Prostate cancer in South Africa
Prostate cancer (PCa) is a leading cancer among aging men worldwide, but its impact varies across different races, ethnicities and geographic locations. Global statistics show Pca to be the second commonest cancer among men but only the sixth in cancer-related deaths. However, in countries with predominant black populations it is not only the most common male cancer but also number one in cancer-related deaths [1].
Within the black population itself there is a five times increased mortality rate in men from the Caribbean and sub-Saharan Africa versus African-Americans in the USA [2]. These differences are believed to be a combination of genetic and environmental factors leading to more aggressive tumor biology as well as healthcare system constraints such as poor screening and limited access across many regions of sub-Saharan Africa. This results in many men already having advanced disease on presentation [3].
Androgen deprivation therapy
Androgen deprivation therapy (ADT) forms the cornerstone of treatment in advanced PCa and is based on the hormonal dependence of PCa, first described by Huggins & Hodges in their landmark paper in 1941 [4].
This discovery, which was the first known drug treatment of any cancer, won them the Nobel Prize in 1966 and nowadays is used to alleviate symptoms in metastatic disease as an adjunct to surgery or radiotherapy in high-risk or locally advanced disease [5].
The aim of ADT is to generate castrate levels of testosterone, conventionally defined as < 1.7 mmol/L but ideally to below 0.7 mmol/L [6]. This can be achieved through surgical castration (bilateral orchiectomy) or medical castration using centrally acting gonadotropin-releasing hormone (GnRH) agents and or anti-androgens, both of which block downstream production/utilization of testosterone. Long-term ADT and the resultant testosterone deficiency can have many physical and psychological adverse side effects.
Metabolic effects of ADT
The general side effects of ADT are most bothersome to patients, and they include loss of libido and erectile dysfunction along with hot flushes, gynecomastia, mood swings, depression and fatigue. The metabolic effects of ADT, however, are more subtle, sometimes overlooked and possibly more dangerous in the long run. ADT leads to altered lipid, glucose, muscle and bone metabolism that can precipitate or exacerbate dyslipidemia and central obesity, insulin resistance and diabetes, sarcopenia and osteoporosis potentially leading to cardiovascular disease, fractures and falls [7].
Weight gain and body composition
Prostate cancer generally affects men over the age of 50 who are prone to age-related changes in body fat accumulation, particularly central fat stores. These changes might be offset by tumor-related cachexia, specifically in men selected for primary ADT who often have advanced disease at presentation. A consistent finding in men started on ADT is significant weight gain with some studies showing increases as high as 4% total body weight [8]. The level of weight gain depends mainly on the duration of treatment rather than the ADT agent used and seems to more severely affect men below the age of 65 [9]. The fat deposition is predominantly seen in subcutaneous stores rather than in visceral fat stores with the latter being the usual finding in classic metabolic syndrome [10, 11]. Prolonged ADT results in a sarcopenic type of obesity which affects the ratio and distribution of fat to muscle stores throughout the body. Reduction in lean muscle mass (often measured with cross-sectional imaging of thigh muscles) has shown rates of loss as high as 15–20% [12]. ADT also results in a decrease of bone mineral density in the first year of treatment with loss rates higher than postmenopausal women (roughly 5% versus 2.5%). Unlike weight gain, these changes do not stabilize with time and after 10 years of ADT the rate of osteoporosis has been found to be as high as 80% versus 35% in hormone naive men [13]. These muscle and bone changes increase the risk for frailty falls and fractures as evidenced by the nearly double rate of falls and fractures in men on ADT versus non-ADT users [14].
Lipid metabolism
Lipid levels are affected by age, gender, diet and obesity. The landmark Framingham heart study highlighted the differences in lipid profiles between men and women [15]. Overall the female lipid profile is less atherogenic with greater high-density lipoprotein (HDL) concentrations and lower low-density lipoprotein (LDL) and triglyceride (TG) concentrations than age-matched men. This benefit is mainly seen in premenopausal women partly due to the ability of estrogens to regulate lipid metabolism through estrogen receptors (ɑ & β) located on adipose and liver cells.
Population studies in men show that LDL levels gradually increase with age until the age of 60 to 65 and thereafter start to decline [16]. HDL levels are also noted to increase in elderly men likely as a result of age-related hypogonadism. TG levels rise with age due to reduced activity by lipoprotein lipase, the enzyme responsible for plasma triglyceride clearance.
