Testosterone supplementation in aging men and women: possible impact on cardiovascular-renal disease
http://www.100md.com
《美国生理学杂志》
Department of Physiology and Biophysics and The Center for Excellence for Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi
ABSTRACT
Treatment of aging men and women with testosterone supplements is increasing. The supplements are given to postmenopausal women mainly to improve their libido and to aging men to improve muscle mass and bone strength, to improve libido and quality of life, to prevent and treat osteoporosis, and, with the phosphodiesterase-5 inhibitors, such as sildenafil, to treat erectile dysfunction. The increased use of testosterone supplements in aging individuals has occurred despite the fact that there have been no rigorous clinical trials examining the effects of chronic testosterone on the cardiovascular-renal disease risk. Studies in humans and animals have suggested that androgens can increase blood pressure and compromise renal function. Androgens have been shown to increase tubular sodium and water reabsorption and activate various vasoconstrictor systems in the kidney, such as the renin-angiotensin system and endothelin. There is also evidence that androgens may increase oxidative stress. Furthermore, the kidney contains the enzymes necessary to produce androgens de novo. This review presents an overview of the data from human and animal studies in which the role of androgens in promoting renal and cardiovascular diseases has been investigated.
androgen receptor; oxidative stress; angiotensin II; endothelin; cytokines
THE USE OF TESTOSTERONE SUPPLEMENTS in aging men and women has increased in recent years. Aging men take testosterone supplements to improve muscle mass and bone strength, to improve libido and quality of life, to prevent and treat osteoporosis, and, with the phosphodiesterase-5 inhibitors, to treat erectile dysfunction. Postmenopausal women receive testosterone supplements mainly to improve their libido. In addition to physicians prescribing testosterone supplements, individuals are able to buy androgens, such as androstenedione, over the counter in health food stores. Serum testosterone levels that are achieved with supplements range from physiological to supraphysiological levels (sometimes as high as 3- to 16-fold higher in men and women than physiological levels) depending on the preparation, dose, and method of administration (9, 13, 42). While urologists are sounding the alarm for caution in using testosterone supplements because of their potential to increase the incidence of prostatic cancer (75), there have been few clinical trials to study the safety of testosterone supplements in aging men and/or women in terms of their effect on cardiovascular-renal disease. Earlier this year, the Food and Drug Administration refused to approve the testosterone "patch" for use in postmenopausal women, however, due to the possibility of cardiovascular side effects (79). In this review, research regarding the impact of androgens on cardiovascular and renal disease from human and animal studies will be discussed.
CHANGES IN TESTOSTERONE WITH AGE
Several cross-sectional (20, 83) and longitudinal (19, 28) studies documented a decline in total and bioavailable circulating testosterone levels with aging in men. More than 60% of healthy, elderly men over 65 yr of age have free testosterone levels below the normal values of men aged 30–35 yr. Because androgen receptors are upregulated in the presence of androgens and downregulated in its absence, it is likely that a reduction in androgen receptors may occur with aging as well. There have been studies in which the expression of androgen receptors in aging men was reduced in reproductive tissues, but there have been no studies in which the expression of androgen receptors has been studied in nonreproductive tissues in aging individuals. The decrease in androgen levels with aging in men appears to be the result of both gonadal and hypothalamic-pituitary failure and is independent of chronic illness, obesity, or medication (28). However, chronic illnesses (52), such as hypertension (81), diabetes (10), chronic kidney disease (33, 74), and end-stage renal disease (38, 39), are associated with a further reduction in serum testosterone levels in men of all ages. The fact that androgen levels decrease with age have led scientists to presume that androgens do not play a role in chronic cardiovascular and renal disease in aging men. However, growing evidence indicates that testosterone, even at levels observed in aging men, can have adverse consequences on cardiovascular-renal function.
Serum testosterone levels are significantly lower in women than in men, and whether serum testosterone levels decrease after menopause is not clear. The conventional wisdom is that androgen levels, like estrogen, do decrease with age in women. However, Jiroutek and colleagues (37) reported that postmenopausal women who were followed for 10 yr after cessation of cycling and had serial measurements of sex hormones showed increases in serum testosterone and androstenedione and decreases in serum estradiol and dihydrotestosterone as they aged. Other investigators have observed that serum testosterone either does not change (30) or is decreased in postmenopausal women (57). In cross-sectional studies of women in the Rancho Bernardo cohort, Laughlin and colleagues (45) reported that serum testosterone decreased immediately following menopause, but thereafter increased with age, reaching premenopausal levels by 70–79 yr. In addition, these investigators found that women who had undergone surgical menopause did not show increases in testosterone with age and the levels of serum testosterone were 40–50% lower than in women who had undergone natural menopause. These data support the contention that the natural postmenopausal period in a woman's life is a relatively hyperandrogenic state (2, 44, 60). Furthermore, Sluijmer and colleagues (77) found that the degree of ovarian stromal hyperplasia, a common characteristic of the ovaries in postmenopausal women, is not correlated with the level of estrone and estradiol measured in the ovarian vein but is positively correlated with the level of testosterone and androstenedione. For example, women with atrophic ovaries had little testosterone measured in the ovarian vein, whereas women with moderate to severe hyperplasia had larger levels of ovarian testosterone produced. In addition, the incidence and degree of stromal hyperplasia were quite variable among the women (77). Because the extent of ovarian stromal hyperplasia is rarely measured in most studies of postmenopausal women, this could explain the discrepancies in androgen levels found in various studies.
ANDROGENS AND CONTROL OF BLOOD PRESSURE
There is growing evidence that androgens can influence blood pressure regulation. Men have higher blood pressure than do women for most of their lives (41, 86). Following menopause, however, blood pressure increases in women to levels not different or even higher than in men (7). The prevalence of hypertension is also higher in men than women until after menopause (7). However, hypertensive men have been shown to have lower serum testosterone levels than normotensive men of the same age (81). These data have called into question the role that androgens could play in mediating or promoting hypertension.
Although there have been few studies in men in which the role of androgens in mediating higher blood pressure has been examined, there are several animal models in which a sex difference in blood pressure has been described and the role of androgens has been studied. For example, the spontaneously hypertensive rat (SHR) is a model of hypertension that is androgen mediated (62, 68). Following puberty, males have higher blood pressure than females (68) (see Fig. 1). Castration of males is associated with reductions in blood pressure to the levels found in females. Furthermore, testosterone treatment of ovariectomized females increases their blood pressure in a dose-dependent manner (68, 69). Sex differences in blood pressure have also been found in Dahl salt-sensitive (DS) rats on a high-salt diet (32). The DS males have higher blood pressure than females when placed on 4% salt diets despite the fact that high-salt diet for 3 wk reduces serum testosterone levels in the males by 50% (n = 5/group) (Yanes LL, Iliescu R, and Reckelhoff JF, unpublished observations). Early studies failed to show a reduction in blood pressure with castration in the male DS on a high-salt diet (73). However, as shown in Fig. 2, we have found that castration attenuates the hypertensive response to high salt in male DS. These data support the contention that despite reductions in serum testosterone in DS males with high salt, there is still enough androgen present to play a role in mediating the salt-induced hypertension. It should be noted, however, that testosterone replacement studies have not been performed yet. Thus it is possible that other factors may play a role in the lower blood pressure with castration, although we doubt this will be the case. Nongenetic models of hypertension also exhibit sex differences, such as DOCA-salt-treated rats, in which the hypertension is more severe in males than females (11), but to our knowledge, serum testosterone levels have not been reported for rats receiving DOCA and salt.
ANDROGENS AND RENAL DISEASE
Androgens in the Kidney
To date, there is a paucity of data regarding the role of androgens and the androgen receptor in regulating renal function. However, the kidney expresses the enzymes capable of producing testosterone and the androgen receptor. For example, Quinkler and colleagues (60) found that kidney tissue obtained from tumor nephrectomy samples from postmenopausal women express 5-reductase type 1, 3-hydroxysteroid dehydrogenase type 2, and 17-hydroxylase/17,20 lyase (P450c17) (see Fig. 3). They also found that radiolabeled pregnenolone, produced from cholesterol, was converted effectively to dehydroepiandrosterone (DHEA), and radiolabeled DHEA was converted via androstenedione to testosterone and dihydrotestosterone. Whether androgens can be produced in kidneys of men via these enzymes was not determined in these studies but is highly likely. In support of this hypothesis, in male rats, treatment of inner medullary collecting duct primary cultures with radiolabeled testosterone or androstenedione resulted in production of 5-dihydrotestosterone and 5-androstanedione (47). Androgen receptor expression has been found in the proximal tubule and in the cortical collecting ducts of human kidneys (43).
Androgens and Proximal Tubule Reabsorption
One of the most important recent findings regarding the effect of androgens in the kidney is the work of Quan and colleagues (59), who found by micropuncture studies that chronic (10 days) dihydrotestosterone (DHT) injections in Sprague-Dawley rats caused an increase in the proximal tubule volume reabsorption, which could be reduced with blockade of the renin-angiotensin system (RAS). Blood pressure was higher in the DHT-treated rats, but the glomerular filtration rate (GFR) was not affected nor was AT1 receptor binding. This is in contrast to acute infusion of testosterone, which causes renal vasodilation with increases in GFR and renal plasma flow and reductions in renal vascular resistance (Reckelhoff JF, unpublished observations). The data of Quan and colleagues (59) suggest that, in the chronic situation, androgens may upregulate ANG II and the Na/H exchanger, leading to increases in sodium and water reabsorption and elevations in blood pressure.
Androgens and Chronic Renal Disease
As in other chronic diseases, serum androgen levels are decreased in men with renal insufficiency (33, 74). Despite the reduction in androgens that occurs with aging, men progress to chronic renal failure at a more rapid rate than do women, even for similar levels of blood pressure (53). For example, Neugarten and colleagues (53) performed a meta-analysis of studies including 11,345 subjects and found that renal disease independent of diabetes progresses at a more rapid rate in men. Several renal diseases are also more common in men than women. Polycystic kidney disease (24, 80) and IgA nephropathy (27) are more common in men and progress more rapidly in men than women. Age-related reductions in renal function also progress at a more rapid rate in men than women (76). Despite the gender differences in the progression of chronic renal disease, Neugarten and colleagues (54) reported that there are few sex differences in normal renal structure that could account for these observations. For example, glomerular number was similar in men and women, and the glomerular volume and kidney weight were similar when corrected for body weight of the individuals.
