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Abstract

Polycystic ovary syndrome (PCOS) is associated with a clustering of metabolic and cardiovascular risk factors. Insulin resistance is implicated as the major player in the metabolic abnormalities and contributes to the increased cardiovascular risk associated with the syndrome. However, androgen excess appears to participate as an independent parameter, which further aggravates the cardiovascular and metabolic aberrations in affected women with PCOS. The resultant impact of hyperandrogenemia possibly acquires clinical significance for women's health in the context of PCOS, particularly since recent data support an increased incidence of coronary artery disease and of cardiovascular events directly related to androgen levels in women with the syndrome.

Keywords

androgen excess cardiovascular disease cardiovascular events metabolic syndrome polycystic ovary syndrome

The polycystic ovary syndrome (PCOS) is the most common endocrinopathy, afflicting 6.8% of reproductive-aged women [1]. PCOS is characterized and diagnosed by the combination of hyperandrogenism and anovulation [2]. Androgen excess is primarily of ovarian origin, although adrenals also contribute to a lesser degree. Increased ovarian androgen production in this syndrome is due to both intrinsic upregulation of theca steroidogenesis and further augmentation of steroidogenesis by high circulating insulin levels [3]. Insulin resistance accompanied by compensatory hyperinsulinemia is an intrinsic feature in 50–70% of patients with PCOS [4], which is only partly attributed to the coexistence of obesity [5].

Reflective of the inherent association of the syndrome with insulin resistance is the clustering of metabolic abnormalities in women with PCOS. The resultant metabolic phenotype imposes a significant burden of cardiovascular (CV) risk upon affected women throughout life [6].

As research in this area evolves [7], androgen excess assumes potential importance in amplifying the cardiovascular risk associated with PCOS [6]. The impact of androgen excess may be dual, involving the aggravation of metabolic abnormalities, as well as direct effects on the CV system ( Figure 1 ).

Figure 1.

Role of androgen excess on metabolic & cardiovascular dysfuction in PCOS.

This review is aimed at presenting the current state of research and knowledge regarding the role of androgen excess in the metabolic and CV risk associated with PCOS. Potential mechanisms underlying this association will be proposed and areas of uncertainties will be considered. We will also cite recent data concerning CV morbidity and mortality in women with PCOS and discuss the emerging role of androgen excess in these final outcomes.

Role of androgen excess in metabolic aberrations in PCOS

Polycystic ovary syndrome has an adverse metabolic impact on affected women who commonly display abnormal metabolic phenotypes. In particular, Type 2 diabetes is more prevalent in women with PCOS than in their counterparts from the general population [8]. Even in the absence of diabetes, glucose intolerance and the metabolic syndrome (MBS) are common occurrences in women with PCOS [8 –10]. PCOS may be associated with metabolic abnormalities even in the absence of obesity [9] or it may interact with obesity to further compound the resultant metabolic phenotype [9,10].

Hyperandrogenemia in PCOS has been linked with several components of the MBS. A positive association between hyperandrogenemia or androgen bioavailability and the MBS has been found in adult women with PCOS [9,10]. A hyperandrogenic hormonal profile, reflected by an increased free androgen index, is a reportedly common feature of MBS in premenopausal women, even in the absence of full-blown PCOS [11]. Accordingly, among obese, hyperandrogenic adolescents, hyperandrogenemia was found to be a significant predictor of the MBS, independently of obesity and insulin resistance [12].

This detrimental linkage has been also unveiled by studies in androgenized animal models. The exposure of pre- and post-pubertal rats to dihydrotestosterone (DHT) was linked with increased adipocyte size and fat mass in both subcutaneous and visceral fat depots, in parallel with an impairment of insulin sensitivity and of serum lipid profile [13,14].

More specifically, androgens can influence adipocyte functions through interaction with androgen receptor (AR), which is expressed in adipose tissue. Differences in AR expression in the two major fat compartments are also present, with androgen-binding sites being higher in human visceral preadipocytes than in subcutaneous preadipocytes [15]. The spectrum of androgen actions may extend beyond the classic ones mediated by the nuclear steroid receptor. Nongenomic pathways may operate in adipose tissue. Western blot analyses have demonstrated the presence of a small amount of AR in the plasma membrane fraction of sheep omental adipose tissue [15]. Adding to the complexity, androgens appear to act in a sex-dimorphic manner in many tissues [15]. Specifically, testosterone replacement to normal testosterone levels may reduce visceral adiposity in hypogonadal men. The beneficial effect of testosterone-replacement therapy in hypogonadal men relies on the restoration of normal testosterone levels [15], while excessive androgen levels (for the female range) in PCOS women are associated with visceral fat accumulation [6].

