concentrations with risk of ovarian cancer risk in the study group as a whole. In analyses restricted to subjects who had developed ovarian cancer at an early age (<55), circulating IGF-I was directly and strongly associated with risk (OR (95% CI): 4.74 (1.20-18.7), p<0.05 for the highest IGF-I tertile). In the endometrial study, previous observations were confimed that elevated circulating estrogens and androgens and decreased SHBG increase risk of developing endometrial malignancy after menopause. Multivariate ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels were: 4.13 (1.76-9.72), p<0.001 for estradiol; 3.67 (1.71-7.88), p=0.001 for estrone; 2.15 (1.05-4.40), p<0.04 for androstenedione; 1.74 (0.88-3.46), p=0.06 for testosterone; 2.90 (1.42-5.90), p<0.01 for DHEAS and 0.46 (0.20-1.05), p<0.01 for SHBG. Prediagnostic IGF-I, IGFBP-1, -2 and –3 were not related to risk of endometrial cancer in the whole study population. In postmenopausal women, levels of IGFBP-1 were inversely related to risk with an OR for the highest quartile of 0.36 (0.13-0.95), p<0.05. Endometrial cancer risk increased with increasing levels of C-peptide (p<0.01), up to an OR of 4.40 (1.65-11.7) for the highest quintile after adjustment for BMI and other confounders. The cross-sectional analyses showed that in both pre- and postmenopausal women SHBG decreased with increasing BMI. In the postmenopausal group, estrogens, testosterone and androstenedione increased with BMI, while the association with IGF-I was non-linear, the highest mean IGF-I concentration being observed in women with BMI between 24 and 25. In postmenopausal women, IGF-I was positively related to androgens, inversely correlated with SHBG, and was not correlated with estrogens. In conclusion, elevated pre-diagnostic sex-steroids, IGF-I or C-peptide increase risk of developing ovarian and endometrial cancer. BMI influences the circulating levels of these hormones, especially after menopause.

Place, publisher, year, edition, pages
2004. , 100 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 878
Keyword [en]
Public health, ovarian cancer, endometrial cancer, sex-steroid hormones, sex-hormone binding globulin, insulin-like growth factor-I, insulin-like growth factor bidning proteins, C-peptide
Keyword [sv]
Folkhälsomedicin
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-215ISBN: 91-7305-612-X (print)OAI: oai:DiVA.org:umu-215DiVA: diva2:142685
Public defence
2004-04-16, Hörsal E04, By 6E, Norrlands universitetssjukhus, Umeå, 09:00
Opponent
Supervisors
Available from: 2004-03-23 Created: 2004-03-23 Last updated: 2010-08-06Bibliographically approved
List of papers
1. Circulating levels of sex steroid hormones and risk of ovarian cancer.
Open this publication in new window or tab >>Circulating levels of sex steroid hormones and risk of ovarian cancer.
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2003 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 104, no 5, 636-642 p.Article in journal (Refereed) Published
Abstract [en]

Experimental and epidemiological evidence supports a role for sex steroid hormones in the pathogenesis of ovarian cancer. We investigated the association between ovarian cancer risk and pre-diagnostic blood concentrations of testosterone, androstenedione, DHEAS, estrone and SHBG. A case-control study nested within 3 cohorts, in New York (USA), Umeå (Sweden) and Milan (Italy), included 132 subjects with primary invasive epithelial ovarian cancer. For each case subject, 2 controls were selected who matched a case on cohort, menopausal status, age and date of recruitment and, if premenopausal, day of the menstrual cycle at blood donation. Only women who did not use exogenous hormones at blood donation were included in the study. Conditional logistic regression was used to relate cancer risk to sex steroid hormone concentrations with adjustment for potential confounders. No clear association was observed between ovarian cancer risk and any of the 5 hormones under study. In the premenopausal group, the risk appeared to increase with increasing blood concentrations of androstenedione (upper vs. lower tertile OR = 2.35; 95% CI = 0.81-6.82.), but the small number of subjects in the sub-group precluded reaching unambiguous conclusions about such association. Our study does not support previous observations relating elevations in blood levels of the major sex steroid hormones to an increased risk of ovarian cancer, but offers some evidence that elevated circulating androstenedione before menopause may be associated with increased ovarian cancer risk.

