Abstract
Objective:
The aim of the study was to quantify baseline estradiol (E2) and estrone (E1) concentrations according to selected patient characteristics in a substudy nested within the MAP.3 chemoprevention trial.
Methods:
E2 and E1 levels were measured in 4,068 postmenopausal women using liquid chromatography-tandem mass spectrometry. Distributions were described by age, years since menopause, race, body mass index (BMI), smoking status, and use and duration of hormone therapy using the Kruskal-Wallis test. Multivariable linear regression was also used to identify characteristics associated with estrogen levels.
Results:
After truncation at the 97.5th percentile, the mean (SD)/median (IQR) values for E2 and E1 were 5.41(4.67)/4.0 (2.4–6.7) pg/mL and 24.7 (14.1)/21 (15–31) pg/mL, respectively. E2 and E1 were strongly correlated (Pearson correlation [r] = 0.8, P < 0.01). The largest variation in E2 and E1 levels was by BMI; mean E2 and E1 levels were 3.5 and 19.1 pg/mL, respectively for women with BMI less than 25 and 7.5 and 30.6 pg/mL, respectively, for women with BMI greater than 30. E2 and E1 varied by age, BMI, smoking status, and prior hormone therapy in multivariable models (P < 0.01).
Conclusions:
There was large interindividual variability observed for E2 and E1 that varied significantly by participant characteristics, but with small absolute differences except in the case of BMI. Although the majority of participant characteristics were independently associated with E1 and E2, together, these factors only explained about 20% of the variation in E1 and E2 levels.
Keywords: Estradiol, Estrone, Postmenopausal women
Synthesized in the ovaries, estradiol (E2) is the primary form of estrogen in premenopausal women, with average levels ranging from 15 to 300 pg/mL. After menopause, however, estrone (E1) is the primary form of estrogen and the main source of E2 in postmenopausal women is via the conversion of androgenic precursors androstenedione and testosterone to E1 and E2, respectively, and occurs in peripheral tissue, including adipose tissue. In postmenopausal women, E2 and E1 levels drop to less than 15 and 7 to 40 pg/mL, respectively in plasma concentrations determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).1
Total lifetime estrogen exposure is associated with breast cancer risk and disease recurrence in both pre- and postmenopausalwomen.2–5Surrogate markers of estrogen exposure including reproductive history and age at menopause have been included in some risk models,6,7 but ideally serum hormone levels should be quantified directly during risk assessment. To date, however, measures of E2 and E1 can be highly variable in postmenopausal women, hampered, in part, by suboptimal measurement methods including automated immunoassays, that can have low sensitivity and can lead to misclassification.8 Non-standardized methods for measuring estrogen have prevented the establishment of reference ranges for E2 and E1. More recently, methods with increased sensitivity, that is, LC-MS/MS have been used to detect estrogen concentrations at low picomolar levels, in postmenopausal women,9 especially those on aromatase inhibitors (AIs), for breast cancer prevention or treatment.10
We conducted a cohort study nested within the MAP.3 breast cancer chemoprevention trial,11 to determine baseline (pre) and on-treatment (post) estrogen levels (E2 and E1) by LC-MS/MS in healthy women treated with exemestane or placebo for up to 5 years. The primary MAP.3 trial results were published in 201111 demonstrating the efficacy of exemestane to reduce the incidence of invasive breast cancer by 65% compared to placebo. Collection of baseline and follow-up blood samples was protocol mandated. Following the primary analysis of MAP.3, the NCI Division of Cancer Prevention provided support for the analyses of estrogen in MAP.3 serum samples, at the Mayo Clinic. Given the growing interest in the standardization of hormone measurements (CDC Hormone Standardization Project [HoSt], 2017)12 and establishing reference values for E2 and E1 in postmenopausal women,13 we also examined baseline estrogen levels in MAP.3 participants according to characteristics that have been associated with estrogen concentrations in prior studies, including age, years since menopause, race, body mass index (BMI), smoking status, and use and duration of hormone therapy (HT).
