Brenner and Rector's The Kidney, 8th ed.

CHAPTER 20. Gender and Kidney Disease

Joel Neugarten   Sharon R. Silbiger   Ladan Golestaneh



Gender and Renal Disease Progression, 674



Factors Contributing to Gender-related Differences in Renal Disease Progression, 675



Gender and Renal Transplantation, 676



Donor Gender, 676



Recipient Gender, 677



Gender and Hypertension, 677



Epidemiology, 677



Factors Contributing to Gender-related Differences in Hypertension, 677


Many renal diseases show clear gender dimorphism.[1] Gender influences not only the incidence of renal disease but also its rate of progression. In animal models, such as aging, renal ablation, and polycystic kidney disease, male animals have a worse renal prognosis than females. [2] [3] Female C57BL6 mice, normally resistant to sclerosis, develop progressive scarring after menopause.[4] Most of these studies evaluate the rate of progression of renal disease in the presence of sex hormone manipulation, such as oophorectomy, orchiectomy, or supplementation of testosterone or estrogen. [5] [6] [7] In most models, testosterone promotes renal disease progression, and estrogen slows progression [3] [8] [9] [10] [11] ( Table 20-1 ). A notable exception is the deleterious effect that estrogen has in certain animals models of renal disease characterized by severe hyperlipidemia in which estrogen markedly exaggerates the lipid disturbance; a circumstance without human counterpart.

TABLE 20-1   -- Animal Models of Renal Disease: Effect of Gender


Rate of Progression

Sex Hormone Effects


↑ In males

T detrimental, E2 beneficial

Renal ablation

↑ In males

T detrimental


↑ In males

E2 beneficial


↑ In females in several models

E2 detrimental in several models

Diabetes mellitus



Lupus nephritis

↑ In females

T beneficial, E2 detrimental


↑, Faster rate of progression; E2, estradiol; PKD, polycystic kidney disease; T, testosterone.




In humans, most literature supports the belief that women with certain renal diseases progress at a slower rate to end-stage renal disease (ESRD) than men, independent of the severity of hypertension or cholesterol levels.[12] This has been evidenced most clearly in membranous glomerulopathy, autosomal dominant polycystic kidney disease, and immunoglobulin A (IgA) nephropathy and has been confirmed by a recent meta-analysis.[12] Included in this meta-analysis is the Modification of Diet in Renal Disease study,[13] which evaluated renal disease progression in 840 participants, nearly 40% of whom were women, assigned to various dietary protein and blood pressure groups. Over the course of the study, the rate of deterioration of glomerular filtration rate (GFR) was slower in the women, but this difference was mitigated when corrected for differences in blood pressure, urinary protein excretion, and high-density lipoprotein (HDL) levels. More recently, two population-based studies from Scandinavia followed patients with chronic renal disease of various etiologies and concluded that male gender confers a poor renal prognosis.[14] [15] Despite certain methodologic limitations, these studies are consistent with earlier observations showing a faster rate of progression of renal disease in men. Conversely, a few studies have concluded that there is no difference in the rate of renal disease progression between men and women or that women progress to renal failure at a faster rate than do men. A recent meta-analysis analyzed 11 randomized studies evaluating the effect of angiotensin-converting enzyme (ACE) inhibitors on the progression of nondiabetic renal disease.[16] After adjusting for differences in systolic blood pressure and urinary protein excretion, the authors concluded that women have a worse renal prognosis than men. However, most of the female participants in these studies were postmenopausal. Therefore, these data are entirely consistent with a renoprotective effect of female gender in premenopausal women, mediated by estrogen.

