Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. Hypertension is a major risk factor for cardiovascular disease. The mechanisms responsible for postmenopausal hypertension have not been completely elucidated.
However, various mechanisms have been implicated to play a role. For example, there is evidence that changes in estrogen/androgen ratios favoring increases in androgens, activation of the renin-angiotensin and endothelin systems, activation of the sympathetic nervous system, metabolic syndrome and obesity, inflammation, increased vasoconstrictor eicosanoids, and anxiety and depression may be important in the pathogenesis of postmenopausal hypertension. There is also evidence that hypertension is less well controlled in aging women than in aging men, but the reasons for this gender differences are not clear.
Postmenopausal hypertension is likely multifactorial. Future studies will be necessary to determine the contribution of these systems listed above in mediating their hypertension and to design treatment options that encompass these mechanisms to improve the quality of life of postmenopausal women as they age.
Polycystic ovary syndrome (PCOS) is the most common reproductive dysfunction in premenopausal women. PCOS is also associated with increased risk of cardiovascular disease at the time of PCOS and later in life. Hypertension, a common finding in women with PCOS, is a leading risk factor for cardiovascular disease. The mechanisms responsible for hypertension in women with PCOS have not been elucidated.
We now have characterized an animal model, the dihydrotestosterone-treated young female rat that has many of the characteristics of women with hyperandrogenemia. HAF rats have 3 fold increases in plasma DHT with normal levels of plasma estradiol levels compared to control females, but they exhibit estrus cycle dysfunction. They also had increased blood pressure, food intake and body weight, increased visceral fat, glomerular filtration rate, renal injury, insulin resistance and metabolic dysfunction, oxidative stress, and increased expression of angiotensinogen and ACE and reduced AT1 receptor expression.
Thus, we have a rat model that mimics the increased blood pressure and metabolic dysfunction that women with PCOS have. We are in the process of studying the mechanisms responsible for the increase in blood pressure.
The role that sex steroids play in CKD and in the progression to ESRD in humans is not clear. Sex steroids may not be causative of CKD in humans but are likely to be permissive of or protective against progression to ESRD. The mechanisms by which sex steroids could modulate renal disease are many, and we have been studying some of the possibilities.
Estradiol is mainly antioxidant, vasodilatory, and Ang II action-“inhibitory,” although not overtly so. The effect of estradiol on renal endothelin is not clear. Progesterone has been less well studied, but it is likely to be vasoconstricting chronically, antioxidant, antinatriuretic. The effect of progesterone on Ang II, AT1 receptor, and endothelin is not clear.
Androgens, testosterone, and dihydrotestosterone are chronically vasoconstricting, pro-oxidant, antinatriuretic, and Ang II and endothelin-action stimulatory. The role of androgens in males and females is not clear since cardiovascular and renal diseases in men is associated with reductions in androgen levels.
Discovery of the mechanisms by which sex steroids impact CKD in humans will allow improvement of treatment paradigms that could be made specific if the patient is male or female. The role played by sex steroids in renal disease remains an exciting area for research in humans or animals.
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