METHODS
Study population
The MAP.3 chemoprevention trial (NCT00083174) was conducted by the Canadian Cancer Trials Group. MAP.3 was an international, multicenter, double-blind, placebo-controlled, phase III randomized trial that aimed to assess the use of exemestane for breast cancer prevention purposes in 4,560 postmenopausal women.11 The primary endpoint of the trial was incidence of invasive breast cancer. Women were eligible to participate in the MAP.3 trial if they were older than 50 years of age with no menses within the past 12 months or if they were 50 years of age or younger and had follicle-stimulating hormone levels within the postmenopausal range. In addition, women must have had at least one of the following breast cancer risk factors: age 60 years or older, Gail risk score greater than 1.66,5 or prior history of benign breast disease. Women who used HT were included in the study if they agreed to discontinue use at least 3 months before randomization.
This current study was nested within the MAP.3 trial and included a cohort of women who provided serum at baseline for analysis of estrogen (n = 4,068). Baseline information on sociodemographic and lifestyle characteristics, and reproductive and medical history including family history of breast cancer was collected by study nurses who also collected anthropometric measures (height and weight). BMI was calculated as weight (kg)/height2 (m2). Women self-identified their ethnicity/race, selecting from seven possible categories: white, African American, Hispanic, Native American, Asian, Pacific Islander, and other. Due to small numbers in the nonwhite categories, race was eventually categorized as white, African American, Asian, and others. Age at menopause was based on the youngest age at which the participant experienced any of the following: no spontaneous menses more than 12 months or age at bilateral oophorectomy. Information on history of HT use, including start and end dates was collected at baseline. Several questions were used to compute the smoking history variable. Women who reported smoking less than 100 cigarettes in their lifetime were considered nonsmokers. Among women who had smoked more than 100 cigarettes in their lifetime, those who provided a start date and reported that they were still consuming tobacco were classified as current smokers, whereas women who reported quitting tobacco with an end date were classified as former smokers.
Estrone and estradiol assays
Participants provided a blood sample at their MAP.3 baseline visit, before allocation to protocol therapy. Blood was processed within 2 hours, and serum was aliquoted and stored at −80°C. Serum samples were sent to the Mayo Clinic where both E2 and E1 levels were measured using Clinical Laboratory Improvement Amendments-approved LC-MS/MS. Pre- and post-AI treatment E1 and E2 levels were measured by Clinical Laboratory Improvement Amendments-approved LC-MS/MS assays in the Immunochemical Core Laboratory at Mayo Clinic. Details of the methodology have been published else- where,9 but in brief, the lower limit of quantification for E1 was 1.0 and 0.3 pg/mL for E2. Intra-assay coefficients of variation (CVs) for E1 were 17.8%, 7.5%, and 6.1% at 0.30, 0.50, and 0.84 pg/mL, respectively. Intra-assay CVs for E2 were 11.8%, 7.3%, and 6.0% at 0.23, 0.50, and 0.74 pg/mL, respectively. Interassay CVs for E1 were 12.0%, 9.5%, and 7.9% at 0.25, 0.51, and 0.85 pg/mL, respectively. Interassay CVs for E2 are 10.8%, 8.5%, and 6.9% at 0.29, 0.50, and 0.77 pg/mL, respectively. Measures under the lower limit of quantification were assigned half the detection limit.Extreme values (outliers) were kept in the analysis but assigned the value truncated at the 97.5th centile (n = 97 E1; n = 98 E2).