Because ESRD due to diabetes makes up a substantial fraction of all incident ESRD, the effect of gender on the progression of diabetic nephropathy merits separate consideration. In the Cohen diabetic rat, females have more rapidly progressive renal disease than do males.[17] In contrast, ovariectomy accelerates loss of renal function in female rats made diabetic with streptozotocin.[18] This effect is mitigated by estrogen supplementation, suggesting a beneficial effect of female sex hormones on the rate of renal disease progression in this model. Similarly, in the db/db rat, a model of type 2 diabetes, ovariectomy worsens diabetic renal pathology, whereas estrogen supplementation mitigates this effect.[19]

In humans, the influence of gender on the course of diabetic nephropathy is also unclear and is further complicated by interactions among gender, race, and age. According to recent data provided by the U.S. Centers for Disease Control and Prevention, the incidence of diagnosed diabetes in individuals 18 to 79 years of age is equivalent in men and women.[20] Among diabetics undergoing renal replacement therapy, the percentage of men and women is also nearly equal.[21] The age-adjusted incidence of diabetes-associated ESRD is highest among black men and lowest among white women.[20] The incidence of diabetes-associated ESRD is increasing at a much faster rate in white men than in white women, whereas in African Americans, the incremental rate in women exceeds that in men.[22]

Several studies suggest that males with type 1 diabetic nephropathy have a poorer renal prognosis than do females. Hovind and associates[23] studied proteinuric type 1 diabetics and concluded that males have a worse renal prognosis. In a study of the rate of progression of diabetic nephropathy in normotensive type 1 diabetics, the authors concluded that male sex is a “progression promoter.”[24] Investigators analyzing the patient cohort of The Diabetes Control and Complications/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Trial concluded that, in type 1 diabetics, male sex was associated with higher urinary albumin excretion.[25] In another study using the DCCT database, Zhang and colleagues[26] found that, among those participants who exhibited good metabolic control, women had a higher risk of developing diabetic nephropathy, whereas among those manifesting extremely poor metabolic control, men had a higher risk of developing nephropathy. In contrast, analysis of a large trial in type 1 diabetics with nephropathy randomized to receive either captopril or placebo found no gender-related differences in the rate of renal disease progression.[27]

Data on the contribution of gender to the rate of progression of nephropathy in type 2 diabetics are limited. Although Torffvit and Agardh[28] concluded that gender had no effect on the rate of progression of nephropathy in type 2 diabetics, Ravid and colleagues[29] found that male sex was associated with the development of microalbuminuria and worsening serum creatinine. In contrast, Nakano and co-workers[30] found that female, not male, gender was a strong predictor of ESRD in type 2 diabetics. Thus, the effect of gender on the progression of diabetic nephropathy remains to be determined.

A role for sex hormones in the pathogenesis of systemic lupus erythematosus (SLE) is suggested by the striking predominance of young women with this disorder.[31] Although gender disparity in the prevalence of SLE also exists before puberty and after menopause, it is markedly less pronounced.[31] These observations may be explained in part by the immunomodulating activity of sex hormones.[32] Estrogens enhance immune responsiveness, whereas androgens are immunosuppressive.[32] In this regard, female lupus patients have abnormal metabolism of estrogenic hormones and male lupus patients have reduced androgen levels.[32] In experimental models of lupus nephritis, androgenic hormones have a protective effect and estrogenic hormones exacerbate disease activity.[32] Most studies have shown that men with SLE, as compared with women with SLE, have a higher prevalence of renal disease, more aggressive nephritis, a higher risk of progressing to renal failure, and a higher renal mortality.[31] However, it should be noted that numerous other studies have failed to demonstrate any gender differences in the prevalence or course of renal disease in lupus patients.[33]

Factors Contributing to Gender-related Differences in Renal Disease Progression

Numerous mechanisms have been suggested to explain the protective effect of female gender on the progression of most nondiabetic renal diseases. These include differences between the sexes in renal structure, systemic and renal hemodynamics, diet, and blood pressure as well as direct effects of sex hormones on cellular processes ( Fig. 20-1 ).



FIGURE 20-1  Factors contributing to gender-related differences in renal disease progression. NO, nitric oxide; RAS, renin-angiotensin system; TGF-b, transforming growth factor-beta.



