Postmenopausal breast cancer risk in relation to sex steroid hormones, prolactin and SHBG (Sweden)

Objective: High levels of sex steroid hormones and prolactin have been suggested to enhance breast cancer development. Low levels of SHBG may indicate high levels of (bio-available) steroid hormones. The present study investigates whether high levels of sex steroid hormones and prolactin, and/or low levels of SHBG, are associated with high breast cancer risk. Methods: Blood samples were collected in about 65,000 women participating in two population-based prospective cohort studies in Sweden. Follow-up yielded 173 postmenopausal breast cancer cases who had not been exposed to HRT. Levels of estrone, estradiol, SHBG, FSH, prolactin, testosterone, androstenedione and DHEAs were analysed in cases and 438 controls. Logistic regression analysis yielded odds ratios (ORs), with 95% confidence intervals, adjusted for potential confounders. Results: The risk of breast cancer was associated with the highest versus lowest quartiles of estrone, OR: 2.58 (1.50–4.44), estradiol (dichotomised: high versus low) (1.73: 1.04–2.88), and testosterone (1.87: 1.08–3.25). High risks, although not statistically significant, were seen for androstenedione (1.58: 0.92–2.72) and DHEAs (1.62: 0.89–2.72). No strong associations were seen between SHBG or prolactin and risk of breast cancer. Conclusions: High levels of estrone, estradiol, testosterone, and possibly androstenedione and DHEAs, in postmenopausal women are associated with a high risk of subsequent breast cancer.     

Relationships between circulating hormone levels, mammographic percent density and breast cancer risk factors in postmenopausal women

Background Endogenous hormones and insulin-like growth factors (IGF) play a central role in breast cancer development. Mammographic density, an important breast cancer risk factor, has been associated with these biomarkers in premenopausal women. The aim of this study was to assess the relationships between circulating hormones, clinical features related to breast cancer risk and mammographic density in postmenopausal women. Subjects and methods The study included 226 postmenopausal women participating in a clinical prevention trial. We performed baseline measurements of mammographic percent density and circulating levels of estradiol, sex-hormone binding globulin (SHBG), follicle stimulating hormone (FSH), prolactin, C-terminal cross-link telopeptide, IGF-I, and IGF binding protein-3. Results Median age and time since last menses were 52 years and 15 months, respectively. Median body mass index was 24.1 kg/m². After adjusting for age and body mass index, estradiol was the only biomarker significantly correlated with mammographic density (r = 0.17; P = 0.04). Women with normal body mass index had higher mammographic density (P < 0.001), higher SHBG (P < 0.0001), higher FSH (P = 0.002) and lower estradiol levels (P = 0.01) than those who were overweight. Women who had previous biopsies for benign breast disease had a higher mammographic density (P = 0.006). Conclusions In these recently postmenopausal women, mammographic percent density is directly associated with circulating estradiol levels. Our results provide further support to the role of circulating hormones in breast cancer risk.     

Racial differences in premenopausal endogenous hormones.

Differences in breast cancer incidence across racial groups are well documented. African Americans have the highest rates of premenopausal breast cancer and Asians have lower breast cancer rates across all age groups. We hypothesized that levels of premenopausal endogenous hormones and growth factors, risk factors that have been predictive of breast cancer, would differ by race. Using a cross-sectional study design, we tested this hypothesis in the Nurses' Health Study II. We assayed estradiol, progesterone, prolactin, sex hormone binding globulin (SHBG), insulin-like growth factor-I (IGF-I), and IGFBP-3 in 111 African American and 111 Asian American women, matched to 111 Caucasian women on age, day of luteal phase, and day, time, and fasting status at blood collection. We analyzed the association between race and hormone levels using robust linear regression methods. In multivariate models, compared with Caucasians, African Americans had 18% higher levels of estradiol (P < 0.01), 17% higher free estradiol (P < 0.01), 11% lower SHBG (P = 0.05), 11% higher IGF-I (P < 0.01), 25% higher free IGF-I (P < 0.01), and 9% lower IGFBP-3 (P < 0.01) levels. In multivariate models, compared with Caucasian women, Asian Americans had 22% higher calculated free estradiol (P < 0.01), 31% lower SHBG (P < 0.01), and 25% higher free IGF-I (P < 0.01) levels. No racial differences were found in progesterone and prolactin levels. Our study showed hormone differences consistent with breast cancer risk between Caucasians and African Americans but inconsistent with breast cancer risk between Asian Americans and Caucasians. Further research is needed to explore differences across racial groups and the link between endogenous hormones and breast cancer risk.     

Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies

BACKGROUND: Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women. METHODS: We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case-control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. RESULTS: The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; P(trend)<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; P(trend)<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (P(trend) =.041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis. CONCLUSION: Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women.     

Serum hormone levels in British and rural Chinese females

The comparison of blood levels of oestradiol, testosterone, prolactin, and sex-hormone binding globulin (SHBG) was made of 3250 rural Chinese and 300 British women, aged 35 to 64. To reduce the number of assays performed the blood samples were combined so as to form 390 and 30 pools, respectively.The Chinese had significantly less oestradiol and testosterone. Prolactin levels were similar in both races. SHBG was significantly lower in postmenopausal British women. In the Chinese women, testosterone was positively and prolactin negatively correlated with breast cancer mortality.     

Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women

BACKGROUND: In animal studies, prolactin has been found to be important for mammary epithelial development and its administration has been shown consistently to increase the rate of mammary tumor formation. Previous epidemiologic studies of prolactin and breast cancer risk in postmenopausal women have been limited in size, and the results have been inconsistent. We conducted a nested case-control study within the prospective Nurses' Health Study cohort to better determine the relationship between plasma prolactin levels and postmenopausal breast cancer risk. METHODS: Blood samples were collected from cohort members during the period from 1989 through 1990. Prolactin levels were measured by use of a microparticle enzyme immunoassay. Included in this analysis were 306 postmenopausal women who were diagnosed with breast cancer after blood donation but before June 1994. One or two postmenopausal control subjects were matched per case subject on the basis of age, postmenopausal hormone use, and time of day and month of blood collection; the study included a total of 448 control subjects. RESULTS: In conditional logistic regression analyses, a significant positive association was observed between plasma level of prolactin and postmenopausal breast cancer risk (highest versus lowest quartile, multivariate relative risk = 2.03; 95% confidence interval = 1.24-3.31; two-sided P for trend = .01). The relationship was independent of plasma sex steroid hormone levels and was similar after excluding case subjects diagnosed in the first 2 years after blood collection. CONCLUSIONS: These prospective data suggest that higher plasma prolactin levels are associated with an increased risk of breast cancer in postmenopausal women.     

Favorable Changes in Serum Estrogens and Other Biologic Factors After Weight Loss in Breast Cancer Survivors Who are Overweight or Obese

BackgroundObesity is associated with an increased risk for recurrence and all-cause mortality in breast cancer survivors. Excess adiposity is associated with increased estrogen, insulin, and leptin, and with decreased sex hormone binding globulin (SHBG) concentrations, which may promote breast cancer progression and recurrence. This study aimed to assess the effects of weight loss on these factors.Patients and MethodsBreast cancer survivors who were overweight or obese (n = 220) and who were enrolled in a weight loss intervention study provided baseline and follow-up blood samples and weight data. Serum estrogens, SHBG, insulin, and leptin were measured at baseline, 6 months, and 18 months.ResultsWeight loss of ≥5% of initial weight decreased leptin and insulin compared with those who did not achieve that amount of weight loss (P < .0001). Weight loss also increased SHBG at 6 and 18 months (P < .01). Postmenopausal women who lost ≥5% of body weight at 6 months had lower estrone (P = .02), estradiol (P = .002), and bioavailable estradiol (P = .001) concentrations than women who did not lose at least 5% of body weight, and weight loss at 18 months was significantly related to a change in serum bioavailable estradiol concentration (P = .02).ConclusionsFavorable changes in estrogens, SHBG, insulin, and leptin were observed in association with weight loss in these women who were overweight or obese and who had been diagnosed and treated for breast cancer. Weight loss appears to have favorable effects on hormonal and biologic factors associated with increased risk for recurrence and poorer prognosis.     