In aging rats, serum testosterone levels also decrease with age as found in men. Several investigators have reported that normotensive and hypertensive males experience a more rapid reduction in GFR and more renal injury with age than do females (6, 22, 64–66, 68). However, the reduction in GFR cannot be fully accounted for by the level of glomerular injury found in the kidneys (22, 68). For example, in old male Sprague-Dawley rats aged 20–22 mo, a model of accelerated renal aging, GFR was reduced by 50% compared with young males and yet only 20% of their glomeruli exhibited any injury (68). These data suggest that aging is a state of renal vasoconstriction. We have made similar findings in the aging SHR. In old male SHR, renal vascular resistance was increased by 30%, whereas blood pressure was only increased by 10% compared with young SHR (22). As in normotensive rats, the reductions in GFR in old male SHR cannot be explained by glomerular injury because <10% of glomeruli are injured in these rats at 18 mo of age, whereas GFR was reduced by 30% (22). In more recent studies in SHR, we found that castration of aging males completely prevents reductions in GFR and glomerular injury (22). In addition, castration prevents the increase in renal vascular resistance found in aging male SHR despite a significant age-related reduction in serum androgens in the intact male. Taken together, these data suggest that remnant androgens mediate the reductions in renal function in the aging animal.
In another model of hypertension and renal injury that is not genetically mediated, the renal wrap hypertension model, Ji and colleagues (36) recently reported that castration of male rats attenuated the glomerular injury and proteinuria. When castrated rats were treated with DHT, the glomerular injury was exacerbated. Similarly, in renal wrap female rats that were ovariectomized (a model of ovarian hormone deficiency), testosterone treatment also exacerbated renal injury and proteinuria. Thus there is compelling evidence that indicates that testosterone promotes renal injury and declines in renal function.
Androgens and the RAS in the Kidney
Androgens play a role in modulating the RAS. Several groups have shown that androgens can stimulate the upregulation of angiotensinogen in the kidneys of normotensive and hypertensive rats (8, 18). In addition, Chen and colleagues (8) reported that renin mRNA was upregulated by androgens in kidneys of SHR. These data suggest that androgens can stimulate the intrarenal RAS. Furthermore, Baltatu and colleagues (4) also reported that renal injury could be abolished by androgen receptor antagonism in a Ren-2 rat model of hypertension that has an overactive RAS.
How androgens affect the systemic RAS is not clear. In humans, plasma renin activity (PRA) is higher in men than in age-matched premenopausal women (35, 58). We have found previously that testosterone repletion in castrated normotensive rats leads to a dose-dependent increase in PRA (62), which is consistent with the data from human studies. In contrast, Quan et al. (59) found that chronic DHT treatment reduced serum ANG II levels. While estradiol has been shown to modulate the synthesis of AT1 receptors in various tissues, including kidneys and vasculature (29, 55), androgens have only been shown to increase AT1 receptor expression in male reproductive tissues (46). Therefore, the effect of androgens on AT1 receptor expression in kidneys should be examined.
There are gender differences in the renal response to infusion of ANG II as well. When graded doses of ANG II were infused into healthy young adults, there was a similar increase in blood pressure and reduction in effective renal plasma flow (ERPF) in men and women, but GFR was maintained in men only, leading to an increase in the filtration fraction (FF), which suggests an increase in glomerular capillary pressure (48). In women, the reduction in ERPF was associated with a concomitant reduction in GFR, resulting in no change in FF. These studies were performed without blockade of the endogenous RAS. Therefore, men may have been more responsive because they have higher basal levels of endogenous renal ANG II than women. In any case, these data further support the notion that the combination of androgens and ANG II is important in modulating renal function.
In SHR, blockade of the RAS with converting enzyme inhibitors (CEI) reduces blood pressure to the same level in both males and females (70), supporting the important role of the RAS in mediating the hypertension in SHR independently of the sex steroids. In addition, CEI also prevents increases in blood pressure in ovariectomized female SHR receiving chronic testosterone supplementation (70). These data suggest that an intact RAS is necessary for androgens to increase blood pressure in SHR. In other words, the mechanism by which androgens are capable of increasing blood pressure in SHR is mediated by their effects on the RAS.
Whether PRA and RAS activity decrease with age in men and women is somewhat controversial. However, James and colleagues (35) reported from serial analyses that PRA was higher in men than in age-matched women, that PRA was higher in postmenopausal women than in premenopausal ones, and that in white men, PRA did not decrease with age. Blood pressure becomes more salt sensitive with aging in both men and women (85), which suggests that RAS activity and ANG II do not respond appropriately in the presence of salt in aging individuals. Therefore, androgen supplements in aging individuals could be expected to both stimulate reabsorption in the proximal tubule and stimulate PRA, which would further aggravate hypertension and renal injury.
Androgens and Endothelin
Endothelin is a potent renal vasoconstrictor and mitogen that plays a role in renal injury associated with aging (5, 25, 26). Goddard and colleagues (26) reported that ETA receptor antagonism in individuals with chronic renal failure caused an increase in renal blood flow and a reduction in blood pressure mainly due to the activation of the ETB receptors, because combined ETA/B receptor antagonism reduced blood pressure but had no effect on renal function. In addition, Elijovich and colleagues (17) reported that hypertensive individuals with nephrosclerosis exhibited increased plasma endothelin that was independent of aldosterone:renin ratios but was positively correlated with the level of proteinuria. In aging male Wistar rats, Ortmann and colleagues (56) recently reported that glomerulosclerosis and proteinuria could be reversed when rats were given darusentan, an ETA receptor antagonist, independently of reductions in blood pressure, changes in renal function, or tubulointerstitial renal injury. In addition, endothelin-1 is secreted from mesangial cells in response to a variety of cytokines, hormones, and oxidative stress (78). There is also evidence that endothelin may play a role in the gender difference in the death rate of rats in response to renal ischemia-reperfusion (51). Muller and colleagues (51) found that 50 min of left vascular pedicle clamping resulted in death in 92% of male rats by day 7, but only 25% of females died during this time period. Castration reduced the number of deaths in males with ischemia-reperfusion to 33%, and pretreatment of males with an endothelin ETA receptor antagonist totally protected males from death (51).
Androgens can upregulate the production of endothelin. In female-to-male transsexuals who receive testosterone supplements chronically, plasma endothelin levels are elevated (82). In addition, in women who suffer from polycystic ovary syndrome, in which serum testosterone is elevated, endothelin is also elevated (15). Whether the effects of androgens on endothelin production are direct or mediated by the effects of androgens on the RAS, which, in turn, increases endothelin production (3), is not clear. In any case, androgen supplementation in both aging men and women could promote renal injury mediated via endothelin. This is especially important following menopause, because estradiol has been shown to reduce expression of endothelin (82), and thus this protection would be lost in postmenopausal women. In support of this hypothesis, we have found that the postmenopausal increases in blood pressure found in aging female SHR are mediated, in part, by endothelin (87). In contrast, endothelin plays no role in the hypertension of young female SHR (87).
Androgens and Oxidative Stress
The role of oxidative stress in acute renal failure and ischemia-reperfusion is widely accepted. However, oxidative stress also plays a role in chronic renal disease (1, 49). Men have higher levels of oxidative stress than do age-matched women as measured by F2-isoprostanes or thiobarbituric acid-reactive substances in plasma (34), despite the reduction in androgen levels in aging men. Postmenopausal women also exhibit higher levels of oxidative stress than premenopausal women (31). Oxidative stress is increased in the kidney with normal aging (72), and we have been able to protect against age-related renal injury in Sprague-Dawley rats by treating them chronically with vitamin E (65).
The major reactive oxygen species in the kidney is thought to be superoxide, which can quench nitric oxide (NO) (67), leading to a reduction in the NO bioavailability for dilation and thereby causing renal vasoconstriction. It is possible then that a reduction in vasodilator substances could play a role in the age-related renal vasoconstriction in males. We have found previously that there are sex differences in the renal vasculature response to NO. Young male normotensive rats without deficiencies in androgen synthesis are more dependent on the NO system for maintenance of renal hemodynamics than are age-matched females (63). Males had 80% lower renal expression of endothelial NO synthase compared with females, yet when NO synthase was blocked with nitro-L-arginine methyl ester, despite similar blood pressure increases in males and females, renal plasma flow (RPF) decreased by 40% and renal vascular resistance (RVR) increased by 23% in males compared with 20% and 60% for RPF and RVR, respectively, in females. The importance of the NO system in preserving renal hemodynamics is even more striking in aging males. When treated with NO synthase inhibitors, GFR and RPF decreased to a much greater extent and glomerular capillary pressure almost doubled in aging males compared with young males (66).
Whether androgens can directly produce oxidative stress has not been fully elucidated. In preliminary studies, we have found that physiological concentrations of dihydrotestosterone are capable of increasing dihydroethidium fluorescence in cultured SHR mesangial cells (Cucchiarelli V, Iliescu R, and Reckelhoff JF, unpublished observations). We have also found that castration reduces superoxide production in the kidneys of male SHR. In addition, tempol, a superoxide scavenger, reduces blood pressure and oxidative stress in young and aging male SHR but has little or no effect in females (21, 23).
Regardless of whether androgen supplementation directly causes oxidative stress, androgens can stimulate the RAS and endothelin production, which have been shown to increase reactive oxygen species. ANG II, at both supraphysiological and physiological levels, can increase oxidative stress (61, 71), mainly via upregulation of the subunits of NADPH oxidase (50). In addition, ANG II can stimulate the production of endothelin (3), which also causes oxidative stress by upregulating NADPH oxidase (16). Furthermore, while endothelin can cause oxidative stress, oxidative stress can also upregulate endothelin synthesis (40), setting up a vicious cycle.
Therefore, because aging is associated with increased oxidative stress, men at all ages have elevated levels of oxidative stress compared with women, and after menopause oxidative stress increases in women, androgen supplements could cause a further increase in oxidative stress in both men and women, leading to reductions in renal function and renal injury. The renal changes could be caused by the direct effect of androgens on oxidative stress or indirectly via their effect on the RAS or endothelin system. Furthermore, because estradiol is a mild antioxidant and has been shown to inhibit synthesis of NADPH oxidase (84), postmenopausal women would be at increased risk for androgen supplement-induced oxidative stress.