Kidney size and weight are greater in male than in female animals even when corrected for differences in body weight.[2] In addition, androgens increase kidney weight in a variety of animal models, predominantly by increasing proximal tubular bulk.[2] Several studies have examined kidney size, nephron number, and glomerular volume in men and women. [34] [35] [36] [37] Hughson and colleagues[34] studied 104 African American and white adults at autopsy and found that women had 15% fewer glomeruli than did men but found no significant difference in mean glomerular volume. Nyengaard and Bendtsen[36] studied 36 autopsy specimens and found 10% fewer glomeruli in women compared with men, but the difference did not achieve statistical significance. Further analysis of these data showed that body surface area, but not gender, was an independent determinant of kidney weight, glomerular size, and total glomerular volume.[37] However, because men are generally larger than women, these parameters also tend to be larger in men.

Although male animals may exhibit a higher total GFR than females, when corrected for kidney weight or body surface area, no significant difference exists between the sexes.[38] In humans, GFR in men and women is similar when corrected for body surface area.[39] In addition, neither testosterone nor estrogen has direct effects on GFR or renal blood flow. [40] [41] Despite these data, evidence suggests that glomerular hemodynamic responses to angiotensin II (AII) may differ in men versus women. Healthy young adult men respond to an infusion of AII by increasing their filtration fraction, suggesting increased glomerular capillary pressure.[42] In contrast, women show no change in filtration fraction. This gender dimorphism may contribute to renoprotection in females by blunting elevations in glomerular capillary pressure and reducing glomerular hemodynamic stress. In a study of normotensive, nonproteinuric type 1 diabetic adolescents, the same investigators[43] found gender-related differences in the renal hemodynamic response to clamped euglycemia and clamped hyperglycemia. It was suggested that these differences may explain the lack of a consistent protective effect of female gender on the course of nephropathy in type 1 diabetics.

Excessive caloric intake or high dietary intake of protein, phosphorus, or sodium promotes the development and progression of renal disease in numerous experimental models. Protein loading increases GFR and glomerular transcapillary hydraulic pressure difference, which, if sustained, may ultimately be detrimental to the kidney. Men consume more calories and protein than do women, which may contribute to the adverse effect of male gender on renal disease progression.

Sex hormones have direct effects on the synthesis and activity of numerous cytokines and vasoactive agents, the serum level and oxidative state of lipids, and the generation and degradation of matrix components. Because these factors influence renal disease severity, interactions between these factors and estrogen may contribute to the renal protection afforded by female gender.

Nitric oxide (NO) contributes to the development and progression of renal injury in numerous experimental models. [2] [44] In addition to its effects on the systemic and renal vasculature and on glomerular ultrafiltration, [45] [46] NO induces apoptosis of mesangial and endothelial cells.[47] In cultured glomerular and vascular endothelial cells, physiologic concentrations of estrogen cause a rapid release of NO via estrogen receptor a. [48] [49] The promoter region of the endothelial NO synthase (eNOS) gene contains an estrogen-responsive element, which may mediate estrogen-induced up-regulation of eNOS mRNA and protein levels.[50] Female rats express higher levels of eNOS than males, an effect that is reversed by ovariectomy. [49] [51] [52] Estradiol also increases local prostaglandin E2 (PGE2) and prostacyclin levels, which in turn activate NO synthase (NOS).[49] Although chronic NO inhibition in rats induces systolic hypertension in both sexes, only male rats develop proteinuria, which is prevented by orchiectomy.[53]

Sex hormones have profound effects on the renin-angiotensin system (RAS). Estrogen up-regulates the expression of angiotensinogen and angiotensin type 2 (AT-2) receptors, but down-regulates the expression of renin, ACE, and AII. [49] [54] [55] [56] [57] AT-1 receptors are also down-regulated in many but not all cell types. [49] [54] [56] [58] In contrast, testosterone activates the RAS. [59] [60] [61] Renal angiotensinogen mRNA levels are higher in adult male rats than in females, an effect that is reversed by orchiectomy and restored by testosterone administration.[60] Prorenin and renin levels and plasma renin activity are higher in men than in women.[60] In cultured mesangial cells, dihydrotestosterone up-regulates the expression of AT-1 receptors.[60] As noted earlier, the effect of infused AII on renal hemodynamics also differs between men and women.[42] Clearly, interactions between sex hormones and the RAS may contribute to gender dimorphism in renal disease progression.

