In this study we report the cross-sectional and longitudinal associations of sex hormones with WHR in a large multi-ethnic population. We principally focused on WHR as an anthropometric measure of central obesity because it has been shown in meta-analyses to be much more strongly associated with prevalent coronary atherosclerosis,19
and as strongly associated with incident diabetes24
when compared to waist circumference or BMI.
In both men and women, higher levels of E2 are associated with larger baseline and follow-up WHR measures. Adjustment for SHBG does not affect the associations of E2 with WHR. This is the first study showing such a strong association of baseline E2 with the longitudinal changes in WHR in a large age range of postmenopausal women, and extends the observation in the immediate postmenopausal period reported for the POAS study.14
The strong cross sectional association we found is consistent with those reported in the Women’s Ischemia Syndrome Evaluation study,25
where there was an independent association of both BMI and waist circumference with E2 levels.
It has been suggested that an androgenic state per se may be associated with greater cardiovascular risk factors in women while the opposite may be true in men.26–28
Though our cross-sectional findings for WHR are consistent with the above studies, when we consider the continued association over the trajectory of WHR over time, such an association was found only in men but not women. Further, in men, the longitudinal association of baseline T levels with WHR was explained by metabolic factors and SHBG levels. The significant cross-sectional associations are only partially explained by the correlation of T with SHBG levels, and remain significant when T was adjusted for SHBG, suggesting that the association is not with the T that is carried tightly bound to SHBG. Our observation of the increasing obesity over follow-up in men with lower SHBG at baseline is consistent with the results from the Massachusetts Male Aging Study that showed an increasing incidence of newly detected metabolic syndrome in men with lower SHBG.29
Also consistent with the metabolic syndrome associations seen in that study, in our analysis, higher SHBG levels at baseline were associated with lower WHR during follow-up, after accounting for WHR at baseline.
Previous cross sectional studies show that obesity is associated with lower levels of free and bioavailable testosterone (T) and sex hormone binding globulin (SHBG) in men.7
In women, SHBG has also been shown to be lower in obese women while testosterone levels are higher9
, and estradiol (E2) has been shown to be higher in overweight or obese women.10
Our study confirms and extends the results of published longitudinal studies. Previous studies show an association between lower SHBG levels and obesity measured 12–15 years after baseline hormone measurements, larger WHR being associated with lower androgens in men,27
but not women,28
though these studies did not assess change in WHR. Recent results from the Massachusetts Male Aging study show that greater baseline obesity, and greater increases in obesity over time, was associated with a greater decrease in androgens, presumably linked to a greater decrease in SHBG.11, 12
In younger men aged 24 to 31 yrs at the time of first hormone measurement, the change in BMI over 8 yrs of follow-up modified the relationships of age with change in SHBG and total T but not bioavailable T.13
It has been shown that among obese men, a decrease in weight achieved by a very low energy diet increases SHBG and total testosterone levels.30
While some studies of weight loss trials in obese adolescent girls31
and amenorrhic women32
have reported reductions in androgens, and population based studies in pre and perimenopausal women have reported the strong longitudinal association of SHBG with obesity, and inconsistent relationships with testosterone levels,15–17
ours is the first study reporting longitudinal WHR findings in a population-based sample of postmenopausal women.
SHBG, in addition to its role as a sex hormone transporter, is thought to modulate sex hormone actions through its membrane bound receptor.33
The secretion of SHBG from the liver is sensitive to nutritional status.34
Insulin is known to suppress the secretion of SHBG in vitro35
and may do so in vivo.36
SHBG levels have been shown to be associated with insulin sensitivity rather than insulin secretion during glucose challenge.37
Consistent with this, we found that the association of SHBG with WHR is much attenuated on adjustment for glucose levels and further by adjustment for the insulin sensitivity measure QUICKI. However in all models, SHBG remains significantly associated with WHR, with the exception of the cross-sectional association in men. In this observational study, it cannot be determined whether this is due to mediation of insulin sensitivity in a mechanistic pathway between SHBG and WHR. However, the residual association of SHBG suggests an independent role for SHBG, by the mechanisms discussed above. In this longitudinal epidemiologic cohort study, insulin sensitivity was assessed by QUICKI, which only uses fasting blood sample measures and not more accurate but invasive and burdensome methods such as insulin and glucose clamps. It is therefore possible that there may be residual confounding by insulin sensitivity.
It is likely that measures of abdominal adiposity track sex hormone levels throughout life. Studies have shown that among young men aged 24–31 years who lost weight over 8 years there was a steep age-related increase in SHBG levels, while among those that gained weight there was an age-related decrease in T levels.13
Our results assess these associations later in the lifespan, showing that that among men 45–84 years of age, those with higher SHBG and T at baseline continue to have lower WHR as they age.
Our study raise some interesting, though not definitive, hypotheses regarding the association of the levels of the adrenal sex steroid DHEA with WHR. In our analysis, the associations of DHEA roughly paralleled those of T, and were attenuated in models adjusting for T. Adjustment for E2, on the other hand, accentuated the parallelism between T and DHEA, especially in men. This suggests that insofar as DHEA levels correlated with T, it was associated with lower WHR in men, and longitudinally in women, but insofar as DHEA levels correlated with E2, they were associated with higher WHR. DHEA is metabolized peripherally both into androgenic hormones including T and estrogenic hormones, including E2, and is thus expected to be correlated with both T and E2. Future studies that include measurements of intermediate metabolites of DHEA may provide more insight into these possibilities.
Another interesting hypothesis raised is whether exogenous hormones may also have effects on central obesity in the direction on the observed associations with endogenous hormones. However, these questions can only be definitively answered in controlled intervention studies.
The longitudinal nature of this multi-center study with rigorous anthropometric measurements, with adequate representation of both men and women, is a significant strength of this study. The large sample size and availability of many measured variables allowed for statistical adjustment of multiple possible confounders and exploration of different mediator variables. A potential weakness is the availability of sex hormones only at the baseline visit, which precludes assessing any changes in sex hormone levels that may have accompanied changes in abdominal adiposity. Further, levels of estrone, the major estrogen in postmenopausal women, were not available in MESA. However, we analyzed the levels of E2, the more potent circulating endogenous estrogen. Further, the cross-sectional associations of estrone and E2 with waist circumference have been shown to be similar in another study.25
Thus we believe that the interpretation of our results are valid.
In summary, we have shown that the strong cross-sectional association of androgens with greater WHR in women but lesser WHR in men does not result in continued longitudinal trends in WHR trajectory, especially when adjusted for levels of SHBG. However, in both men and women endogenous E2 levels are associated with a higher level of central obesity cross-sectionally and an increasing trend in obesity over follow-up. Low SHBG levels are strong correlates of current adiposity and a predictor of future increases in adiposity. This is only partially explained by being a marker of insulin resistance or a transporter for sex hormones. Future research is needed to investigate if SHBG directly affects adipose tissue metabolism and to determine if manipulation of hormones is associated with changes in central obesity.