The effects of a low-fat dietary intervention and tamoxifen adjuvant therapy on the serum estrogen and sex hormone-binding globulin concentrations of postmenopausal breast cancer patients

Summary The purpose of the study was to determine the effect of a low-fat dietary intervention, with or without concomitant tamoxifen adjuvant therapy, on serum estrogen and sex hormone-binding globulin (SHBG) levels in postmenopausal patients with resected breast cancer. Ninety-three patients were randomized to either reduce their fat intake to 15–20% of total calories, or to a dietary control group. Serum estradiol, estrone, estrone sulfate, and SHBG concentrations were assayed at baseline, and at 6, 12, and 18 months thereafter. In 19% of patients, the preintervention serum estradiol levels were below the sensitivity of the assay (5 pg/ml). Tamoxifen had no significant effect on serum estrogen levels, but produced an elevation in SHBG. Patients with reliably quantifiable preintervention estradiol concentrations ( 10 pg/ml) showed a significant reduction in serum estradiol after 6 months on the low-fat diet (average, 20%; p < 0.005); this was sustained over the 18 month study period. Serum SHBG levels were increased by tamoxifen therapy, but were reduced significantly (p = 0.01) after 12 months on the low-fat diet in patients not receiving tamoxifen. No changes in serum estrone or estrone sulfate resulted from the dietary intervention. While the low-fat diet produced significant weight loss, patients treated with tamoxifen without dietary intervention showed a gain in body weight. These weight changes produced disruptions in the normal positive correlation between body weight and serum estrone sulfate, and the negative correlation with SHBG concentration.     

Serum concentrations of estrogens, sex hormone binding globulin, and androgens and risk of breast hyperplasia in postmenopausal women.

OBJECTIVE: We sought to determine whether serum concentrations of estrogens, androgens, and sex hormone binding globulin in postmenopausal women were related to the presence of mammary hyperplasia, an established breast cancer risk factor. METHODS: Study participants provided serum before breast biopsy or mastectomy in three hospitals in Grand Rapids, Michigan, between 1977 and 1987. A total of 179 subjects with breast hyperplasia were compared with 152 subjects with nonproliferative breast changes that are not associated with increased breast cancer risk. RESULTS: The odds ratios (OR) associated with the three upper quartiles of estradiol in comparison with the lowest quartile were 2.2 [95% confidence interval (95% CI) 1.1-4.6], 2.5 (95% CI, 1.1-5.3), and 4.1 (95% CI, 2.0-8.5; Ptrend = 0.007). The corresponding ORs for bioavailable estradiol, estrone, and estrone sulfate were of generally similar magnitude (Ptrend = 0.003 for bioavailable estradiol, 0.0004 for estrone, and 0.0009 for estrone sulfate). Relative to women concurrently in the lowest tertile for serum estradiol, estrone, and estrone sulfate, women concurrently in the highest tertile for all three hormones had an OR of 5.8 (95% CI, 2.2-15.2). Serum concentrations of sex hormone binding globulin, testosterone, dehydroepiandrosterone, androstenedione, and androstenediol were not associated with risk of hyperplasia. CONCLUSIONS: Serum concentrations of estrogens, but not of androgens or sex hormone binding globulin, were strongly and significantly associated with risk of breast hyperplasia in postmenopausal women, suggesting that estrogens are important early in the pathologic process towards breast cancer.     

Endogenous sex steroids in premenopausal women and risk of breast cancer: the ORDET cohort

Introduction

Previous studies showed that higher testosterone levels are associated with greater risk of breast cancer in premenopausal women, but the literature is scant and inconsistent.

Methods

In a prospective nested case-control study of 104 premenopausal women with incident breast cancer and 225 matched controls, all characterized by regular menstrual cycles throughout their lifetime, we measured the concentration of estradiol, total and free testosterone (FT), progesterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in blood samples collected on days 20 through 24 of their cycles.

Results

In logistic regression models, the multivariate odds ratios (ORs) of invasive breast cancer for women in the highest tertile of circulating FT compared with the lowest was 2.43 (95% confidence interval (95% CI), 1.15 to 5.10; P_trend = 0.03), whereas for total testosterone, the association had the same direction but was not statistically significant (OR, 1.27; 95% CI, 0.62 to 2.61; P_trend = 0.51). Endogenous progesterone was not statistically associated with breast cancer (OR, 1.16; 95% CI, 0.60 to 2.27; P_trend = 0.75), nor were the other considered hormones.