Although lipids promote renal injury in experimental models, their role in the progression of renal disease in humans is less clear. Premenopausal women have lower levels of total cholesterol and low density lipoproteins (LDLs) and higher levels of HDLs than age-matched men.[62] After menopause, this difference narrows, but estrogen replacement therapy returns lipids to premenopausal levels.[63] At high concentrations, estrogen has a direct inhibitory effect on lipid oxidation.[64] At physiologic concentrations, however, estrogen may promote oxidation.[65] Further studies are needed to determine whether estrogen reduces oxidative stress associated with renal injury in vivo. In contrast, testosterone has no effect on lipid oxidation.[64]

Estrogens exert numerous effects on mesangial cells that may slow renal disease progression ( Table 20-2 ). Estrogens and selective estrogen receptor modulators suppress the synthesis of type I and type IV collagen by cultured mesangial cells.[66] Estrogen also up-regulates the activity of two collagen degrading enzymes, metalloproteinase-2 and metalloproteinase-9. [67] [68] Another mechanism by which estrogen may ameliorate renal injury is via antagonism of the actions of transforming growth factor-β (TGF-β). In cultured mesangial cells, physiologic concentrations of estradiol inhibit the pro-fibrotic effects of TGF-β and reverse TGF-b-mediated mesangial cell apoptosis by interfering with the activity of protein kinase CK2. [69] [70] In the TGF-β transgenic mouse, estradiol supplementation mitigates the extensive sclerosis that develops in untreated males. [71] [72] Because TGF-β and mesangial matrix accumulation contribute to progressive renal injury, the interaction of sex hormones with these factors may help explain gender-related differences in renal disease progression.

TABLE 20-2   -- Direct Effects of Estradiol on Mesangial Cells

Reverses TGF-β–induced type I and type IV collagen synthesis

Reverses TGF-β–induced apoptosis

Increases collagenase activity

Inhibits oxidation of LDL

Affects cellular proliferation


LDL, low-density lipoprotein; TGF-β, transforming growth factor-β.





An effect of gender on the outcome of renal transplantation was first noted in the 1980s. Despite extensive research and commentary, the precise nature of this effect and its underlying mechanisms have not been clearly elucidated.

Donor Gender

Donor gender has a significant impact on allograft survival. Analysis of death-censored data from nearly 125,000 first renal allograft recipients collected by the Collaborative Transplant Study confirmed earlier reports of lower graft survival in recipients of female compared with male donor kidneys.[73] Poorest graft and patient survival was observed among male recipients of female donor kidneys. Renal function was also superior in recipients of male donor kidneys irrespective of recipient gender. In this study, graft survival in recipients of female donor kidneys was inferior to recipients of male donor kidneys only when the female donor was below 45 years of age. This observation is in striking contrast to earlier reports from smaller registries indicating that the survival of female donor kidneys was inferior only in kidneys from older female donors. In these studies, kidneys from young female donors were found to have a survival rate equivalent to that of kidneys from young male donors. These markedly disparate observations cannot be easily reconciled.

A survival advantage for male donor kidneys has also been observed among recipients of a living donor kidney. [74] [75] However, in another analysis of over 32,000 cadaver allograft recipients, the effect of donor gender on late graft survival was no longer significant after donor and recipient body surface area was taken into account.[76] The survival advantage associated with male donor kidneys was attributed in large part to favorable donor/recipient size-matching.

Mechanisms to Explain the Donor Gender Effect

Nephron Supply/Functional Demand Mismatch

It has been suggested that the diminished long-term survival of kidneys from female versus male donors may be explained by a mismatch between the donor's nephron supply and the recipient's functional demand. [77] [78] [79] A small kidney with fewer nephrons transplanted into a large recipient would be expected to undergo greater hypertrophy and enhanced hyperfiltration. Resultant hemodynamic-mediated glomerular injury might then give rise to progressive nephron loss leading to graft failure. Because females generally have smaller kidneys and fewer nephrons, transplantation of a female kidney into a male recipient may be functionally inadequate to meet the needs of the recipient.[34] The lower graft survival among recipients of kidneys from older female donors, demonstrated in some studies, may reflect age-related nephron loss, which exaggerates the mismatch between donor nephron number and recipient functional demand.[75]