Androgens and Cytokines
Aging renal disease is associated with increases in inflammation and cytokine release. Both TNF- and IL-6 have been shown to upregulate or activate the androgen receptor (12, 14). In addition, upregulation of many inflammatory mediators involve the transcription factor, NF-B, and the androgen receptor promoter contains several NF-B enhancer elements. Although the role of the androgen receptor in the inflammation associated with aging renal disease has not been studied, it is attractive to propose that the androgen receptor could be upregulated in renal tissue in response to inflammation. Androgens have also been shown to activate a Fas/Fas ligand-dependent apoptotic pathway in proximal tubule cells, which is characteristic of chronic renal diseases (24). Androgens could, therefore, activate an apoptotic mechanism, leading to renal tubular loss and interstitial fibrosis in the elderly.
SUMMARY
Aging men and women frequently receive androgen supplements. Aging men are already at greater risk for cardiovascular and renal disease than women, despite the fact that serum testosterone levels decrease significantly with age and with chronic diseases. We hypothesize that the reduction in testosterone with age and chronic disease is a protective mechanism against even greater cardiovascular-renal disease incidence and poorer outcomes. Therefore, androgen supplements in aging men could offset this natural protective mechanism.
In women, menopause increases a woman's risk for cardiovascular and renal diseases. However, women are somewhat protected compared with men, but androgen supplements may increase the risk of renal injury and cardiovascular disease in postmenopausal women to levels similar to those in men. It is also possible that androgen levels may increase naturally with age in some women and may further impact disease risk factors naturally.
As with estradiol-progesterone replacement therapy in postmenopausal women, it is likely that some healthy, active, aging men and women would not have adverse cardiovascular consequences with androgen supplementation. However, in view of the increasing experimental evidence that androgens promote cardiovascular and renal disease, even when the serum levels are decreased, aging men and women who have the predisposition to cardiovascular-renal diseases should take androgen supplements with caution until rigorous clinical trials have been performed.
As shown in Fig. 4, we hypothesize that androgens can stimulate proximal reabsorption of sodium and water, causing a reduction in the sodium delivery to the macula densa, and, by tubuloglomerular feedback, cause a reduction in afferent resistance that could lead to an increase in glomerular capillary pressure. Androgens could also activate the RAS, leading to further increases in tubular sodium reabsorption, but also increases in efferent resistance and glomerular capillary pressure. ANG II has been shown to increase endothelin synthesis and upregulate NADPH oxidase to increase oxidative stress. Endothelin has also been shown to increase oxidative stress. Furthermore, androgens may directly increase both endothelin and oxidative stress. ANG II, endothelin, and oxidative stress can then increase blood pressure, leading to further increases in glomerular pressure, ultimately leading to glomerular injury and loss of renal function.
GRANTS
This work was supported by National Heart, Lung, and Blood Institute Grants HL-66072, HL-69194, and HL-05197.
FOOTNOTES
REFERENCES
Agarwal R. Chronic kidney disease is associated with oxidative stress independent of hypertension. Clin Nephrol 61: 377–383, 2004.
Ala-Fossi SL, Maenpaa J, Aine R, and Punnonen R. Ovarian testosterone secretion during perimenopause. Maturitas 29: 239–245, 1998.
Alexander BT, Cockrell KL, Rinewalt AN, Herrington JN, and Granger JP. Enhanced renal expression of preproendothelin mRNA during chronic angiotensin II hypertension. Am J Physiol Regul Integr Comp Physiol 280: R1388–R1392, 2001.
Baltatu O, Cayla C, Iliescu R, Andrew D, Jordan C, and Bader M. Abolition of hypertension-induced end organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene. J Am Soc Nephrol 13: 2681–2687, 2002.
Barton M, Lattmann T, d'Ushio LV, Luscher TF, and Shaw S. Inverse regulation of endothelin-1 and nitric oxide metabolites in tissue with aging: implications for the age-dependent increase of cardiorenal disease. J Cardiovasc Pharmacol 36: S153–S156, 2000.
Baylis C. Age-dependent glomerular damage in the rat. Dissociation between glomerular injury and both glomerular hypertension and hypertrophy. Male gender as a primary risk factor. J Clin Invest 94: 1823, 1994.
Burl VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ, and Labarthe D. Prevalence of hypertension in the US adult population. Results from the third National Health and Nutrition Examination Survey, 1988–1991. Hypertension 25: 305–313, 1995.
Chen YF, Naftilan AJ, and Oparil S. Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats. Hypertension 19: 456–463, 1992.
Cherrier MM, Matsumoto AM, Amory JK, Ahmed S, Bremner W, Peskind ER, Raskind MA, Johnson M, and Craft S. The role of aromatization in testosterone supplementation. Effects on cognition in older men. Neurology 64: 290–296, 2005.
Corrales JJ, Burgo RM, Garca-Berrocal B, Almeida M, Alberca I, Gonzalez-Buitrago JM, Orfao A, and Miralles JM. Partial androgen deficiency in aging type 2 diabetic men and its relationship to glycemic control. Metabolism 53: 666–672, 2004.
Crofton JT and Share L. Gonadal hormones modulate deoxycorticosterone-salt hypertension in male and female rats. Hypertension 29: 494–499, 1997.
Culig Z. Androgen receptor cross-talk with cell -signalling pathways. Growth Factors 22: 179–184, 2004.
Davison S, Thipphawong J, Blanchard J, Liu K, Morishinge R, Gonda I, Okikawa J, Adams J, Evans A, Otulana B, and Davis S. Pharmacokinetics and acute safety of inhaled testosterone in postmenopausal women. J Clin Pharmacol 45: 177–184, 2005.
Delfino FJ, Boustead JN, Fix C, and Walker WH. NF-B and TNF- stimulate androgen receptor expression in Sertoli cells. Mol Cell Endocrinol 201: 1–12, 2003.
Diamanti-Kandarakis E, Spina G, Kouli C, and Migdalis I. Increase in endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin treatment. J Clin Endocrinol Metab 86: 4666–4673, 2001.
Duerrschmidt N, Wippich N, Goettsch W, Broemme HJ, and Morawietz H. Endothelin-1 induces NAD(P)H oxidase in human endothelial cells. Biochem Biophys Res Commun 269: 713–717, 2000.
Elijovich F, Laffer CL, Schiffrin EL, Gavras H, and Amador E. Endothelin-aldosterone interaction and proteinuria in low-renin hypertension. J Hypertens 22: 573–582, 2004.
Ellison KE, Ingelfinger JR, Pivor M, and Dzau VJ. Androgen regulation of rat renal angiotensinogen messenger RNA expression. J Clin Invest 83: 1941–1945, 1989.
Feldman H, Longcope C, Derby C, Johannes C, Araujo A, Coviello A, Bremner W, and McKinlay J. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 87: 589–598, 2002.
Ferrini R and Barrett-Conner E. Sex hormones and age—a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am J Epidemiol 147: 750–754, 1998.
Fortepiani LA and Reckelhoff JF. Tempol from birth abrogates the sex difference in the depressor response to tempol in SHR. J Hypertens. In press.
Fortepiani LA, Yanes L, Zhang H, Racusen LC, and Reckelhoff JF. Role of androgens in mediating renal injury in aging SHR. Hypertension 42: 952–955, 2003.
Fortepiani LA, Zhang H, Racusen LC, Roberts LJII, and Reckelhoff JF. Characterization of an animal model of postmenopausal hypertension in SHR. Hypertension 41: 460–463, 2003.
Gandolfo MT, Verzola D, Salvatore F, Gianiorio G, Procopio V, Romagnoli A, Giannoni M, and Garibotto G. Gender and the progression of chronic renal diseases: does apoptosis make the difference Minerva Urol Nefrol 56: 1–14, 2004.
Goddard J, Eckart C, Johnston NR, Cumming AD, Rankin AJ, and Webb DJ. Endothelin A receptor antagonism an angiotensin-converting enzyme inhibition are synergistic via an endothelin B receptor-mediated and nitric oxide-dependent mechanism. J Am Soc Nephrol 15: 2601–2610, 2004.
Goddard J, Johnston NR, Hand MF, Cumming AD, Rabelink TJ, Ranki AJ, and Webb DJ. Endothelin-A receptor antagonism reduces blood pressure and increases renal blood flow in hypertensive patients with chronic renal failure: a comparison of selective and combined endothelin-receptor blockade. Circ 109: 1186–1193, 2004.
Hall YN, Fuentes EF, Chertow GM, and Olson JL. Race/ethnicity and disease severity in IgA nephropathy. BMC Nephrol 5: 10, 2004.
Harman S, Metter E, Tobin J, Pearson J, and Blackman M. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86: 724–731, 2001.
Harrison-Bernard L, Schulman I, and Raij L. Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity. Hypertension 42: 1157–1163, 2003.
Hartmann BW, Kirchengast S, Albrecht A, Laml T, Soregi G, and Huber JC. Androgen serum levels in women with premature ovarian failure compared to fertile and menopausal controls. Gynecol Obstet Invest 44: 127–131, 1997.
Helmersson J, Mattson P, and Basu S. Prostaglandin F2 metabolite and F2-isoprostane excretion in migraine. Clin Sci (Lond) 102: 39–43, 2002.
Hinojosa-Laborde C, Lange DL, and Haywood JR. Role of female sex hormones in the development and reversal of Dahl hypertension. Hypertension 35: 484–489, 2000.
Holley JL. The hypothalamic-pituitary axis in men and women with chronic kidney disease. Adv Chronic Kidney Dis 11: 337–341, 2004.
Ide T, Tsutsui H, Ohashi N, Hayashidani S, Suematsu N, Tsuchihyasm M, Tamai H, and Takeshita A. Greater oxidative stress in healthy young men compared with premenopausal women. Arterioscler Thromb Vasc Biol 22: 1239–1242, 2002.
James GD, Sealey JE, Muller F, Alderman M, Madhavan S, and Laragh JH. Renin relationship to sex, race and age in normotensive population. J Hypertens 4: S387–S389, 1986.
Ji H, Menini S, Mok K, Zheng W, Pesce C, Kim J, Mulroney S, and Sandberg K. Gonadal steroid regulation of renal injury in renal wrap hypertension. Am J Physiol Renal Physiol 288: F513–F520, 2005.