Indicators of lifetime estrogen exposure: effect on breast cancer incidence and interaction with raloxifene therapy in the multiple outcomes of raloxifene evaluation study participants.

PURPOSE: To test the hypothesis that risk factors related to lifetime estrogen exposure predict breast cancer incidence and to test if any subgroups experience enhanced benefit from raloxifene. PATIENTS AND METHODS: Postmenopausal women with osteoporosis (N = 7,705), enrolled onto the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, were randomly assigned to receive placebo, raloxifene 60 mg/d, or raloxifene 120 mg/d for 4 years. Breast cancer risk was analyzed by the following baseline characteristics indicative of estrogen exposure: previous hormone replacement therapy, prevalent vertebral fractures, family history of breast cancer, estradiol level, bone mineral density (BMD), body mass index, and age at menopause. Therapy-by-subgroup interactions were assessed using a logistic regression model. RESULTS: Overall, women with the highest one-third estradiol levels (> or = 12 pmol/L) had a 2.07-fold increased invasive breast cancer risk compared with women with lower levels. Raloxifene significantly reduced breast cancer risk in both the low- and high-estrogen subgroups for all risk factors examined (P <.05 for each comparison). The women with the highest BMD and those with a family history of breast cancer experienced a significantly greater therapy benefit with raloxifene, compared with the two thirds of patients with lower BMD or those without a family history, respectively; the subgroup-by-therapy interactions were significant (P =.005 and P =.015, respectively). CONCLUSION: The MORE trial confirms that increased lifetime estrogen exposure increases breast cancer risk. Raloxifene therapy reduces breast cancer risk in postmenopausal osteoporotic women regardless of lifetime estrogen exposure, but the reduction is greater in those with higher lifetime exposure to estrogen.     

Serum prolactin levels are positively associated with mammographic density in postmenopausal women

Background Prolactin is a polypeptide hormone that promotes normal breast proliferation and differentiation, but it is also implicated in the development and growth of mammary tumors. Mammographic density is a strong, independent predictor of breast cancer and, therefore, a potential surrogate indicator of breast cancer risk. Methods To test the hypothesis that serum prolactin is positively related to mammographic density, we conducted a cross-sectional analysis of baseline data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Mammographic Density Study. Based on prior work, we further hypothesized that this association would be apparent only in women who had not recently used postmenopausal hormone therapy (HT). Results In linear regression models adjusted for age, body mass index, race, smoking, alcohol use, parity and physical activity, among the 400 women who were not recent users of HT, prolactin was positively and statistically significantly associated with mammographic density (Beta log base 2 prolactin 0.0369 [95% CI: 0.0094–0.0645]. Thus, for each doubling of serum prolactin, there was an absolute increase in mammographic density of 3.69%. Additional adjustment for serum levels of estradiol, progesterone, sex hormone binding globulin and age at first pregnancy did not affect this result. There was no association between prolactin and mammographic density among the 169 participants who had recently used HT. Conclusion The correspondence between higher prolactin and higher mammographic density is consistent with prolactin’s mitogenic properties and the associations between prolactin and breast tumor promotion. These results support the thesis that prolactin deserves investigation as a target for breast cancer risk reduction.     

The effect of weight-loss on estimated breast-cancer risk and sex-hormone levels

The effect of weight loss on estimated breast cancer risk, sex hormone binding globulin (SHBG), total and free estradiol levels was evaluated. Increasing weight loss reduced upper body fat distribution progressively. Women with a family history of breast cancer who lost more than 7.0 kilograms decreased their estimated breast cancer risk by 25.7% while women without such a family history decreased their risk by 42.8%. A significant (P<0.001) increase in SHBG with a 4.0 to 7.4 kg weight loss was seen in both pre and postmenopausal women (P<0.05). No significant change in total or free estradiol levels was observed.     

Birthweight and body size throughout life in relation to sex hormones and prolactin concentrations in premenopausal women.

