Our analysis demonstrates that concentration and mass of estrogens among postmenopausal control women are highly correlated and relate similarly to BMI. However, as BMI increases, total body mass of hormones rises more steeply than concentration. In contrast to relationships for estrogens, higher BMI was related only to androstenedione mass, but not to concentration. This may represent a chance finding, but could indicate that concentration and mass associations with BMI vary by analyte, reflecting differences in homeostatic mechanisms, hormone interconversions or other factors. In particular, conversion of androgens to estrogens in peripheral adipose tissue may blunt the rise in androgen concentrations relative to total body mass among heavier women.
The mathematical conversion of concentration to mass is derived from computation of body surface area and plasma volume (13
). We acknowledge that the masses of the sex steroid hormones were calculated and not measured. However, we suspect that our estimation is based on a reasonable formula and assessment using an alternative method (20
) yielded the same interpretation. Estimation of plasma volume is more strongly related to height than weight, raising the possibility that differences in body habitus might differentially influence total body mass of analytes. Recently, Baglietto et al reported that fat mass was the strongest anthropometric determinant of estradiol concentration, whereas waist circumference was the best indicator of estrone sulfate and androstenedione (2
). Given that anthropometry adds information about the variance in hormone concentrations, continued assessment of different hormone metrics may also be warranted.
Although we applied the same formula to convert hormone concentration to hormone mass for each hormone, it is plausible that relationships between BMI and these metrics might vary by analyte. Adiposity is related to both hormone metabolism and hemodilution, consistent with our finding that total body mass rises more quickly than concentration with increasing BMI. Mechanisms that maintain sex steroid hormones levels may be more closely tied to plasma concentrations, irrespective of blood volume or total body mass (11
). Furthermore, limited data suggest that hormone concentrations in blood and tissues of benign atrophic endometrium, endometrial cancer precursors and cancer are not correlated (21
). Thus, a more comprehensive understanding of hormonal biology may require simultaneous analysis of levels in multiple tissue compartments and new strategies for comparing measurements in fluids and compositionally heterogeneous solid tissues.
Biologically, the homeostatic mechanisms that control sex steroid hormone production after menopause are poorly understand and may differ among analytes. Among postmenopausal women, most androgens are produced in the adrenal cortex and to a much lesser degree in the ovaries (22
), but there may be considerable variation among women with regard to production, inter-conversion to estrogens and regulatory mechanisms. One study reported that elevated concentrations of free androgens was associated with weight gain during the menopausal transition among obese women (23
), suggesting that understanding relationships between hormone concentrations and total body hormone mass may be important. Our findings suggest the possible importance of considering concentrations in combination with other metrics in assessing such questions.
The major strengths of our study include the use of measured BMI and the availability of extensive epidemiological data and valid serum hormone measurements. However, we used a cross-sectional design with only a modest number of subjects and relatively few obese patients. We also measured serum rather than plasma hormones, but given the strong correspondence of these measurements this would be unlikely to have affected our conclusions. Finally, we estimated plasma volume from surface area rather than performing direct measurements, but this conversion has been previously validated and represents a much more feasible approach for large epidemiologic studies (13
In conclusion, we found that relationships of sex steroid hormone concentrations and mass were generally related similarly to BMI. However, there was some indication that the mass of sex steroid hormone, which accounts for obesity related hemodilution, might differentially affect relationships for certain analytes, such as androstenedione. Future prospective studies in which circulating hormones are measured at multiple time points, expressed as concentrations and masses, and compared with morphometric values may shed light on obesity, steroid hormone biology and endometrial cancer risk. Continued efforts to assess different metrics of hormone levels in multiple body compartments, including target tissues, may also contribute to increased understanding of hormonal carcinogenesis.