Open access peer-reviewed chapter
Abstract
Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. Clinical or biochemical signs of androgen excess is a cardinal feature of the syndrome and are present in approximately 80% of women with PCOS. Increased blood pressure and insulin resistance, two major cardiovascular risk factors, are frequently present in women with PCOS. This chapter aims to highlight the fundamental role of androgens in mediating the increased blood pressure and insulin resistance in women with PCOS. This chapter is also a call for action to develop new pharmacological therapies that target the androgen synthesis and androgen receptor activation dysregulation present in women with PCOS. These novel therapies will allow to prevent or mitigate the excess androgen-mediated cardiovascular risk factors that affect women with PCOS.
Keywords
- polycystic ovary syndrome
- androgens
- androgen receptor
- blood pressure
- insulin resistance
1. Introduction
Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder and cause of androgen excess in reproductive-age women [1, 2]. The etiology of the syndrome is unknown, and the pathophysiological characteristics are complex. There are three different sets of diagnostic criteria available to diagnose PCOS; the Rotterdam criteria is the most commonly used. The key difference among those three criteria is that hyperandrogenism is considered an essential component of the syndrome for the Androgen Excess Society guidelines [3] and National Institutes of Health (NIH) [4], but not for the Rotterdam criteria [5]. More recently, the Rotterdam criteria for PCOS diagnosis were endorsed by the NIH at an NIH-sponsored workshop [6] as well as by the International evidence-based guideline for the assessment and management of PCOS [7]. Insulin resistance (IR) is frequently present in lean and obese women with PCOS, but it is not included in the diagnostic criteria. Women with PCOS may seek medical care due to a broad range of clinical manifestations such as infertility, menstrual dysfunction, excessive hair growth or hirsutism, alopecia, or acne. More recently, it became clear that the cardiometabolic risk factors, such as IR, increases in blood pressure (BP), and obesity affect a high percentage of women with PCOS compared to normal cycling women [8, 9, 10, 11]. Importantly, in women with PCOS, plasma levels of androgens positively correlate with BP and IR. Whether and how androgen excess causes increased BP and IR in women with PCOS is unknown. Unfortunately, limited effective evidence-based therapeutic agents are available to treat those cardiovascular risk factors in PCOS patients. Furthermore, the use of antiandrogens in PCOS is often only recommended to manage the dermatological manifestations of the syndrome, but neither the IR nor increases in BP [12]. This chapter aims to highlight the fundamental role of androgens in mediating increases in BP and IR in women with PCOS and the lack of therapeutic options to ameliorate the hyperandrogenism and cardiometabolic complications in these patients.
Advertisement
2. Androgen synthesis in PCOS
In women, the concentration of plasmatic androgens is higher than of estrogens [13]. Excess androgens are secreted by the ovaries in most women with PCOS, but in 20–30% of them, excess androgens are also secreted by the adrenal gland. Plasma levels of total and free testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenedione are significantly elevated in PCOS [2, 14]. Androstenedione, DHEA, and DHEAS are pro-hormones synthesized by the adrenal gland, they circulate at a higher concentration than T. Those pro-hormones could be converted into more potent T and DHT in the adipose tissue, liver, and the skin [3, 15]. Depending on the type of androgens measured, hyperandrogenemia is present in ~80% of PCOS diagnosed cases [16]. Recently, a study showed that the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, and 11-ketotestosterone, represent the majority of circulating androgens in women with PCOS [17]. Moreover, 11β-hydroxyandrostenedione, 11-ketoandrostenedione circulating levels positively correlate with circulating insulin and IR assessed by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in women with PCOS [17]. The HOMA-IR is an index of IR calculated according to the formula: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5 [18]. The HOMA-IR is extensively used in epidemiological studies, but rarely in the clinical setting. On the other hand, the hyperinsulinemic eulgycemic clamp is considered the gold standard to determine IR; but, unfortunately, it is impractical for routine use in the clinic [19]. Local production or activation of androgens at the tissular level have been reported, and they may constitute a key factor in the cardiometabolic abnormality in these patients. For example, the subcutaneous adipose tissue in women with PCOS has a higher concentration of androgens than in control subjects [20, 21]. Testosterone can be converted to its more biologically active form, DHT, by the 5α-reductase, and to estradiol by the aromatase. DHT is more biologically active than testosterone, binding to the androgen receptor (AR) with a 2-fold higher affinity and a 5-fold decreased dissociation rate compared to testosterone [22]. The synthesis of androgens in women is complex. The local activation of androgens is not well understood during normal physiology or diseases such as PCOS.