Conclusions

Consistent with previous prospective studies in premenopausal women and our own earlier investigation, we observed that higher levels of FT are positively associated with breast cancer risk in women with regular menstrual cycles throughout their lifetimes. No evidence of risk was found associated with the other endogenous sex steroids.     

Smoking is associated with postmenopausal breast cancer in women with high levels of estrogens

We investigated the association between smoking and risk of postmenopausal breast cancer in groups defined by high levels of estrogens, a factor known to enhance tumour progression. Two prospective cohorts of Swedish women provided 260 postmenopausal breast cancer cases and 514 controls. Blood samples were collected at baseline, and anthropometry, life-style factors and reproductive history had been assessed. Subjects were classified into quartiles with regard to the level of estrone, and into three categories with regard to estradiol. All analyses of the relation between smoking and breast cancer were repeated in different categories of these hormones. Logistic regression analysis, adjusted for matching factors, i.e., age at baseline, storage time and sub-cohort, yielded odds ratios (OR) with 95% confidence intervals (CI). Ever-smoking was associated with breast cancer in the top category of estrone, 2.02 (1.17-3.49). The highest risk was seen among ex-smokers, 2.96 (1.53-5.75). The pattern was similar for estradiol. Recent smoking cessation was associated with a high OR in top categories of estrone, 4.38 (1.27-15.2) and estradiol 10.0 (1.14-88.7). Smoking initiation before the age of 20 was associated with breast cancer in the top category of estrone, 2.73 (1.27-5.91). Several potential confounders were introduced into the statistical model, but none remained using backward selection. We conclude that ever-smoking was associated with the risk of breast cancer in women with high levels of estrone, and that ex-smoking was associated with breast cancer in women with high levels of estrone or estradiol.     

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies

Background:

Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood.

Methods:

Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies.

Results:

Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer.

Conclusion:

Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.     

Biological activity of anastrozole in postmenopausal patients with advanced breast cancer: effects on estrogens and bone metabolism.

BACKGROUND: To study the short-term biological effect of anastrozole on serum estrogens, androgens, 17-hydroxyprogesterone (17OH-PGR), gonadotrophins, sex hormone binding globulin (SHBG) and bone metabolism markers. MATERIALS AND METHODS: Thirty-four consecutive patients with advanced breast cancer received anastrozole 1 mg/day. Blood samples were taken before commencement of treatment and at 2, 4, 8 and 12 weeks during treatment to measure serum levels of estrogens (E(1), E(2) and E(1)-S), androgens [androstenedione (Delta(4)), dihydrotestosterone (DHT), testosterone (TST), free TST, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S)], 17OH-PGR, SHBG and gonadotrophins. As an indicator of bone resorption, we measured serum levels of C-terminal telopeptide of type I collagen (ICTP) and the cross-linked N-telopeptide of type I collagen (NTx), and for osteoblastic activity, intact osteocalcin (BGP) and bone alkaline phosphatase (BAP). RESULTS: After 2 weeks E(1 )and E(1)-S levels decreased on average by 56% (range 23.1-88.8%) and 75.8% (range 52.4-87.2%), respectively; E(2) decreased on average by 62% (range 31.4-89.6%). No significant changes were detected in levels of androgens or 17OH-PGR. There was a significant increase in gonadotrophins over time (P = 0.0001 for both luteinizing hormone and follicle-stimulating hormone), and a significant decrease in SHBG (P = 0.0001). A progressive significant increase in bone metabolism serum markers was detected in all patients: BAP, P = 0.039; BGP, P = 0.016; ICTP, P = 0.0021; and NTx, P = 0.0013. In particular, patients with bone metastases had a statistically significant increase of bone resorption markers (ICTP, P = 0.0019; NTx, P = 0.025) and borderline for bone formation markers. In patients without bone disease, BAP, BGP and ICTP remained unchanged, whereas serum NTx significantly increased (P = 0.019). CONCLUSIONS: Anastrozole is a selective aromatase inhibitor as it does not modify serum levels of androgens and 17OH-PGR. In our experience no relationship was found in the short-term period between serum estrogen suppression and bone metabolism.     

