Doxorubicin-induced cardiotoxicity is suppressed by estrous-staged treatment and exogenous 17β-estradiol in female tumor-bearing spontaneously hypertensive rats

Abstract

BackgroundDoxorubicin (DOX), an anthracycline therapeutic, is widely used to treat a variety of cancer types and known to induce cardiomyopathy in a time and dose-dependent manner. Postmenopausal and hypertensive females are two high-risk groups for developing adverse effects following DOX treatment. This may suggest that endogenous reproductive hormones can in part suppress DOX-induced cardiotoxicity. Here, we investigated if the endogenous fluctuations in 17β-estradiol (E2) and progesterone (P4) can in part suppress DOX-induced cardiomyopathy in SST-2 tumor-bearing spontaneously hypersensitive rats (SHRs) and evaluate if exogenous administration of E2 and P4 can suppress DOX-induced cardiotoxicity in tumor-bearing ovariectomized SHRs (ovaSHRs).MethodsVaginal cytology was performed on all animals to identify the stage of the estrous cycle. Estrous-staged SHRs received a single injection of saline, DOX, dexrazoxane (DRZ), or DOX combined with DRZ. OvaSHRs were implanted with time-releasing pellets that contained a carrier matrix (control), E2, P4, Tamoxifen (Tam), and combinations of E2 with P4 and Tam. Hormone pellet-implanted ovaSHRs received a single injection of saline or DOX. Cardiac troponin I (cTnI), E2, and P4 serum concentrations were measured before and after treatment in all animals. Cardiac damage and function were further assessed by echocardiography and histopathology. Weight, tumor size, and uterine width were measured for all animals.ResultsIn SHRs, estrous-staged DOX treatment altered acute estrous cycling that ultimately resulted in prolonged diestrus. Twelve days after DOX administration, all SHRs had comparable endogenous circulating E2. Thirteen days after DOX treatment, SHRs treated during proestrus had decreased cardiac output and increased cTnI as compared to animals treated during estrus and diestrus. DOX-induced tumor reduction was not affected by estrous-staged treatments. In ovaSHRs, exogenous administration of E2 suppressed DOX-induced cardiotoxicity, while P4-implanted ovaSHRs were partly resistant. However, ovaSHRs treated with E2 and P4 did not have cardioprotection against DOX-induced damage.ConclusionsThis study demonstrates that estrous-staged treatments can alter the extent of cardiac damage caused by DOX in female SHRs. The study also supports that exogenous E2 can suppress DOX-induced myocardial damage in ovaSHRs.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0183-9) contains supplementary material, which is available to authorized users.

Sexual dimorphism of acute doxorubicin-induced nephrotoxicity in C57Bl/6 mice

“…Although intriguing, this hypothesis needs to be confirmed in future studies by administering testosterone to DOX-treated male mice. In female mice, we also demonstrate that acute DOX administration caused a significant reduction in uterus widths, indicating DOX-induced ovarian suppression as previously reported [37, 38]. Interestingly, ovariectomy of female mice did not alter the expression of renal sEH protein expression.…”

Clinical and preclinical evidence of sex-related differences in anthracycline-induced cardiotoxicity

“…Similarly, a recent study has shown that exogenous 17-β-estradiol administration suppressed DOX-induced cardiotoxicity in ovariectomized female tumor-bearing SHR rats. Surprisingly, co-administration of progesterone negated the protective effect of 17-β-estradiol [ 75 ]. In contrast to these findings, Gonzalez et al showed that ovariectomy did not exacerbate acute DOX-induced cardiotoxicity in tumor-bearing SHRs [ 64 ].…”

Cardioprotective Effects of Exercise Training on Doxorubicin-Induced Cardiomyopathy: A Systematic Review With Meta-Analysis of Preclinical Studies

“…We also explored the in uence of the features of animal model on cardiac function of DOX-treated trained animals, i.e., species, sex, cumulative dose of DOX and timing of nal cardiac function assessment. Although the role of estrogen on gender-related cardioprotection [48], including in the context of DOX-induced cardiomyopathy, is well documented [49], FS was similar between male and female animals. None of the studies using female animals [17-19, 23, 24, 27, 28] discussed the choice of this gender, took into consideration the in uence of female hormones in the outcomes of interest or reported particular methodological/monitoring aspects, such as handling estrous cycle.…”