Obese patients classically have elevated TG levels and low HDL levels. Excess adipose tissue, particularly visceral stores, causes an increase in the level of circulating free fatty acids, many of which get converted into triglyceride-rich lipoproteins by the liver. This affects the balance of other cholesterol-rich lipoproteins, specifically HDL, in a reciprocal fashion so that elevated TG levels cause a drop in HDL levels. The inverse relationship and ratio of TG:HDL are clinically relevant and are often used as a surrogate marker for insulin resistance, which is also related to central adiposity [17].
Testosterone plays an important role in regulation of lipid metabolism. Testosterone allows for upregulation of hepatic LDL receptors which are necessary in lowering serum LDL levels. Hypogonadism results in excess circulating LDL which can then be oxidized in sub-endothelial tissues leading to atheroma plaque formation [18]. Testosterone (both endogenous and exogenous) suppresses atheroprotective HDL levels [19], while suppression of testosterone with androgen deprivation therapy results in elevated HDL levels, at least in the early phases of treatment [10].
Lipids and cancer
Lipids may play a role in carcinogenesis [20], and there have been multiple studies trying to establish elevated cholesterol as a risk factor for development of PCa [21,22,23,24]. Their findings are somewhat contradictory, and in a recent meta-analysis of 14 prospective studies, dyslipidemia was not found to be associated with the risk of either overall prostate cancer [25].
Testosterone, which itself arises from a lipid precursor—cholesterol, is mainly linked with progression of established prostate cancer but is not a risk factor for development of prostate cancer. This is not surprising as prostate cancer is generally a disease of older men rather than in young men who are at their peak with regard to testosterone levels [26].
Obesity however, usually defined as a body mass index (BMI) ≥ 30 kg/m2, has been linked to PCa mortality and aggressiveness in many populations [27,28,29,30] and recently linked to intermediate risk disease in African men [31]. Possible mechanisms leading to this association relate to hormonal and metabolic pathways. Hormonally, obese men tend to have lower levels of adiponectin as well as higher levels of insulin and insulin-like growth factor which have been associated with an increased risk of PCa [32]. Likewise excess adipose tissue leads to elevated free fatty acids which are necessary for cell growth and turnover, cell membrane formation and oncogenic cell signaling pathways. These pathways have been found to be highly upregulated in PCa cells [33].
In addition, activation of the androgen receptor increases expression of lipogenic enzymes such as phosphatase and tensin homolog (PTEN), an enzyme that once deleted is linked to 40% of primary Pca and over 70% of metastatic Pca cases. Even after castrate resistance has developed, prostate cancer cells continue to produce de novo androgens which in turn signal increased fatty acid synthesis and tumor progression [34]. This has led to increased interest in the role of cholesterol-lowering agents such as statins in management of prostate cancer both in preventing progression of disease and by reducing the dyslipidemic changes caused by ADT [35].
Lipids in African men
Dyslipidemia has a high prevalence worldwide and is an independent risk factor for atherosclerotic cardiovascular disease [36]. The reference values for lipid levels are tabulated below.
Importantly, nearly half of all ischemic heart attacks and more than one quarter of all ischemic strokes are due to abnormal cholesterol levels [37].
A recent South African population study of over 4000 participants aged 40 years and older showed that over two-thirds (67%) met criteria for dyslipidemia, yet only 1% were aware of their condition and even less on treatment [38].
When studying the interethnic differences in lipid profiles, it has been found that men of African descent had significantly lower TC, LDL and TG levels than other ethnic populations within Africa. These differences were seen even after adjusting for age, gender and BMI. Compared to Europeans and Indians, men of African descent have the lowest mortality attributable to ‘sub-optimal’ lipid levels (defined as TC ≥ 3.8 mmol/l). This was seen in the Soweto population as well as in other studies across Africa.
However, in terms of underlying cardiovascular risk, South African men as a whole are at a higher risk than other black Africans with among the highest prevalence of obesity, undiagnosed diabetes mellitus, smoking and high cholesterol in all of Africa [37]. This is most notable in black South Africans living in rapidly urbanizing areas, such as Soweto where our study was conducted, which have increasing rates of cardiovascular (CVS) disease and morbidity [39].