In vitro data clearly indicate a depot-specific effect of testosterone on lipolytic regulation in human adipose tissue. In differentiated pre-adipocytes from the abdominal subcutaneous but not from the omental fat depot from human subjects, testosterone caused a dose-dependent, AR-mediated decrease of catecholamine-stimulated lipolysis. The inhibitory (antilipolytic) effect of testosterone in subcutaneous adipocytes was as marked in men as in women [16]. Interestingly, previous results with DHT demonstrated inhibition of protein expression of hormone sensitive lipase in isolated mature human subcutaneous adipocytes exposed to the hormone for 48 h [16]. The major inhibitory effect of testosterone appears to be exerted on β-adrenoreceptor-mediated lipolysis, downstream of cAMP formation [17]. The negative interference of testosterone with activation of lipolysis has been also unveiled by clinical human studies. In healthy postmenopausal women, 3 months treatment with testosterone undecanoate decreased hormone sensitive lipase expression in abdominal subcutaneous adipocytes. Remarkably, testosterone-induced changes were positively correlated with the downregulation of lipolytic activity, as assessed by measurements of plasma glycerol levels during the euglycemic, hyperinsulinemic clamp [18]. The above data converge to the concept that testosterone may be able to suppress catecholamine-dependent lipolysis in subcutaneous fat, thereby promoting the expansion of this fat compartment.

By this token, high circulating testosterone levels could account for the selective inhibition of catecholamine-induced lipolysis in abdominal subcutaneous adipocytes isolated from women with PCOS [19]. Reduced ability of catecholamines to mobilize lipids from the abdominal subcutaneous region could lead to greater fat accumulation in this depot and, consequently, to upper-body obesity, which is associated with insulin resistance that is commonly found in women with PCOS.

However, the aforementioned data on the regulation of adipose tissue lipolysis do not explain the association of androgen excess with visceral adiposity, suggested by clinical observations. In particular, fat tends to accumulate in the visceral region in hyperandrogenic women with PCOS [20] and in testosterone-treated female-to-male transsexuals [21]. Conversely, treatment with flutamide, an AR blocker, attenuates visceral adiposity in women with PCOS [22].

It is possible that lipogenesis and lipid deposition is the major factor behind expansion of visceral adipose tissue in hyperandrogenic states, regardless of lipolytic activity. Androgens appear to modulate lipoprotein lipase (LPL). LPL is the key enzyme for the hydrolysis of circulating triglycerides into free fatty acids and glycerol and the subsequent lipid storage in adipose tissue. In obese women, fasting postheparin plasma LPL activity demonstrated a positive correlation with plasma free testosterone [15]. Accordingly, DHT stimulated LPL protein expression in cultured abdominal subcutaneous adipocytes from women, while this effect was inhibited by an AR blocker [16]. In addition, androgens appear to stimulate lipogenesis in visceral adipose tissue. DHT administration to ovariectomized mice increased the expression of lipogenic genes (fatty acid synthase, sterol regulatory element-binding protein-2 and LPL) in visceral fat, leading to increased visceral fat mass associated with triglyceride accumulation [23].

Androgen excess has been also incriminated as a contributor to a more atherogenic lipid profile in women [24,25]. Longitudinal human studies describing metabolic adaptations during puberty could provide inferences regarding the role of androgens in determining lipid parameters. Prepubertal boys and girls do not differ significantly in their serum lipid profiles. However, during puberty, boys experience a decrease in high-density lipoprotein (HDL)-cholesterol and an increase in low-density lipoprotein (LDL)-cholesterol, in contrast to girls whose lipid profile does not change significantly. Although this observation seemingly points to the adverse androgenic effect on lipid metabolism, these changes may not merely reflect sex steroids effects. Other endocrine changes occurring throughout puberty, such as the reduction of insulin sensitivity and alterations in the somatotropic axis, also regulate lipoprotein metabolism [24].