Non-contraceptive exogenous estrogens and risk of breast cancer: A review

Summary Results from epidemiologic and related studies of non-contraceptive estrogens and breast cancer are reviewed. Exogenous estrogens in high doses can enhance the risk of breast cancer. Moderate use of estrogens for menopausal symptoms probably has little effect on risk, but long-term users, and women who take high-strength preparations, appear to be at slightly increased risk. Exogenous estrogens probably reduce the protective effect of premenopausal oophorectomy, and may preferentially enhance the risk of breast cancer in women with some types of benign breast disease, although data from some studies do not support these conclusions. There is no evidence that the influence on risk of breast cancer is different for synthetic and conjugated estrogens. Needs for reanalyses of data from existing studies, and for additional investigations, are summarized. Address for Reprints: David B. Thomas, M.D., Dr.P.H., Program in Epidemiology and Biostatistics, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104, USA.     

Low‐risk factor profile,estrogen levels,and breast cancer risk among postmenopausal women

Obesity, alcohol consumption, physical inactivity and postmenopausal hormone use are known modifiable risk factors for breast cancer. We aim to measure incidence rates of breast cancer for women with favorable levels on all 4 risk factors (BMI ≤ 30 kg/m², alcohol <1 drink/week, physically active and no current hormone use) and to evaluate their associations with estrogen. The 5,054 postmenopausal women in the Copenhagen City Heart Study were asked about risk factors at baseline in 1981–3 and were followed until 2002 in the Danish Cancer Registry, with <0.1% loss to follow‐up. Estradiol was measured in a subset of 1,042 women. During follow‐up, 263 women developed breast cancer. Twenty‐six percent of the women had a favourable risk factor profile, and their breast cancer rates were markedly lower (154 per 100,000 years) than women with 3+ risk factors (460 per 100,000 years). One, two and three risk factors were associated with hazard ratios of 1.38 (95% CI: 0.99; 1.92), 1.84 (1.26; 2.67) and 2.79 (1.59; 4.88) compared to women with a favourable profile. Each of the risk factors was associated with estrogen. In conclusion, the risk of breast cancer was markedly lower for women with a favourable risk profile than for other women and lower estrogen levels is a possible explanation. © 2008 Wiley‐Liss, Inc.     

Serum and urinary androgens and risk of breast cancer in postmenopausal women

Serum levels of testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone-binding globulin and urinary levels of testosterone and androstanediol were compared in 75 women with breast carcinoma and 150 age-matched healthy controls. Odds ratios for quartiles of hormones, adjusted for known potential confounders, were computed using conditional logistic regression. Risk of breast cancer was positively associated with levels of all androgens in serum and urine but appeared stronger for testosterone (for trend, P = 0.03) and dehydroepiandrosterone sulfate (for trend, P = 0.06) in serum and for testosterone (for trend, P = 0.001) and androstanediol (for trend, P = 0.04) in urine. The adjusted odd ratios for high versus low quartiles were 2.7 (95% confidence interval, 1.1-6.5) for serum testosterone, 2.8 (1.1-7.4) for dehydroepiandrosterone sulfate, 4.7 (1.8-12.1) for urinary testosterone, and 3.4 (1.4-8.7) for urinary androstanediol. These observations suggest that endogenous androgenic hormones may play an important role in the epidemiology of postmenopausal breast cancer in women.     

Metabolic disorders and breast cancer risk (United States)

Objective: To clarify the hormonal context of breast cancer etiology we used data from a large, population-based case–control study to investigate the relationship between breast cancer risk and a history of diabetes mellitus, disorders associated with estrogen stimulation (uterine fibroids, endometriosis, gallstones), and disorders associated with androgen stimulation (acne, hirsutism, and polycystic ovaries). Methods: Breast cancer patients between 50 and 75 years old were identified from state-wide tumor registries in Wisconsin, Massachusetts, and New Hampshire; controls were randomly selected from drivers' license lists (age less than 65) or Medicare enrollment files (age 65–74). Information on reproductive history, medical history, and personal habits was obtained by telephone interview. A total of 5659 cases and 5928 controls were interviewed and provided suitable data. Results: There was no overall association between breast cancer risk and reported history of diabetes mellitus, endometriosis, uterine fibroids, gallstones, or cholecystectomy. However, the disorders with androgenic associations all conferred an increased risk: the overall odds ratio (OR) for a history of acne was 1.4 (95% CI 1.0–1.9), that for hirsutism was 1.2 (95% CI 0.81–1.8), and that for polycystic ovaries 1.6 (95% CI 0.8–3.2). Diabetes mellitus diagnosed before age 35 conferred an odds ratio of 0.52 (95% 0.25–1.1), while diabetes diagnosed at a later age was associated with an increased risk (OR = 1.2, 95% CI 1.0–1.4). Conclusions: Androgen-related phenomena are likely to be important in the etiology of breast cancer.     