Cardiovascular risk of ADT
Testosterone has a host of cardioprotective metabolic effects, and hypogonadism is known to be an independent risk factor for cardiovascular disease [40]. These effects are related to the direct vasodilatory effect of testosterone and by its ability to indirectly modify CVS risk factors such as insulin resistance, central adiposity and exercise tolerance [41].
The exact level of CVS risk depends on the type of androgen deprivation used. Historically, hormone manipulation in prostate cancer was achieved by surgical castration (bilateral orchiectomy) or by medical castration using diethylstilbestrol (DES), an oral tablet containing synthetic estrogen.
Estrogen therapy, although cost-effective and bone protective, was eventually discontinued in the 1980s when adverse cardiovascular events (CVE) were reported, particularly in the first year of DES therapy [42]. Estrogen was replaced with oral anti-androgens which, despite a favorable safety profile (and even preserved erectile function in the non-steroidal group), failed to achieve survival outcomes similar to surgical castration when used as monotherapy [43].
Surgical castration has a more favorable CVS risk profile than estrogen but is often underutilized due to its irreversible nature and psychological impact on masculinity. It does remain an important option in resource-constrained environments such as Africa as it is a once off, simple and cost-effective procedure that can even be done under local anesthetic.
The landscape of ADT changed with the development of long-acting GnRH agents (initially only agonists) such as leuprolide or goserelin, which appeared safe and had similar survival outcomes when compared to surgical castration. These agents work as analogs to the naturally occurring gonadotropin hormone produced in the hypothalamus which is normally only cyclically released in response to low circulating testosterone levels. GnRH agonists cause continuous stimulation and eventual downregulation of luteinizing hormone (LH) and testosterone production. When starting these agents one must co-administer a short course of antiandrogens to prevent the testosterone flare from the agonistic effect which can initially worsen symptoms. These effects can be avoided if using a GnRH antagonist such as degarelix, which came on to the market in 2008 [44].
However, the CVS safety profile of these agents was brought into question in 2006 when Keating and colleagues identified an increased risk of CVS disease and incident diabetes mellitus in patients treated with GnRH analogs. This raised concern that more men might die from treatment of the disease rather than from the disease itself, something which had been demonstrated in previous studies [45]. These concerns were validated by other large observational studies which demonstrated an association between ADT and CVS disease [27]. Despite causation being difficult to prove based on heterogeneity of population study designs, there was enough concern for the US Food and Drug Administration (FDA) in 2010 to issue safety warnings on GnRH agonists labels pertaining to the increased risk of diabetes, heart attack, sudden cardiac death and stroke. Similar advisory statements were published by the American Heart Association, American Cancer Society and American Urological Association [46]. The highest level of adverse CVE was seen in men with pre-existing CVS disease particularly in the early phases of treatment when treated with agonists vs antagonists [47].
Different theories have been proposed to explain how ADT can lead to acute CVE (when one would expect slow metabolic changes leading to increased risk), and they center around atheromatous plaque destabilization. The one theory relates to T cells which when stimulated by GnRH agonists (T cells have GnRH receptors) can cause intra-plaque T cell expansion, leading to fibrotic cap disruption and plaque destabilization [48]. This fits well with the current understanding that atherosclerosis is largely an inflammatory-driven process with adaptive T cell immunity playing an important role [49].
Another theory relates to follicle-stimulating hormone (FSH) which mediates lipid storage and also plays a role in endothelial function and is higher in men treated with GnRH agonists. Unlike GnRH antagonists which suppress both LH and FSH, GnRH agonists primarily suppress LH but not FSH. Likewise treatment with GnRH agonists may cause microsurges of FSH and testosterone between dosing intervals [50]. FSH surges of up to 300% have also been documented after surgical castration [51]. The FSH theory helps explain why surgical castration and GnRH agonists had a higher rate of cardiovascular thrombotic events when compared to GnRH antagonists [52].
There has yet to be a head to head study between GnRH agonists and antagonists with a primary outcome of CVEs, but many authors and clinicians already recommend GnRH antagonists rather than GnRH agonists for ADT in patients with pre-existing CVS disease [53].
Rationale for the study
Given the prevalence of advanced prostate cancer and the unique lipid profile in men of African descent in this study, we undertake to investigate the dyslipidemia induced by ADT, something which has been studied elsewhere but never in South Africa.
