Sex Hormones and Their Influence on Chronic Kidney Disease

José Manuel Valdivielso; Conxita Jacobs-Cachá; María José Soler

Disclosures

Curr Opin Nephrol Hypertens. 2019;28(1):1-9. 

In This Article

Introduction

There is a clear sexual dimorphism in the incidence and prevalence of end-stage chronic kidney disease (ESRD).[1,2] Registry data indicate that the incidence of ESRD is significantly lower in women compared with men across all age groups and has been maintained over the years.[1,3] Surprisingly, the registry data also demonstrates that the incidence of chronic kidney disease (CKD) is significantly higher in women compared with men.[1] The sex imbalance between CKD and ESRD patients has been classically related to faster CKD progression in men. In agreement with this thinking, ESRD progression has been reported to be slower in women affected by nondiabetic renal disease on the basis of studies involving human patients or animals with IgA or membranous nephropathy, hypertensive nephropathy, polycystic kidney disease, and others.[4–6] In contrast, Jafar et al.,[7] in a meta-analysis of 11 randomized trials that used angiotensin-converting enzyme inhibitors in patients with CKD found that the rate of renal disease progression might not be slower among women and in fact might even be faster among women than in men. This contradictory result and the nonagreement between the previous mentioned studies may be ascribed to different factors such as the patients included in the study. In the last study, the majority of included women were postmenopausal, whereas in the previous studies were not the case.[8] As reviewed by Carrero et al.,[8] data from population-based studies, that are a mirror of the population as a whole, reinforce the idea that men experience faster renal function decline than women. An interesting study by van den Brand et al .[9] also focused on the effect of age and sex in lifetime risk of renal replacement therapy (RRT) using data from The European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) registry. Lifetime risk of RRT was defined as the cumulative incidence of RRT up to age 90 years. This study demonstrated that lifetime risk of RRT is lower in women compared with men of the same age.[9] In United States Renal Data System (USRDS) 2017 data, there was a slightly lower incidence of transplantation as a percentage of RRT modalities in women than in men.[1,10] As fewer women than men start dialysis programs, the finding that a smaller number of women than men receive deceased donor kidneys seems to be logical (Figure 1). These results again reinforce the protective effects of estrogens (in premenopausal women) versus of the deleterious effects of testosterone on kidney function. This review will focus on the clinical and experimental evidence that postulates an important role for sex hormones in the incidence and progression of CKD, the effect of sex hormones and its receptors, specifically estrogens and androgen effects on diabetic and nondiabetic experimental nephropathy, and the imbalance of sex hormones in patients with CKD.

Figure 1.

Sex dimorphism in CKD progression. As showed in the figure, the majority of CKD stage 3–4 patients are women. However, as kidney disease worsens and renal replacement, namely, dialysis and kidney transplantation is needed there is a clear imbalance favoring the male gender. This sex dimorphism may be ascribed to the faster CKD progression in men as compared to women (1, 2).

Sex Hormones and its Receptors

Sex steroid hormones are essential for the correct development and function of the reproductive system but they are also involved in other physiological and pathological processes. Estrogens and progestins have a significant role in the regulation of skeletal homeostasis,[11,12] the central nervous,[13] and cardiovascular system[14] among others, and androgens exert an anabolic function in several tissues (bone, muscle, and red blood cells). In the pathological context, estrogens and progestins are responsible for hormone-dependent carcinomas[15] and androgens have a role in benign and malignant prostatic hyperplasia.[16]

Cholesterol is the precursor of all sex hormones. Cholesterol is first converted into pregnenolone, the direct precursor of progesterone and also, through a series of enzymatic reactions, of estrogens and androgens. A complex metabolic pathway mediates the transformation of pregnenolone into dehydroepiandrosterone (DHEA). DHEA is converted into testosterone in the Leydig cells and afterward into dihydrotestosterone (DHT) in extragonadal tissues. In the ovaries but also in other extragonadal tissues, DHEA can be aromatized to estrone and 17-β-estradiol, the most active estrogen isoform. Estrone and estradiol can be transformed to estriol, a third isoform of estrogens, in the liver and in the placenta of pregnant women.[17]