Serum concentrations of IGF-I, IGFBP-3 and c-peptide and risk of hyperplasia and cancer of the breast in postmenopausal women

Experimental evidence suggests that insulin and insulin-related growth factors may play a role in breast pathology through their mitogenic and anti-apoptotic effects on breast cells. Our objective was to assess the relationship between serum concentrations of insulin-like growth factor-I (IGF-I), its major binding protein (IGFBP-3), the ratio IGF-I:IGFBP-3, c-peptide (a marker of insulin secretion) and the ratio c-peptide:fructosamine (a marker of insulin resistance) and the risk of epithelial hyperplasia (an established breast cancer risk factor) and localized breast cancer among postmenopausal women. Study subjects were patients who provided serum before breast biopsy or mastectomy in 3 hospitals in Grand Rapids, MI between 1977 and 1987. Two case groups, 186 subjects with epithelial hyperplasia of the breast and 185 subjects with localized breast cancer, were compared to 159 subjects with nonproliferative breast changes that have not been associated with increased breast cancer risk. Serum concentrations of IGF-I, IGFBP-3 and the ratio IGF-I:IGFBP-3 were not related to risk of either hyperplasia or breast cancer. For women in the highest quartile of c-peptide or of c-peptide:fructosamine compared to those in the lowest quartile, the odds ratios (ORs) for hyperplasia were 3.0 (95% confidence interval [CI] 1.4-6.5) and 3.3 (95% CI 1.5-7.3), respectively (p trend = 0.02 and 0.02, respectively). The corresponding ORs for breast cancer were 1.5 (95% CI 0.7-3.0) and 1.6 (95% CI 0.8-3.2), respectively (p trend = 0.35 and 0.25, respectively). Our results suggest that insulin and insulin resistance may play a role in breast pathology in postmenopausal women.     

Influence of plasma estrogen levels on the length of the disease-free interval in postmenopausal women with breast cancer

Summary The influence of plasma estrogen levels on disease-free interval (time from primary treatment to first relapse, DFI) in breast cancer patients is not known. Any relation between plasma estrogens and the outcome in breast cancer patients may have implications considering use of hormone replacement therapy (HRT) in patients treated for breast cancer. We measured plasma estradiol (E₂), estrone (E₁), and estrone sulfate (E₁S) in 92 postmenopausal women with breast cancer relapse and correlated plasma estrogen levels to the length of their disease-free interval (DFI₁) and the length of the DFI in the subgroup of patients in whom this extended a time period of more than 2 years (DFI₂). The length of DFI₂ correlated negatively to plasma level of E₁S (p < 0.025) and E₂ (p < 0.05) and to the E₂/E₁ and E₁S/E₁ ratios (p < 0.05), while the length of DFI₁ correlated negatively to plasma level of E₁S (p < 0.025) and the E₁S/E₁ ratio (p < 0.005). We also analyzed for possible correlations between DFIs and plasma estrogen levels in subgroups based on tumor stage at diagnosis and previous therapy. In general, these subgroup analyses revealed negative correlations of statistical significance or borderline significance between the DFI₁ and DFI₂ and E₂ and the E₂/E₁ ratio and non-significant negative correlations between plasma levels of E₁S and DFI₁ and DFI₂. In particular, strong negative correlations between plasma estrogen levels and the length of DFI₁ and DFI₂ were found among patients responding to first line endocrine treatment for relapse and among patients with primar stage III tumors. Our findings suggest plasma E₂ and E₁S to stimulate the growth of micrometastases in patients treated for breast cancer.     