One of the major effects of testosterone on lipid profile is the lowering of HDL-cholesterol levels. Testosterone is involved in the upregulation of scavenger receptor-B1 (SRBI) gene and protein expression in a human hepatocyte cell line [26]. SRBI binds HDL and mediates the selective uptake of cholesteryl esters into hepatocytes without internalizing HDL, thereby producing small, cholesterol-depleted HDL particles, which are prone to accelerated clearance. At supraphysiological dosages (100 ng/ml), testosterone also increases the expression of hepatic lipase in cultivated human hepatocytes, which contributes to HDL catabolism by hydrolyzing phospholipids on the surface of HDL [26].

Furthermore, androgen excess may contribute to increased circulating LDL levels. In particular, androgens, through interaction with the AR, decrease the catabolic removal of LDL by attenuating estrogen receptor (ER)-mediated induction of LDL-receptor activity [25]. The mechanism of interaction between the two receptors has not been elucidated. One potential mechanism could be that AR directly interacts with ER, thus blocking ER activation. Another possibility is the existence of a cofactor shared by AR and ER, whereby dominance of AR prohibits the activation of ER-induced genes [25]. The aforementioned data provide some pathophysiologic explanation for the ameliorating effects of anti-androgen therapy on lipid parameters in women with PCOS [27].

Furthermore, several observations incriminate androgen excess in women in the direct perpetuation of insulin resistance, a typical metabolic feature common of PCOS. Clinical data have demonstrated a positive correlation between serum androgen levels and mathematical indices of insulin resistance among women with PCOS [28]. In addition, experimental exposure of pre- or peri-pubertal rats to an androgenic milieu led to impaired insulin sensitivity [13,14]. In female-to-male transsexuals, androgen administration has been linked with reduced insulin sensitivity in one study [29], but not in a subsequent report [30].

The potential linkage between insulin resistance and ovarian hyperandrogenism is also reflected in the beneficial metabolic effects of laparoscopic ovarian electrocautery (LOE) in women with PCOS. A relevant study demonstrated improved insulin sensitivity in parallel with the reduction of androgen levels in patients who underwent LOE, possibly indicating a causal interrelationship between androgens and insulin resistance. In support of clinical findings, the same investigators provided molecular evidence of partial reversal of insulin signaling defects in visceral adipocytes of patients undergoing LOE [31].

At the molecular level, androgens may act directly upon the insulin signaling cascade. In cultured skeletal myotubes, androgens induced insulin resistance via increased phosphorylation in Akt, mTOR and ribosomal S6-kinase (S6K), leading to increased serine 636/639 phosphorylation of insulin receptor substrate-1 [32]. An older study of oophorectomized female rats has suggested another mechanism by which testosterone might impair glucose utilization in skeletal muscle. In these rats, testosterone-replacement therapy led to reduced glycogen synthase protein expression in skeletal muscle [33] In addition, chronic testosterone administration has been demonsrated to trigger insulin resistance in human subcutaneous adipocytes. The striking finding was that testosterone acted through the AR to induce insulin resistance, selective for metabolic signaling pathways in subcutaneous adipocytes from healthy women. The signaling defect was independent of phosphatidylinositide 3-kinase and involved the impaired phosphorylation of protein kinase Cζ [34]. In addition to putatitive direct actions, androgens may aggravate insulin resistance through indirect mechanisms, such as the suppression of adiponectin secretion, which is an adipokine known for its insulin-sensitizing properties [35].

Overall, hyperandrogenemia could aggravate metabolic abnormalities associated with PCOS. However, women with PCOS also carry an inherent burden of insulin resistance, which can exacerbate the metabolic phenotype. In these women, insulin resistance is considered a primary defect that arouses the metabolic disarray, independent of obesity [4]. Androgen excess, in the context of PCOS, appears to not be the primary or the sole determining factor of metabolic abnormalities, but rather it superimposes an additional adverse metabolic burden upon these inherently predisposed individuals. However, isolated hyperandrogenemia, outside the hormonal and metabolic milieu of PCOS, has not yet be documented to have an adverse impact on women's health issues [36].