Sex hormones act via specific receptors in the target tissues that can be located in both the cytoplasm and the plasma membrane of the cell, thus transcription-dependent and independent pathways can be activated. The first and the most studied signaling pathway of sex hormones is the transcription-dependent pathway that is mediated by the cytoplasmic estrogen receptors, androgen receptors (AR), and progesterone receptors. There are two isoforms for each sex hormone receptor: estrogen receptors: estrogen receptor-α and estrogen receptor-β;[18] ARs: AR-A and AR-B;[19] and progesterone receptors: progesterone receptor-A and progesterone receptor-B.[20] These isoforms are selectively expressed on the target tissues and have differential affinity to their ligands so they can promote specific responses. Normally, sex steroids circulate in blood stabilized by the sex hormone-binding globulin (SHBG) or by albumin, but they can also be found in a free form (around 5% of the total depending on the sex hormone and the sex) that diffuses through the plasma membrane to the cytoplasm in which the specific receptors are found. Once the hormone binds to the receptor, dimerization happens (in a homo or heterodimeric way) and a conformational change promotes the coupling of regulator proteins to the hormone–receptor complex. The whole complex translocates into the nucleus in which it binds with specific sequences of DNA (sex steroid response elements) promoting or repressing gene expression.[21,22] The activation of this kind of signaling pathway leads to late effects that can even take several days; however, it is well known that sex hormone can induce fast responses (from seconds to 10 min). These early responses cannot be ascribed to the transcription-dependent pathway.[21,23] It has been described that the previously mentioned sex hormone receptors and other forms such as the G-protein-coupled estrogen receptor (GPER), the G protein-coupled receptor family C group 6 member A (GPRC6A) (for androgens), and the SHBG receptor can be found on the plasma membrane. These receptors can be activated directly by the sex hormone or by the sex hormone–SHBG complex, induce several nongenomic signaling mechanisms mediated by phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), proto-oncogene tyrosine-protein kinase (c-Src), protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) among others, and subsequently modulate the activity of transcription factors (Figure 2).[19,23] Finally, estrogen-related receptors have been described. These receptors are named 'orphan' as these kinds of transcription factors are constitutively activated without the need of estrogen binding and modulated by estrogen-dependent gene expression.[24]

Figure 2.

Sex steroids hormones direct and indirect effects. Sex hormones induce direct genomic effects through their binding to cytoplasmic steroid receptors (late response). Sex hormones also induce indirect effects on gene expression by regulating nongenomic signaling mechanisms mediated by PI3K/Akt, c-Src, PKA, PKC, and MAPK, and subsequently modulate the activity of transcription factors (fast response).

Estrogen and Androgen in Experimental Diabetic Nephropathy

In a model of type 1 diabetes, STZ-induced 6-week-old Sprague–Dawley rats, de Alencar Franco Costa et al.[25] demonstrated that 12 weeks of T1DM led to significantly higher albuminuria and SBP in diabetic males compared with females. In addition, diabetic males, but not females, showed increased renal collagen I and fibronectin mRNA levels compared with controls. Furthermore, when exploring the renin-angiotensin system (RAS), renal angiotensinogen (AOGEN) mRNA levels were significantly increased by diabetes in males but not in females. Interestingly, this increase in AOGEN was strongly correlated with albuminuria. In this study, AR blockade by flutamide attenuated diabetes-induced albuminuria but not renal fibrosis or AOGEN expression. In concordance with these findings, we also demonstrated that the modulation of the renin–angiotensin system by angiotensin converting enzyme 2 (ACE2) deletion in STZ-diabetic mice is sex-dependent. Thus, we simultaneously studied the influence of ACE2 deficiency and gonadectomy (GDX) on hypertension and kidney damage in STZ-diabetic male mice. GDX angiotensin converting enzyme 2 knockout (ACE2KO) diabetic mice showed lower blood pressure (BP) values and decreased nephropathy compared to male ACE2KO diabetic mice. These animals exhibited modulation of circulating and renal RAS favoring the 'pro-Ang (1–7)' axis.[26] In addition, histological evidence of renal protection, namely, a reduction in mesangial expansion and attenuation of glomerular hypertrophy, attenuation of podocyte loss, and reduction in interstitial fibrosis and collagen deposition in the GDX ACE2KO mice were also found. These two studies that decrease male sex hormones by either chemical or surgical castration contribute to the knowledge of sex differences in RAS in DN.[26] Later on, we also studied the effect of angiotensin II (ANGII) infusion on DN progression in both male and female diabetic mice with or without ACE2 deficiency.[27] We demonstrated that Ace2 deletion accentuates diabetes and ANGII-induced alterations in a sex-dependent manner and these differences could be ascribed to a different imbalance of the RAS. Thus, a sex dimorphism was clearly observed between ACE2, DN, and angiotensin II (ANGII)-related hypertension. In diabetic wild-type (WT) animals, ANGII infusion markedly increased albuminuria, glomerular filtration rate, and mesangial expansion in males but not in females. Of note, ACE2 deficiency accentuated ANGII-induced hypertension and albuminuria in diabetic females, whereas in males, ACE2 deficiency accentuated glomerular lesions such as glomerular hypertrophy, mesangial expansion, and podocyte depletion. At the molecular level, ANGII induced a greater down-regulation of renal angiotensin converting enzyme (ACE) in ACE2KO diabetic males, suggesting a sex-specific ANGII-mediated cross-talk between the two ACEs.[27] These studies reinforce the hypothesis that sex-hormone differences in diabetes can in part be ascribed to differences in the intrarenal RAS balance.

