Sex, diabetes and the kidney

Christine Maric

Abstract

The incidence and the rate of progression of nondiabetic renal disease is generally greater in men compared with age-matched women, suggesting that the female sex is protective and/or that the male sex is a risk factor for the development and progression of nondiabetic renal disease. In diabetes, even though the male sex still appears to be a risk factor, this relationship is not as strong as it is in nondiabetic renal disease. Experimental evidence suggests that both estrogens and androgens play an important role in the pathophysiology of renal disease. Thus one of the potential mechanisms for the absence of a clear sex difference in the setting of diabetes may be alterations in sex hormone levels. Indeed, studies suggest that diabetes is a state of an imbalance in sex hormone levels; however, whether these changes correlate with the decline in renal function associated with diabetes is unclear. Furthermore, diabetic renal disease rarely develops before puberty, and the onset of puberty accelerates microalbuminuria, supporting the idea of the involvement of sex hormones in the development and progression of the disease. However, other than a handful of experimental studies indicating that treatment with or removal of sex hormones alters the course of diabetic renal disease, very few studies have actually directly examined the correlation between sex hormones and the disease development and progression. Further studies are necessary to determine the precise contribution of sex hormones in the pathophysiology of diabetic renal disease to develop novel and potentially sex-specific therapeutic treatments.

  • estrogen
  • testosterone
  • diabetes
  • kidney
  • diabetic nephropathy

although numerous studies show a relative female protection with respect to the incidence and rate of progression of nondiabetic renal disease (32, 73, 96, 98), the relationship between sex and the incidence and rate of progression of diabetic renal disease is unclear. Several studies indicate that, in the setting of either type 1 or type 2 diabetes, there are no differences in the incidence and/or rate of progression of renal disease between men and women (12, 69, 84). Many studies, however, report that the male sex is still a risk factor for the development of renal disease in diabetes (40, 41, 45, 87, 95) but that the female sex appears to accelerate the disease progression (39, 57, 74, 91). There are several possible reasons for these conflicting observations, including differences in the patient populations examined, relatively small sample sizes, uncontrolled study designs, the type of diabetes, and methods of data analysis. However, the most likely reason for the lack of understanding whether or not sex differences exist in diabetic renal disease is because no single study has thus far been designed to specifically examine this issue. Further supporting the importance of one's sex in diabetes are reports on altered levels of sex hormones in patients with either type 1 or type 2 diabetes (22, 35, 36, 54, 101). However, few studies have examined the relationship between this alteration in sex hormone levels and the decline in renal function associated with diabetes. In support of the importance of sex hormones in diabetic renal disease are experimental studies showing that either treatment with or absence of sex steroids alters the course of renal diseases in diabetes (50, 60, 62, 102, 111). These observations strongly support the notion that sex hormones play an important role in the pathophysiology of diabetic renal disease, despite the fact that the precise mechanisms by which sex hormones exert their actions in the kidney are not completely understood. The aim of this review is to provide a summary of our current understanding on the relationship between sex hormone levels and diabetes and how sex hormones may contribute to the development and progression of diabetic renal disease.

Sex Hormones and Type 1 Diabetes

Women with type 1 diabetes often present with impaired ovarian function, delayed age at menarche, sexual dysfunction, menstrual irregularities, and high risk of adverse pregnancy outcomes, including abortions, stillbirths, and congenital anomalies (13, 26, 27, 88). Men with type 1 diabetes commonly present with erectile dysfunction, which has been shown to correlate with the decline in renal function (11, 46, 110). Puberty has been shown to accelerate the onset of type 1 diabetes in both boys and girls; however, the peak age of pubertal onset of diabetes is around two years earlier in girls than boys (34). Although this sex difference in the age of onset of diabetes may be related to the fact that puberty develops at an earlier age in girls than boys, the common factor in both sexes is that puberty itself appears to accelerate the development of type 1 diabetes. These observations suggest an association between the reproductive system, sex hormones, and the development of type 1 diabetes and related end-organ complications. However, very few studies have actually measured sex hormone levels in patients with type 1 diabetes and whether changes in sex hormone levels correlate with the development of diabetes and its complications. Moreover, the few existing reports provide inconsistent findings in both men and women.