The effect of donor gender on graft survival is already evident within 3 to 6 months post-transplantation.[75] It seems unlikely that hyperfiltration-induced glomerular injury due to size mismatch could entirely account for shortened graft survival in the very early post-transplant period because longer periods of hyperfiltration would presumably be required to damage the transplanted kidney. However, a reduced nephron reserve in female donor kidneys may enhance susceptibility to ischemic injury, acute rejection, or cyclosporine nephrotoxlcity and accelerate allograft failure. In this context, grafts from female donors are less likely to survive after a rejection episode than are male donor kidneys.[75] This observation may be explained if compromise of the female donor kidney by rejection further reduces nephron number and exaggerates supply/demand mismatch.

The mismatch hypothesis also predicts that differences in graft loss between the sexes would increase steadily with increasing duration of exposure to hyperfiltration. Although some investigators have found that the survival advantage of male donor kidneys is exaggerated by the passage of time after transplantation, [80] [81] others have found that the difference in survival is maximum soon after transplantation and then plateaus.[82]

Cyclosporine Nephrotoxicity

Donor gender was first recognized as a factor influencing graft survival in the early to mid 1980s, corresponding in time to the introduction and widespread use of cyclosporine. [75] [82] Consistent with observations made by earlier investigators, we[82] found no effect of donor gender on allograft survival in recipients who were transplanted in the pre-cyclosporine era, whereas a clear effect was demonstrated in cyclosporine-treated recipients. Recipients treated with tacrolimus rather than cyclosporine also failed to show a donor gender effect.[83] The equivalence of graft survival between male and female donor kidneys in non-cyclosporine-treated recipients suggests that a mismatch between nephron supply and donor functional demand is alone insufficient to explain the adverse effect of female donor gender observed in cyclosporine-treated recipients.

Gender-related differences in susceptibility to cyclosporine nephrotoxicity or in the therapeutic response to cyclosporine may contribute to the shortened graft survival of female donor kidneys under cyclosporine immunosuppression. Whereas cyclosporine increases the survival of young female donor kidneys to the same extent as that of male donor kidneys, cyclosporine does not increase the survival of older female kidneys.[75] Enhanced susceptibility of older female kidneys to the nephrotoxic effects of cyclosporine may help explain this observation.[69]

Higher doses of cyclosporine are administered to male recipients, who generally weigh more than females.[75] Transplantation of a small female donor kidney into a male recipient results in the largest relative dosing of cyclosporine, which may enhance nephrotoxicity and explain the poor graft survival in this group.

Recipient Gender

Females show enhanced immune responsiveness.[75] In animal models, estrogen administration antagonizes the immunosuppressive activity of cyclosporine and leads to shortened allograft survival.[75] Notwithstanding these observations, most studies have failed to show a significant effect of recipient gender on the outcome of renal transplantation.[75] Meier-Kriesche and co-workers [84] [85] analyzed data from over 73,000 recipients of primary renal allografts and found that graft survival censored for death was no different in male versus female recipients. However, patient survival and uncensored graft survival were better in female recipients. Female recipients showed a 10% increased risk of acute rejection. However, this effect was offset by a 10% decreased risk of graft loss secondary to chronic allograft failure. Reduced risk of chronic allograft failure was observed only in female recipients above the age of 45. In contrast, the sex of the kidney donor was not a significant factor in determining chronic allograft failure.

The effect of gender and sex hormones on the development of chronic allograft nephropathy has been examined in numerous animal models.[75] These studies have consistently demonstrated that the progression of chronic allograft nephropathy is ameliorated by estrogen and accelerated by testosterone. However, these experimental data do not explain the observation made by Meier-Kriesche and associates [84] [85] that only female recipients above the age of 45 demonstrate a reduced risk of chronic allograft failure.



