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 , and cardiovascular system  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  and androgens have a role in benign and malignant prostatic hyperplasia .
In a model of type 1 diabetes, STZ-induced 6-week-old Sprague–Dawley rats, de Alencar Franco Costa et al.  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 . 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 . 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.
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 . 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 . 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 . 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 vivo and in vitro . 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▪▪].
Premenopausal women had lower CKD progression than males of the same age. This difference is not observed in postmenopausal women . Although there are data in conflict with this view  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 ; it is mostly thought that estrogens have a protective role and/or testosterone, by contrast, damages the kidney . 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 , aging Dahl salt sensitive rats , or kidney damage due to ischemia–reperfusion injury  or adenine treatment , 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.  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 . Recently, Fanelli et al.  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 . 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.
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 . 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 . 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  and the inhibition of luteinizing hormone effects in Leydig cells  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 . After successful transplantation, fertility is restored in a high percentage of women .
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  and impaired cognition level , two common complications of CKD patients . Furthermore, testosterone deficiency could cause anemia, and a reduced response to erythropoietin stimulating agents , as testosterone stimulates erythroid progenitor cells . In addition, lower testosterone levels are independently associated with lower muscle mass . However, the effect of testosterone administration on muscle mass in CKD patients has yielded negative results , 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 . 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 .
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 , and with a meta-analysis determining a positive effect of testosterone supplementation in bone health . 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 .
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 . 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 . Furthermore, in a recent meta-analysis, the use of hormone replacement therapy was associated with lower odds of albuminuria .
In summary, male gender is associated with faster CKD progression to ESRD when compared to females. Sex hormones and its receptors play a critical role in the progression of the damaged kidney through different pathophysiological pathways such as the RAS system, oxidative stress, and fibrosis. Strategies aimed to enhance female sex hormones and decrease male sex hormones may exert a future positive effect on the damaged kidney.
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