Women with type 1 diabetes have been reported to have either reduced (88) or no change (99) in circulating estradiol levels compared with nondiabetic women, whereas total or free testosterone levels have been reported to be either elevated (67) or similar to those of nondiabetic women (86, 88). One of the possible reasons for these disparate findings are the different ages of the patients and not taking into account the variation of estradiol levels with the hormonal cycle. Experimental models of type 1 diabetes, namely streptozotocin (STZ)-induced diabetic rodents, have shown a more consistent hormonal profile characterized by reduced estradiol alongside increased testosterone levels in females (52, 109). The results in men with type 1 diabetes are just as scarce and inconclusive as in women. Although some studies report elevated levels of testosterone (22, 67, 112), another study showed reduced free testosterone and no changes in total testosterone levels in type 1 diabetic men (106). To the best of my knowledge, there is only one published report on estradiol levels in men with type 1 diabetes. This study showed that there was a trend toward increased levels of both total and free estradiol levels; however, neither of these parameters reached statistical significance (112). A recent observation from our laboratory has shown that men with type 1 diabetes exhibit decreased levels of total and free testosterone as well as estradiol (unpublished observation). The vast majority of studies in the male STZ-induced diabetic rat show decreased levels of testosterone and, in studies that have also measured estradiol, increased levels of estradiol (8, 81, 90, 102, 111). Only one study showed decreased levels of estradiol with no difference in testosterone levels in male STZ-induced diabetic rats (70).

Most of the circulating estradiol and testosterone are reversibly bound to sex hormone-binding globulin (SHBG) or, to a lesser extent, weakly bound to albumin (107). Only ∼2–3% of estradiol and testosterone circulate in plasma unbound or “free” and, together with the albumin-bound, constitute the biologically active hormone. Sex hormones that are bound to SHBG constitute the biologically inactive fraction of the hormone. Therefore, by virtue of binding to sex hormones, SHBG influences their biological activity (the higher the SHBG levels, the higher the capacity to bind the hormone, reducing its biological activity and vice versa). Furthermore, SHBG, by having a higher affinity for testosterone compared with estradiol, influences the relative balance of the free fraction of these two sex hormones (83). Based on these properties, SHBG should be considered, in addition to changes in total or free hormone, to determine the physiological significance of circulating sex hormones. Furthermore, estimation of free hormone or direct measure thereof may be more appropriate than measuring total levels of hormones.

In type 1 diabetes, SHBG levels have been reported to be decreased during puberty in boys and in young men (22), whereas increased SHBG levels have been shown in adult type 1 diabetic men (106). No differences (22) or decreased SHBG levels (88) have been observed in women with type 1 diabetes. These changes in SHBG levels could thus influence the relative proportion of the biologically active to inactive fraction of sex hormones and thus their overall physiological impact.

Overall, whereas the available data regarding sex hormone levels in type 1 diabetics are scarce and inconsistent, the common thread in these studies appears to be that both males and females have a tendency toward higher testosterone levels, suggesting hyperandrogenism. Tables 1 and 2 summarize the data on changes in sex hormone levels in type 1 diabetics vs. their nondiabetic counterparts in humans and experimental models, respectively.

View this table:
Table 1.

Sex hormone levels in humans and experimental models of diabetes compared with nondiabetic controls of the same sex

View this table:
Table 2.

Sex hormone levels in experimental models of diabetes compared with nondiabetic controls of the same sex

