Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Abstract

Abstract-Studies suggest that the presence of testosterone exacerbates, whereas the absence of testosterone attenuates, the development of nondiabetic renal disease. However, the effects of the absence of testosterone in diabetic renal disease have not been studied. The study was performed in male Sprague-Dawley nondiabetic, streptozotocin-induced diabetic, and streptozotocin-induced castrated rats (nϭ10 to 11 per group) for 14 weeks. Diabetes was associated with the following increases: 3.2-fold in urine albumin excretion, 6.3-fold in glomerulosclerosis, 6.0-fold in tubulointerstitial fibrosis, 1.6-fold in collagen type I, 1.2-fold in collagen type IV, 1.3-fold in transforming growth factor-␤ protein expression, and 32.7-fold in CD68-positive cell abundance. Diabetes was also associated with a 1.3-fold decrease in matrix metalloproteinase protein expression and activity. Castration further exacerbated all of these parameters. Diabetes was also associated with a 4.7-fold decrease in plasma testosterone, 2.9-fold increase in estradiol, and 2.1-fold decrease in plasma progesterone levels. Castration further decreased plasma testosterone levels but had no additional effects on plasma estradiol and progesterone. These data suggest that diabetes is associated with abnormal sex hormone levels that correlate with the progression of diabetic renal disease. Most importantly, our results suggest an important role for sex hormones in the pathophysiology of diabetic renal complications. (Hypertension. 2008;51:1218-1224.)Key Words: diabetes Ⅲ kidney Ⅲ sex hormones Ⅲ glomerulosclerosis Ⅲ tubulointerstitial fibrosis E pidemiological studies show that the incidence and the rate of progression of nondiabetic renal disease are greater in men compared with age-matched women. 1,2 These observations lead to the belief that the male sex is a risk factor and/or that the female sex is a protective factor against the development of renal disease. In the setting of diabetes, however, this relationship is not so clear. Although some studies indicate that the male sex is still a risk factor for the development of diabetic nephropathy and progression to end-stage renal disease, 3,4 other studies suggest either no difference 5,6 or that females progress at a faster rate. 7,8 The actual truth is that the existing data are inadequate for the precise determination of whether sex differences, which clearly exist in nondiabetic renal disease, exist or "disappear" in the setting of diabetes.Our previous studies have shown that diabetes is associated with reduced plasma levels of estradiol in the female streptozotocin (STZ)-induced diabetic rat. 9 Supplementation of estradiol in these animals either from the onset 10,11 or 2 months after the induction of diabetes 12 attenuates the development of renal disease. Clinical studies indicate that diabetes is associated with decreased testosterone levels in men with diabetes, 13,14 suggesting that testosterone deficiency may contribute or at least be associated with the development of diabetic renal disea...

Sex-related differences in the long-term risk of microvascular complications by age at onset of type 1 diabetes

“…Several experimental studies have demonstrated a renoprotective role of exogenous oestrogens in models of type 1 diabetic retinopathy and nephropathy [36][37][38][39]. However, an experimental model of type 1 diabetes has also, however, shown that relative balance, rather than the absolute levels of sex hormones, correlates with conditions associated with diabetic complications [40].…”

Sex and the Kidney

“…In addition, removal of the anabolic effects of testosterone in the setting of the wasting syndrome of uncontrolled diabetes may contribute to further deterioration of renal function. Also, expression of profibrotic molecules, such as transforming growth factor-␤ and matrix degradation enzymes, may be differentially controlled by sex hormones, 15 which may explain the effect of castration on these parameters as found by Xu et al 10 In summary, one thing is certain: sex matters. The study of Xu et al, 10 far from exhausting the possible explanations, opens new avenues for research into the role of sex hormones in altering the course of diabetic nephropathy.…”

“…Also, expression of profibrotic molecules, such as transforming growth factor-␤ and matrix degradation enzymes, may be differentially controlled by sex hormones, 15 which may explain the effect of castration on these parameters as found by Xu et al 10 In summary, one thing is certain: sex matters. The study of Xu et al, 10 far from exhausting the possible explanations, opens new avenues for research into the role of sex hormones in altering the course of diabetic nephropathy. As conventional paradigms fail to encompass the wealth of contemporary experimental evidence, clinical practice would certainly benefit from a thorough understanding of the mechanisms underlying the effects of sex hormones on the kidney and cardiovascular system.…”

“…Indeed, a clinical study of estrogen administration to men after myocardial infarction was interrupted in the 1970s because of increased deaths and incidence of reinfarction. 13 Whether the increase in estradiol alone or rather the decrease in the ratio of testosterone/ estradiol in male diabetic rats is responsible for the progression of diabetic renal disease, as suggested by correlation analysis in the study by Xu et al, 10 remains to be established.…”

Вплив Інгібіторів Ароматази Третього Покоління На Окремі Компоненти Перебігу Експериментального Метаболічного Синдрому

“…У роботі Qin Xu та співавт. було продемонстровано, що діабет і гіперглікемія асоційовані зі зниженням плазмового рівня тестостерону й підвищенням плазмового рівня естрадіолу [8]. Також наявні дані щодо зв'язку між збільшенням рівня естрогенів і зменшенням чутливості клітин до інсуліну.…”