Statistical analysis
The means and standard deviations (SD), medians, and interquartile ranges were computed for E2 and E1 and compared according to the following characteristics: age, years since menopause, race, BMI, smoking history, prior HT use and duration of HT use using the Kruskal-Wallis test. A Pearson correlation coefficient was used to assess correlation between E1 and E2 serum concentrations. We evaluated the association between participant characteristics and E2 and E1 levels in separate bivariable and multivariable linear regression models. In these regression analyses, participants with missing data were excluded from each model. P values derived from the t test and the 95% confidence intervals were used to determine statistical significance of each characteristic; the coefficient of determination (R2) was used to quantify the variability explained in E1 and E2 by each characteristic. The final models for E2 and E1 included age, race, BMI (continuous), smoking status, and prior HT use. Years since menopause and HT duration were not included because of concerns of collinearity with age and HT use, respectively. In multivariable analyses, participants with missing values for any of the included covariates (n=44 participants) were excluded from the analyses. The analysis was performed using SAS version 9.4 (SAS Institute, Cary, NC).
RESULTS
Approximately 90% of the MAP.3 study population (4,068/4,560) provided baseline serum samples that were evaluable for E2 and E1 analyses. Figure 1 represents a participant flow diagram for the selection of the study sample of the 4,068 women with baseline serum samples. A total of 4,066 women had baseline samples that were included in the analyses for E2 and 4,064 baseline samples that were included in the E1 analyses. The mean age of the cohort of women was 66 years and the mean duration since menopause was 18 years with approximately 10% transitioning through menopause less than 5 years before study entry. The majority of participants were white (93%) and were overweight or obese (71%). Approximately half (53%) of the women had never smoked and 40% had never used HT (Table 1). Participant characteristics of this study population (n = 4,068) were similar to the distribution of the main trial (n = 4,560) participant characteristics.11
FIG. 1.
Consort diagram.
TABLE 1.
Baseline participant characteristics in the MAP.3 estrogen substudy
| Characteristics (N=4,068) | N (%)/mean (SD) |
|---|---|
| Sociodemographic factors | |
| Age, y | |
| <50 | 37 (0.9) |
| 50-<59 | 888 (21.8) |
| 60-<74 | 2,482 (61.0) |
| ≥75 | 661 (16.3) |
| Mean (continuous) | 65.7 (8.6) |
| Duration since menopause, y | |
| <5 | 425 (10.4) |
| 5–10 | 813 (20.0) |
| >10 | 2,818 (69.3) |
| Missing | 12 (0.3) |
| Mean (continuous) | 17.7 (11.2) |
| Race | |
| White | 3,793 (93.2) |
| African American | 192 (4.7) |
| Asian | 60 (1.5) |
| Other | 11 (0.3) |
| Missing | 12 (0.3) |
| Lifestyle factors | |
| Body mass index (BMI) | |
| Normal (<25 kg/m2) | 1,154 (28.4) |
| Overweight (25–29 kg/m2) | 1,393 (34.2) |
| Obese (>29 kg/m2) | 1,506 (37.0) |
| Missing | 15 (0.4) |
| Mean (continuous) | 29.0 (6.1) |
| Tobacco smoking | |
| Never smoker | 2,171 (53.4) |
| Former smoker | 1,624 (39.9) |
| Current smoker | 256 (6.3) |
| Missing | 17 (0.4) |
| Previous hormone therapy (HT) use | |
| Previous HT user | 2,473 (60.8) |
| HT nonuser | 1,595 (39.2) |
| Hormone therapy duration | |
| Nonuser | 1,595 (39.2) |
| <24 mo | 517 (12.7) |
| 24-<72 mo | 725 (17.8) |
| 72-<132 mo | 598 (14.7) |
| ≥ 132 mo | 625 (15.4) |
| Missing | 8 (0.2) |
The distributions for E2 and E1 were both highly right skewed (Figs. 2 and 3). The mean concentration of E2, before truncation at the 97.5th centile, was 6.6 pg/mL (SD=16.5 pg/mL). More than 97% of the cohort had E2 levels less than 23 pg/mL. After truncation, the mean concentration of E2 was 5.4 (SD=4.7). The mean concentration of E1, before truncation at the 97.5th centile, was 25.4 pg/mL (SD=17.7 pg/mL). More than 97% of the cohort had E1 levels less than 68 pg/mL. After truncation at the 97.5th centile, the mean concentration of E1 was 24.7 (SD=14.1). The two forms of estrogen were strongly correlated with a Pearson correlation coefficient (r) of 0.80 (P < 0.01).