Keyword
testosterone, androstenedione, DHEAS, estrone, SHBG, sex steroid hormones, ovarian cancer, cohort study
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-35183 (URN)10.1002/ijc.10990 (DOI)12594820 (PubMedID)
Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
2. Circulating levels of insulin-like growth factor-I and risk of ovarian cancer.
Open this publication in new window or tab >>Circulating levels of insulin-like growth factor-I and risk of ovarian cancer.
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2002 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 101, no 6, 549-554 p.Article in journal (Refereed) Published
Abstract [en]

Insulin-like growth factor (IGF)-I, a mitogenic and anti-apoptotic peptide, has been implicated in the development of several cancers. We hypothesized that high circulating IGF-I concentrations may be associated with an increased risk of ovarian cancer. A case-control study was nested within 3 prospective cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). One hundred thirty-two women with primary invasive epithelial ovarian cancer diagnosed at least 1 year after blood donation were case subjects. For each case, 2 control subjects were selected, matching the case subject on cohort, menopausal status, age and date of recruitment (n = 263). Only women who did not use exogenous hormones at blood donation were included in the study. There was no association between IGF-I concentrations and ovarian cancer risk in the study group as a whole. In analyses restricted to subjects who had developed ovarian cancer at a young age (<55), circulating IGF-I was directly and strongly associated with ovarian cancer risk (OR = 4.97; 95% CI = 1.22-20.2 for the top vs. the bottom IGF-I tertile after adjustment for parity, BMI categories and smoking). There was no significant association of IGF binding protein-3 with ovarian cancer risk. We found a strong direct relationship between circulating IGF-I levels and risk of developing ovarian cancer before age 55. Additional, larger studies of this association are needed to provide more precise estimates of effect.

Keyword
insulin-like growth factor-I, insulin-like growth factor binding protein-3, ovarian cancer, cohort study
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-35184 (URN)10.1002/ijc.10613 (DOI)12237896 (PubMedID)
Available from: 2010-08-06 Created: 2010-08-06 Last updated: 2017-12-12Bibliographically approved
3. Risk of ovarian cancer in relation to prediagnostic levels of C-peptide, insulin-like growth factor binding proteins-1 and -2 (USA, Sweden, Italy).
Open this publication in new window or tab >>Risk of ovarian cancer in relation to prediagnostic levels of C-peptide, insulin-like growth factor binding proteins-1 and -2 (USA, Sweden, Italy).
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2003 (English)In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 14, no 3, 285-292 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To investigate the association of prediagnostic circulating levels of C-peptide, as a marker of pancreatic insulin secretion, and IGF binding proteins -1 and -2, as indicators of the biologically active IGF-I concentration, with risk of developing ovarian cancer. METHODS: The study was nested within three prospective cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). Case subjects were 132 women with primary invasive epithelial ovarian cancer diagnosed at least one year after blood donation. For each case, two control subjects were selected, matching the case subject on cohort, menopausal status, age and date of recruitment (n = 263). Only women who did not use exogenous hormones at blood donation were included in the study. RESULTS: Odds ratios and their 95% confidence intervals for risk of developing ovarian cancer over quartiles of peptides concentrations after adjustment for BMI and fasting were: 1.00, 0.66 (0.35-1.23), 0.96 (0.51-1.82) and 0.89 (0.44-1.81) for C-peptide; 1.00, 1.10 (0.58-2.09), 1.07 (0.55-2.04) and 0.79 (0.38-1.62) for IGFBP-1; and 1.00, 1.01 (0.54-1.89), 0.98 (0.51-1.88) and 0.87 (0.45-1.68) for IGFBP-2. In women who had ovarian cancer diagnosis before age 55 the ORs for the top tertiles of IGFBP-1 and IGFBP-2 were 0.51 (0.18-1.49) and 0.53 (0.18-1.54), respectively. CONCLUSIONS: This study does not support an independent direct etiological role of C-peptide in ovarian cancer pathogenesis, but suggests a possible protective effect of circulating IGFBP-1 and -2 in women who develop ovarian cancer before age 55.

