In this cross-sectional study, a strong inverse association between blood pressure and SHBG was observed. Post-menopausal women with hypertension had significantly lower SHBG concentrations, and this association was significant even after adjusting for major risk factors for hypertension such as age, BMI, diabetes and insulin resistance. In men, we observed an inverse association between systolic blood pressure and SHBG. This association was independent of major confounders. Both these findings indicate that low concentrations of SHBG may have independent negative effects in the control of blood pressure.
To our knowledge this is the first study to estimate the specific role of SHBG in blood pressure control. There are some publications concerning the association between hypertension and SHBG in men, but very few in women. The majority of studies, aimed to estimate the effects of testosterone on blood pressure in men, provided information about the level of SHBG. This was done in order to estimate the concentrations of free testosterone. However, only a few studies have presented information about the association between SHBG and hypertension. In a prospective study in men, aimed to investigate the role of sex hormones in hypertension, Khaw et al.  observed that total testosterone but not SHBG was associated with hypertension. However, in accordance with our results, they found an inverse association between SHBG and diastolic blood pressure adjusted for age. The definition of hypertension in that study was different from our definition based on JNC7 (160/95 in Rancho Bernard and 140/90 in VSC). A cross-sectional study in men conducted in Tromsö , which aimed to investigate the association between testosterone on one hand and hypertension and left ventricular hypertrophy on the other hand, found an age-independent association between SHBG and both systolic and diastolic blood pressure. The association remained borderline significant for the systolic blood pressure (p=0,057) even after adjusting for BMI and alcohol consumption, but for diastolic blood pressure it was not significant (p=0,370). Significantly lower concentrations of SHBG were found in hypertensive men even after adjusting for age, BMI and SHBG concentrations in accordance with our results in women .
Some gender differences were, however observed in our study (Figure 1). In accordance with Khaw et al.  levels of SHBG decreased in a linear fashion in men when the blood pressure increased. In contrary in women the decrease in SHBG were firstly observed when they had developed hypertension. As the association between SHBG and hypertension in women was stronger over the age of 50 we suppose that these gender differences can at least in part be addressed to the menopause. In a prospective study including men and post-menopausal women, Ding et al.  observed a predictive value of SHBG concentrations concerning incident cases of type 2 diabetes, in both men and women. They reported an association between hypertension and low concentrations of SHBG in women in the crude analysis. However, the authors did not report whether any multivariate statistical tests accounting for possible confounders were computed. Neither was the association between SHBG and hypertension in males at baseline reported.
We did not found studies comparing the strength of the association between SHBG and hypertension with other risk factors for hypertension. In order to compare the SHBG with other conventional risk factors for hypertension, we standardized age, BMI, HOMA-IR and SHBG. In our study a weak association between insulin resistance and hypertension was observed in men were SHBG had stronger association with hypertension than HOMA-Ir.
Tot-T but not free testosterone was associated with hypertension in our population. Testosterone deficiency has been indicated as a risk factor for obesity and cardiovascular diseases. The question as to whether T has a direct effect on blood vessels remains to be investigated. We cannot confirm the vasodilatative effects of free testosterone that were shown by Webb et al. . Our results suggest that the association between SHBG and blood pressure may explain the association between testosterone and blood pressure, at least partially. A recent study has shown that SHBG but not testosterone is associated with increasing of blood pressure . In the matter of diabetes risk, Lakshman et al.  speculate on a modulatory effect of SHBG that enhances the effects of testosterone. In fact, a membrane receptor for SHBG is present in uterine endometrial cell membranes, isolated prostatic cell membranes, human placenta, normal breast, liver and epididymis but not in striated muscle . This receptor, when activated after contact with SHBG, can stimulate the production of c-AMP. It must be emphasized that in a minor study with men with hypertension it was found a strong association between SHBG and renin that can be another pathway for direct effects of SHBG on the control of blood pressure . Whether this association occurs in the blood vessel and if it influences the blood pressure remains to be confirmed by studies of a different design. For example, experimental studies on mice with knocked gene for SHBG could help in understanding the functions of the protein, and determine whether this protein only has carrying functions or if the functions of the protein are extended inside the target cells for androgen effect.
In accordance with previous studies, we found a positive linear association between SHBG and age in men while in women the association is inverse before 50 years of age [31, 32]. The mechanisms lying behind this gender duality are not fully understood. Some authors suggest that in men a decrease of testosterone concentrations due to age is the cause of increasing SHBG concentrations as testosterone is supposed to have an inhibitory effect on SHBG production. Such an effect does not seem to be determinant in increasing SHBG concentrations in aging men according to De Ronde et al..
This was a large population based study that included both men and women. Therefore, we could compare the association of oestradiol, SHBG and testosterone in both men and women. The study had a high participation rate of 76%, including a younger middle-aged population. The diagnosis of hypertension was précised with the trained nurse. In this large study population, we also had information about the medication influencing the blood pressure that gave us the possibility to exclude subjects with blood pressure lowering medication or with hormonal medication that could have influenced the analyses. Blood samples were collected in the morning, thereby avoiding influences of circadian changes in the hormonal concentrations.
A potential weakness of this study might be the lack of information with regard to menopausal status. Still, the use of 50 years as cut-off point for menopause is supported by findings from previous studies [34, 35]. It should also be emphasized that as this is a cross-sectional study the causality between SHBG and hypertension cannot be established and it is possible that hypertension or associated factors lead to decreased concentrations of sex hormone-binding globulin. Another limitation of the study is the low accuracy of the measurements of testosterone in the low range of the distribution thus concerns especially women . Moreover there is a circadian variation of concentrations of testosterone and SHBG which probably dilute our findings .