FIG. 2.
Distribution of estradiol concentrations. Arrow indicates the extreme observations (outliers) above 97.5 percentile that were assigned values at the 97.5 percentile.
FIG. 3.
Distribution of estrone concentrations. Arrow indicates the extreme observations (outliers) above 97.5 percentile that were assigned values at the 97.5 percentile.
In the bivariable analyses, E2 and E1 varied significantly (P < 0.01) by age, years since menopause, race, BMI, smoking status, and prior HT use/HT duration (Tables 2 and 3). The largest variation in E2 and E1 levels was by BMI; mean E2 and E1 levels were 3.5 and 19.1 pg/mL, respectively for women with BMI less than 25 and 7.5 and 30.6 pg/mL respectively, for women with BMI more than 30.
TABLE 2.
Baseline estradiol levels by selected participant characteristics (n = 4,066)
| Characteristics (n) | Mean [SD], pg/mL | Median, pg/mL | IQR | Pa |
|---|---|---|---|---|
| Age | <0.01 | |||
| <50 y (37) | 7.3 [6.9] | 4.8 | 2.6–11.0 | |
| 50-<59 y (888) | 5.7 [5.6] | 3.8 | 2.3–6.6 | |
| 60-<74 y (2,481) | 5.2 [4.4] | 4.0 | 2.4–6.6 | |
| ≥75 y (660) | 5.6 [4.2] | 4.5 | 2.7–7.4 | |
| Duration since menopause | <0.01 | |||
| <5 y (425) | 6.4 [6.3] | 4.1 | 2.4–7.6 | |
| 5–10 y (812) | 5.0 [4.5] | 3.7 | 2.2–5.9 | |
| >10 y (2,817) | 5.4 [4.4] | 4.1 | 2.5–6.9 | |
| Race (Pa < 0.01) | <0.01 | |||
| White (3,791) | 5.3 [4.7] | 4.0 | 2.4–6.6 | |
| African American (192) | 7.0 [4.7] | 6.1 | 3.6–9.2 | |
| Asian (60) | 4.2 [4.2] | 3.5 | 1.9–5.0 | |
| Other (11) | 4.4 [3.7] | 3.2 | 1.6–7.0 | |
| Body mass index (BMI) (Pa<0.01) | <0.01 | |||
| Normal (<25 kg/m2) (1,154) | 3.5 [3.8] | 2.6 | 1.5–3.9 | |
| Overweight (25–29 kg/m2) (1,391) | 4.7 [3.8] | 3.8 | 2.4–5.5 | |
| Obese (>29 kg/m2) (1,506) | 7.5 [5.1] | 6.2 | 4.0–9.5 | |
| Tobacco smoking | < 0.01 | |||
| Never smoker (2,170) | 5.6 [4.8] | 4.2 | 2.5–7.0 | |
| Former smoker (1,623) | 5.1 [4.4] | 3.8 | 2.3–6.4 | |
| Current smoker (256) | 5.5 [4.9] | 4.1 | 2.3–6.6 | |
| Previous hormone therapy (HT) use | <0.01 | |||
| Previous HT user (2,472) | 5.1 [4.1] | 3.9 | 2.3–6.4 | |
| HT nonuser (1,594) | 6.0 [5.4] | 4.2 | 2.5–7.3 | |
| Hormone therapy duration | <0.01 | |||
| Nonuser (1,594) | 6.0 [5.4] | 4.2 | 2.5–7.3 | |
| <24 mo (517) | 5.8 [4.7] | 4.3 | 2.7–7.4 | |
| 24-<72 mo (724) | 4.9 [3.9] | 4.0 | 2.3–6.1 | |
| 72-<132 mo (598) | 5.1 [4.1] | 4.2 | 2.5–6.5 | |
| ≥132 mo (625) | 4.6 [3.9] | 3.4 | 2.1–5.8 |
Kruskal-Wallis test for significance.