The association of birthweight and body size throughout life with premenopausal breast cancer risk may be due, in part, to relationships with sex hormones. Therefore, we assessed whether birthweight, body shape at ages 5 and 10, body mass index (BMI) at age 18 and adulthood, adult waist circumference and waist-to-hip ratio (WHR), and attained height were associated with the plasma concentrations of estrogens, androgens, progesterone, prolactin, and sex hormone-binding globulin (SHBG) in 592 premenopausal women, ages 33 to 52 years old, from the Nurses' Health Study II. About 85% of women provided blood samples during follicular and luteal menstrual phases; other women had a single untimed sample. We observed few associations between sex hormone levels and birthweight or body shape in childhood. However, adult BMI was inversely associated with SHBG (P trend < 0.001) and positively associated with free testosterone (P trend < 0.001) concentrations. Adult BMI was not associated with follicular or luteal free estradiol levels (P trend >or= 0.15) because it was inversely associated with total estradiol levels (P trend < 0.001 for follicular and luteal estradiol levels). Testosterone, androstenedione, and progesterone were inversely associated with BMI. Comparing women with a BMI of >or=30 versus <20 kg/m2, levels were higher by 53% for free testosterone and lower by 51% for SHBG, 39% for follicular estradiol, 20% for luteal estradiol, 14% for androstenedione, 13% for testosterone, and 20% for progesterone. We observed no clear associations between BMI at age 18, waist circumference, WHR, or height, and sex hormone concentrations. Our results suggest that effects on premenopausal sex hormone levels may be one mechanism through which adult adiposity, but not birthweight or childhood body size, affects premenopausal breast cancer risk.     

Circulating hormones and breast cancer risk in premenopausal women: a randomized trial of low-dose tamoxifen and fenretinide

Tamoxifen and fenretinide have been extensively studied and exhibit breast cancer-preventing activity. We aimed to assess their effect on sex hormones, sex hormone binding globulin (SHBG) and retinol, and their association with mammographic density (MD) and breast cancer events. In a double-blind, placebo-controlled trial, premenopausal women at risk for breast cancer were randomized to tamoxifen 5 mg/day, fenretinide, both agents, or placebo for 2 years. We measured MD and circulating concentrations of follicle-stimulating hormone, luteinizing hormone (LH), estradiol, progesterone, testosterone, androstenedione, dehydro-epiandrosteronesulfate, prolactin, SHBG, and retinol at baseline and on yearly intervals. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models. Low-dose tamoxifen markedly and enduringly increased SHBG, whereas the increases in testosterone, estradiol, and prolactin and reduction in LH weakened after 1 year. Fenretinide increased testosterone and androstenedione and decreased retinol. MD correlated directly with SHBG and inversely with retinol. After a median follow-up of 12 years, the 10-year cumulative incidence of breast cancer events was 37 % in women with SHBG ≤ 59.3 nmol/L, 22 % in women with SHBG between 59.3 and 101 nmol/L, and 19 % in women with SHBG > 101 nmol/L (P = 0.018). The difference among SHBG tertiles remained statistically significant at multivariable analysis: HR = 2.26 (95 % CI 1.04, 4.89) for the lowest versus the highest tertile. We conclude that low-dose tamoxifen or fenretinide exhibits favorable hormonal profiles as single agents, further supporting their administration for prevention of breast cancer in premenopause. Notably, SHBG levels were inversely associated with breast neoplastic events.     

Effect of raloxifene on insulin-like growth factor-I, insulin-like growth factor binding protein-3, and leptin in premenopausal women at high risk for developing breast cancer.