Jiroutek MR, Chen MH, Johnston CC, and Longcope C. Changes in reproductive hormones and sex hormone-binding globulin in a group of postmenopausal women measured over 10 years. Menopause 5: 90–94, 1998.
Johansen KL. Treatment of hypogonadism in men with chronic kidney disease. Adv Chronic Kidney Dis 11: 348–356, 2004.
Johansen KL. Testosterone metabolism and replacement therapy in patients with end stage renal disease. Semin Dial 17: 202–208, 2004.
Kaehler J, Sill B, Koester R, Mittmann C, Orzechowski HD, Muenzel T, and Meinertz T. Endothelin-1 mRNA and protein in vascular wall cells is increased by reactive oxygen species. Clin Sci (Lond) 103, Suppl 48: 176S–178S, 2002.
Khoury S, Yarows SA, O'Brien TK, and Sowers JR. Ambulatory blood pressure monitoring in a nonacademic setting. Effects of age and sex. Am J Hypertension 5: 616–623, 1992.
Kicman AT, Bassindale T, Cowan DA, Dale S, Hutt AJ, and Leeds AR. Effect of androstenedione ingestion on plasma testosterone in young women; a dietary supplement with potential health risks. Clin Chem 49: 167–169, 2003.
Kimura N, Mizokami A, Oonuma T, Sasano H, and Nagura H. Immunocytochemical localization of androgen receptor with polyclonal antibody in paraffin-embedded human tissues. J Histochem Cytochem 41: 671–678, 1993.
Krug E and Berga SL. Postmenopausal hyperthecosis: functional dysregulation of androgenesis in climacteric ovary. Obstet Gynecol 99: 893–897, 2002.
Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, and von Muhlen D. Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Endocrinol Metab 85: 645–651, 2000.
Leung PS, Wong TP, Chung YW, and Chan HC. Androgen dependent expression of AT1 receptor and its regulation of anion secretion in the rat epididymis. Cell Biol Int 26: 117–122, 2002.
Matsuzaki K, Arai T, Inumaru T, Mihori M, Momose T, Sano M, Koide K, and Shimizu N. Androgen metabolism in cultured rat renal inner medullary collecting duct (IMCD) cells. Steroids 63: 105–110, 1998.
Miller JA, Anacta LA, and Cattran C. Impact of gender on the renal response to angiotensin II. Kidney Int 55: 278–285, 1999.
Modlinger P, Wilcox C, and Aslan S. Nitric oxide, oxidative stress and progression of chronic renal failure. Semin Nephrol 24: 354–365, 2004.
Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M, Li H, Bodenschatz H, August M, Kleschyov A, Tsilimingas N, Walter F, Forstermann U, Meinertz T, Griendling K, and Munzel T. Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 90: E58–E65, 2002.
Muller V, Losonczy G, Heemann U, Vannay A, Fekete A, Reusz G, Tulassay T, and Szabo A. Sexual dimorphism in renal ischemia-reperfusion injury in rats: possible role of endothelin. Kidney Int 62: 1364–1371, 2002.
Neirman DM and Mechanick JI. Hypotestosteronemia in chronically critically ill men. Crit Care Med 27: 2418–2421, 1999.
Neugarten J, Acharya A, and Silbiger SR. Effect of gender on the progression of nondiabetic renal disease: a meta-analysis. J Am Soc Nephrol 11: 319–329, 2000.
Neugarten J, Kasiske B, Silbiger SR, and Nyengaard JR. Effects of sex on renal structure. Nephron 90: 139–144, 2002.
Nickenig G, Baumer AT, Grohe C, Kahlert S, Strehlow K, Rosenkranz S, Stablein A, Beckers F, Smits JFM, Daemen MJAP, Vetter H, and Bohm M. Estrogen modulates AT1 receptor gene expression in vitro and in vivo. Circulation 97: 2197–2201, 1998.
Ortmann J, Amann K, Brandes R, Kretzler M, Munter K, Parekh N, Traupe T, Lange M, Lattmann T, and Barton M. Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition. Hypertension 44: 974–981, 2004.
Overlie I, Moen MH, Morkrid L, Skjaeraasen JS, and Holte A. The endocrine transition around menopause—a five years prospective study with profiles of gonadotropins, estrogens, androgens and SHBG among healthy women. Acta Obstet Gynecol Scand 78: 642–647, 1999.
Phillips GBJT, Resnick LM, Barbagallo M, Laragh JH, and Sealey JE. Sex hormones and hemostatic factors for coronary heart disease in men with hypertension. J Hypertension 11: 699–702, 1993.
Quan A, Chakravarty S, Chen JK, Chen JC, Loleh S, Saini N, Harris R, Capdevila J, and Quigley R. Androgens augment proximal tubule transport. Am J Physiol Renal Physiol 287: F452–F459, 2004.
Quinkler M, Bumke-Vogt C, Meyer B, Bahr V, Oelkers W, and Diederich S. The human kidney is a progesterone-metabolizing and androgen-producing organ. J Clin Endocrinol Metab 88: 2803–2809, 2003.
Rajagopalan K, Kurz S, Munzel T, Tarpey M, Freeman B, Griendling K, and Harrison D. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 97: 1916–1923, 1996.
Reckelhoff JF. Gender differences in the regulation of blood pressure. Hypertension 37: 1199–1208, 2001.
Reckelhoff JF, Hennington B, Moore A, Blanchard E, and Cameron J. Gender differences in the renal nitric oxide (NO) system. Dissociation between expression of endothelial NO synthase and renal hemodynamic response to NO synthase inhibition. Am J Hypertens 11: 97–104, 1998.
Reckelhoff JF, Hennington BS, Kanji V, Racusen LC, Schmidt AM, Yan SD, Morrow JD, Roberts LJ II, and Salahudeen A. Chronic aminoguanidine attenuates renal dysfunction and injury in aging rats. Am J Hypertens 12: 492–498, 1999.
Reckelhoff JF, Kanji V, Racusen LC, Schmidt AM, Yan SD, Morrow JD, Roberts LJ II, and Salahudeen AK. Vitamin E ameliorates enhanced renal lipid peroxidation and accumulation of F2-isoprostanes in aging kidneys. Am J Physiol Regul Integr Comp Physiol 274: R767–R774, 1998.
Reckelhoff JF and Manning, RD Jr. Role of endothelial-derived nitric oxide in the control of the renal microvasculature in aging male rats. Am J Physiol Regul Integr Comp Physiol 265: R1126–R1131, 1993.
Reckelhoff JF and Romero JC. Role of oxidative stress in angiotensin-induced hypertension. Am J Physiol Regul Integr Comp Physiol 284: R893–R912, 2003.
Reckelhoff JF, Samsell L, Dey R, Racusen L, and Baylis C. The effect of aging on glomerular hemodynamics in the rat. Am J Kidney Dis 20: 70–75, 1992.
Reckelhoff JF, Zhang H, and Granger JP. Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats. Hypertension 31: 435–439, 1998.
Reckelhoff JF, Zhang H, and Srivastava K. Gender differences in the development of hypertension in SHR: role of the renin-angiotensin system. Hypertension 35: 480–483, 2000.
Reckelhoff JF, Zhang H, Srivastava K, Roberts LJ II, Morrow J, and Romero JC. Subpressor doses of angiotensin II increases plasma F2-isoprostanes in rats. Hypertension 35: 476–479, 2000.
Roberts LJ II and Reckelhoff JF. Measurement of F2-isoprostanes unveils profound oxidative stress in aged rats. Biochem Biophys Res Commun 87: 254–256, 2001.
Rowland NE and Fregly MJ. Role of gonadal hormones in hypertension in the Dahl salt-sensitive rat. Clin Exp Hypertens A 14: 367–375, 1992.
Schmidt A, Luger A, and Walter Horl. Sexual hormone abnormalities in male patients with renal failure. Nephrol Dial Transplant 17: 368–371, 2002.
Schultheiss D, Machtens S, and Jonas U. Testosterone therapy in the ageing male: what about the prostate Andrologia 36: 355–365, 2004.
Silbiger SR and Neugarten J. The role of gender in the progression of renal disease. Adv Ren Replace Ther 10: 3–14, 2003.
Sluijmer A, Heineman M, Konstaal J, Theunissen P, deJong F, and Evers J. Relationship between ovarian production of estrone, estradiol, testosterone and androstenedione and the ovarian degree of stromal hyperplasia in postmenopausal women. Menopause 3: 207–216, 1998.
Sorokin A and Kohan D. Physiology and pathology of endothelin-1 in renal mesangium. Am J Physiol Renal Physiol 285: F579–F589, 2003.
Spark RF. Intrinsa fails to impress FDA advisory panel. Int J Impot Res 17: 283–284, 2005.
Terada N, Arai Y, Kinukawa N, Yoshimura K, and Terai A. Risk factors for renal cysts. BJU Int 93: 1300–1302, 2004.
Turner H and Wass J. Declining gonadal function in men with chronic disease. Clin Endocrinol 47: 379–403, 1997.
Van Kesteren PJ, Kooistra T, Lansink M, van Kamp GJ, Asscheman H, Gooren LJ, Emeis JJ, Vischer UM, and Stehouwer CD. The effects of sex steroids on plasma levels of marker proteins of endothelial cell functioning. Thromb Haemost 79: 1029–1033, 1998.
Vermeulen A, Rubens R, and Verdonck L. Testosterone secretion and metabolism in male senescence. J Clin Endocrinol Metab 34: 730–735, 1979.
Wagner A, Schroeter M, and Hecker M. 17-Estradiol inhibition of NADPH oxidase expression in human endothelial cells. FASEB J 15: 2121–2130, 2001.
Weinberger M. Sodium and blood pressure 2003. Curr Opin Cardiol 19: 353–356, 2004.
Wiinber N, Hoegholm A, Christensen H, Bang L, Mikkelsen K, Nielsen P, Svendsen T, Kampmann J, Madsen N, and Bentzon M. 24-h Ambulatory blood pressure in 352 normal Danish subjects, related to age and gender. Am J Hypertens 8: 978–986, 1995.