Sex Hormones and Type II Diabetes

A number of studies in humans have shown that serum testosterone levels are related to type 2 diabetes, insulin resistance, and other components of the metabolic syndrome, including visceral obesity and dyslipidemia (17, 29, 35, 36, 38, 54, 101, 105). Specifically, men with type 2 diabetes commonly exhibit low levels of total testosterone and SHBG (17, 29, 35, 36, 38, 48, 54, 105). In contrast, postmenopausal women with type 2 diabetes exhibit elevated levels of bioavailable testosterone and low levels of SHBG (23, 35). These women also have higher levels of total and bioavailable estradiol, whereas men exhibit either elevated (23) or no changes in estradiol levels (35). The findings on increased estradiol levels in women are somewhat surprising given the postmenopausal status of these women and thus the expected decline in ovarian hormone levels. This finding, however, is not universal. Another study reported no changes in estradiol levels in postmenopausal women with type 2 diabetes (5). Furthermore, in nonobese Caucasian and African-American premenopausal type 2 diabetic women, decreased levels of plasma estradiol were reported (55, 100). Further studies are clearly needed to determine whether estradiol levels vary in type 2 diabetes in both men and women. What does seem to be clear is that type 2 diabetes in men is associated with hypogonadism, whereas, in women, type 2 diabetes is associated with hyperandrogenism. Hypogonadism in type 2 diabetic men appears to be a consequence of alterations in hormone synthesis, whereas hyperandrogenism in women appears to be a consequence of alterations in the hypothalamic-pituitary axis (4, 108). In addition, both the reduced testosterone in men and increased testosterone levels in women appear to be associated with insulin resistance, as determined by the homeostatic model assessment of insulin resistance (36). These observations suggest that improving insulin resistance, rather than restoring hormone levels directly to those of nondiabetic subjects, may be a more effective treatment for the male hypogonadism and female hyperandrogenicity rather than restoring hormone levels themselves.

Findings in experimental models are generally in agreement with the data in humans in that female db/db mice (16) and Goto-Kakizaki rats (65) exhibit increased testosterone levels alongside either no change (16) or decreased (65) estradiol levels. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats exhibit either reduced (94) or no changes (53) in testosterone or estradiol levels. It is highly likely that changes in sex hormone levels are species and strain-specific, which may be one of the reasons for the somewhat conflicting data in rodents.

Although highly unlikely, it is possible that gonadal disturbances may be a cause rather than a consequence of diabetes. A study in the OLETF rat provides some, albeit weak, support for this idea by showing that the incidence of type 2 diabetes in these rats is 100% in the male and 0% in the female (93). Gonadectomy at an early age, before the development of diabetes, results in reduced incidence of diabetes to 20% in males, whereas ovariectomy increases the incidence to 30% in the females. Women with polycystic ovary syndrome, a condition that is characterized by hyperandrogenism (18), have a greater risk of developing type 2 diabetes than healthy women (78). Furthermore, a high prevalance of hyperandrogenism and polycystic ovarian syndrome has been found in adult women with type 1 diabetes (18). While these observations may suggest that a state of high testosterone levels provides a platform for development of diabetes, further studies are needed to directly examine whether alterations in sex hormone levels can impact the susceptibility to developing diabetes.

Although it is clear that further studies are needed to accurately assess changes in sex hormone levels in patients with both type 1 and type 2 diabetes, it should be stressed that measuring testosterone and estradiol in both women and men should be performed. It is most likely that the relative balance between testosterone and estradiol plays a more important role in the onset of diabetes and disease progression rather than the absolute levels of one or the other hormone.

Do Sex Hormones Play a Role in Diabetic Renal Disease?

Several observations point toward an association between sex hormones and diabetic renal disease. First, puberty is the turning point for the development of diabetic nephropathy. Second, the protection of the female sex against the development of renal disease is lost in the setting of diabetes. Third, chronic and end-stage renal disease, both of which diabetes is the leading cause of, is associated with sexual dysfunction and altered sex hormone profiles (4, 47).

Puberty and diabetic renal disease.

