Influence of sex and hormone status on circulating natriuretic peptides

Abstract

Objectives: The aim of this study was to assess the relationship between sex hormones and natriuretic peptide levels in community-based adults.

Background: Women have higher circulating natriuretic peptide concentrations than men, but the mechanisms for these sex-related differences and the impact of hormone therapy are unclear. Experimental studies suggest that androgens may suppress natriuretic peptide secretion.

Methods: We measured N-terminal pro-B-type natriuretic peptide (NT-proBNP), total testosterone, and sex hormone-binding globulin plasma levels in 4,056 men and women (mean age 40 ± 9 years) from the Framingham Heart Study Third-Generation cohort. Sex/hormone status was grouped as: 1) men; 2) post-menopausal women not receiving hormone replacement therapy; 3) pre-menopausal women not receiving hormonal contraceptives; 4) post-menopausal women receiving hormone replacement therapy; and 5) pre-menopausal women receiving hormonal contraceptives.

Results: Circulating NT-proBNP levels were associated with sex/hormone status (overall p < 0.0001). Men had lower NT-proBNP levels than women of all menopause or hormone groups, and women receiving hormonal contraceptives had higher NT-proBNP levels than women who were not receiving hormone therapy (all p < 0.0001). These relationships remained significant after adjusting for age, body mass index, and cardiovascular risk factors. Across sex/hormone status groups, free testosterone (FT) levels decreased and sex hormone-binding globulin levels increased in tandem with increasing NT-proBNP levels. In sex-specific analyses, NT-proBNP levels decreased across increasing quartiles of FT in men (p for trend <0.01) and women (p for trend <0.0001). Adjustment for FT markedly attenuated the association between sex/hormone status and NT-proBNP concentrations.

Conclusions: These findings suggest that lower levels of circulating androgens and the potentiating effect of exogenous female hormone therapy contribute to the higher circulating NT-proBNP concentrations in women.

Figure 1. Classification of sex/hormone status

Flowchart illustrates the classification of sex/hormone status into: 1) Men; 2) Postmenopausal women not receiving hormone replacement therapy (HRT); 3) Premenopausal women not receiving hormonal contraceptives (HC); 4) Current HRT users; and 5) Current HC users. The age range of participants in each group is indicated in brackets.

Figure 2. Association of sex/hormone status with circulating NT-proBNP, testosterone and sex hormone-binding globulin

[A] Columns and bars represent the age-adjusted least squares means and standard errors of log NT-proBNP by sex/hormone status (1=men, 2=postmenopausal women not receiving hormone replacement therapy [HRT], 3=premenopausal women not receiving hormonal contraceptives [HC], 4=postmenopausal HRT users and 5=premenopausal HC users). P value for the association between NT-proBNP and sex/hormone status overall; for pair-wise comparisons within sex/hormone status groups please refer to the text. [B] Bivariate plot showing the age-adjusted least squares means and standard errors of log free testosterone (FT; horizontal axis) and log NT-proBNP (vertical axis) in each sex/hormone status group. [C] Bivariate plot showing the age-adjusted least squares means and standard errors of log sex hormone-binding globulin (SHBG; horizontal axis) and log NT-proBNP (vertical axis) in each sex/hormone status group.

Figure 3. Association between circulating NT-proBNP and free testosterone

Least squares means and standard errors of log NT-proBNP are shown for each sex-specific quartile (I-IV) of free testosterone (FT) in men (triangles; A) and women (circles; B) respectively.