Role of androgen excess in cardiovascular dysfunction in PCOS beyond metabolic aspects

Beyond metabolic effects, testosterone may also act directly upon the vasculature and other organs, mainly the kidney, in order to modulate physiological processes that are closely related to CV function ( Figure 1 ). Testosterone interacts with its cognate nuclear receptor (AR) to initiate gene transcription through the classic genomic pathway. ARs are abundantly present in endothelial cells, vascular smooth muscle cells, cardiomyocytes and macrophages [37]. ARs are also expressed in human renal tubules, thereby allowing androgens to modulate renal mechanisms of blood pressure regulation [38,39].

In addition to its classic genomic effects, testosterone has been shown to cause rapid vasomotor responses [40] that are clearly untypical of genomic mechanisms. Recent studies have demonstrated nontranscriptional pathways of androgen action through receptors located in or near the plasma membrane in endothelial cells and vascular smooth muscle cells macrophages [41,42]. An explosion has emerged in dissecting the relevant effects of membrane-bound steroid receptors, which only represent 2% of the steroid-receptor pool, but can impact on physiological processes [43].

Direct actions of androgens on the vasculature

Polycystic ovary syndrome has been associated with endothelial dysfunction and accelerated atherosclerotic disease. This fact assumes importance considering that functionally and structurally evident vascular dysfunction is already present even in young women with PCOS, without other identifiable CV risk factors [44]. Although insulin resistance appears to comprise a central pathophysiologic mechanism of vascular dysfunction in PCOS, a role of androgens has been also implicated. In affected women, androgen levels were shown to correlate positively with endothelial dysfunction, assessed by biochemical and functional markers [45 –48]. In addition, among young women with PCOS, androgen excess was shown to be the major, independent determinant of increased carotid intima-media thickness, which is a morphological measure of early atherosclerotic disease [49].

The mechanisms that could mediate this potential relationship remain unknown; however, endothelin (ET)-1 may play a part in the interlinkage between androgen excess and endothelial dysfunction. In particular, a positive correlation of ET-l with serum testosterone levels has been reported in women with PCOS [46]. Furthermore, cross-sex testosterone administration in female-to-male transsexuals was associated with increased ET-1 levels [50]. However, these findings do not necessarily prove a causal link. The above association in female-to-male transsexuals could be secondary to the androgen-induced central adiposity, which is in turn linked with insulin resistance and endothelial dysfunction. Alternatively, lipid abnormalities could be an indirect mechanism of endothelial dysfunction induced by long-term androgen treatment in female-to-male transsexuals.

Testosterone may not only increase production, but also enhance the potency of ET-1 action. Acute exposure to low nanomolar doses of testosterone was demonstrated to potentiate ET-1-induced vasoconstriction in porcine coronary artery rings [40]. This effect was not blocked either by AR antagonists or by de novo protein synthesis inhibitors, and exhibited an acute time course, all suggesting a nongenomic mechanism of action [40].

However, there are also data implying either neutral or positive effects of exogenously induced hyperandrogenemia on endothelial function, assessed by flow-mediated dilatation (FMD) of the brachial artery. Specifically, in female-to-male transsexuals receiving long-term testosterone treatment, FMD was not significantly different from that in age-matched female controls, despite the reduced endothelium-independent nitrate-induced response in the former group [51]. It is worth noting that these findings are incompatible with the aforementioned data demonstrating that testosterone administration was accompanied by an increase in ET-1 levels in female-to-male transsexuals [50]. In another uncontrolled study involving estrogen-treated postmenopausal women, parenteral testosterone administration was associated with improved FMD [52]. However, these findings are difficult to interpret, since the observed alterations in FMD were induced by supraphysiological testosterone concentrations, several folds higher than the normal female range. In addition, the fact that testosterone-treated women and controls were not well-matched for baseline FMD values limits the validity of the above results [52].

In general, findings from in vivo, ex vivo and in vitro experiments addressing the vascular properties of testosterone are mixed, depending on the type of androgen, the dose, the duration of exposure, the presence of underlying vascular disease and the biological sex [53]. The role of estrogens produced by aromatization of androgens should also be considered [54].