Although few studies have directly examined the effects of estrogens in diabetic nephropathy, numerous reports indicate that 17β-estradiol modulates cellular processes in the kidney that are involved in the pathophysiology of DN.[28] In an experimental model of type 2 diabetes, Otsuka–Long–Evans–Tokushima–Fatty (OLETF) strain, Tomiyoshi et al.[30] found that castration attenuated proteinuria, glomerular sclerosis, mesangial expansion, and glomerular basement membrane (GBM) thickening, whereas estrogen treatment did not attenuate proteinuria or glomerular sclerosis despite having the ability to attenuate mesangial expansion and GBM thickening. These findings suggest that apart from the mechanisms involved in the development of DN, other mechanisms such as growth hormone (GH), age, and blood pressure (BP) may contribute to progression of glomerulosclerosis in the estrogen-treated OLETF rats.[29,30] Whitney et al.[31] demonstrated that GH administration worsened renal injury in diabetes in a sex-specific manner (GH significantly increased glomerulosclerosis and tubulointerstitial fibrosis by 30 and 25% in male rats, but not in female rats) and was associated with an increase in pro-inflammatory mediators. In contrast with the previous study in estrogen-treated OLETF rats, Mankhey et al.[32] in a model of type 1 diabetes, the STZ-diabetic rat, replacement with E2 for 12 weeks exerted a renoprotective effect, by reducing albuminuria, improving creatinine clearance, attenuating glomerulosclerosis, and renal fibrosis in terms of tubulointerstitial fibrosis, and reducing transforming growth factor beta (TGF-β) protein expression. Another study confirmed that diabetes is associated with mild glomerulosclerosis and tubulointerstitial fibrosis and that these changes are attenuated with E2 supplementation. Supplementation with E2 early on from the onset of diabetes both decreases extracellular matrix (ECM) synthesis and increases ECM degradation, thus having a dual renoprotective role relating to ECM metabolism. The major regulators of ECM degradation in the kidney are MMP-2 and MMP-9. Mankhey et al.[33] demonstrated that E2 supplementation increased the expression and activity of both matrix metalloproteinase (MMP)-2 and MMP-9 in the diabetic kidney. In addition, both Tissue Inhibitor of Metalloproteinase (TIMP)-1 and TIMP-2 protein expression are upregulated in DN and E2 supplementation reduced TIMP protein expression, thus providing further evidence that E2 is not only renoprotective by reducing ECM synthesis but also by increasing ECM degradation.[33] In concordance, in the db/db mouse, a model of type 2 diabetes, E2, and raloxifene, another elective estrogen receptor modulator reduces fibronectin expression in the diabetic kidney.

In the STZ-diabetic ovariectomized rats, E2 and E2+ α-tocopherol administration may strengthen the antioxidant defense system by reducing lipid peroxidation, as a mechanism of DN protection.[34] Interestingly, recent in-vitro studies of podocytes, demonstrated that icariin (which is a GPER 1 agonist) inhibits podocyte oxidative stress, reduces reactive oxygen species production, and protects the integrity of the mitochondrial membrane. Icariin may also attenuate high glucose-induced podocyte apoptosis by inhibiting reactive oxygen species production and inducing the mitochondrial translocation of B-cell lymphoma 2 (Bcl-2) via a GPER-dependent pathway. By evaluating this, the important role of GPER and Bcl-2 mitochondrial translocation in icariin-inhibited apoptosis was demonstrated.[35] Further studies are needed to prove that icariin can selectively inhibit apoptosis and provide sex-specific kidney protection in DN.