Yanes LL, Romero D, Cucchiarelli V, Fortepiani LA, Gomez-Sanchez C, Santacruz F, and Reckelhoff JF. Role of endothelin in mediating postmenopausal hypertension in a rat model. Am J Physiol Regul Integr Comp Physiol 288: R229–R233, 2005.(Jane F. Reckelhoff, Licy )
ABSTRACT
Treatment of aging men and women with testosterone supplements is increasing. The supplements are given to postmenopausal women mainly to improve their libido and to aging men to improve muscle mass and bone strength, to improve libido and quality of life, to prevent and treat osteoporosis, and, with the phosphodiesterase-5 inhibitors, such as sildenafil, to treat erectile dysfunction. The increased use of testosterone supplements in aging individuals has occurred despite the fact that there have been no rigorous clinical trials examining the effects of chronic testosterone on the cardiovascular-renal disease risk. Studies in humans and animals have suggested that androgens can increase blood pressure and compromise renal function. Androgens have been shown to increase tubular sodium and water reabsorption and activate various vasoconstrictor systems in the kidney, such as the renin-angiotensin system and endothelin. There is also evidence that androgens may increase oxidative stress. Furthermore, the kidney contains the enzymes necessary to produce androgens de novo. This review presents an overview of the data from human and animal studies in which the role of androgens in promoting renal and cardiovascular diseases has been investigated.
androgen receptor; oxidative stress; angiotensin II; endothelin; cytokines
THE USE OF TESTOSTERONE SUPPLEMENTS in aging men and women has increased in recent years. Aging men take testosterone supplements to improve muscle mass and bone strength, to improve libido and quality of life, to prevent and treat osteoporosis, and, with the phosphodiesterase-5 inhibitors, to treat erectile dysfunction. Postmenopausal women receive testosterone supplements mainly to improve their libido. In addition to physicians prescribing testosterone supplements, individuals are able to buy androgens, such as androstenedione, over the counter in health food stores. Serum testosterone levels that are achieved with supplements range from physiological to supraphysiological levels (sometimes as high as 3- to 16-fold higher in men and women than physiological levels) depending on the preparation, dose, and method of administration (9, 13, 42). While urologists are sounding the alarm for caution in using testosterone supplements because of their potential to increase the incidence of prostatic cancer (75), there have been few clinical trials to study the safety of testosterone supplements in aging men and/or women in terms of their effect on cardiovascular-renal disease. Earlier this year, the Food and Drug Administration refused to approve the testosterone "patch" for use in postmenopausal women, however, due to the possibility of cardiovascular side effects (79). In this review, research regarding the impact of androgens on cardiovascular and renal disease from human and animal studies will be discussed.
CHANGES IN TESTOSTERONE WITH AGE
Several cross-sectional (20, 83) and longitudinal (19, 28) studies documented a decline in total and bioavailable circulating testosterone levels with aging in men. More than 60% of healthy, elderly men over 65 yr of age have free testosterone levels below the normal values of men aged 30–35 yr. Because androgen receptors are upregulated in the presence of androgens and downregulated in its absence, it is likely that a reduction in androgen receptors may occur with aging as well. There have been studies in which the expression of androgen receptors in aging men was reduced in reproductive tissues, but there have been no studies in which the expression of androgen receptors has been studied in nonreproductive tissues in aging individuals. The decrease in androgen levels with aging in men appears to be the result of both gonadal and hypothalamic-pituitary failure and is independent of chronic illness, obesity, or medication (28). However, chronic illnesses (52), such as hypertension (81), diabetes (10), chronic kidney disease (33, 74), and end-stage renal disease (38, 39), are associated with a further reduction in serum testosterone levels in men of all ages. The fact that androgen levels decrease with age have led scientists to presume that androgens do not play a role in chronic cardiovascular and renal disease in aging men. However, growing evidence indicates that testosterone, even at levels observed in aging men, can have adverse consequences on cardiovascular-renal function.
Serum testosterone levels are significantly lower in women than in men, and whether serum testosterone levels decrease after menopause is not clear. The conventional wisdom is that androgen levels, like estrogen, do decrease with age in women. However, Jiroutek and colleagues (37) reported that postmenopausal women who were followed for 10 yr after cessation of cycling and had serial measurements of sex hormones showed increases in serum testosterone and androstenedione and decreases in serum estradiol and dihydrotestosterone as they aged. Other investigators have observed that serum testosterone either does not change (30) or is decreased in postmenopausal women (57). In cross-sectional studies of women in the Rancho Bernardo cohort, Laughlin and colleagues (45) reported that serum testosterone decreased immediately following menopause, but thereafter increased with age, reaching premenopausal levels by 70–79 yr. In addition, these investigators found that women who had undergone surgical menopause did not show increases in testosterone with age and the levels of serum testosterone were 40–50% lower than in women who had undergone natural menopause. These data support the contention that the natural postmenopausal period in a woman's life is a relatively hyperandrogenic state (2, 44, 60). Furthermore, Sluijmer and colleagues (77) found that the degree of ovarian stromal hyperplasia, a common characteristic of the ovaries in postmenopausal women, is not correlated with the level of estrone and estradiol measured in the ovarian vein but is positively correlated with the level of testosterone and androstenedione. For example, women with atrophic ovaries had little testosterone measured in the ovarian vein, whereas women with moderate to severe hyperplasia had larger levels of ovarian testosterone produced. In addition, the incidence and degree of stromal hyperplasia were quite variable among the women (77). Because the extent of ovarian stromal hyperplasia is rarely measured in most studies of postmenopausal women, this could explain the discrepancies in androgen levels found in various studies.
ANDROGENS AND CONTROL OF BLOOD PRESSURE
There is growing evidence that androgens can influence blood pressure regulation. Men have higher blood pressure than do women for most of their lives (41, 86). Following menopause, however, blood pressure increases in women to levels not different or even higher than in men (7). The prevalence of hypertension is also higher in men than women until after menopause (7). However, hypertensive men have been shown to have lower serum testosterone levels than normotensive men of the same age (81). These data have called into question the role that androgens could play in mediating or promoting hypertension.
Although there have been few studies in men in which the role of androgens in mediating higher blood pressure has been examined, there are several animal models in which a sex difference in blood pressure has been described and the role of androgens has been studied. For example, the spontaneously hypertensive rat (SHR) is a model of hypertension that is androgen mediated (62, 68). Following puberty, males have higher blood pressure than females (68) (see Fig. 1). Castration of males is associated with reductions in blood pressure to the levels found in females. Furthermore, testosterone treatment of ovariectomized females increases their blood pressure in a dose-dependent manner (68, 69). Sex differences in blood pressure have also been found in Dahl salt-sensitive (DS) rats on a high-salt diet (32). The DS males have higher blood pressure than females when placed on 4% salt diets despite the fact that high-salt diet for 3 wk reduces serum testosterone levels in the males by 50% (n = 5/group) (Yanes LL, Iliescu R, and Reckelhoff JF, unpublished observations). Early studies failed to show a reduction in blood pressure with castration in the male DS on a high-salt diet (73). However, as shown in Fig. 2, we have found that castration attenuates the hypertensive response to high salt in male DS. These data support the contention that despite reductions in serum testosterone in DS males with high salt, there is still enough androgen present to play a role in mediating the salt-induced hypertension. It should be noted, however, that testosterone replacement studies have not been performed yet. Thus it is possible that other factors may play a role in the lower blood pressure with castration, although we doubt this will be the case. Nongenetic models of hypertension also exhibit sex differences, such as DOCA-salt-treated rats, in which the hypertension is more severe in males than females (11), but to our knowledge, serum testosterone levels have not been reported for rats receiving DOCA and salt.
ANDROGENS AND RENAL DISEASE
Androgens in the Kidney
To date, there is a paucity of data regarding the role of androgens and the androgen receptor in regulating renal function. However, the kidney expresses the enzymes capable of producing testosterone and the androgen receptor. For example, Quinkler and colleagues (60) found that kidney tissue obtained from tumor nephrectomy samples from postmenopausal women express 5-reductase type 1, 3-hydroxysteroid dehydrogenase type 2, and 17-hydroxylase/17,20 lyase (P450c17) (see Fig. 3). They also found that radiolabeled pregnenolone, produced from cholesterol, was converted effectively to dehydroepiandrosterone (DHEA), and radiolabeled DHEA was converted via androstenedione to testosterone and dihydrotestosterone. Whether androgens can be produced in kidneys of men via these enzymes was not determined in these studies but is highly likely. In support of this hypothesis, in male rats, treatment of inner medullary collecting duct primary cultures with radiolabeled testosterone or androstenedione resulted in production of 5-dihydrotestosterone and 5-androstanedione (47). Androgen receptor expression has been found in the proximal tubule and in the cortical collecting ducts of human kidneys (43).
Androgens and Proximal Tubule Reabsorption
One of the most important recent findings regarding the effect of androgens in the kidney is the work of Quan and colleagues (59), who found by micropuncture studies that chronic (10 days) dihydrotestosterone (DHT) injections in Sprague-Dawley rats caused an increase in the proximal tubule volume reabsorption, which could be reduced with blockade of the renin-angiotensin system (RAS). Blood pressure was higher in the DHT-treated rats, but the glomerular filtration rate (GFR) was not affected nor was AT1 receptor binding. This is in contrast to acute infusion of testosterone, which causes renal vasodilation with increases in GFR and renal plasma flow and reductions in renal vascular resistance (Reckelhoff JF, unpublished observations). The data of Quan and colleagues (59) suggest that, in the chronic situation, androgens may upregulate ANG II and the Na/H exchanger, leading to increases in sodium and water reabsorption and elevations in blood pressure.
Androgens and Chronic Renal Disease
As in other chronic diseases, serum androgen levels are decreased in men with renal insufficiency (33, 74). Despite the reduction in androgens that occurs with aging, men progress to chronic renal failure at a more rapid rate than do women, even for similar levels of blood pressure (53). For example, Neugarten and colleagues (53) performed a meta-analysis of studies including 11,345 subjects and found that renal disease independent of diabetes progresses at a more rapid rate in men. Several renal diseases are also more common in men than women. Polycystic kidney disease (24, 80) and IgA nephropathy (27) are more common in men and progress more rapidly in men than women. Age-related reductions in renal function also progress at a more rapid rate in men than women (76). Despite the gender differences in the progression of chronic renal disease, Neugarten and colleagues (54) reported that there are few sex differences in normal renal structure that could account for these observations. For example, glomerular number was similar in men and women, and the glomerular volume and kidney weight were similar when corrected for body weight of the individuals.