Advertisement
3. Androgen receptor in PCOS
AR is a member of the steroid hormone receptor superfamily, a class of receptors that function through their ability to regulate the transcription of specific genes. It contains an N-terminal transactivation domain, a central DNA-binding domain, and a C-terminal ligand-binding domain [23]. Androgens act by binding to the AR and subsequently translocate to the nucleus to act as a transcription factor and promote gene expression. The unbound AR is inactive in the cytoplasm as a large dynamic heterocomplex, together with heat shock proteins (Hsp70 and Hsp90) and their co-chaperones [24]. Ligand binding dissociates the AR from heat shock proteins, causing its activation and translocation to the nuclei to exert its transcription regulatory role.
Androgen actions in the cardiovascular system could be genomic or non-genomic [25], although most of the basic research data available derived from experiments performed in male rats. The activity of AR is modulated by a polyglutamine tract of variable size in its N-terminal transactivation domain. This polyglutamine tract is encoded by a highly polymorphic CAG repeat sequence in exon 1 of the AR gene located on the X-chromosome. Shorter CAG repeats lengths in exon 1 of the AR gene are associated with a stronger transcriptional activity of the AR. The shorter CAG repeats have been associated with the androgen actions in male conditions such as prostate cancer [24] and benign prostatic hyperplasia [26]. Moreover, abnormal expansion of the CAG repeat length leads to Kennedy’s disease, which is associated with hypogonadism and impaired spermatogenesis in men [27, 28]. However, studies in women with PCOS did not find significant differences in the mean values of CAG repeat sizes compared to controls [29, 30]. The fundamental role of AR in the development of metabolic and reproductive features of PCOS was demonstrated by the lack of effect of DHT in AR knockout (ARKO) mice, supporting the fundamental concept that androgen excess, via AR activation, is a key factor in PCOS [31]. More recent studies further demonstrated that AR signaling pathways within the brain and adipocytes are key in the physiopathology of metabolic PCOS characteristics [32]. Pharmacological strategies safely targeting the brain and adipocyte AR-could constitute a novel and effective way to ameliorate the cardiometabolic complications in PCOS.
Advertisement
4. Cardiovascular disease in PCOS
Several studies have shown that the odds ratio for cardiovascular disease (CVD) is significantly higher in women with PCOS compared to the control women [33, 34, 35]. Whether women with PCOS suffer from higher mortality from CVD is still unclear, pending high-quality data. Obesity is frequently observed in women with PCOS, but, even after BMI adjustment, the increased risk for cardiovascular events in PCOS persists, suggesting that additional factors play a role in mediating the higher prevalence of CVD in women with PCOS [35]. Hypertension, the most important modifiable cardiovascular risk factor for cardiovascular disease, is commonly diagnosed in women with PCOS. Moreover, insulin resistance, another risk factor for CVD, is also frequently present in women with PCOS, and independent of those subjects’ BMI. Data from clinical and basic research suggest that hyperandrogenism may underlie these cardinal cardiovascular risk factors in patients with PCOS. Below we describe whether and how androgens mediate the increases in BP and IR in women with PCOS.
Advertisement
5. Hyperandrogenism is a key factor mediating increases in blood pressure in women with PCOS
Increased BP remains the leading risk factor for death globally, accounting for 10.4 million deaths per year [36]. There is a sexual dimorphic relationship between androgens and BP in women compared to men. Free androgen index (FAI), a measure of bioavailable androgens, is positively correlated with systolic and diastolic blood pressure [37]. A recent meta-analysis reported a greater risk of developing hypertension in reproductive age women with PCOS [38]. In contrast, epidemiological studies have shown an inverse relationship between androgens and BP in men, and this association persisted after adjusting for age and body mass index [39]. The mechanisms behind the elevated BP in response to hyperandrogenism in women remain unclear. Some of the possible mechanisms involved in androgen-mediated regulation of BP are discussed below.
