Role of Androgens in Sex Differences in Cardiac Damage During Myocardial Infarction

University of Sydney, Sydney, New South Wales, Australia
Endocrinology (Impact Factor: 4.5). 12/2013; 155(2):en20131755. DOI: 10.1210/en.2013-1755
Source: PubMed


Age-specific incidence of ischemic heart disease in men is higher than in women, although women die more frequently without previous symptoms; the molecular mechanism(s) are poorly understood. Most studies focus on protection by estrogen, with less attention on androgen receptor (AR) mediated androgen actions. Our aim was to determine the role of androgens in the sex differences in cardiac damage during myocardial infarction (MI). Mature age-matched male and female Sprague Dawley rats - intact or surgically gonadectomized (Gx) - received testosterone (T) or estradiol (E2) via subdermal silastic implants; a subset of male rats received dihydrotestosterone (DHT). After 21 days, animals were anesthetized, hearts excised and subjected to ex vivo regional ischemia-reperfusion (I-R). Hearts from intact males had larger infarcts than those from females following I-R; Gx produced the opposite effect, confirming a role for sex steroids. In Gx males, androgens (DHT, T) and E2 aggravated I-R induced cardiac damage, whereas in Gx females, T had no effect and E2 reduced infarct area. Increased circulating T levels upregulated AR and receptor for advanced glycation end products (RAGE), which resulted in enhanced apoptosis aggravating cardiac damage in both males and females. In conclusion, our study demonstrates for the first time that sex steroids regulate autophagy during MI, and shows that a novel mechanism of action for androgens during I-R is downregulation of antiapoptotic protein Bcl-xL, a key controller for crosstalk between autophagy and apoptosis, shifting the balance towards apoptosis and leading to aggravated cardiac damage.

5 Reads
  • Source
    • "Differential regulation of these receptors may differ between males and females and whether there is cross-reactivity should also be considered. In recent studies , we did not find any differences in protein levels of AR, ER-a and ER-b, between male and female rats [58], in agreement with previous reports [70] [75]. In contrast, sex differences in MR mRNA levels have been reported in rat brain, while treatment with estrogen decreased MR mRNA expression and binding in the hippocampus [66]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ischemic heart disease (IHD) continues to be the most common cause of death globally, although mortality rates are decreasing with significant advances in treatment. Higher prevalence of co-morbidities in women only partly explains the lack of decrease in mortality rates in younger women due to. Until recently there has been gender bias in pre-clinical studies and many clinical trials, resulting in a significant gap in knowledge whether there are differential responses to therapy for women, particularly younger women. There is increasing evidence that there are significant gender-specific differences in the outcome of post-infarction remodelling, prevalence of hypertension and sudden cardiac death. These differences indicate that cardiac tissue in females displays significant physiological and biochemical differences compared to males. However, the mechanisms mediating these differences, and how they change with age, are poorly understood. Circulating levels and physiological effects of aldosterone vary across the menstrual cycle suggesting female steroid sex hormones may not only regulate production of, but also responses to, aldosterone in pre-menopausal women. This modified tissue response may foster a homeostatic environment where higher levels of aldosterone are tolerated without adverse cardiac effect. Moreover, there is limited data on the direct regulation of this signalling axis by androgens in female animals/subjects. This review explores the relationship between gender and the effects of aldosterone in cardiovascular disease (CVD), an issue of significant need that may lead to changes in best practice to optimise clinical care and improve outcomes for females with CVD.
    Full-text · Article · Dec 2014 · Steroids
  • [Show abstract] [Hide abstract]
    ABSTRACT: Use of testosterone among men is increasing rapidly. Low serum testosterone is positively associated with cardiovascular disease and its risk factors. No large randomized controlled trial (RCT) has assessed the effects of testosterone on cardiovascular outcomes. Here recent evidence accumulating from other sources - pharmacoepidemiology, Mendelian randomization studies and meta-analysis of small RCTs - is reviewed to inform current testosterone usage. In a large, well conducted pharmacoepidemiology study specifically testosterone prescription was associated with myocardial infarction. Two Mendelian randomization studies did not corroborate beneficial effects of higher endogenous testosterone on cardiovascular risk factors, but suggested higher endogenous testosterone raised LDL cholesterol and lowered HDL cholesterol. A comprehensive meta-analysis of RCTs summarizing 27 trials including 2994 men found increased risk of cardiovascular-related events on testosterone (odds ratio 1.54, 95% confidence interval 1.09-2.18). Contrary to expectations from observational studies, current indications suggest testosterone causes ischemic cardiovascular disease with corresponding implications for practice. A large RCT would undoubtedly settle the issue definitively. Given mounting evidence of harm and the urgency of the situation assembling all the evidence from completed RCTs of testosterone or androgen deprivation therapy and use of Mendelian randomization might generate a definitive answer most quickly.
    No preview · Article · Apr 2014 · Current opinion in endocrinology, diabetes, and obesity
  • [Show abstract] [Hide abstract]
    ABSTRACT: A cause is proposed for several forms of reproductive suboptimality (viz foetal loss, preterm birth and low birth weight). The point is illustrated here in the case of miscarriage. I suggest that all these forms of reproductive suboptimality are partially caused by high levels of stress-related maternal adrenal androgens. The argument is supported by both experimental and epidemiological data.
    No preview · Article · Sep 2014 · Journal of Theoretical Biology
Show more