Ex vivo studies of isolated vessel preparations and in vivo studies in intact animal models have demonstrated both vasoconstrictive and vasodilatory actions of androgens [53]. The physiological significance of this diversity is unclear at this time. A significant portion of the testosterone-induced vascular relaxation appears to be endothelium independent because minimal differences could be observed between the relaxation in intact or endothelium-denuded vessels. Furthermore, inhibition of synthesis of endothelium-derived factors, such as nitric oxide and prostaglandin, do not appear to affect the vasorelaxing effect of testosterone [37], suggesting that testosterone-induced relaxation relies significantly upon an endothelium-independent direct action on vascular smooth muscle.

However, even if the vasorelaxant effect of androgens is presumed, this effect is significantly weaker than the estrogen-induced vasorelaxant effect [37]. By this token, subjects exposed to a predominantly androgenic milieu, reflected by an increased androgen:estrogen ratio, may have a compromised vasodilatory response as compared with subjects exposed to a predominantly estrogenic milieu.

Literature addressing other vascular effects of androgens is also dichotomized. Using varying doses of testosterone or DHT, some in vitro studies have demonstrated harmful effects, including arterial stiffening, acceleration of endothelial cell apoptosis and precipitation of LDL binding to arterial walls owing to changes in the synthesis of vascular proteoglycans ( Table 1 ) [55 –57]. Several in vitro studies have investigated the endothelial expression of adhesion molecules following androgen administration. Both an accentuating [58,59] and an inhibitory effect of androgens on the expression of adhesion molecules have been reported [60,61]. The use of different endothelial cell lines as well as differences in the type and the dose of androgens administered may account for the discrepant findings. The use of supraphysiological doses of androgens in some studies challenges their relevance to human physiology (summarized in Table 1 ). While both AR- and ER-mediated effects of testosterone have been documented [54], human endothelial cells from male donors were shown to respond differentially to androgen exposure as compared with cells female donors ( Table 1 ) [59]. This gender disparity may reside in differences in the abundance of ARs in endothelial cells. Remarkably, human artery samples from male donors have demonstrated fivefold more AR-positive cells than arteries obtained from female donors [59].

Table 1.

In vitro studies addressing the vascular effects of androgens.

Study	Cell type	Sex of donor cells	Administered doses of androgens	Effect of androgen administration	Ref.
Hashimura (2005)	Human SMCs from internal mammary arteries	Undefined	DHT: 10 nM; T: 10 nM Supraphysiological	Increased LDL binding capacity of proteoglycans	[57]
Natoli (2005)	Human aortic SMCs	Female	T: 0.15 nM (150 pM) Physiological	Relative to E2 Reduced elastin deposition Increased arterial stiffness	[55]
Ling (2002)	HUVECs	Male	T: 1 nM (Physiological), 10 nM	Increased endothelial apoptosis (not E2 mediated)	[56]
Death (2004)	HUVECs	Male and female	DHT: 400 nM Supraphysiological	Male donors: increased NF-κB-dependent expression of Ad mols
Norata (2006)	HUVECs	Undefined	DHT: 0.1 nM Physiological	Reduced NF-κB-dependent expression of Ad mols cytokines & chemokines	[61]
Mukherjee (2002)	HUVECs	Female	T: 30 nM; 1 μM DHT: 3 nM–1 μM Supraphysiological	T: reduced expression of Ad mols (ER mediated) DHT: no effect	[54]
Zhang (2002)	HUVECs	Undefined	T: 10 nM Supraphysiological	T: increased expression of Ad mols (AR mediated)	[58]
Hatakeyama (2002)	HAECs Undefined	T: 100 nM; 1 μM Supraphysiological	Reduced NF-κB-dependent expression of Ad mols (AR mediated)	[60]

Ad mols: Adhesion molecules; AR: Androgen receptor; DHT: Dihydrotestosterone; E2: Estradiol; ER: Estrogen receptor; HAEC: Human aortic endothelial cell; HUVEC: Human umbilical vein cell; LDL: Low-density lipoprotein; NF-κB: Nuclear factor-κB; SMC: Smooth muscle cell; T: Testosterone.

