The Association of age at Menarche and Adult Height With Mammographic Density in the International Consortium of Mammographic Density

Sarah V. Ward; Anya Burton; Rulla M. Tamimi; Ana Pereira; Maria Luisa Garmendia; Marina Pollan; Norman Boyd; Isabel dos-Santos-Silva; Gertraud Maskarinec; Beatriz Perez-Gomez; Celine Vachon; Hui Miao; Martín Lajous; Ruy López-Ridaura; Kimberly Bertrand; Ava Kwong; Giske Ursin; Eunjung Lee; Huiyan Ma; Sarah Vinnicombe; Sue Moss; Steve Allen; Rose Ndumia; Sudhir Vinayak; Soo-Hwang Teo; Shivaani Mariapun; Beata Peplonska; Agnieszka Bukowska-Damska; Chisato Nagata; John Hopper; Graham Giles; Vahit Ozmen; Mustafa Erkin Aribal; Joachim Schüz; Carla H. Van Gils; Johanna O. P. Wanders; Reza Sirous; Mehri Sirous; John Hipwell; Jisun Kim; Jong Won Lee; Caroline Dickens; Mikael Hartman; Kee-Seng Chia; Christopher Scott; Anna M. Chiarelli; Linda Linton; Anath Arzee Flugelman; Dorria Salem; Rasha Kamal; Valerie McCormack; Jennifer Stone

Disclosures

Breast Cancer Res. 2022;24(49) 

In This Article

Discussion

Within one of largest international MD studies consisting of populations with different ethnic backgrounds, we found that later age at menarche was positively associated with both per cent and absolute dense area and that increased height was positively associated with absolute dense area. Thus, the protective effect of later age at menarche on breast cancer risk is not likely mediated through MD. However, the increased risk of breast cancer associated with height could be mediated through MD, particularly DA. These results are consistent with previous findings[25] but are the first to demonstrate these associations across 22 different countries representing at least seven broad ethnic groups.

Earlier menarche is an established risk factor for breast cancer, perhaps explained by an increased number of regular menstrual cycles over the lifetime.[1,26] As the relative amounts of epithelial, stromal and adipose tissue determine the radiological appearance of the adult breast, puberty is likely a key developmental stage in the establishment of MD.[11] As increased MD is associated with increased breast cancer risk, the paradoxical positive association between later menarche and MD is not well understood. It is well established that adipose tissue deposition is needed for the onset of menarche and increased body adiposity is associated with earlier pubertal development.[27] In this study, we found that the magnitude of the association between age at menarche and PD was doubled without adjustment for BMI, whilst the DA-associated estimates remained similar. This finding highlights the importance of adjustment for BMI whenever estimating associations with PD. The estimates of association stratified by BMI were strongest (and largely driven by) women of average or below mean BMI (< = 25 kg/m2).

A recent review postulates that the timing of menarche, in terms of timing of availability of ovarian hormones, can impact breast morphology and, in turn, affect MD.[11] Women who experience a longer pubertal tempo, the time between the development of breast buds and menarche, have been shown to have increased dense area and increased breast cancer risk (independent of the age of onset of puberty).[11] The review authors concluded that prolonged exposure of breast tissue to ovarian hormones could mediate these associations but further investigations are required.

The positive association of tall stature with breast cancer risk is not completely understood but the primary hypothesized mechanism is through the role of hormones and growth factors, particularly insulin-like growth factor-1 (IGF-1) via its stimulation of bone growth, the promotion of cell proliferation and inhibition of apoptosis.[28,29] Genetic variants in the IGF pathway and circulating levels of IGF-1 have been associated with increased adult height.[2,30,31,32] A Mendelian randomization study using height-associated genetic variants (including variants in the IGF pathway) suggested that adult height was not only a risk factor for breast cancer, but that the association was causal.[2] Circulating IGF-1 has also been independently associated with an increased risk of breast cancer, although with some inconsistent results regarding the effects of menopausal status and tumour subtype.[31] Further, increased levels of IGF-1 have also been associated with increased mammographic density.[33,34] The increased production of cells in the breast due to increased IGF-1 is thought to lead to increased breast density and eventually to an increased risk of breast cancer.[33,34]

In this study, we found that increased adult height was positively associated with DA. The magnitude of the DA association was also largely independent of adjustment for BMI or age at menarche. Conversely, the association between height and PD is more complex, largely due to increased confounding and the large (expected) heterogeneity between PD and anthropometric measures across 22 international study populations. We found only marginal evidence of a positive association between PD and height but only without adjustment for BMI. Otherwise, PD was negatively associated with height. Taller women tended to have larger breasts (i.e. increased total breast area; data not shown) which may explain why increased height could be associated with lower PD.

The key strengths of this study were the large and ethnically and geographically diverse sample of women, and the comprehensive and harmonized data available across all studies. This also enabled reporting of both population- and group-specific associations, summarized using a meta-analytic approach, as well as overall associations estimated from the pooled individual-level data. The results were largely consistent using both approaches and for both mammographic measures (PD and DA), although the height–PD association depended upon the degree of body size adjustment. This suggests that the results are generalizable to women in populations worldwide.

There are limitations inherent in using existing data that were collected from multiple studies. In this case, this included some evidence of differences in associations with height when stratified by type of measurement (self-reported or measured), introducing a potential source of bias that needs to be taken into account when considering results. Previous studies that have shown the heritability of height vary depending on whether the height data were measured or self-reported.[35] Conversely, other studies have found high correlations between self-reported and measured height and weight in the same individuals, suggesting that the potential for bias may be minimized.[36] Unfortunately, we do not have self-reported and measured height and weight in the same individuals in the ICMD, which would be required to accurately assess the degree of bias. Adjustment for other anthropometric measures such as waist-to-hip ratio and percentage of body fat also warrant future investigation. A further complexity arises given measures of height vary with age. Adult height reflects the body's linear growth, and maximum adult height is achieved in a woman's adolescent or early adult years.[37,38] However, height measured in later life, especially during post-menopausal ages, includes a degree of shrinkage. A further potential source of bias is therefore introduced depending on the age at which height was measured in each study.

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