Circulating estrogens and progesterone during primiparous pregnancies and risk of maternal breast cancer

Pregnancy reduces maternal risk of breast cancer in the long term, but the biological determinants of the protection are unknown. Animal experiments suggest that estrogens and progesterone could be involved, but direct human evidence is scant. A case-control study (536 cases and 1,049 controls) was nested within the Finnish Maternity Cohort. Eligible were primiparous women who delivered at term a singleton offspring before age 40. For each case, two individually matched controls by age (± 6 months) and date of sampling (± 3 months) were selected. Estradiol, estrone and progesterone in first-trimester serum were measured by high-performance liquid chromatography tandem mass spectrometry and sex-hormone binding globulin (SHBG) by immunoassay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. In the whole study population there was no association of breast cancer with any of the studied hormones. In analyses stratified by age at diagnosis, however, estradiol concentrations were positively associated with risk of breast cancer before age 40 (upper quartile OR, 1.81; CI, 1.08-3.06), but inversely associated with risk in women who were diagnosed ≥ age 40 (upper quartile OR, 0.64; CI, 0.40-1.04), p(interaction) 0.004. Risk estimates for estrone mirrored those for estradiol but were less pronounced. Progesterone was not associated with risk of subsequent breast cancer. Our results provide initial evidence that concentrations of estrogens during the early parts of a primiparous pregnancy are associated with maternal risk of breast cancer and suggest that the effect may differ for tumors diagnosed before and after age 40.     

Urinary androgens and breast cancer risk: results from a long-term prospective study based in Guernsey

Between 1961 and 1967 a cohort of over 5000 women volunteered for a prospective study to determine the relationship between the urinary androgen metabolites, androsterone (A) and aetiocholanolone (E), and risk of breast cancer. During the first 10 years of the study the concentration of urinary A and E was determined in 1887 of the urine specimens. In 1971 we reported that subnormal amounts of urinary A and E were associated with a significantly increased risk of breast cancer. The cohort has been followed regularly during the 37 years since inception of the study and, by May 1998, 248 women had been diagnosed with breast cancer. Urinary androgen metabolites had been measured in 116 of these cases. Analysis of these data confirmed that women diagnosed in the first decade of the study were more likely to have low levels of urinary androgen metabolites. In the following decades, however, those who developed breast cancer were more likely to have manifested an increased A and E excretion. The reversal in the relationship between androgen metabolite excretion and risk suggests that age, or probably more importantly, menopausal status at diagnosis is an important modifying factor. Dichotomizing at age 50 it was found that in the younger age group (predominantly premenopausal) the rate ratios in the lowest tertile of A or E excretion were two- to threefold greater than for those in the highest tertile (chi2(1) = 3.57; P = 0.06: chi2(1) = 4.70; P = 0.03 for A and E respectively). In contrast, in the older age group comprising predominantly post-menopausal women, the rate ratios associated with the lowest tertile of A or E were half that of those in the highest tertile (chi2(1) = 4.10; P = 0.04; chi2(1) = 8.72; P = 0.003 for A and E respectively). This suggests that there may be different endocrine promotional factors for pre-and post-menopausal breast cancer. Hormonal risk factors may vary during the lifetime of an individual woman and this may have profound consequences for prevention strategies.     

Serum sex hormones and breast cancer risk factors in postmenopausal women.

Postmenopausal women with elevated serum estrogens and androgens are at an increased risk of breast cancer. We evaluated associations of serum estrogen and androgen levels with age, anthropometry, and reproductive history to assess whether these characteristics could potentially modify breast cancer risk through hormonal mechanisms. A cross-sectional study was conducted among 133 postmenopausal women who donated blood to the serum bank (Columbia, MO) and served as controls in a previous prospective nested case control study of serum hormones and breast cancer risk. Standard regression methods were used to calculate adjusted means and test for trends in relationships of serum hormone concentrations with breast cancer risk factors. All analyses were performed on the log(e) scale, and all models included assay batch, date, and time of blood collection. Serum levels of estradiol, non-sex hormone binding globulin bound estradiol, estrone, estrone sulfate, and testosterone increased significantly with increasing body mass index (BMI), whereas sex hormone binding globulin levels decreased. After adjusting for BMI, nulliparous women tended to have higher testosterone levels compared with parous women (P = 0.05), but there was no evidence of a trend of decreasing testosterone with increasing parity. Dehydroepiandrosterone, its sulfate, and androstenediol decreased significantly with increasing age. Although BMI and parity could potentially modify breast cancer risk through hormonal mechanisms, age-related increases in breast cancer incidence do not appear to be mediated through changes in serum levels of the hormones evaluated.     