Overall, these in vitro studies cannot simulate the complex interplay between sex steroids, sex steroid receptors and the vasculature, which occurs in vivo. Beyond the sex steroid metabolism and the conversion of one steroid to the other, androgens are also able to inhibit estrogenic effects by mechanisms potentially involving the activation of ARs. DNA cotransfection studies have demonstrated that ligand-activated AR is able to physically interact with the ER-α (ERα) (but not ER-β [ERβ]), producing heterodimers with less transactivational activity [62]. This mechanism may be pertinent to the pathophysiology of PCOS, since it has been reported that women with PCOS exhibit elevated endometrial expression of AR, which is upregulated by androgens [63]. Conceivably, chronic hyperandrogenemia may also upregulate the expression of ARs in other tissues, such as the vasculature.

Alternatively, the antagonism of estrogen actions by androgens might be through the inhibition of ER expression. For instance, in the mammary gland of rhesus monkeys, testosterone partially blocked the upregulation of ERa mRNA induced by estradiol-17β (E2) [64]. In another study, simultaneous administration of DHT and E2 to ovariectomized gilts inhibited the typical effects observed in the uterus after administration of E2 alone. These effects of DHT were associated with decreases in ERa immunostaining in the myometrium and endometrium and with downregulation of the ERα and ERβ mRNAs in whole endometrial preparations [65]. Future studies should investigate whether the aforementioned mechanisms, demonstrated in nonvascular tissues, also apply to the sex steroid effects on vascular function.

Androgens as regulators of blood pressure

There is no ample evidence of a direct association of androgen excess with hypertension in young women with PCOS. Based on office blood pressure measurements, a cross-sectional study investigating 151 women with PCOS demonstrated that bioavailable testosterone levels were directly associated with the risk for elevated blood pressure after adjusting for age, anthropometric measures, insulin resistance and dyslipidemia [66]. However, using ambulatory blood pressure monitoring and office blood pressure determinations, another case–control study demonstrated that obesity is the major determinant of blood pressure in these women [67].

Despite the lack of consistent clinical evidence for an association between androgen excess and hypertension in women with PCOS, experimental findings unveil prohypertensive effects of androgens. Genetically hypertensive female rats, chronically treated with testosterone, experience increases in mean blood pressure and vascular resistance [68].

The previously discussed impact of androgens on functional as well as structural properties of the vascular system should be factored in the regulation of blood pressure. In addition, ARs expressed in renal tubules appear to mediate prohypertensive effects of androgens on the intra-renal renin–angiotensin–aldosterone system and on renal sodium homeostasis [69].

Androgens have been involved in renal mechanisms of hypertension through the following effects:

Increased expression of renal angiotensinogen and renin gene in rats [70];

Upregulation of the Na⁺/H⁺ exchanger, a brush-border membrane transporter regulated by Ang II in the proximal tubule [38];

Upregulation of the α-subunit of the epithelial sodium channel (ENaC), which mediates sodium reabsorption in distal tubules under regulation by mineralocorticoids. A remarkable finding was the localization of an androgen-responsive element in the promoter of the ENaC gene expressed in a human renal cell line [39].

All of the above mechanisms share a common denominator: the stimulation of the intra-renal renin–angiotensin–aldosterone system. In addition, in a rat model, androgens were shown to stimulate P450 monooxygenases, which metabolize arachidonic acid to the vasoconstrictor 20-hydroxyeicosatetraenoic acid (HETE) in the renal microcirculation. Increased formation of 20-HETE leads to increased renal vascular resistance and raised systemic blood pressure, thus offering another potential mechanism of androgen-induced hypetension [71].

Androgen actions on the inflammatory cascade

Another putative link to atherogenesis is the potential role of androgen excess in the perpetuation of inflammation and oxidative stress. The combination of inflammation and oxidative stress is recognized to serve a triggering role in the progression of atherosclerosis [72].

The monocyte–macrophage system is a potential target for the regulation of the inflammatory response by androgens, since ARs have been identified in primary human monocyte-derived macrophages [73].

Strikingly, androgens have been reported to upregulate the expression of genes related to inflammation and atherosclerosis in human macrophages from male donors, but not in macrophages from female donors [74]. This gender-specific effect may be attributed to the higher levels of AR expression in macrophages from males than in those from females [73]. However, chronic hyperandrogenemia in women with PCOS might be able to upregulate AR expression, thereby allowing androgens to activate proinflammatory genes in women, as they do in men.