Elevated insulin-like growth factor I (IGF-I) is associated with an increased risk for developing breast cancer in premenopausal women, whereas lower leptin levels have been documented in premenopausal breast cancer cases. We determined the effect of raloxifene on IGF-I, insulin-like growth factor binding protein 3 (IGFBP-3), and leptin in premenopausal women at high risk for developing invasive breast cancer. Twenty-eight premenopausal women (median age 43 years) participating in a pilot breast cancer prevention trial provided 56 matched serum samples. Specimens were collected at baseline and after treatment with 60 mg of raloxifene daily. Median treatment duration was 3 months (range: 6 weeks to 12 months). Samples were frozen at -70 degrees C until analysis. IGF-I, IGFBP-3, and leptin were measured by ELISA. Significance was evaluated by the Wilcoxon signed rank test. Raloxifene administration increased serum IGFBP-3 [mean change 245 ng/ml; P = 0.017; 95% confidence interval (CI), 76-415] and leptin (mean change 2.1 ng/ml; P = 0.005; 95% CI, 0.6-3.7). No significant change in serum IGF-I was detected (mean change 2.6 ng/ml; P = 0.84; 95% CI, -15.4 to 20.6). IGF-I:IGFBP-3 molar ratio was stable (mean change -0.014; P = 0.30; 95% CI, -0.041 to 0.012). Raloxifene administration is associated with an increase in IGFBP-3 and leptin in premenopausal high risk women. Increases in IGFBP-3 may potentially decrease the activity of circulating IGF-I. The effect of modulating the IGF pathway and leptin on breast cancer risk needs additional evaluation.     

Endocrine status of premenopausal node-positive breast cancer patients following adjuvant chemotherapy and long-term tamoxifen

The endocrine status of 49 premenopausal women taking tamoxifen after completion of adjuvant chemotherapy for breast cancer was determined by radioimmunoassay from serial blood samples. Of these 49 women, 7 had regular menses, 14 had irregular menses, 23 were amenorrheic, and 5 had undergone hysterectomies. A group of 12 premenopausal women who had no history of breast cancer and were not taking tamoxifen served as a control group. Evidence of ovarian function (estradiol levels of greater than 100 pg/ml) was seen in 7 of 7, 9 of 14, 2 of 23, and 1 of 5 women with a clinical history of regular menses, irregular menses, amenorrhea, and hysterectomy, respectively. Supraphysiological levels of estradiol (greater than 350 pg/ml) were noted in 13 of 19 women with endocrine evidence of ovarian function. Supraphysiological progesterone levels (greater than 20 ng/ml) were also seen in 5 of 7 of the regularly menstruating women taking tamoxifen. Supraphysiological levels of estradiol were associated with elevated follicle-stimulating hormone levels, but there was no mean change in the luteinizing hormone levels. Minimum and maximum serum follicle-stimulating hormone levels were 1.9 and 9.0 mIU/ml in the 12 normal women and 5.2 and 24.3 mIU in the 13 women with supraphysiological estradiol levels. Our findings demonstrate that the majority of women who continue to menstruate while taking continuous tamoxifen following cytotoxic chemotherapy have supraphysiologic estradiol levels. This is a potential mechanism for failure of tamoxifen therapy in these premenopausal women.     

Serum C-peptide levels and breast cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)

It has been hypothesized that chronic hyperinsulinemia, a major metabolic consequence of physical inactivity and excess weight, might increase breast cancer risk by direct effects on breast tissue or indirectly by increasing bioavailable levels of testosterone and estradiol. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), we measured serum levels of C-peptide--a marker for pancreatic insulin secretion--in a total of 1,141 incident cases of breast cancer and 2,204 matched control subjects. Additional measurements were made of serum sex hormone binding globulin (SHBG) and sex steroids. Conditional logistic regression models were used to estimate breast cancer risk for different levels of C-peptide. C-peptide was inversely correlated with SHBG and hence directly correlated with free testosterone among both pre and postmenopausal women. C-peptide and free estradiol also correlated positively, but only among postmenopausal women. Elevated serum C-peptide levels were associated with a nonsignificant reduced risk of breast cancer diagnosed up to the age of 50 years [odds ratio (OR)=0.70, (95% confidence interval (CI), 0.39-1.24); ptrend=0.05]. By contrast, higher levels of C-peptide were associated with an increase of breast cancer risk among women above 60 years of age, however only among those women who had provided a blood sample under nonfasting conditions [OR=2.03, (95% CI, 1.20-3.43); ptrend=0.01]. Our results do not support the hypothesis that chronic hyperinsulinemia generally increases breast cancer risk, independently of age. Nevertheless, among older, postmenopausal women, hyperinsulinemia might contribute to increasing breast cancer risk.     

