Association for Academic SurgeryLow testosterone elevates interleukin family cytokines in a rodent model: a possible mechanism for the potentiation of vascular disease in androgen-deficient males
Introduction
Androgen deficiency (AD) is an increasingly prevalent diagnosis among today's aging male population. Androgen replacement therapy (ART) in patients with idiopathic AD has seen growing popularity with the advent of multiple exogenous replacement forms and is largely aimed at health maintenance and improving quality of life. However, we may underappreciate the benefits of ART in AD subjects regarding cardiovascular and vascular disease [1], [2], [3], [4], [5]. Likewise, we may not fully appreciate the consequences of androgen deprivation therapy routinely used in the treatment of patients with high-risk prostate cancer [6].
Regardless of whether a physiological consequence of primary testicular failure or a result of a medical or surgical intervention in the management of prostate cancer, AD has been associated with an increased risk of atherosclerosis, cardiovascular, and peripheral arterial disease [7], [8], [9], [10], [11]. Peripheral arterial disease is a major risk factor for cardiovascular and cerebral ischemic events, is often debilitating with claudication and loss of mobility, and can ultimately lead to limb loss. In spite of the vast magnitude of clinical and epidemiologic research investigating their correlation, the molecular and biochemical mechanisms underlying the role of AD in vascular disease remain unclear.
Both clinical and experimental studies have shown AD is associated with various autoimmune diseases [12], [13], [14] and that higher testosterone (TST) levels correlate to significant immunoprotective molecular and cellular responses [15]. Additionally, low TST levels have been linked to increased inflammatory markers in hypogonadal men [16]. It is well established that cytokines, growth factors, stress, and inflammation affect the regulation of matrix metalloproteinases (MMPs), enzymes largely responsible for vascular remodeling [17], [18], [19], [20]. Others and we have shown that female sex hormones influence vascular pathogenesis via inflammatory-modulated signaling and that there is a positive correlation with dysfunctional MMP regulation [21], [22], [23], [24], [25], [26]. Additionally, we have demonstrated a role for TST in the modulation of these MMP regulatory mechanisms and in the cellular processes of hyperplasia development in vitro [27]. Here we aim to identify other critical mechanisms modulated by AD that could be playing a role in the development of vascular pathogenesis. Our working hypothesis is that AD is acting as a proinflammatory modulator contributing to dysfunctional vascular remodeling.
Section snippets
Animal groups, induction of AD, and ART experimental design
Male Sprague–Dawley rats, beginning the study at the age of 8–10 mo (weighing 425–525 g) to best represent the older male population affected by the pathology of this study, were orchiectomized when obtained from Charles River Laboratories, Inc (Wilmington, MA). After 4 wk of hormone deficiency, each aged orchiectomized rat was randomly assigned to one of seven treatment groups with n = 6. Subcutaneous insertion of a 90-d slow-release water-soluble placebo pellet (Plac; 10 mg) or TST pellet
AD induction and ART dose response
To assay the efficiency of our experimental ART conditions and regime, a time interval dose–response curve was performed as described and resulting serum TST levels were measured via ELISA. Expected physiological and therapeutic TST levels were defined based on published TST levels of 0.66–5.4 ng/mL with a mean of 3.06 in normal male rats (parameters provided by the manufacturers). When compared with levels in Plac, AI, and YI controls (∗0.15 ± 0.07 ng/mL, ∗∗2.31 ± 0.66, and ∗∗2.72 ± 0.35,
Discussion
A variety of studies have shown that low TST levels are associated with increased risk of cardiovascular and vascular disease. Epidemiologic studies have shown an inverse relationship between TST levels and atherosclerosis, cardiovascular, and peripheral vascular disease [7], [8], [9], [10], [11]. Vascular risk factors such as obesity, hypertension, and dyslipidemia have been linked to primary AD [28], [29], [30], [31], [32]. Furthermore, low TST has been linked to increased intimal hyperplasia
Acknowledgment
The authors gratefully thank Eva Bukovska, MS, Wendy Packan, Trey Fisher, and Wes Spears for their technical assistance and Dr Joe Spengler for his support through the Spengler Research Gift Fund. This work was supported in part by funding from the Physician Medical Education Research Foundation.
Author contribution: B.M.F. contributed toward data collection, analysis and interpretation, and writing of article. D.J.H.M. contributed toward conception and design, data collection, analysis and
References (51)
- et al.
The relationship of natural androgens to coronary heart disease in males: a review
Atherosclerosis
(1996) - et al.
Sex hormones as novel risk biomarkers for atherosclerosis in peripheral vascular disease
J Am Coll Cardiol
(2007) - et al.
Matrix metalloproteinases
J Biol Chem
(1999) - et al.
Matrix metalloproteinases in peripheral vascular disease
J Vasc Surg
(2007) - et al.
Effect of hormone replacement therapy in matrix metalloproteinase expression and intimal hyperplasia development after vascular injury
Ann Vasc Surg
(2013) - et al.
Regulation of vascular smooth muscle cell expression and function of matrix metalloproteinases is mediated by estrogen and progesterone exposure
J Vasc Surg
(2009) - et al.
Effect of hormones on matrix metalloproteinases gene regulation in human aortic smooth muscle cells
J Surg Res
(2008) - et al.
Role of MT1-MMP in estrogen-mediated cellular processes of intimal hyperplasia
J Surg Res
(2012) - et al.
Serum levels of matrix metalloproteinase-2 as a marker of intimal hyperplasia
J Surg Res
(2010) - et al.
Androgens regulate MMPs and the cellular processes of intimal hyperplasia
J Surg Res
(2013)