TABLE 3.
Baseline estrone (E1) levels by selected participant characteristics (n=4,064)
| Characteristics (n) | Mean [SD], pg/mL | Median, pg/mL | IQR | Pa |
|---|---|---|---|---|
| Age | <0.01 | |||
| <50 y old (37) | 27.6 [16.8] | 23.0 | 16.0–35.0 | |
| 50-<59 y old (888) | 23.5 [13.9] | 20.0 | 14.0–29.0 | |
| 60-<74 y old (2,479) | 24.5 [14.0] | 21.0 | 14.0–31.0 | |
| ≥75 y old (660) | 26.7 [14.6] | 24.0 | 16.0–35.0 | |
| Duration since menopause | <0.01 | |||
| <5 y (425) | 25.0 [14.7] | 21.0 | 15.0–30.0 | |
| 5–10 y (813) | 23.0 [13.4] | 20.0 | 14.0–28.0 | |
| >10 y (2,814) | 25.1 [14.2] | 22.0 | 15.0–32.0 | |
| Race | <0.01 | |||
| White (3,790) | 24.5 [14.1] | 21.0 | 14.0–31.0 | |
| African American (192) | 30.1 [15.2] | 28.5 | 19.0–38.0 | |
| Asian (59) | 20.9 [10.7] | 18.0 | 14.0–27.0 | |
| Other (11) | 19.4 [9.9] | 21.0 | 9.2–23.0 | |
| Body mass index (BMI) | <0.01 | |||
| Normal (<25 kg/m2) (1,151) | 19.1 [10.8] | 17.0 | 12.0–24.0 | |
| Overweight (25–29 kg/m2) | 22.9 [12.3] | 20.0 | 14.0–28.0 | |
| (1,392) | ||||
| Obese (>29 kg/m2) (1,506) | 30.6 [15.6] | 28.0 | 19.0–39.0 | |
| Tobacco smoking | <0.01 | |||
| Never smoker (2,170) | 25.1 [14.2] | 22.0 | 15.0–31.0 | |
| Former smoker (1,622) | 23.7 [13.8] | 20.0 | 14.0–30.0 | |
| Current smoker (255) | 26.9 [14.4] | 23.0 | 16.0–34.0 | |
| Previous hormone therapy (HT) use | <0.01 | |||
| Previous HT user (2,471) | 23.6 [13.4] | 21.0 | 14.0–30.0 | |
| HT nonuser (1,593) | 26.3 [15.0] | 23.0 | 15.0–33.0 | |
| Hormone therapy duration | <0.01 | |||
| Nonuser (1,593) | 26.3 [15.0] | 23.0 | 15.0–33.0 | |
| <24 mo (517) | 25.2 [14.1] | 23.0 | 15.0–32.0 | |
| 24-<72 mo (724) | 23.8 [13.0] | 21.0 | 14.0–30.0 | |
| 72-<132 mo (598) | 23.7 [13.3] | 21.0 | 14.0–29.0 | |
| ≥132 mo (624) | 22.2 [13.3] | 19.0 | 13.0–28.0 |
Kruskal-Wallis test for significance.