Diabetic end-organ complications, including diabetic nephropathy, are uncommon before the onset of puberty (56, 66, 91). Although this may be the result of the short length of time for the complications to develop between the onset of puberty and time of diagnosis of diabetes, studies suggest that there are other factors that contribute to this association between puberty and development of diabetes-related organ complications. Young girls with type 1 diabetes are at a greater risk for developing microalbuminuria during puberty than age-matched boys (91). The decline in renal function accelerates after puberty in women (10–40 yr of age) with type 1 diabetes more so than in age-matched men (56, 66, 91). Furthermore, prepubertal onset of type 1 diabetes in STZ-induced Sprague-Dawley diabetic rats has been shown to reduce the development of diabetic renal disease, albeit only in males (6, 56, 102). Although perturbations in the growth hormone/insulin-like growth factor-I axis have been reported to be the major contributing factor for this sex difference (3), other mechanisms such as alterations in sex hormone levels are likely to be involved. Indeed, increased testosterone levels have been observed in young girls with microalbuminuria associated with type 1 diabetes (85), whereas decreased testosterone levels have been observed in juvenile diabetic male STZ-induced Sprague-Dawley rats with increased urine albumin excretion (102). Furthermore, treating prepubertal male STZ-induced diabetic rats with testosterone permits tubulointerstitial kidney damage, as demonstrated by increased expression of transforming growth factor-β (TGF-β) and connective tissue growth factor, major intracellular signals for renal growth in diabetes (102). These observations indicate that alterations in sex hormone levels that occur with puberty may contribute to the onset and the rate of progression of diabetic renal disease.

Sex differences in the incidence and rate of progression of diabetic renal disease.

Several studies suggest that the incidence and the rate of progression of most nondiabetic renal diseases are generally higher in men than age-matched women (72, 73, 92, 97), suggesting that androgens may permit and/or accelerate intrinsic renal damage. The opposite has also been proposed [that estrogens afford renoprotection, since the incidence and rate of progression of nondiabetic renal disease appears to be greater in postmenopausal women compared with age-matched men (42)]. However, the data on the incidence and rate of progression of renal disease resulting from diabetes are inconsistent, mainly because of the fact that no study to date directly examined this issue. However, what does appear to be consistent is that, unlike nondiabetic renal disease in which the female sex appears to be a protective factor, this female advantage seems to be lost in diabetes. The incidence and the rate of progression of renal disease is far greater in diabetic compared with nondiabetic females, suggesting that sex hormones may be differentially regulated in diabetes and contribute to the pathophysiology of diabetic renal disease.

RENAL DISEASE IN TYPE 1 DIABETES.

In adult patients with type 1 diabetes with initially normal renal function or mild renal insufficiency, the male sex has been shown to be a risk factor for the development of microalbuminuria and macroalbuminuria (61). Similarly, in a large, prospective cohort of patients with type 1 diabetes with childhood and adolescent onset of diabetes, the male sex was also a risk factor for the development of macroalbuminuria (76). In patients with established diabetic nephropathy, the male sex has been shown to be associated with a more rapid decline in glomerular filtration rate (GFR) over 5 years of patient follow-up (41). The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study has shown that the male sex was a risk for microalbuminuria, but this effect was lost when adjusted for waist-to-hip ratio (95), suggesting a role for visceral adiposity in the progression of diabetic nephropathy associated with type 1 diabetes. In the same cohort, women have been shown to have a tendency toward developing diabetic nephropathy more often under good metabolic control, whereas they seems to be more protected than men from developing the disease under poor metabolic control (114). One of the mechanisms by which women with type 1 diabetes seem to be protected from developing renal disease compared with men is an augmented renal hemodynamic response to hyperglycemia. A study in humans with type 1 diabetes examining the renal hemodynamic responses in early stages of diabetic nephropathy showed that males do not exhibit any changes in renal hemodynamics during hyperglycemia, whereas females exhibit a reduction in effective renal plasma flow and renal blood flow and decreased renal vascular resistance (15). In addition, although both males and females exhibit a decline in arterial pressure after angiotensin-converting enzyme (ACE) inhibition, only females showed a reduction in GFR (15). These observations suggest that one of the possible reasons for the relative protection of female kidneys in diabetes is reduced glomerular capillary pressure, at least in early stages of diabetes without apparent renal disease. Similar studies in patients with advanced renal disease have thus far not been performed.

