Androgens and hypertension: Role in both males and females?

It is now well accepted that blood pressure in normotensive men and prevalence of hypertension in men is greater than in women ¹. After menopause, the prevalence of hypertension increases in women until it exceeds that in men ¹. Since cardiovascular disease (CVD) is the leading cause of morbidity and mortality in both men and women, and hypertension is a leading risk factor for CVD, determining the mechanisms responsible for the gender differences in blood pressure (BP) and prevalence of hypertension is important in protecting against CVD. Evidence suggests that androgens can contribute to BP control in women just as in men, since androgens are elevated in young women with conditions, such as polycystic ovary syndrome ², and there is evidence that androgens tend to increase in women after menopause ³. The mechanisms by which androgens control blood pressure in both men and women remain to be elucidated.

In the current issue of Hypertension, Wu and colleagues extend their previous observations on the mechanisms responsible for androgen-mediated hypertension ⁴. They previously reported that treatment of male rats 5α-dihydrotestosterone (DHT) (40–120 mg/kg body weight) caused an increase in BP and intrarenal expression of CYP4A and 20-HETE ⁵, that was prevented by CYP4A ω-hydroxylase inhibition (with HET-0016) ⁶. In addition, DHT increased, and HET-0016 decreased, renal microvascular markers of oxidative stress. These data were the first to suggest that 20-HETE contributes to androgen-induced increases in oxidative stress. Subsequently, Ishizuka and colleagues reported that adenoviral vector-mediated overexpression of CYP4A in endothelial cells increased 20-HETE, activated NF-κB, and increased expression of inflammatory mediators⁷.

In the current issue of Hypertension and based on these previous studies, Wu and colleagues addressed whether 20-HETE–mediated activation of NF-κB contributes to androgen-mediated hypertension ⁴. In fact, they found that DHT in male rats activated NF-κB (p65 nuclear translocation), and blockade of 20-HETE abolished the activation of NF-κB. Furthermore, the IκK inhibitor, parthenolide, reduced androgen-dependent, 20-HETE-mediated increases in BP without affecting basal or DHT-mediated increases in 20-HETE in renal interlobular arteries. As shown in Figure 1, the data suggest the following schema: androgens upregulate CYP4A ω-hydroxylases and increase vascular 20-HETE. 20-HETE activates NF-κB which activates NADPH oxidase and production of reactive oxygen species (ROS), that would decrease bioavailability of NO for vasodilation, and thus renal vasoconstriction would occur to increase BP.

Figure 1. Potential mechanisms by which androgens could increase blood pressure.

Androgens could upregulate cytochrome P450 4A ω-hydroxylases which would increase 20-HETE levels. 20-HETE would activate NF-κB which would activate NADPH oxidase to increase production of reactive oxygen species (ROS) and decrease nitric oxide (NO) bioavailability. The reduction in NO would increase renal vasoconstriction leading to hypertension.

One reason that BP is higher in normotensive men compared to women may be due to androgen-mediated upregulation of 20-HETE and increased renal microvascular reactivity in men. 20-HETE then could activate NF-κB leading to increases in oxidative stress and together increase BP. The androgen receptor gene contains NF-κB enhancer sequences, and NF-κB can upregulate expression of TNF-α and IL-6, both of which increase the expression of the androgen receptor ⁹, thus setting a positive feedback to promote further androgen-stimulated increase in BP, 20-HETE and inflammation.

One problem with this scenario is that in men, androgens are thought to be anti-inflammatory ¹⁰. In fact, a reduction in androgens is associated with increases in CVD and endothelial dysfunction in men ¹¹. One differences between men and studies in rats may be the level of androgens. Doses used to cause a rapid increase in BP in rats, as in the present study, are significantly higher than in men. It is possible that androgens promote CVD and hypertension in men, but by the time of diagnosis, a compensatory downregulation of androgen synthesis has occurred that attempts to protect against CVD. No studies have determined whether normotensive men with elevated levels of androgens are predisposed to CVD and hypertension and then develop hypo-androgenemia.

In contrast, women who have hyperandrogenemia, such as those with polycystic ovary syndrome (PCOS), exhibit increases in inflammation and inflammatory cytokines, hypertension, oxidative stress, NF-κB activation, and are at increased risk for CVD both during their reproductive years as well as after menopause ². Thus these observations strongly fit the data found in the current paper and in previous studies by these investigators. Whether 20-HETE levels are increased in women with PCOS has not been determined, however.

The other condition in which androgens may be increased in women is after menopause although this remains controversial. Laughlin and colleagues reported that while plasma testosterone and estradiol levels fall shortly after menopause, testosterone then begins to increase, and by age 70 years, testosterone levels were similar to those found in premenopausal women without increasing estradiol levels ³. Again to our knowledge, there are no studies in which changes in 20-HETE have been measured in postmenopausal women nor are there studies as yet to address the role of 20-HETE or EETs in the development of postmenopausal hypertension.

In the present study by Wu and colleagues, the studies were performed in male rats. However, in 2008 Singh and Schwartzman reported that intrarenal microvascular 20-HETE and EET levels were higher in females than males, but that the ratio of 20-HETE to EETs was lower in females than males ¹². Chronic DHT increased systolic BP and 20-HETE and reduced EETs in both females and males, but the 20-HETE to EET ratios were similar in the two sexes. These data showed that the increase in BP in females was likely due to DHT-mediated increases in vasoconstrictor 20-HETE as well as reductions in vasodilator EETs. One caveat to this study is that the doses of DHT were significantly higher than in women with either PCOS or post menopause in which serum androgen levels are only increased by 3–4 fold. Thus the question remains whether small increases in androgens in women or female rats also upregulates 20-HETE synthesis and contributes to the increases in BP.

In summary, from the data collected by Dr. Schwartzman and her colleagues over the past few years, it is clear that androgens increase the expression of enzymes of the CYP4A family and vascular 20-HETE production, and that 20-HETE contributes to oxidative stress, endothelial dysfunction, and inflammation through a mechanism involving activation of NFκB. That being said, since low levels of serum androgens in men are thought to promote CVD and hypertension, whereas elevated levels of androgens in women are thought to promote CVD and hypertension, the results of these studies suggest that androgen-mediated activation of the 20-HETE pathway and its sequellae may be more important in mediating CVD and hypertension in hyperandrogenemic women than in men. Given the importance of these findings, it is clear that additional studies are needed to define the role of eicosanoids in mediating hypertension and CVD in hyperandrogenemic syndromes, and that eicosanoid levels should be measured and considered as a primary endpoint in studies involving sex steroids and gender differences in CVD.