In STZ-diabetic castrated male rats, a low dose of DHT attenuated, whereas a high dose accentuated the severity of several hallmarks of kidney disease such as albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis.[36] These observations suggested that DHT may play an important role in the pathophysiology of diabetic renal disease, but that its effects are dose dependent and may be related to its action at higher doses on the estrogen receptor.[37] The deleterious effects of androgens have also been studied in podocytes, in which testosterone induced an increase in the percentage of terminal transferase-mediated dUTP nick end labeling (TUNEL)-positive cells in ovariectomized B6 mice. In addition, testosterone also induced podocyte apoptosis in vitro by AR activation, but independent of the TGF-β1 signaling pathway. In this sense, testosterone administration was associated with podocyte damage and augmented apoptosis both in vivoand in vitro.[38] Clotet et al.[39] have recently performed a proteomic study with stable isotope labeling with amino acids in an indirect spike-in fashion to accurately quantify the proteome in DHT and 17β-estradiol-treated human primary proximal tubular epithelial cells. That study demonstrated that DHT alone led to dysregulated metabolic processes that are also altered in the diabetic kidney. These processes, including glucose metabolism, the hexosamine biosynthetic pathway, and fatty acid β-oxidation, are associated with diabetes and CKD. Sex-specific regulation by DHT of glucose-6-phosphate isomerase, mitochondrial trifunctional protein subunit α, and glucosamine-6-phosphate-N-acetyltransferase 1 was demonstrated in vitro and in vivo, suggesting that the detrimental effects of androgens in diabetic DN may be, at least in part, mediated by altered energy metabolism within the tubular cell. In addition, they also demonstrated sexual dimorphism in renal nitrotyrosine levels in the diabetic kidney.[39]

Estrogen and Androgen in Experimental Nondiabetic Kidney Disease

Premenopausal women had lower CKD progression than males of the same age. This difference is not observed in postmenopausal women.[6] Although there are data in conflict with this view[7] and the differences may not only be related to the effect of the sex steroids on the kidney but also by different habits among the sexes;[8] it is mostly thought that estrogens have a protective role and/or testosterone, by contrast, damages the kidney.[40] In this sense, studies using animal models of natural aging support the idea that estrogens slow progression of CKD as male rats developed kidney impairment faster than their female littermates.[41,42] In several rat models of kidney injury like experimental polycystic disease,[43] aging Dahl salt sensitive rats,[44] or kidney damage due to ischemia–reperfusion injury[45] or adenine treatment,[46] estrogens retard the progression of apoptosis and fibrotic processes in the kidney. Testosterone seems to have the opposite action.[46,47] The estrogen protective effect is not only related to a direct action on the kidney but also to its protective role in the cardiovascular system. dos Santos et al.[48] elegantly review the effect of sex hormones on different aspects of the cardiovascular system. Estrogens have a positive effect on myocardial contractility and also on the vasculature promoting nitric oxide synthesis and release. Nitric oxide is a potent vasodilator and its deficiency leads to endothelial dysfunction and, consequently, to the progression of CKD. In rat models, nitric oxide production is better preserved in female animals as a result of estrogen activity than in male littermates.[49] Recently, Fanelli et al.[50] showed using a rat model of chronic nitric oxide inhibition that female animals showed less histological damage and fibrosis in the kidney but curiously higher BP than male under the same conditions. This experimental model avoids the effect of the estrogens on the nitrous oxide systems (NOS) as a potent inhibitor of NOS enzyme is used, N-(ω)-nitro-L-arginine methyl ester. The fact is that in this model, female animals showed less kidney damage than male littermates demonstrating again the direct protective effect of estrogens on the kidney. Surprisingly, long-term treatment with N-(ω)-nitro-L-arginine methyl ester leads to a feedback loop that produces an inverse effect on NOS, that is activation of the enzyme.[51] As the enzyme can be reactivated by a feedback mechanism, estrogens can have an impact on nitric oxide synthesis and contribute to renoprotective mechanism of estrogens in this model as well.

Sex Hormone Levels in Chronic Kidney Disease

The prevalence of sexual dysfunction and infertility are very common in CKD patients, both in men and in women, and is caused by abnormalities in multiple areas of reproductive physiology.[52] Thus, the levels of sex hormones in CKD patients have been extensively reported, at least in men. Testosterone deficiency is common in CKD patients, both in early stages and in dialysis.[53,54] Furthermore, the CKD stage is inversely associated with the levels of free testosterone.[55] In addition, an increase in testosterone has also been reported after renal transplantation, and this increase is dependent on the time after receiving the graft.[56,57] The mechanisms for the decreased testosterone levels in men have not been completely elucidated, but an increase in prolactin clearance[58] and the inhibition of luteinizing hormone effects in Leydig cells[59] seem to be involved.