In contrast to these studies implicating the male sex as a risk factor for development of diabetic renal disease, a large epidemiologic study of patients (8–48 yr of age) with type 1 diabetes diagnosed in childhood, the female sex was found to be a risk factor for the development of microalbuminuria, but only in women with shorter-term diabetes; the risk for the development of microalbuminuria decreased with the duration of diabetes in women, whereas it steadily increased in men (74). In a large cohort of adolescents with type 1 diabetes, the female sex was reported to contribute to the development of microalbuminuria independent of the duration of diabetes (39, 91). No sex differences in the rate of progression of diabetic nephropathy were observed after a 3-year follow-up in a randomized trial of ACE inhibition in adult patients with type 1 diabetes (7, 12), or in a Danish cohort of normoalbuminuric patients followed for 11 years (84), even after adjustment for glycemic control. Although the current data, even though inconsistent, lean toward the male sex as a risk factor for the development and rate of progression of diabetic renal disease in type 1 diabetes, a recent study investigating the familial risk factors for microvascular complications associated with type 1 diabetes reported that the percentage of females exhibiting a second end-organ complication is far greater that the percentage of males with a second complication (69). These observations underscore the complexity of the interaction between one's sex and the etiology of renal and other end-organ complications associated with diabetes.

Virtually nothing is known about the potential correlation between the rate of decline in renal function associated with diabetic nephropathy in type 1 diabetes and sex hormone levels. A recent study from our laboratory suggested that development of microalbuminuria and macroalbuminuria in men with type 1 diabetes is associated with reduced testosterone levels, whereas progression to end-stage renal disease is associated with increased levels of both free testosterone and estradiol (unpublished observation). This increase in testosterone and estradiol levels persists even in the Cox regression analysis that accounts for the decline in GFR, suggesting that sex hormone levels do not just accumulate as a result of reduced renal clearance but that there indeed may be increased synthesis that may further contribute to the decline in renal function. Although these studies are clearly a step forward, further studies are needed to determine if indeed sex hormones correlate with and play a role in the decline in renal function associated with diabetic nephropathy in type 1 diabetes.

RENAL DISEASE IN TYPE 2 DIABETES.

Similar to type 1 diabetes, several studies have shown a greater incidence of diabetic nephropathy, as evidenced by micro- or macroalbuminuria, in type 2 diabetes in men compared with age-matched women (30, 75, 77, 89). The most recent U. S. Renal Data System and the Centers for Disease Control reports show that the incidence of end-stage renal disease due to diabetes is marginally greater in white men compared with age-matched, white, type 2 diabetic women (14, 71), supporting the hypothesis that the male sex is a risk factor for the development of diabetic nephropathy in type 2 diabetes in white subjects. This relationship is reversed in the black population (71). White men have a greater prevalence of micro- and macroalbuminuria as shown in a cross-sectional analysis of a large multicenter randomized controlled trial (89), as well as two separate prospective studies in adults with type 2 diabetes (75, 77). Furthermore, in a prospective, observational study, the male sex was found to be a risk factor for the development of incipient (persistent microalbuminuria) and overt (persistent macroalbuminuria) diabetic nephropathy (30). Evidence also exists supporting the notion that renal function declines at a more rapid rate in women compared with age-matched men. The Irbesartan in Diabetic Nephropathy Trial (58) and the Reduction in ENdpoints in type 2 diabetes with ANG II Antagonist Losartan trial (49) have both shown that proteinuria develops at a more rapid rate in women compared with age-matched type 2 diabetic men. It should be noted that most of the women included in these trials were postmenopausal; thus, caution should be taken in interpreting these data, since the hormonal status associated with menopause itself is likely to have an impact on disease progression, even in nondiabetic controls. Furthermore, premenopausal African American, Hispanic, and Pima Indian women have a higher incidence and greater rate of progression of diabetic nephropathy compared with men (20, 59, 113), suggesting that diabetic renal disease develops and progresses differently in different races and ethnic groups and that these differences may also be sex specific.

Collectively, these studies indicate that diabetic nephropathy appears to be more prevalent in white men compared with white women, but that this trend is opposite in black subjects. Some evidence also suggests that the decline in renal function may be greater in type 2 diabetic women compared with age-matched men; however, these observations require further investigation. Despite this evidence that sex plays a role in the development and progression of diabetic renal disease, little is known about the mechanisms by which sex hormones regulate renal function in the diabetic kidney.

Mechanisms of Action of Sex Hormones in the Diabetic Kidney

Estrogens.