Effect of a 12-month randomized clinical trial of exercise on serum prolactin concentrations in postmenopausal women.

Prolactin is associated with an increased risk of postmenopausal breast cancer; however, few modifiable factors are known to reduce prolactin concentrations. Therefore, we examined the effect of a 12-month moderate-intensity exercise intervention on serum prolactin concentrations as a secondary end point (primary end points were estrogens and androgens). We randomly assigned 173 postmenopausal women who were sedentary, overweight (body mass index >24 kg/m(2), body fat >33%), ages 50 to 75 years, and not using hormone therapy to an exercise intervention or stretching control group. The intervention was facility- and home-based (45 min, 5 days/wk moderate-intensity sports/recreational exercise). One hundred and seventy (98%) women completed the study. Prolactin concentrations were similar at baseline (P = 0.25, geometric mean exercisers = 6.9 and controls = 7.5 ng/mL). Overall, the intervention was not associated with changes in prolactin concentrations between exercisers and controls at 3 months (P = 0.46) or 12 months (P = 0.29). The intervention effect did not vary by baseline age, body mass index, parity, or change in percent body fat during the intervention. Among exercisers, there was a significant difference in prolactin concentrations by change in fitness (VO(2)max) between baseline and 12 months. Exercisers whose VO(2)max changed by <5% had a 5% increase in prolactin concentrations, whereas those who increased their VO(2)max by 5% to 15% and >15% had a 11% (P = 0.03) and 7% (P = 0.01) decrease in prolactin concentrations, respectively. Although the exercise intervention had little effect on prolactin concentrations overall, increasing physical fitness was associated with reduced prolactin concentrations among postmenopausal women.     

Circulating Hormones and Mammographic Density in Premenopausal Women

Prior research suggests that several endogenous hormones in premenopausal women are associated with breast cancer risk; however, few studies have evaluated associations of endogenous hormones with mammographic density (MD) in premenopausal women. We conducted a cross-sectional study of plasma hormone levels in relation to MD among 634 cancer-free premenopausal women in the Nurses’ Health Study II. We measured percent MD from screening mammograms using a computer-assisted method. We assayed estradiol, estrone, and estrone sulfate in blood samples timed in early follicular and mid-luteal phases of the menstrual cycle as well as testosterone, androstenedione, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate, sex hormone–binding globulin (SHBG), and anti-Müllerian hormone in luteal or untimed samples. We used multivariable linear regression to quantify the association of %MD with quartiles of each hormone, adjusting for age, body mass index, and breast cancer risk factors. Women in the highest quartile of follicular estradiol levels had significantly greater %MD compared to those in the lowest quartile [difference, 6.7 percentage points; 95% confidence interval (CI) 2.2, 11.3; p-trend?<?0.001]. Similar associations were observed for follicular free estradiol but not luteal-phase estradiol. Also, women in the top (vs. bottom) quartile of free testosterone had significantly lower %MD (difference, ??4.7; 95% CI ??8.7, ??0.8; p-trend?=?0.04). Higher SHBG was significantly associated with higher percent MD (difference, 4.8; 95% CI 1.1, 8.6; p-trend?=?0.002). Percent MD was not strongly associated with other measured hormones. Results were similar in analyses that excluded women with anovulatory cycles. Our findings suggest that follicular estradiol and SHBG may play an important role in premenopausal percent MD.     

Estrogen and sex hormone-binding globulin levels in nulliparous and parous women

The hormone profiles of nulliparous and parous women on day 11 of their menstrual cycle have been studied in an attempt to seek evidence for the hormonal basis of the protective effect of first birth on breast cancer risk. A previous publication reported that there were significantly lower (26%) early morning prolactin levels in parous women as compared to those levels in nulliparous women but that there were no differences in plasma and urinary estrogen levels. The present study shows, however, that parous women had significantly shorter cycle lengths than nulliparous women of the same age, and the data were reevaluated with this difference being taken into account. After adjustment for cycle length (within the range of 24-32 days) and age, estrogen levels were significantly lower (22%) in parous women compared to those in nulliparous women. Two further aspects of estrogen metabolism were measured in the plasma samples of these women: the binding capacity of sex hormone-binding globulin (SHBG) and the percentage of free estradiol (E2). SHBG levels were 12% higher in parous women, but there was no difference in percentage of free E2. In the previous publication it was suggested that the protective effect of first birth on breast cancer risk was mediated in part by permanently lowering prolactin levels. The current findings suggest that changes in estrogen metabolism also are a factor.     