Polycystic ovary syndrome is associated with low-grade, chronic inflammation and oxidative stress [75 –77]. C-reactive protein [75 –77], adhesion molecules [75], prothrombotic factors [78], proinflammatory interleukins (i.e., IL-6 and IL-18) [79,80], advanced glycated end products (AGEs) [81,82] and markers of oxidative stress [77,83,84] are all increased in sera of women with PCOS. This pathological state is also evident at the cellular level. Monocyte-derived macrophages of PCOS women are in a proinflammatory state, as evidenced by their exaggerated response to physiologic hyperglycemia, which is driven by the overactivated nuclear factor-κB (NF-κB) cascade [83,85].

Androgen excess may play a role in this situation. Serum androgen levels were shown to correlate positively with serum AGEs levels in lean, normoglycemic and non-insulin-resistant women with PCOS [81,82]. AGEs, from endogenous or exogenous sources, are potent atherogenic molecules that initiate inflammatory and oxidative intracellular pathways by binding to a transmembrane receptor, receptor for advanced glycation end products (RAGE) and, subsequently, activating the NF-κB cascade. Other investigators have reported an inverse association of androgen levels with antioxidant markers in these women [86]. In addition, serum testosterone levels were positively associated with reactive oxygen species generation and with intranuclear expression of NF-κB in macrophages from women with PCOS following stimulation by physiologic hyperglycemia [83,85]. Future studies will clarify whether these associations translate into causal links. If causality is proven to be true, it should be clarified whether androgens perpetuate inflammation or vice versa. It is equally possible that inflammation and androgen excess are indirectly linked with each other through another factor, such as insulin resistance [83,85], contributing to the multiple phenotypes of the syndrome [28].

Implications for long-term cardiovascular morbidity & mortality in PCOS

Overall, the effects of androgen excess on women's tissues appear to involve a complex (pathologic) physiologic network [43,87]. At the local tissue level, androgens are convertible to estrogens by aromatase. Thus, circulating androgen and estrogen levels do not necessarily mirror the tissue-specific sex steroid balance [43].

The androgen:estrogen ratio may be even more important than the absolute concentrations of individual hormones. In women from across a wide age range, it was reported that relative estrogen deficiency unmasks the adverse metabolic impact of androgens [88]. Most strikingly, a cross-sectional study demonstrated that a higher testosterone:estradiol ratio was a significant predictor of angiographic coronary artery disease (CAD) in postmenopausal women [89].

In the postmenopausal period, the loss of the ‘estrogenic privilege’ appears to magnify the potential CV impact of androgen excess [90], while aging or underlying disease states also have major bearings to this vulnerable state [53]. It is worth noting that the definition of relative or absolute androgen excess versus normoandrogenemia in the postmenopausal period remains vague and arbitrary. The inadequate accuracy and sensitivity of the available assays for measurements of testosterone levels in women should be cautiously considered [91]. The lack of normative data on serum total or free testosterone concentrations in women across their lifespan poses a major obstacle in the extraction of clear conclusions regarding the association of androgens with clinical outcomes [91].

Even though androgen levels within the normal range may be inversely associated with the extent of carotid atherosclerosis in postmenopausal women [92,93], the presence of androgen excess in the setting of estrogen deficiency appears to be a deleterious combination. By this token, menopause may be a crucial period for the emergence of CV complications in hyperandrogenic women with PCOS. However, examination of biochemical evidence of hyperandrogenemia alone was ineffective in identifying women with an elevated risk of ischemic heart disease death [94]. A recent study among postmenopausal women also supports the limited importance of isolated androgen excess in predicting CV disease and events [95]. In this study, the concomitant presence of a history of irregular menses and of elevated androgen levels resulted in a significant predictive accuracy for CV disease/events. More specifically, this study included postmenopausal women undergoing angiographic evaluation for suspected ischemia [95] and attempted to dissect those women with clinical features of PCOS, defined as a history of irregular menses combined with current biochemical evidence of hyperandrogenemia. The major finding was that postmenopausal women with clinical features of PCOS had lower 5-year CV event-free survival than women without clinical features of PCOS. This finding was maintained in models controlling for traditional risk factors as well as angiographic CAD. This study is also important in demonstrating the decrement of CV event-free survival along with increasing free testosterone levels in postmenopausal women. Remarkably, this relationship was independent of insulin resistance indices, waist circumference and the presence of diabetes. This appears to be the most convincing evidence available to date, suggesting that long-lasting androgen excess in the setting of PCOS may be an independent CV risk factor, which acts undercover premenopausally leading to clinical CV consequences postmenopausally [95].