Despite the fact that it is unclear whether diabetic nephropathy is characterized by an imbalance in sex hormone levels and whether restoring this imbalance may be renoprotective, a few studies have gone ahead and tested the effects of estrogens in diabetic nephropathy. Short-term administration of estrogen in combination with a synthetic progestin has been shown to reduce proteinuria and improve creatinine clearance in postmenopausal women with type 2 diabetes (103). Similarly, in the Insulin Resistance Atherosclerosis Study, in which hormone therapy was initiated at the start of menopause, a combination therapy of estrogen and progestin attenuated the development of albuminuria (1). Short-term treatment with the selective estrogen receptor (ER) modulator raloxifene also attenuated the progression of albuminuria in postmenopausal women with type 2 diabetes, most likely via activating ERα (37). In contrast, a cross-sectional study in pre- and postmenopausal women with type 2 diabetes has shown an association between longer-term (5 years) treatment with conjugated estrogens or estradiol valerate alone or in combination with progestin and an increased risk for microalbuminuria (68). However, this study included only a small number of women in each treatment group, and, by virtue of being a prospective study, caution should be taken when interpreting the findings on a cause-and-effect relationship between hormone therapy and microalbuminuria. Supporting the detrimental effect of hormone therapy is also a randomized, placebo controlled, crossover trial in postmenopausal women with type 2 diabetes showing that a 6-mo treatment with conjugated equine estrogen and medroxyprogesterone acetate does not reverse microalbuminuria caused by prolonged hyperglycemia (64). It should be noted that the hormone therapy in this study was initiated after at least 2 years of menopause, suggesting that the timing of initiation of hormone therapy relative to the onset of menopause may be a key factor in determining the overall benefit on the therapy on albuminuria. Furthermore, the detrimental effect of hormone therapy on albuminuria has only been noted in the combination therapy of estrogens and progestin. Future, long-term, randomized, controlled trials are needed to examine whether estrogen alone therapy may be beneficial in preventing the development of albuminuria.

Treatment of the STZ-induced diabetic rat with 17β-estradiol (E2) either from the onset (50, 62, 63) or after 8 wk of untreated diabetes (24) reduces albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis via reducing the expression of TGF-β, collagen type I, collagen type IV, fibronectin, and laminin and increasing the expression and activity of matrix metalloproteinases (MMPs), namely MMP-2 and MMP-9. Likewise, treatment with raloxifene attenuates albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis via similar mechanisms (16, 25). Interestingly, in the OLETF rat, treatment with E2 has no effect on albuminuria but decreases mesangial expansion (104). In contrast, Rosenmann et al. (82) found that, in sucrose-fed diabetic rats, ovariectomy reduced while E2 supplementation exacerbated diabetic renal disease, suggesting that the absence rather than the presence of estradiol is renoprotective. It is conceivable that the effects of estradiol, and other hormones for that matter, are strain specific. Thus, in the Cohen sucrose-fed rat, ovariectomy may be renoprotective by virtue of removing the source of testosterone, since increased testosterone levels have been observed, at least in women with diabetic nephropathy (67, 88). Indeed, treatment of ovariectomized female Cohen rats with testosterone results in adverse effects on the diabetic kidney (19). However, an adverse effect of estrogens cannot be ruled out either in this model. In fact, the use of oral contraceptives containing high doses of estrogen has been linked to the development of macroalbuminuria in women with type 1 diabetes (2). In contrast, oral contraceptives containing low doses of estrogen do not affect urine albumin excretion in women with type 1 diabetes (33), suggesting that, similar in type 2 diabetes, the dosage, and most likely timing, of treatment plays a critical role in the overall effect of sex hormones on target organs.