In aging rats, serum testosterone levels also decrease with age as found in men. Several investigators have reported that normotensive and hypertensive males experience a more rapid reduction in GFR and more renal injury with age than do females (6, 22, 64–66, 68). However, the reduction in GFR cannot be fully accounted for by the level of glomerular injury found in the kidneys (22, 68). For example, in old male Sprague-Dawley rats aged 20–22 mo, a model of accelerated renal aging, GFR was reduced by 50% compared with young males and yet only 20% of their glomeruli exhibited any injury (68). These data suggest that aging is a state of renal vasoconstriction. We have made similar findings in the aging SHR. In old male SHR, renal vascular resistance was increased by 30%, whereas blood pressure was only increased by 10% compared with young SHR (22). As in normotensive rats, the reductions in GFR in old male SHR cannot be explained by glomerular injury because <10% of glomeruli are injured in these rats at 18 mo of age, whereas GFR was reduced by 30% (22). In more recent studies in SHR, we found that castration of aging males completely prevents reductions in GFR and glomerular injury (22). In addition, castration prevents the increase in renal vascular resistance found in aging male SHR despite a significant age-related reduction in serum androgens in the intact male. Taken together, these data suggest that remnant androgens mediate the reductions in renal function in the aging animal.
In another model of hypertension and renal injury that is not genetically mediated, the renal wrap hypertension model, Ji and colleagues (36) recently reported that castration of male rats attenuated the glomerular injury and proteinuria. When castrated rats were treated with DHT, the glomerular injury was exacerbated. Similarly, in renal wrap female rats that were ovariectomized (a model of ovarian hormone deficiency), testosterone treatment also exacerbated renal injury and proteinuria. Thus there is compelling evidence that indicates that testosterone promotes renal injury and declines in renal function.
Androgens and the RAS in the Kidney
Androgens play a role in modulating the RAS. Several groups have shown that androgens can stimulate the upregulation of angiotensinogen in the kidneys of normotensive and hypertensive rats (8, 18). In addition, Chen and colleagues (8) reported that renin mRNA was upregulated by androgens in kidneys of SHR. These data suggest that androgens can stimulate the intrarenal RAS. Furthermore, Baltatu and colleagues (4) also reported that renal injury could be abolished by androgen receptor antagonism in a Ren-2 rat model of hypertension that has an overactive RAS.
How androgens affect the systemic RAS is not clear. In humans, plasma renin activity (PRA) is higher in men than in age-matched premenopausal women (35, 58). We have found previously that testosterone repletion in castrated normotensive rats leads to a dose-dependent increase in PRA (62), which is consistent with the data from human studies. In contrast, Quan et al. (59) found that chronic DHT treatment reduced serum ANG II levels. While estradiol has been shown to modulate the synthesis of AT1 receptors in various tissues, including kidneys and vasculature (29, 55), androgens have only been shown to increase AT1 receptor expression in male reproductive tissues (46). Therefore, the effect of androgens on AT1 receptor expression in kidneys should be examined.
There are gender differences in the renal response to infusion of ANG II as well. When graded doses of ANG II were infused into healthy young adults, there was a similar increase in blood pressure and reduction in effective renal plasma flow (ERPF) in men and women, but GFR was maintained in men only, leading to an increase in the filtration fraction (FF), which suggests an increase in glomerular capillary pressure (48). In women, the reduction in ERPF was associated with a concomitant reduction in GFR, resulting in no change in FF. These studies were performed without blockade of the endogenous RAS. Therefore, men may have been more responsive because they have higher basal levels of endogenous renal ANG II than women. In any case, these data further support the notion that the combination of androgens and ANG II is important in modulating renal function.
In SHR, blockade of the RAS with converting enzyme inhibitors (CEI) reduces blood pressure to the same level in both males and females (70), supporting the important role of the RAS in mediating the hypertension in SHR independently of the sex steroids. In addition, CEI also prevents increases in blood pressure in ovariectomized female SHR receiving chronic testosterone supplementation (70). These data suggest that an intact RAS is necessary for androgens to increase blood pressure in SHR. In other words, the mechanism by which androgens are capable of increasing blood pressure in SHR is mediated by their effects on the RAS.
Whether PRA and RAS activity decrease with age in men and women is somewhat controversial. However, James and colleagues (35) reported from serial analyses that PRA was higher in men than in age-matched women, that PRA was higher in postmenopausal women than in premenopausal ones, and that in white men, PRA did not decrease with age. Blood pressure becomes more salt sensitive with aging in both men and women (85), which suggests that RAS activity and ANG II do not respond appropriately in the presence of salt in aging individuals. Therefore, androgen supplements in aging individuals could be expected to both stimulate reabsorption in the proximal tubule and stimulate PRA, which would further aggravate hypertension and renal injury.
Androgens and Endothelin
Endothelin is a potent renal vasoconstrictor and mitogen that plays a role in renal injury associated with aging (5, 25, 26). Goddard and colleagues (26) reported that ETA receptor antagonism in individuals with chronic renal failure caused an increase in renal blood flow and a reduction in blood pressure mainly due to the activation of the ETB receptors, because combined ETA/B receptor antagonism reduced blood pressure but had no effect on renal function. In addition, Elijovich and colleagues (17) reported that hypertensive individuals with nephrosclerosis exhibited increased plasma endothelin that was independent of aldosterone:renin ratios but was positively correlated with the level of proteinuria. In aging male Wistar rats, Ortmann and colleagues (56) recently reported that glomerulosclerosis and proteinuria could be reversed when rats were given darusentan, an ETA receptor antagonist, independently of reductions in blood pressure, changes in renal function, or tubulointerstitial renal injury. In addition, endothelin-1 is secreted from mesangial cells in response to a variety of cytokines, hormones, and oxidative stress (78). There is also evidence that endothelin may play a role in the gender difference in the death rate of rats in response to renal ischemia-reperfusion (51). Muller and colleagues (51) found that 50 min of left vascular pedicle clamping resulted in death in 92% of male rats by day 7, but only 25% of females died during this time period. Castration reduced the number of deaths in males with ischemia-reperfusion to 33%, and pretreatment of males with an endothelin ETA receptor antagonist totally protected males from death (51).
Androgens can upregulate the production of endothelin. In female-to-male transsexuals who receive testosterone supplements chronically, plasma endothelin levels are elevated (82). In addition, in women who suffer from polycystic ovary syndrome, in which serum testosterone is elevated, endothelin is also elevated (15). Whether the effects of androgens on endothelin production are direct or mediated by the effects of androgens on the RAS, which, in turn, increases endothelin production (3), is not clear. In any case, androgen supplementation in both aging men and women could promote renal injury mediated via endothelin. This is especially important following menopause, because estradiol has been shown to reduce expression of endothelin (82), and thus this protection would be lost in postmenopausal women. In support of this hypothesis, we have found that the postmenopausal increases in blood pressure found in aging female SHR are mediated, in part, by endothelin (87). In contrast, endothelin plays no role in the hypertension of young female SHR (87).
Androgens and Oxidative Stress
The role of oxidative stress in acute renal failure and ischemia-reperfusion is widely accepted. However, oxidative stress also plays a role in chronic renal disease (1, 49). Men have higher levels of oxidative stress than do age-matched women as measured by F2-isoprostanes or thiobarbituric acid-reactive substances in plasma (34), despite the reduction in androgen levels in aging men. Postmenopausal women also exhibit higher levels of oxidative stress than premenopausal women (31). Oxidative stress is increased in the kidney with normal aging (72), and we have been able to protect against age-related renal injury in Sprague-Dawley rats by treating them chronically with vitamin E (65).
The major reactive oxygen species in the kidney is thought to be superoxide, which can quench nitric oxide (NO) (67), leading to a reduction in the NO bioavailability for dilation and thereby causing renal vasoconstriction. It is possible then that a reduction in vasodilator substances could play a role in the age-related renal vasoconstriction in males. We have found previously that there are sex differences in the renal vasculature response to NO. Young male normotensive rats without deficiencies in androgen synthesis are more dependent on the NO system for maintenance of renal hemodynamics than are age-matched females (63). Males had 80% lower renal expression of endothelial NO synthase compared with females, yet when NO synthase was blocked with nitro-L-arginine methyl ester, despite similar blood pressure increases in males and females, renal plasma flow (RPF) decreased by 40% and renal vascular resistance (RVR) increased by 23% in males compared with 20% and 60% for RPF and RVR, respectively, in females. The importance of the NO system in preserving renal hemodynamics is even more striking in aging males. When treated with NO synthase inhibitors, GFR and RPF decreased to a much greater extent and glomerular capillary pressure almost doubled in aging males compared with young males (66).
Whether androgens can directly produce oxidative stress has not been fully elucidated. In preliminary studies, we have found that physiological concentrations of dihydrotestosterone are capable of increasing dihydroethidium fluorescence in cultured SHR mesangial cells (Cucchiarelli V, Iliescu R, and Reckelhoff JF, unpublished observations). We have also found that castration reduces superoxide production in the kidneys of male SHR. In addition, tempol, a superoxide scavenger, reduces blood pressure and oxidative stress in young and aging male SHR but has little or no effect in females (21, 23).
Regardless of whether androgen supplementation directly causes oxidative stress, androgens can stimulate the RAS and endothelin production, which have been shown to increase reactive oxygen species. ANG II, at both supraphysiological and physiological levels, can increase oxidative stress (61, 71), mainly via upregulation of the subunits of NADPH oxidase (50). In addition, ANG II can stimulate the production of endothelin (3), which also causes oxidative stress by upregulating NADPH oxidase (16). Furthermore, while endothelin can cause oxidative stress, oxidative stress can also upregulate endothelin synthesis (40), setting up a vicious cycle.
Therefore, because aging is associated with increased oxidative stress, men at all ages have elevated levels of oxidative stress compared with women, and after menopause oxidative stress increases in women, androgen supplements could cause a further increase in oxidative stress in both men and women, leading to reductions in renal function and renal injury. The renal changes could be caused by the direct effect of androgens on oxidative stress or indirectly via their effect on the RAS or endothelin system. Furthermore, because estradiol is a mild antioxidant and has been shown to inhibit synthesis of NADPH oxidase (84), postmenopausal women would be at increased risk for androgen supplement-induced oxidative stress.