In women, the cyclic nature of hormonal control of the reproductive system complicates its study. Infertility is common in women with early stages of CKD, but the precise mechanisms have not been adequately explored. However, it is suggested that in women on dialysis, the lack of stimulation of luteinizing hormone by estradiol (and not a deficiency of estradiol levels per se) could be the cause of the lack of ovulation and the abnormal menstruation and dysfunctional uterine bleeding reported in women on dialysis.[52] After successful transplantation, fertility is restored in a high percentage of women.[60]

Effects of Sexual Hormone Changes in Chronic Kidney Disease Patients

Apart from the expected effects of the changes in sexual hormones on fertility and sexual activity, several other related complications have been reported in CKD patients. Thus, lower testosterone levels have been associated with depression[61] and impaired cognition level,[62] two common complications of CKD patients.[63] Furthermore, testosterone deficiency could cause anemia, and a reduced response to erythropoietin stimulating agents,[64] as testosterone stimulates erythroid progenitor cells.[65] In addition, lower testosterone levels are independently associated with lower muscle mass.[66] However, the effect of testosterone administration on muscle mass in CKD patients has yielded negative results,[67] although the results of this trial showed no increase in circulating testosterone levels after the treatment. Lower levels of testosterone have been also reported to be an independent predictor of increased mortality in all CKD stages.[55] The cause of this increase mortality is not clear, but low testosterone levels have been associated with many comorbidities of CKD patients like atherosclerosis, metabolic syndrome, cardiovascular disease, and systemic inflammation.[68,69] Conversely, comorbid conditions frequently found in CKD, like diabetes, hypertension, or obesity, can also have an effect decreasing testosterone levels.[70]

A serious consequence of CKD is the increase in bone abnormalities. Testosterone also plays a role in bone mineral density by increasing osteoblastic activity and reducing osteoclastic activity,[71] and with a meta-analysis determining a positive effect of testosterone supplementation in bone health.[72] However, the data in CKD patients are reduced to one report showing that free testosterone levels are associated with bone mineral density in male kidney-transplanted patients.[73] In women on dialysis, higher estradiol levels have been also associated with a better bone mineral density.[74]

The role of sex hormones in the incidence and progression of CKD is still a matter of debate. Although a recent article reviewing population-based studies showed a higher prevalence of women affected by CKD,[8] specific CKD cohorts display the opposite result.[75–77] In any case, this discrepancy seems to be only in early stages of CKD, as the incidence of RRT has been reported to be lower in women, at least in Europe.[3,10] Indeed, the normal decline of glomerular filtration rate (GFR) with age is lower in females than in males[78] and the progression rate of CKD follows the same pattern.[6,79] Furthermore, a peak in the prevalence of ESRD is observed in women aged between 40 and 50, when the activity of female sexual hormones begins to decline.[80]

Therefore, it seems that sex hormones could be playing a role in protecting women from progression of CKD. Indeed, several potential deleterious effects of testosterone have been described in experimental animals. Thus, testosterone induces apoptosis of podocytes[38] and proximal tubular cells,[81] whereas estrogens antagonize TGF-β induced apoptosis in podocytes[38] and mesangial cells.[82] Estrogens have also shown protective effects in potentially kidney-damaging pathways like collagen synthesis,[82] nitric oxide production,[83] the renin–angiotensin system,[84] the formation of free radical species,[85] and the synthesis of endothelin[86] (Figure 3).

Figure 3.

Sex hormones modulated pathways within the kidney. Sex hormones induce beneficial (mainly estrogens) or deleterious (mainly androgens) effects within the kidney by different pathways such as renin–angiotensin system, oxidative stress, and inflammation.

Data about the effect of estrogen treatment on CKD progression are scarce. A very early report in 1955 showed remission of the symptoms of three patients with severe nephrotic syndrome after treatment with estrogens.[87] Nowadays, we have better therapeutic options with the availability of selective estrogen receptor modulators. A recent post-hoc analysis of the Multiple Outcomes of Raloxifene Evaluation study has shown that women receiving raloxifene showed a lower rate of decline in renal function over 3 years.[88] Furthermore, in a recent meta-analysis, the use of hormone replacement therapy was associated with lower odds of albuminuria.[89]

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