Conclusion

Women with PCOS appear to be exposed to an aggregate of CV risk factors from a young age. Recent data suggest that this heightened CV risk translates into increased rates of CV disease and events after menopause. Available studies, mostly in cell cultures and in animals, have demonstrated androgen-induced alterations in fat mass and fat distribution, in insulin resistance, in glucose and lipid metabolism as well as in the direct actions of androgens on the vasculature. Despite this experimental evidence, androgen excess per se may be not causative for CV disease in women, since there is no clinical evidence that isolated hyperandrogenemia premenopausally is associated with cardiometabolic aberrations. However, within the pathophysiologic context of PCOS, androgen excess is likely to play a permissive role in the development and the progression of CV disease, from a subclinical state premenopausally to a clinical state postmenopausally. Most importantly, androgen excess appears to acquire pathological importance when combined with low estrogen relative to androgen levels. This deleterious synergy may underlie the unfolding of CV sequelae in women with PCOS after menopause.

Future perspective

Available experimental and clinical data are still inadequate to establish knowledge; however, they open avenues for research into the role of androgen excess in cardiometabolic abnormalities in women. Clinical practice would benefit from a thorough understanding of the mechanisms underlying the effects of sex hormones on CV system. Molecular research can prove instrumental in unravelling the complexities of sex steroid action in normal physiology and disease states.

From the clinical perspective, longitudinal prospective studies of well-characterized PCOS cases and controls followed into menopause are strongly required. These studies should first focus on primary clinical end points in order to determine the rates of CV morbidity and mortality and then investigate potential determinants of the CV outcome in women with PCOS. Recognition of the role of androgen excess in these aspects will rationalize therapeutic options aimed to reverse the course of CV disease in PCOS. Until then, the query remains as to whether treating hyperandrogenemia per se can confer a specific CV benefit to women with PCOS.

Executive summary

Androgens have potential sex-specific effects and the estrogen:androgen ratio may be more important than andogens per se in determining the net cardiometabolic impact of sex steroids on women's tissues.

Androgen excess in women may contribute to the following metabolic effects:

– Accumulation of visceral fat and expansion of abdominal subcutaneous adipose tissue.

– Insulin resistance in adipose tissue and skeletal muscle.

– Proatherogenic lipid profile consisting of low high-density lipoprotein levels and high low-density lipoprotein levels.

Androgens may act directly upon the vasculature and modulate vascular reactivity, biomechanical properties of arterial walls and the expression of molecules involved in the atherogenic process.

Androgens appear to exert prohypertensive effects through the modulation of renal tubular exchange of sodium and the activation of the intrarenal renin–angiotensin system.

There is no evidence suggesting that androgen excess per se is associated with a worse cardiometabolic profile in women.

In the context of polycystic ovary syndrome, androgen excess appears to have an additional cardiometabolic impact superimposed upon the one conferred by insulin resistance and obesity.

The potential cardiovascular implications of protracted androgen excess in women with polycystic ovary syndrome are likely to manifest after menopause.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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63.

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68.

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69.

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75.

Yanes

Sartori-Valinotti

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76.

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77.

Tatchum-Talom

Martel

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78.

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79.

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80.

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Role of Androgen Excess on Metabolic Aberrations and Cardiovascular Risk in Women with Polycystic Ovary Syndrome

Abstract

Keywords

Role of androgen excess in metabolic aberrations in PCOS

Role of androgen excess in cardiovascular dysfunction in PCOS beyond metabolic aspects

Direct actions of androgens on the vasculature

Androgens as regulators of blood pressure

Androgen actions on the inflammatory cascade

Implications for long-term cardiovascular morbidity & mortality in PCOS

Conclusion

Future perspective

Footnotes

References