IS BREAST DENSITY RELATED TO ENDOGENOUS HORMONE LEVELS?
Breast density refers to the relative amount of radiopaque epithelial and stromal elements compared to radiolucent fatty elements. It is now well known that women with dense breasts have a 4-6-fold increase in breast cancer risk than those with more fatty replaced breasts. Breast density patterns are not new. Raul Leborgne first described breast density patterns in 1953! Over 20 years later, in 1976, John Wolfe (Wolfe) from Weymouth University described in detail breast parenchymal patterns. He noticed an increased risk of breast cancer with various mammographic patterns, most showing increased mammographic density. In the late 1980s, Breast Imaging Reporting and Data System (BI-RADS) lexicon included breast density in a separate category. In March 2019, the FDA suggested that they were considering a recommendation for an amendment requiring notification of breast density to both patients and referring healthcare professionals. In 2019, 38 states and the District of Columbia required breast density notification to referring physicians and patients.
Whereas there is little controversy regarding breast density and heightened risk of breast cancer, there is a question of whether hormonal determinates are involved in density. Enter a study by Gabrielson et al. from the Karolinska Institute. The researchers studied the association of endogenous plasma hormones and mammographic breast density (MD) and density changes over time. It is well-known that mammographic density (MD) decreases with age during breast involution. It is also interesting to note that the typical breast cancer risk factors do not strongly influence mammographic density except BMI and physical activity. However, mammographic density decreased over time during treatment with selective estrogen receptor modulators such as tamoxifen. The authors noted that no studies have thus far investigated the association between endogenous plasma hormones and natural MD change.
This study included 1040 clinically healthy controls with no prior cancer and not using hormone therapy at the time of blood sampling. At the entrance to the study, the average age of the participants was 57.9 years. Three hundred thirty-five women were premenopausal, and 705 were postmenopausal. At the beginning of the study, the average mammographic density was significantly less in postmenopausal than in premenopausal women. The researchers measured 17 different hormones from the progesterone, androgen, estrogen, and corticoid pathways. Hormone levels were generally lower in postmenopausal than premenopausal women.
The authors found that progesterone had the strongest association with MD. Estrone and prolactin were also positively associated with MD, though to a lesser degree compared to progesterone. Progesterone and MD's positive association is not surprising in that progesterone plays a significant role in both breast maturation and involution. Higher concentrations of DHEA (dehydroepiandrosterone) and deoxycortisol were inversely associated with baseline mammographic density. When the authors stratified the cohort for menopausal status, progesterone was positively associated with MD only in premenopausal women. The authors also noted that MD was positively and significantly associated with sex hormone binding globulin (SHBG) levels in both pre-and postmenopausal women.
When the authors examined MD hormonal determinates over time, they noted that an increase in hormones associated with the androgen pathway (androstenedione, testosterone, and free testosterone) was inversely associated with a reduction in mammographic density, only when adjusted for BMI, age, and physical activity. Testosterone levels in the highest third had a three times lower MD change per year compared to those with testosterone levels in the lowest third.
Additionally, researchers found that the relationship between plasma hormones and MD were non-linear. They also found that adjusting results for the menstrual cycle did not influence MD. The overall findings suggest that timing in the menstrual cycle does not influence the association between MD and endogenous progesterone concentrations. Most studies, including this one, found a positive association between SHBG (sex hormone binding globulin) and MD. In this study, SHBG levels in the top third had a 24% higher MD than those in the lowest third.
In summary, the researchers found a positive association between MD and both estrogen and more significantly with progesterone. Additionally, they found a significant positive association between SHBG and MD. Meta-analyses have suggested that high levels of SHBG are protective against breast cancer. The data from this study suggests that any influence of SHBG on breast cancer risk is likely independent of MD.