The relation of reported alcohol ingestion to plasma levels of estrogens and androgens in premenopausal women (Maryland,United States)

We undertook a cross-sectional study in 107 premenopausal women in Maryland (United States) of alcohol intake and hormonal status in order to evaluate whether plasma hormone levels might mediate the reported positive relation between alcohol ingestion and breast cancer risk. Alcohol ingestion was estimated using a drinking pattern questionnaire, a food frequency questionnaire, and seven-day food records. Fasting blood specimens were collected on days 5–7, 12–15, and 21–23 of each participant's menstrual cycle and pooled to create follicular, midcycle, and luteal phase samples, respectively, for analysis. Estrone, estrone sulfate, estradiol, androstenedione, and dehydropiandrosterone sulfate (DHEAS) in plasma were measured by radioimmunoassay, and sex-hormone binding globulin (SHBG) was measured by an immunoradiometric assay. After adjusting for age, weight, and total energy intake, alcohol ingestion was not associated with plasma estrogens in the follicular, midcycle, or luteal phases of the menstrual cycle, nor with the level of SHBG or DHEAS in plasma averaged from the three phases of the cycle. Alcohol, however, was significantly positively associated with the average level of plasma androstenedione. Based on these cross-sectional findings among premenopausal women, the increased risk of breast cancer related to alcohol ingestion does not appear to be mediated by elevated plasma estrogen levels. Androstenedione, however, may mediate the alcohol/breast cancer-association.Division of Cancer Prevention and Control     

The association of plasma androgen levels with breast,ovarian and endometrial cancer risk factors among postmenopausal women

Although androgens may play an etiologic role in breast, ovarian and endometrial cancers, little is known about factors that influence circulating androgen levels. We conducted a cross‐sectional analysis among 646 postmenopausal women in the Nurses' Health Study to examine associations between adult risk factors for cancer, including the Rosner/Colditz breast cancer risk score, and plasma levels of testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). All analyses were adjusted for age, laboratory batch and other cancer risk factors. Free testosterone levels were 79% higher among women with a body mass index of ≥30 vs. <22 kg/m² (p‐trend <0.01) and 25% higher among women with a waist circumference of >89 vs. ≤74 cm (p‐trend = 0.02). Consuming >30 g of alcohol a day vs. none was associated with a 31% increase in DHEA and 59% increase in DHEAS levels (p‐trend = 0.01 and <0.01, respectively). Smokers of ≥25 cigarettes per day had 35% higher androstenedione and 44% higher testosterone levels than never smokers (p‐value, F‐test = 0.03 and 0.01, respectively). No significant associations were observed for height or time since menopause with any androgen. Testosterone and free testosterone levels were ～30% lower among women with a hysterectomy vs. without (both p‐values < 0.01). Overall breast cancer risk was not associated with any of the androgens. Thus, several risk factors, including body size, alcohol intake, smoking and hysterectomy, were related to androgen levels among postmenopausal women, while others, including height and time since menopause, were not. Future studies are needed to clarify further which lifestyle factors modulate androgen levels.     

Blood concentrations of estradiol and sex hormone-binding globulin in relation to age at menarche in premenopausal British and Japanese women

In a cross-sectional study, serum estradiol (E2) and sex hormone-binding globulin (SHBG) concentrations were not significantly related to age at menarche in premenopausal British women in the luteal or follicular phases of the cycle. In Japanese subjects in the luteal phase, a marginally higher concentration of E2 was observed in those who had undergone an early rather than a late menarche. In British women, previous oral contraceptive users had significantly lower luteal phase E2 concentrations than never users.     

Birth order and breast cancer risk

It has been hypothesized that prenatal exposure to maternal estrogens may be a risk factor for breast cancer in the offspring. In two recent studies, maternal estradiol levels in the first pregnancy have been compared to those in the second, and in both studies levels were higher in the first pregnancy. If both the hypothesis and the reported findings were true, women born as their mother's second child would be expected to have lower risk for breast cancer than first-born women. Data from 1,468 cases of breast cancer and 4,175 hospital controls from three previously published studies were modelled through multiple logistic regression to evaluate this possibility. The size of the woman's sibship was not related to breast cancer risk. On the other hand, second-born women had, as predicted, lower breast cancer risk than first-born women, although the difference was nominally significant only among premenopausal women. The relative risk for breast cancer, contrasting second-born to first-born women, and the corresponding 95 per cent confidence intervals, were 0.71 (0.54–0.94) among premenopausal women, 0.94 (0.76–1.17) among postmenopausal women, and 0.86 (0.73–1.02) among all women, controlling for menopausal status.