Both the overall prevalence of hypertension and the incidence of uncontrolled hypertension are higher among men than women. [86] [87] [88] [89] [90] [91] [92] There is no difference in systemic blood pressure between prepubescent boys and girls, and it is only after puberty that boys exhibit higher blood pressure than girls.[88] Blood pressure increases in age in both men and women, but the rate of rise in blood pressure is steeper in women beginning in their 60s such that, after the 7th decade, women have higher systolic blood pressures and pulse pressures than men.[87]

Blood pressure tends to parallel estrogen levels, being lower during ovulation and in the luteal phase of the menstrual cycle than in the follicular phase.[93] Pregnancy is characterized by a marked elevation in the serum concentration of estrogen, associated with a decline in blood pressure. After menopause, the serum concentration of estradiol falls to levels similar to or lower than those found in men, associated with an elevation in blood pressure.[50] The increase in blood pressure observed after the onset menopause develops over 5 to 20 years. Other factors that may contribute to the development of postmenopausal hypertension include higher testosterone levels, higher body mass index, decreased renal function, endothelial dysfunction, and oxidative stress associated with aging as well as a higher incidence of co-morbid conditions including diabetes and atherosclerotic disease. [87] [94]

Exogenous hormone intake and its effects on blood pressure are more complicated and do not parallel the seemingly clear-cut dose-response effect seen with endogenous estrogen levels. [93] [95] A recent meta-analysis suggested a mild increase in blood pressure in women using oral contraceptives and a mild decrease in those using estrogen replacement therapy.[96] Women taking oral contraceptives are two to three times more likely to have high blood pressure than nonusers.[97] At the high levels of estrogen seen in oral contraceptives, estrogen may exert a vasoconstrictor effect via greater activation of the RAS and enhanced sympathetic tone.[17] At lower levels, comparable with those used in hormone replacement therapy, estrogen tends to reduce blood pressure via enhanced production of vasodilators. However, the clinical data on the effect of hormone replacement therapy on blood pressure are conflicting.[91] [95] [98]

The evidence supporting a benefit from treatment of hypertension is based on combined results for men and women. A recent meta-analysis of blood pressure-lowering treatments showed a lower absolute risk reduction in women than in men. [90] [92] The benefits of adequate blood pressure control in women was reflected in a lower incidence of strokes but not in reduced mortality, whereas in men there was a significant reduction in mortality. Despite established benefit from treatment of hypertension, only about a quarter of treated hypertensive women achieve blood pressure control with prescribed antihypertensives.[86]

Factors Contributing to Gender-related Differences in Hypertension

Estrogen receptors a and b are found in vascular endothelial and smooth muscle cells, and both have been implicated in small vessel dilatation, as well as protection against endothelial injury.[50] Although the mechanisms that mediate the vascular effects of estrogen have not yet been fully elucidated, it appears that both genomic and nongenomic pathways are involved ( Table 20-3 ). Estrogen induces vasodilatation and increases blood flow within 5 to 20 minutes of administration through both endothelium-dependent and endothelium-independent mechanisms.[49] Estrogen activates endothelium-dependent vascular relaxation factors including NO, cyclic guanosine monophosphate, and prostacyclin. As discussed earlier, estrogen up-regulates the NO pathway at multiple levels.

TABLE 20-3   -- Role of Sex Hormones in the Pathogenesis of Hypertension



Vascular Smooth Muscle


Oxidative Injury




↓ Renin, ACE, and AII levels



↓ AT-1 receptors in many cell types



↑ Angiotensinogen levels



↑ AT-2 receptors

↑ Opening of calcium-activated potassium channels



↑ eNOS levels and NOS activity



↑ NO and cGMP levels



↑ Prostacyclin and PGE2 levels



↑ Kininogen, kallikrein, and bradykinin levels



↓ Endothelin levels



↓ Kininase (ACE) levels



↓ Oxygen free radicals (supraphysiologic concentrations of E2)



↓ Experimental endothelial oxidative injury




↑ Proximal tubular sodium reabsorption



↑ Prorenin, renin, angiotensinogen, and AII levels



↑ Renin activity



↑ ACE activity



↑ AT-1 receptors

↑ Vasoconstriction induced by sympathetic hormones



↑ Endothelin levels and actions



↓ Adenosine-induced vasodilation



↓ NO levels and local actions

↑ Oxygen free radicals (direct and indirect actions)


AII, angiotensin II; ACE, angiotensin-converting enzyme; AT-1, angiotensin type 1 receptors; AT-2, angiotensin type 2 receptors; cGMP, cyclic guanosine monophosphate; E2, estradiol; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; PGE2, prostaglandin E2; RAS, renin-angiotensin system.