Plasma prolactin concentrations and risk of postmenopausal breast cancer

Prolactin is important in human breast development, and substantial laboratory and in vitro data suggest a role in mammary carcinogenesis. Therefore, we conducted a prospective case-control study nested within the Nurses' Health Study cohort to examine, in detail, the association between plasma prolactin concentrations and postmenopausal breast cancer by cancer invasiveness, estrogen receptor/progesterone receptor status, and other subject characteristics, including postmenopausal hormone use. Blood samples were collected from 1989 to 1990 and prolactin was measured by microparticle enzyme immunoassay. The analysis included 851 cases of postmenopausal breast cancer diagnosed after blood collection and before June 2000, in which there were one or two controls (n=1,275) matched on age, postmenopausal hormone use, fasting status, and time of day and month of blood collection. Prolactin was associated with a modestly increased risk of postmenopausal breast cancer [relative risk, top versus bottom quartile, 1.34; 95% confidence interval (CI), 1.02-1.76; P-trend = 0.01]. The association differed by estrogen receptor/progesterone receptor status (P-heterogeneity=0.03). The relative risk was 1.78 (95% CI, 1.28, 2.50; P-trend < 0.001) for estrogen receptor+/progesterone receptor+, 0.76 (95% CI, 0.43, 1.32; P-trend=0.28) for estrogen receptor-/progesterone receptor-, and 1.94 (95% CI, 0.99, 3.78; P-trend=0.12) for estrogen receptor+/progesterone receptor- breast cancers. Associations generally were similar for ductal and lobular carcinomas (P-heterogeneity=0.43) and by tumor size (P-heterogeneity=0.24). Among estrogen receptor+/progesterone receptor+ cancers, the association did not significantly differ by postmenopausal hormone use, years between blood draw and diagnosis, or after adjustment for estradiol (relative risk, 1.93; 95% CI, 1.16, 3.22; P-trend=0.01). Our prospective data suggest that plasma prolactin concentrations are associated with an increased risk of postmenopausal breast cancer, particularly for estrogen receptor+/progesterone receptor+ cancers, and independently of estradiol.     

Effects of parity on pregnancy hormonal profiles across ethnic groups with a diverse incidence of breast cancer.

Epidemiologic evidence suggests that a full-term pregnancy may affect maternal risk of breast cancer later in life. The objective of this cross-sectional study was to compare circulating levels of maternal hormones affecting breast differentiation (human chorionic gonadotropin and prolactin) and proliferation [alpha-fetoprotein, insulin-like growth factor I (IGF-I), and estradiol] between women at a low to moderate risk (Asians and Hispanics), as compared with women at a high risk for breast cancer (Caucasians and African-Americans). Between May 2002 and December 2004, a total of 586 pregnant women were approached during a routine prenatal visit. Among them, 450 women (206 Caucasian, 126 Asian, 88 Hispanic, and 30 African-American) met the inclusion criteria and signed the informed consent. Only singleton pregnancies were considered. Blood samples were drawn during the second trimester of pregnancy. Laboratory analyses were done using the IMMULITE 2000 immunoassay system. Gestational age standardized mean levels of estradiol, IGF-I, and prolactin were significantly higher in Hispanic women compared with Caucasian women. Mean concentration of IGF-I was significantly higher in African-American women compared with Caucasian and Asian women. No significant differences in pregnancy hormone levels were observed between Caucasian and Asian (predominantly second-generation Chinese) women in this study. Irrespective of ethnicity, women who had their first pregnancy had substantially higher mean levels of alpha-fetoprotein, human chorionic gonadotropin, estradiol, and prolactin compared with women who previously had at least one full-term pregnancy. These data suggest that circulating pregnancy hormone levels may explain some of the ethnic differences in breast cancer risk.