Keyword
C-peptide, cohort study, insulin-like growth factor binding protein-1 and -2, ovarian cancer
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-35185 (URN)10.1023/A:1023688603547 (DOI)12814208 (PubMedID)
Available from: 2010-08-06 Created: 2010-08-06 Last updated: 2017-12-12
4. Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women.
Open this publication in new window or tab >>Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women.
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2004 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 108, no 3, 425-432 p.Article in journal (Refereed) Published
Abstract [en]

Experimental and epidemiological data support a role for sex steroid hormones in the pathogenesis of endometrial cancer. The associations of pre-diagnostic blood concentrations of estradiol, estrone, testosterone, androstenedione, DHEAS and SHBG with endometrial cancer risk were investigated. A case-control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). Cases were 124 postmenopausal women with invasive endometrial cancer. For each case, 2 controls were selected, matching the case on cohort, age and date of recruitment. Only postmenopausal women who did not use exogenous hormones at the time of blood donation were included. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated by conditional logistic regression. ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels, relative to the lowest were as follows: 4.13 (1.76-9.72), p(trend) = 0.0008 for estradiol, 3.67 (1.71-7.88), p(trend) = 0.0007 for estrone, 2.15 (1.05-4.40), p(trend) = 0.04 for androstenedione, 1.74 (0.88-3.46), p(trend) = 0.06 for testosterone, 2.90 (1.42-5.90), p(trend) = 0.002 for DHEAS and 0.46 (0.20-1.05), p(trend) = 0.01 for SHBG after adjustment for body mass index, use of oral contraceptives and hormone replacement therapy. The results of our multicenter prospective study showed a strong direct association of circulating estrogens, androgens and an inverse association of SHBG levels with endometrial cancer in postmenopausal women. The effect of elevated androstenedione and testosterone levels on disease risk seems to be mediated mainly through their conversion to estrogens, although an independent effect of androgens on tumor growth cannot be ruled out, in particular in the years close to diagnosis.

Keyword
Estradiol, estrone, testosterone, androstenedione, DHEAS, SHBG, endometrial cancer, cohort study
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-15447 (URN)10.1002/ijc.11529 (DOI)14648710 (PubMedID)
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2017-12-14Bibliographically approved
5. Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer.
Open this publication in new window or tab >>Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer.
Show others...
2004 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 108, no 2, 262-268 p.Article in journal (Refereed) Published
Abstract [en]

Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF-I and decreased levels of IGF-binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre-diagnostic blood concentrations of C-peptide (a marker of pancreatic insulin production), IGF-I, IGFBP-1, -2 and -3 with endometrial cancer risk. A case-control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C-peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91-11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65-11.7)]. IGFBP-1 levels were inversely related to endometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15-0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in the upper quintile = 0.49 (0.22-1.07)]. Risk was unrelated to levels of IGF-I, IGFBP-2 and IGFBP-3. Chronic hyperinsulinemia, as reflected by increased circulating C-peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer.

Keyword
C-peptide, insulin-like growth factor-I, insulin-like growth factor binding proteins, endometrial cancer, cohort study
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-15439 (URN)10.1002/ijc.11544 (DOI)14639613 (PubMedID)
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2017-12-14Bibliographically approved
6. Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women.
Open this publication in new window or tab >>Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women.
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2004 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 150, no 2, 161-171 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGF-binding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3. DESIGN AND METHODS: A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre- and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk. RESULTS: In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre- and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed. CONCLUSIONS: These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-35186 (URN)14763914 (PubMedID)
Available from: 2010-08-06 Created: 2010-08-06 Last updated: 2017-12-12

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