At physiologic concentrations, estrogen stimulates the opening of calcium-activated potassium channels, leading to smooth muscle relaxation and vasodilatation.[49] Vascular smooth muscle contraction in response to vasopressors is greater in the aorta of male rats compared with female rats and is enhanced in females by ovariectomy. [49] [87] The ability of estrogen to directly inhibit vascular smooth muscle contraction is demonstrated by its vasodilatory effect on de-endothelialized coronary arteries. [49] [87]

As discussed earlier, estrogen has profound effects on the RAS at multiple levels. In experimental models, estrogen replacement reduces AII levels associated with a reduction in blood pressure. Estrogen increases AT-2 receptor density in the renal medulla and down-regulates AT-1 receptor density in the kidney and in vascular smooth muscle. [49] [54] Enhanced AT-2 receptor expression stimulates bradykinin synthesis, which in turn stimulates NO release and up-regulates PGE2 expression. [50] [87] Down-regulation of AT-1 receptor density antagonizes sodium retention and vasoconstriction.

Endothelin is a potent vasoconstrictor that enhances renal sodium reabsorption, promotes oxidative stress, and contributes to increased blood pressure.[49] Estradiol inhibits not only the synthesis of endothelin but also its vasocon-strictor effects. [49] [87] Endothelin levels increase after menopause. Because AII stimulates endothelin synthesis, the ability of estrogen to decrease AII levels may contribute to a reduction in endothelin levels. Estrogen stimulates the synthesis of bradykinin, a vasorelaxant agent, and enhances its vasodepressor effects. [49] [87] [99] Estrogen also stimulates kallikrein and kininogen expression and reduces kininase (ACE) levels.[100]

Recent data indicate that oxidant injury to blood vessels may contribute to the development of hypertension. Estradiol is a potent antioxidant in supraphysiologic concentration and protects against endothelial damage mediated by oxidative stress in experimental models.[50] If estrogens were to exert antioxidative effects in vivo, these actions might contribute to the protective effect of female gender on the development of hypertension. [50] [87]

The action of androgens to up-regulate vasoconstrictors, promote oxidative stress, and enhance sodium retention may contribute to the development and aggravation of hypertension[87] (see Table 20-3 ). Androgen receptors are found in proximal tubules and may directly increase proximal tubular sodium reabsorption. In animal models, castration of males shifts pressure-natriuresis curves toward those of intact females. Testosterone also stimulates tyrosine hydroxylase, which is the rate-limiting step for catecholamine synthesis, blocks adenosine-mediated vasodilatation, and enhances the contractile effects of endothelin. [52] [59]

In genetic models of hypertension, castration of males attenuates the development of hypertension, and blockade of androgen receptors with flutamide reduces blood pressure to levels found in females.[87] Serum testosterone levels rise after the onset of menopause and may contribute to the development of hypertension in postmenopausal women. In this regard, women with virilizing tumors develop hypertension.

As discussed earlier, testosterone activates the RAS and increases efferent arteriolar resistance.[59] Stimulation of the RAS promotes oxidative stress and increases superoxide production, which in turn quenches NO; all of which decrease vascular response to vasodilators.[87] These effects may explain why androgen withdrawal enhances endothelium-dependent vasodilatation.[59]

The nonmodulator phenotype is an intermediate marker for hypertension and is characterized by a blunted natriuretic response to elevated pressure in the renal vasculature and higher than expected aldosterone levels in response to a salt load. [99] [101] The nonmodulator phenotype is much more common in men than in women. As our awareness of genetic influences on the pathophysiology of hypertension increases, it is important to note that genetic polymorphisms in the ACE, AII, and AT-1 receptor genes have a more profound influence on the development of hypertension in men than in women. [99] [101] [102]


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