Androgens and Cytokines
Aging renal disease is associated with increases in inflammation and cytokine release. Both TNF- and IL-6 have been shown to upregulate or activate the androgen receptor (12, 14). In addition, upregulation of many inflammatory mediators involve the transcription factor, NF-B, and the androgen receptor promoter contains several NF-B enhancer elements. Although the role of the androgen receptor in the inflammation associated with aging renal disease has not been studied, it is attractive to propose that the androgen receptor could be upregulated in renal tissue in response to inflammation. Androgens have also been shown to activate a Fas/Fas ligand-dependent apoptotic pathway in proximal tubule cells, which is characteristic of chronic renal diseases (24). Androgens could, therefore, activate an apoptotic mechanism, leading to renal tubular loss and interstitial fibrosis in the elderly.
SUMMARY
Aging men and women frequently receive androgen supplements. Aging men are already at greater risk for cardiovascular and renal disease than women, despite the fact that serum testosterone levels decrease significantly with age and with chronic diseases. We hypothesize that the reduction in testosterone with age and chronic disease is a protective mechanism against even greater cardiovascular-renal disease incidence and poorer outcomes. Therefore, androgen supplements in aging men could offset this natural protective mechanism.
In women, menopause increases a woman's risk for cardiovascular and renal diseases. However, women are somewhat protected compared with men, but androgen supplements may increase the risk of renal injury and cardiovascular disease in postmenopausal women to levels similar to those in men. It is also possible that androgen levels may increase naturally with age in some women and may further impact disease risk factors naturally.
As with estradiol-progesterone replacement therapy in postmenopausal women, it is likely that some healthy, active, aging men and women would not have adverse cardiovascular consequences with androgen supplementation. However, in view of the increasing experimental evidence that androgens promote cardiovascular and renal disease, even when the serum levels are decreased, aging men and women who have the predisposition to cardiovascular-renal diseases should take androgen supplements with caution until rigorous clinical trials have been performed.
As shown in Fig. 4, we hypothesize that androgens can stimulate proximal reabsorption of sodium and water, causing a reduction in the sodium delivery to the macula densa, and, by tubuloglomerular feedback, cause a reduction in afferent resistance that could lead to an increase in glomerular capillary pressure. Androgens could also activate the RAS, leading to further increases in tubular sodium reabsorption, but also increases in efferent resistance and glomerular capillary pressure. ANG II has been shown to increase endothelin synthesis and upregulate NADPH oxidase to increase oxidative stress. Endothelin has also been shown to increase oxidative stress. Furthermore, androgens may directly increase both endothelin and oxidative stress. ANG II, endothelin, and oxidative stress can then increase blood pressure, leading to further increases in glomerular pressure, ultimately leading to glomerular injury and loss of renal function.
GRANTS
This work was supported by National Heart, Lung, and Blood Institute Grants HL-66072, HL-69194, and HL-05197.
FOOTNOTES
REFERENCES
Agarwal R. Chronic kidney disease is associated with oxidative stress independent of hypertension. Clin Nephrol 61: 377–383, 2004.
Ala-Fossi SL, Maenpaa J, Aine R, and Punnonen R. Ovarian testosterone secretion during perimenopause. Maturitas 29: 239–245, 1998.
Alexander BT, Cockrell KL, Rinewalt AN, Herrington JN, and Granger JP. Enhanced renal expression of preproendothelin mRNA during chronic angiotensin II hypertension. Am J Physiol Regul Integr Comp Physiol 280: R1388–R1392, 2001.
Baltatu O, Cayla C, Iliescu R, Andrew D, Jordan C, and Bader M. Abolition of hypertension-induced end organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene. J Am Soc Nephrol 13: 2681–2687, 2002.
Barton M, Lattmann T, d'Ushio LV, Luscher TF, and Shaw S. Inverse regulation of endothelin-1 and nitric oxide metabolites in tissue with aging: implications for the age-dependent increase of cardiorenal disease. J Cardiovasc Pharmacol 36: S153–S156, 2000.
Baylis C. Age-dependent glomerular damage in the rat. Dissociation between glomerular injury and both glomerular hypertension and hypertrophy. Male gender as a primary risk factor. J Clin Invest 94: 1823, 1994.
Burl VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ, and Labarthe D. Prevalence of hypertension in the US adult population. Results from the third National Health and Nutrition Examination Survey, 1988–1991. Hypertension 25: 305–313, 1995.
Chen YF, Naftilan AJ, and Oparil S. Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats. Hypertension 19: 456–463, 1992.
Cherrier MM, Matsumoto AM, Amory JK, Ahmed S, Bremner W, Peskind ER, Raskind MA, Johnson M, and Craft S. The role of aromatization in testosterone supplementation. Effects on cognition in older men. Neurology 64: 290–296, 2005.
Corrales JJ, Burgo RM, Garca-Berrocal B, Almeida M, Alberca I, Gonzalez-Buitrago JM, Orfao A, and Miralles JM. Partial androgen deficiency in aging type 2 diabetic men and its relationship to glycemic control. Metabolism 53: 666–672, 2004.
Crofton JT and Share L. Gonadal hormones modulate deoxycorticosterone-salt hypertension in male and female rats. Hypertension 29: 494–499, 1997.
Culig Z. Androgen receptor cross-talk with cell -signalling pathways. Growth Factors 22: 179–184, 2004.
Davison S, Thipphawong J, Blanchard J, Liu K, Morishinge R, Gonda I, Okikawa J, Adams J, Evans A, Otulana B, and Davis S. Pharmacokinetics and acute safety of inhaled testosterone in postmenopausal women. J Clin Pharmacol 45: 177–184, 2005.
Delfino FJ, Boustead JN, Fix C, and Walker WH. NF-B and TNF- stimulate androgen receptor expression in Sertoli cells. Mol Cell Endocrinol 201: 1–12, 2003.
Diamanti-Kandarakis E, Spina G, Kouli C, and Migdalis I. Increase in endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin treatment. J Clin Endocrinol Metab 86: 4666–4673, 2001.
Duerrschmidt N, Wippich N, Goettsch W, Broemme HJ, and Morawietz H. Endothelin-1 induces NAD(P)H oxidase in human endothelial cells. Biochem Biophys Res Commun 269: 713–717, 2000.
Elijovich F, Laffer CL, Schiffrin EL, Gavras H, and Amador E. Endothelin-aldosterone interaction and proteinuria in low-renin hypertension. J Hypertens 22: 573–582, 2004.
Ellison KE, Ingelfinger JR, Pivor M, and Dzau VJ. Androgen regulation of rat renal angiotensinogen messenger RNA expression. J Clin Invest 83: 1941–1945, 1989.
Feldman H, Longcope C, Derby C, Johannes C, Araujo A, Coviello A, Bremner W, and McKinlay J. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 87: 589–598, 2002.
Ferrini R and Barrett-Conner E. Sex hormones and age—a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am J Epidemiol 147: 750–754, 1998.
Fortepiani LA and Reckelhoff JF. Tempol from birth abrogates the sex difference in the depressor response to tempol in SHR. J Hypertens. In press.
Fortepiani LA, Yanes L, Zhang H, Racusen LC, and Reckelhoff JF. Role of androgens in mediating renal injury in aging SHR. Hypertension 42: 952–955, 2003.
Fortepiani LA, Zhang H, Racusen LC, Roberts LJII, and Reckelhoff JF. Characterization of an animal model of postmenopausal hypertension in SHR. Hypertension 41: 460–463, 2003.
Gandolfo MT, Verzola D, Salvatore F, Gianiorio G, Procopio V, Romagnoli A, Giannoni M, and Garibotto G. Gender and the progression of chronic renal diseases: does apoptosis make the difference Minerva Urol Nefrol 56: 1–14, 2004.
Goddard J, Eckart C, Johnston NR, Cumming AD, Rankin AJ, and Webb DJ. Endothelin A receptor antagonism an angiotensin-converting enzyme inhibition are synergistic via an endothelin B receptor-mediated and nitric oxide-dependent mechanism. J Am Soc Nephrol 15: 2601–2610, 2004.
Goddard J, Johnston NR, Hand MF, Cumming AD, Rabelink TJ, Ranki AJ, and Webb DJ. Endothelin-A receptor antagonism reduces blood pressure and increases renal blood flow in hypertensive patients with chronic renal failure: a comparison of selective and combined endothelin-receptor blockade. Circ 109: 1186–1193, 2004.
Hall YN, Fuentes EF, Chertow GM, and Olson JL. Race/ethnicity and disease severity in IgA nephropathy. BMC Nephrol 5: 10, 2004.
Harman S, Metter E, Tobin J, Pearson J, and Blackman M. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86: 724–731, 2001.
Harrison-Bernard L, Schulman I, and Raij L. Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity. Hypertension 42: 1157–1163, 2003.
Hartmann BW, Kirchengast S, Albrecht A, Laml T, Soregi G, and Huber JC. Androgen serum levels in women with premature ovarian failure compared to fertile and menopausal controls. Gynecol Obstet Invest 44: 127–131, 1997.
Helmersson J, Mattson P, and Basu S. Prostaglandin F2 metabolite and F2-isoprostane excretion in migraine. Clin Sci (Lond) 102: 39–43, 2002.
Hinojosa-Laborde C, Lange DL, and Haywood JR. Role of female sex hormones in the development and reversal of Dahl hypertension. Hypertension 35: 484–489, 2000.
Holley JL. The hypothalamic-pituitary axis in men and women with chronic kidney disease. Adv Chronic Kidney Dis 11: 337–341, 2004.
Ide T, Tsutsui H, Ohashi N, Hayashidani S, Suematsu N, Tsuchihyasm M, Tamai H, and Takeshita A. Greater oxidative stress in healthy young men compared with premenopausal women. Arterioscler Thromb Vasc Biol 22: 1239–1242, 2002.
James GD, Sealey JE, Muller F, Alderman M, Madhavan S, and Laragh JH. Renin relationship to sex, race and age in normotensive population. J Hypertens 4: S387–S389, 1986.
Ji H, Menini S, Mok K, Zheng W, Pesce C, Kim J, Mulroney S, and Sandberg K. Gonadal steroid regulation of renal injury in renal wrap hypertension. Am J Physiol Renal Physiol 288: F513–F520, 2005.