Estradiol exerts its actions through both ERα and ERβ receptors. Experimental studies have shown that ERα receptors are more predominant in the kidney of female rats, whereas ERβ receptors are predominant in males (80). Interestingly, the kidney has been suggested to be an organ in which the ability of estrogen, mainly via ERα receptors, to regulate gene expression is the greatest, excluding the reproductive and neuroendrocrine tracts (43). However, the physiological significance of these observations is poorly understood. Likewise, the precise biological actions mediated through ERα and ERβ in either the nondiabetic or diabetic kidney are largely unknown. One of the few studies examining this issue showed that the female ERα knockout mice are protected from the development of albuminuria and glomerulosclerosis associated with diabetes (60), suggesting that the ERα receptor mediates a detrimental effect in the female diabetic kidney. Further supporting the notion that ERα receptors may mediate adverse effects in the diabetic kidney is the observation that the expression of ERα receptors is upregulated in the kidney of female STZ-induced diabetic rats (60, 109), whereas no changes in the expression of either ERα or ERβ have been observed in the male rats (109), at least not after short-term (2 wk) disease. However, the physiological significance of these findings is yet to be determined. Similar to experimental models, ERα receptors have also been linked to diabetic kidney disease in humans. A study in African American and European-American women with diabetic nephropathy has identified an association between functional polymorphisms in introns 1 and 2 of the ERα gene and the susceptibility to development of diabetic nephropathy (31, 51). This observation clearly supports the importance of ERα receptors in the diabetic kidney; however, as in rodents, the mechanisms of action of estradiol specifically through ERα receptors is yet to be determined.

Androgens.

The vast majority of studies in experimental models of nondiabetic renal disease suggest that testosterone is detrimental to the male kidney (28, 44, 79). Castration, as well as treatment with the androgen receptor antagonist flutamide, in these animals attenuates albuminuria and glomerulosclerosis, suggesting that the absence of testosterone is renoprotective (9, 10, 28). Surprisingly, studies from our laboratory in the STZ-induced diabetic rat have shown just the opposite: that castration exacerbates, rather than attenuates, diabetic renal disease via promoting albuminuria, glomerulosclerosis, tubulointerstitial fibrosis, collagen type I and IV synthesis, TGF-β expression, and macrophage infiltration (111). These observations suggest that, in the setting of diabetes, testosterone may in fact be renoprotective. Contradicting these findings is the study in young STZ-induced diabetic rats showing that treatment with testosterone promotes tubular damage (102). However, these studies were performed in prepubertal rats in which sex hormones are highly likely to exert a different effect than that in adult rats. Given that studies suggest that diabetes is associated with an imbalance in sex hormone levels in both men and women, it is conceivable that it is this very hormonal balance that ultimately mediates the adverse or beneficial effect of hormones in the kidney. Specifically, because diabetes is associated with reduced testosterone levels in males, it is conceivable that its complete absence, as in castration, would be detrimental, since testosterone may be important in regulating renal function. In addition, castration not only removes testosterone but also removes the source of estradiol, and, if estradiol has renoprotective effects, its complete absence may contribute to the adverse effects of castration in the diabetic kidney. Interestingly though, castration in these animals appears to be associated not with a decrease, but rather an increase, in estradiol levels (102, 111), suggesting an extragondal origin of estradiol in diabetes. One of the most likely sources would be the adrenal gland; however, data suggest that the kidney also expresses the machinery necessary for steroidogenesis (21), raising the possibility that the kidney itself may be producing sex hormones that may have local effects. Further studies are needed to examine the physiological significance of the intrarenal sex steroidogenesis.

Summary and Perspectives

In summary, women have a lower risk for the development and a slower rate of progression of nondiabetic renal disease than men; however, this female protection disappears in diabetes. One of the potential reasons for the loss of the female sex as a protective factor in diabetes may be an imbalance in sex hormone levels. Indeed, accumulating evidence suggests that diabetes is a state of an imbalance in sex hormone levels in both women and men. This observation, along with the fact that diabetic renal complications rarely develop before puberty, implicates sex hormones in the pathophysiology of diabetic renal disease. However, the precise mechanisms by which sex hormones contribute to the pathophysiology of diabetic renal disease are poorly understood. Future studies in this direction may lead to development of sex-specific interventions to reduce the incidence and rate of progression of diabetic renal disease.

GRANTS

This work was funded by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-075832 to C. Maric.

Acknowledgments

I thank Drs. Licy Yanes and Julio Sartori-Valinotti for a critical review and discussion of the manuscript.

REFERENCES

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