Multivariable linear regression models (Table 4) for E2 and E1 included age, race, BMI, smoking status, and prior HT use. Combined, age, race, BMI, smoking status, and prior HT use explained 22% and 20% of the variability in the E2 and E1 regression models, respectively, based on the coefficient of determination (R2) of the models. BMI was modeled as a continuous variable in the regression models and was the strongest predictor of E2 and E1 concentration levels; BMI alone explained the most variability in the E2 (20%) and E1 (17%) models. None of the other predictors had an R2 greater than 1% in bivariate analyses. For every 1 kg/m2 increase in BMI, the mean E2 and E1 levels increased by 0.34 (P < 0.01) and 0.95 pg/mL (P < 0.01), respectively. In general, increasing age was associated with lower levels of E2 and E1. Women who identified as African American had significantly higher E1 (2.3 pg/mL, P = 0.02) and E2 (0.65 pg/mL, P=0.04) levels compared to white women and former smokers and women who had previously used HT had significantly (P < 0.01) lower E2 and E1 levels compared to never smokers and non-HT users, respectively.
TABLE 4.
Baseline estrogen levels and association with selected participant characteristics from multivariate analysesa
| Estradiol (E2) | Estrone (E1) | |||||
|---|---|---|---|---|---|---|
| Characteristics | N | Mean difference (P)b | 95% CI | n | Mean difference (P)a | 95% CI |
| Sociodemographic factors | ||||||
| Age, y | ||||||
| <50 | 37 | Reference | — | 37 | Reference | — |
| 50-<59 | 876 | −1.29 (0.064) | −2.66 to 0.08 | 876 | −3.09 (0.148) | −7.28 to 1.10 |
| 60-<74 | 2,459 | −1.68 (0.015) | −3.03 to −0.33 | 2,457 | −1.55 (0.463) | −5.69 to 2.59 |
| ≥75 | 650 | −1.10 (0.119) | −2.48 to 0.28 | 650 | 1.42 (0.512) | −2.82 to 5.65 |
| Race | ||||||
| White | 3,761 | Reference | — | 3,760 | Reference | — |
| African American | 190 | 0.65 (0.038) | 0.04–1.26 | 190 | 2.26 (0.018) | 0.39–4.13 |
| Asian | 60 | −0.15 (0.781) | −1.21 to 0.91 | 59 | −1.09 (0.516) | −4.38 to 2.20 |
| Other | 11 | −1.85 (0.141) | −4.31 to 0.61 | 11 | −8.19 (0.0033) | −15.73 to −0.65 |
| Lifestyle factors | ||||||
| BMI, kg/m2 | 4,022 | 0.34 (<0.001) | 0.32–0.36 | 4,020 | 0.95 (<0.001) | 0.88–1.01 |
| Tobacco use | ||||||
| Never smoker | 2,155 | Reference | — | 2,155 | Reference | — |
| Former smoker | 1,612 | −0.49 (<0.001) | −0.76 to −0.22 | 1,611 | −1.40 (<0.001) | −2.22 to −0.57 |
| Current smoker | 255 | 0.15 (0.585) | −0.39 to 0.69 | 254 | 2.86 (<0.001) | 1.19–4.52 |
| Prior HT use | ||||||
| HT nonuser | 1,575 | Reference | — | 1,574 | — | |
| Prior HT user | 2,447 | −0.74 (<0.001) | −1.01 to −0.47 | 2,446 | −2.80 (<0.001) | −3.64 to −1.96 |
BMI, body mass index; HT, hormone therapy.
All variables are included in the multivariable models simulataneously.
Least squares estimate and t test for significance.