Jiroutek MR, Chen MH, Johnston CC, and Longcope C. Changes in reproductive hormones and sex hormone-binding globulin in a group of postmenopausal women measured over 10 years. Menopause 5: 90–94, 1998.
Johansen KL. Treatment of hypogonadism in men with chronic kidney disease. Adv Chronic Kidney Dis 11: 348–356, 2004.
Johansen KL. Testosterone metabolism and replacement therapy in patients with end stage renal disease. Semin Dial 17: 202–208, 2004.
Kaehler J, Sill B, Koester R, Mittmann C, Orzechowski HD, Muenzel T, and Meinertz T. Endothelin-1 mRNA and protein in vascular wall cells is increased by reactive oxygen species. Clin Sci (Lond) 103, Suppl 48: 176S–178S, 2002.
Khoury S, Yarows SA, O'Brien TK, and Sowers JR. Ambulatory blood pressure monitoring in a nonacademic setting. Effects of age and sex. Am J Hypertension 5: 616–623, 1992.
Kicman AT, Bassindale T, Cowan DA, Dale S, Hutt AJ, and Leeds AR. Effect of androstenedione ingestion on plasma testosterone in young women; a dietary supplement with potential health risks. Clin Chem 49: 167–169, 2003.
Kimura N, Mizokami A, Oonuma T, Sasano H, and Nagura H. Immunocytochemical localization of androgen receptor with polyclonal antibody in paraffin-embedded human tissues. J Histochem Cytochem 41: 671–678, 1993.
Krug E and Berga SL. Postmenopausal hyperthecosis: functional dysregulation of androgenesis in climacteric ovary. Obstet Gynecol 99: 893–897, 2002.
Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, and von Muhlen D. Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Endocrinol Metab 85: 645–651, 2000.
Leung PS, Wong TP, Chung YW, and Chan HC. Androgen dependent expression of AT1 receptor and its regulation of anion secretion in the rat epididymis. Cell Biol Int 26: 117–122, 2002.
Matsuzaki K, Arai T, Inumaru T, Mihori M, Momose T, Sano M, Koide K, and Shimizu N. Androgen metabolism in cultured rat renal inner medullary collecting duct (IMCD) cells. Steroids 63: 105–110, 1998.
Miller JA, Anacta LA, and Cattran C. Impact of gender on the renal response to angiotensin II. Kidney Int 55: 278–285, 1999.
Modlinger P, Wilcox C, and Aslan S. Nitric oxide, oxidative stress and progression of chronic renal failure. Semin Nephrol 24: 354–365, 2004.
Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M, Li H, Bodenschatz H, August M, Kleschyov A, Tsilimingas N, Walter F, Forstermann U, Meinertz T, Griendling K, and Munzel T. Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 90: E58–E65, 2002.
Muller V, Losonczy G, Heemann U, Vannay A, Fekete A, Reusz G, Tulassay T, and Szabo A. Sexual dimorphism in renal ischemia-reperfusion injury in rats: possible role of endothelin. Kidney Int 62: 1364–1371, 2002.
Neirman DM and Mechanick JI. Hypotestosteronemia in chronically critically ill men. Crit Care Med 27: 2418–2421, 1999.
Neugarten J, Acharya A, and Silbiger SR. Effect of gender on the progression of nondiabetic renal disease: a meta-analysis. J Am Soc Nephrol 11: 319–329, 2000.
Neugarten J, Kasiske B, Silbiger SR, and Nyengaard JR. Effects of sex on renal structure. Nephron 90: 139–144, 2002.
Nickenig G, Baumer AT, Grohe C, Kahlert S, Strehlow K, Rosenkranz S, Stablein A, Beckers F, Smits JFM, Daemen MJAP, Vetter H, and Bohm M. Estrogen modulates AT1 receptor gene expression in vitro and in vivo. Circulation 97: 2197–2201, 1998.
Ortmann J, Amann K, Brandes R, Kretzler M, Munter K, Parekh N, Traupe T, Lange M, Lattmann T, and Barton M. Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition. Hypertension 44: 974–981, 2004.
Overlie I, Moen MH, Morkrid L, Skjaeraasen JS, and Holte A. The endocrine transition around menopause—a five years prospective study with profiles of gonadotropins, estrogens, androgens and SHBG among healthy women. Acta Obstet Gynecol Scand 78: 642–647, 1999.
Phillips GBJT, Resnick LM, Barbagallo M, Laragh JH, and Sealey JE. Sex hormones and hemostatic factors for coronary heart disease in men with hypertension. J Hypertension 11: 699–702, 1993.
Quan A, Chakravarty S, Chen JK, Chen JC, Loleh S, Saini N, Harris R, Capdevila J, and Quigley R. Androgens augment proximal tubule transport. Am J Physiol Renal Physiol 287: F452–F459, 2004.
Quinkler M, Bumke-Vogt C, Meyer B, Bahr V, Oelkers W, and Diederich S. The human kidney is a progesterone-metabolizing and androgen-producing organ. J Clin Endocrinol Metab 88: 2803–2809, 2003.
Rajagopalan K, Kurz S, Munzel T, Tarpey M, Freeman B, Griendling K, and Harrison D. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 97: 1916–1923, 1996.
Reckelhoff JF. Gender differences in the regulation of blood pressure. Hypertension 37: 1199–1208, 2001.
Reckelhoff JF, Hennington B, Moore A, Blanchard E, and Cameron J. Gender differences in the renal nitric oxide (NO) system. Dissociation between expression of endothelial NO synthase and renal hemodynamic response to NO synthase inhibition. Am J Hypertens 11: 97–104, 1998.
Reckelhoff JF, Hennington BS, Kanji V, Racusen LC, Schmidt AM, Yan SD, Morrow JD, Roberts LJ II, and Salahudeen A. Chronic aminoguanidine attenuates renal dysfunction and injury in aging rats. Am J Hypertens 12: 492–498, 1999.
Reckelhoff JF, Kanji V, Racusen LC, Schmidt AM, Yan SD, Morrow JD, Roberts LJ II, and Salahudeen AK. Vitamin E ameliorates enhanced renal lipid peroxidation and accumulation of F2-isoprostanes in aging kidneys. Am J Physiol Regul Integr Comp Physiol 274: R767–R774, 1998.
Reckelhoff JF and Manning, RD Jr. Role of endothelial-derived nitric oxide in the control of the renal microvasculature in aging male rats. Am J Physiol Regul Integr Comp Physiol 265: R1126–R1131, 1993.
Reckelhoff JF and Romero JC. Role of oxidative stress in angiotensin-induced hypertension. Am J Physiol Regul Integr Comp Physiol 284: R893–R912, 2003.
Reckelhoff JF, Samsell L, Dey R, Racusen L, and Baylis C. The effect of aging on glomerular hemodynamics in the rat. Am J Kidney Dis 20: 70–75, 1992.
Reckelhoff JF, Zhang H, and Granger JP. Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats. Hypertension 31: 435–439, 1998.
Reckelhoff JF, Zhang H, and Srivastava K. Gender differences in the development of hypertension in SHR: role of the renin-angiotensin system. Hypertension 35: 480–483, 2000.
Reckelhoff JF, Zhang H, Srivastava K, Roberts LJ II, Morrow J, and Romero JC. Subpressor doses of angiotensin II increases plasma F2-isoprostanes in rats. Hypertension 35: 476–479, 2000.
Roberts LJ II and Reckelhoff JF. Measurement of F2-isoprostanes unveils profound oxidative stress in aged rats. Biochem Biophys Res Commun 87: 254–256, 2001.
Rowland NE and Fregly MJ. Role of gonadal hormones in hypertension in the Dahl salt-sensitive rat. Clin Exp Hypertens A 14: 367–375, 1992.
Schmidt A, Luger A, and Walter Horl. Sexual hormone abnormalities in male patients with renal failure. Nephrol Dial Transplant 17: 368–371, 2002.
Schultheiss D, Machtens S, and Jonas U. Testosterone therapy in the ageing male: what about the prostate Andrologia 36: 355–365, 2004.
Silbiger SR and Neugarten J. The role of gender in the progression of renal disease. Adv Ren Replace Ther 10: 3–14, 2003.
Sluijmer A, Heineman M, Konstaal J, Theunissen P, deJong F, and Evers J. Relationship between ovarian production of estrone, estradiol, testosterone and androstenedione and the ovarian degree of stromal hyperplasia in postmenopausal women. Menopause 3: 207–216, 1998.
Sorokin A and Kohan D. Physiology and pathology of endothelin-1 in renal mesangium. Am J Physiol Renal Physiol 285: F579–F589, 2003.
Spark RF. Intrinsa fails to impress FDA advisory panel. Int J Impot Res 17: 283–284, 2005.
Terada N, Arai Y, Kinukawa N, Yoshimura K, and Terai A. Risk factors for renal cysts. BJU Int 93: 1300–1302, 2004.
Turner H and Wass J. Declining gonadal function in men with chronic disease. Clin Endocrinol 47: 379–403, 1997.
Van Kesteren PJ, Kooistra T, Lansink M, van Kamp GJ, Asscheman H, Gooren LJ, Emeis JJ, Vischer UM, and Stehouwer CD. The effects of sex steroids on plasma levels of marker proteins of endothelial cell functioning. Thromb Haemost 79: 1029–1033, 1998.
Vermeulen A, Rubens R, and Verdonck L. Testosterone secretion and metabolism in male senescence. J Clin Endocrinol Metab 34: 730–735, 1979.
Wagner A, Schroeter M, and Hecker M. 17-Estradiol inhibition of NADPH oxidase expression in human endothelial cells. FASEB J 15: 2121–2130, 2001.
Weinberger M. Sodium and blood pressure 2003. Curr Opin Cardiol 19: 353–356, 2004.
Wiinber N, Hoegholm A, Christensen H, Bang L, Mikkelsen K, Nielsen P, Svendsen T, Kampmann J, Madsen N, and Bentzon M. 24-h Ambulatory blood pressure in 352 normal Danish subjects, related to age and gender. Am J Hypertens 8: 978–986, 1995.
Yanes LL, Romero D, Cucchiarelli V, Fortepiani LA, Gomez-Sanchez C, Santacruz F, and Reckelhoff JF. Role of endothelin in mediating postmenopausal hypertension in a rat model. Am J Physiol Regul Integr Comp Physiol 288: R229–R233, 2005.(Jane F. Reckelhoff, Licy )