DISCUSSION
Postmenopausal estrogen levels have been recently characterized by various case-control studies and randomized controlled trials (RCTs) using LC-MS/MS. Average E2 and E1 concentrations obtained from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (n=423),19 the National Cancer Institute’s Biological Markers Project (n = 215),20 range between 6.0 and 9.8 and 23.7 and 106.2 pg/mL, respectively. The Laboratory Corporation of America provides a list of laboratory reference ranges when interpreting laboratory values.1 For postmenopausal women, the E2 range is less than 10 pg/mL and the E1 range is 7 to 40 pg/mL. In this population of healthy postmenopausal women at elevated risk for breast cancer, the average E2 level was less than 10 pg/mL, whereas the average E1 concentration was less than 30 pg/mL, in keeping with previous literature based on LC-MS/MS assays.19,20 These values are, however, considerably lower than the average E2 levels of less than 25 pg/mL and E1 levels of less than 60 pg/mL observed in women after menopause, based on well-validated radioimmunoassay methods, which may be less specific than the LC-MS/MS method, especially at low concentrations, typically observed in postmenopausal women.21
Large interindividual variability was observed, and E2 and E1 concentrations varied significantly by selected sociodemographic and lifestyle factors, although most absolute differences were small. E2 and E1 levels differed most profoundly by BMI. The relationship between adiposity and sex steroid hormones has been previously reported in several studies,14–18 some of which were nested within the Nurses’ Health Study16 or the Women’s Health Initiative.18 The majority of these studies were small (n<500), included women who had recently transitioned to menopause, and used immunoassays to quantify E2 and E1 levels in postmenopausal women. All but one,14 observed a positive relationship between increasing adiposity and increasing estrogen concentrations. Our results in a population of more than 4,000 women who had transitioned an average of 10 years earlier to menopause, support the observation that BMI is an important predictor of circulating E2 and E1 levels.
E1 levels also differed substantially by race, and in the multivariable analysis, E1 concentrations were significantly higher in African American women compared to white women, controlling for age, BMI, smoking status, and prior HT use. Although average E2 concentrations were marginally higher in African American women compared to white women, the difference was not statistically significant, potentially due to study power, given the small proportion of nonwhite women in MAP.3. Controlling for BMI may also have attenuated the effect of race on E2 concentrations.
In the final multivariable regression models, BMI explained the majority of the variation in E2 and E1 levels, and while statistically significant, age, race, smoking status, and prior HT use explained very little additional variation of estrogen levels. Strengths of this study include the large study population of postmenopausal women, who transitioned through menopause more than a decade ago, robust data collection with minimal missing data, and analysis of serum samples with LC-MS/MS, a highly sensitive measurement assay for postmenopausal levels of E2 and E1.
An important limitation of this study was the inability to measure precursors of estrogen formation in peripheral tissue, including androstenedione and testosterone concentrations and E1 sulfate and E2 sulfate levels, which could shed additional light on the interindividual differences observed in this study. Differences in the clearance of estrogens may also be influenced by genetic factors that could affect metabolic reactions. For instance, various mutations in the aromatase gene (CYP19), the gene responsible for the conversion of androgens into estrogens, have been found to lead to aromatase insufficiency22 or excess.23 Modified aromatase activity in postmenopausal women results in lower or higher than average estrogen levels. Genome-wide association studies have also found that single nucleotide polymorphisms in the CYP19,24,25 estrogen receptor,26 sex hormone binding globulin,24 and TSPYL527 genes influence circulating estrogen levels in postmenopausal women. The uridine 5’-diphospho–glucuronosyltransferase gene is also known to catalyze the metabolism of steroid hormones such as testosterone and xenobiotics, including AIs, used in the prevention and treatment of breast cancer.28–30 In a study population of premenopausal and postmenopausal women who never used HT, a double delection in the UGT2B17 genotype was associated with higher femoral and lumbar spine bone density,29 which is typically a marker of higher levels of serum estrogen.28
CONCLUSIONS
Large interindividual variability in E2 and E1 was observed and varied significantly by participant characteristics, but with small absolute differences except in the case of BMI.
Funding/support:
This study was supported in part by NIH (NCI) grants P50CA116201 (Mayo Clinic Breast Cancer Specialized Program of Research Excellence) and QUE-182363 (Subaward to Queen’s University).
Footnotes
Presented, in part, at The North American Menopause Society Workshop on Normal Ranges for Estradiol in Postmenopausal Women, Chicago, IL, September 23, 2019.
Financial disclosure/conflicts of interest: None reported.
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