Advertisement
6. Potential mechanisms that could mediate increases in blood pressure in PCOS
The kidneys are a key regulator of long-term BP control and body fluid homeostasis in the body. The renin-angiotensin-aldosterone system (RAAS) plays a major role in several forms of hypertension, and it is composed of the classical and non-classical arms with opposite physiological effects [40, 41]. The classical RAS pathway starts with angiotensinogen (AGTN) which is enzymatically cleaved to Angiotensin I (ANG I) by renin. ANG I is then cleaved by angiotensin I converting enzyme (ACE) to Angiotensin II (ANG II), which binds to the ANG II receptor type 1 (AT1R) and ANG II type 2 receptor (AT2R). High levels of ANG II had been related to metabolic disorders. The non-classical pathway, the angiotensin I converting enzyme 2 (ACE2) reduces Ang II levels by transforming it in Angiotensin (1–7) (ANG (1–7)), which also can be generated from ANG I passing through Angiotensin (1–9) (ANG (1–9)) by the action of the endopeptidases: prolyl-endopeptidase and neutral endopeptidase. The main known biological effects of ANG (1–7) are associated with Mas receptor activation, causing an improvement in metabolic syndrome, obesity, and hypertension.
The rate-limiting step of the RAS is the conversion of AGTN to ANG I by renin [42]. Women with PCOS have hyperreninemia [43], and blockade of the AT1R is effective in decreasing their BP [44]. We and others have shown that androgens stimulate the synthesis of intrarenal AGTN in male and female rats [45, 46, 47, 48]. In the kidney, the AR is highly expressed in proximal tubule cells [49], glomerular endothelial cells [50], and podocytes [51]. Moreover, the enzymes involved in androgen biosynthesis are expressed and active in the kidney [52]. In experimental models of hypertension, androgens can shift the pressure-natriuresis curve to the right, promoting sodium reabsorption [53, 54]. Androgens could also directly increase sodium reabsorption via upregulation of epithelial sodium channel (ENaC) α, β, and γ subunits expression [55]. Renal medullary blood flow and the sensitivity of the pressure-natriuresis response are regulated by various paracrine and humoral factors known to play an important role in the control of renal function and BP. Those regulatory factors include ANG II, kinins, prostaglandins, atrial natriuretic peptide (ANP), and nitric oxide (NO). Whether changes in the renal medulla microcirculation play a role in mediating the increases in BP under excess of androgens in women with PCOS remains unclear.
Plasma ACE2 activity is low in healthy subjects but elevated in patients with cardiovascular risk factors or cardiovascular disease. Hypertensive men have a high higher level of plasma ACE2 compared to women [56]. The role of increased levels of plasmatic ACE2 in men remains unknown. It has been reported that male mice have higher renal ACE2 mRNA and protein expression, as well as higher ACE2 activity, than their female counterparts [57, 58]. However, the effect of androgen excess in the non-classical RAS pathway is still not well understood. Androgens downregulate AT2R expression levels in the aorta,
Our research teams’ studies focus on the cardiometabolic complications associated with androgen excess in female rats. The hyperandrogenic female (HAF) rat, an animal experimental model of PCOS, is generated by the chronic administration of the non-aromatizable androgen DHT. This model exhibits upregulation of intrarenal angiotensinogen and ACE mRNA expression, which are associated with a ~ 10 mmHg increase in BP compared to control female rats [46]. When HAF rats are treated with enalapril, an ACE inhibitor, their BP is lowered to values comparable to that of control rats, suggesting that the RAAS activation has a role in mediating androgens’ effect on BP [64]. The stimulatory effect of androgens upon the intrarenal RAAS persisted after discontinuation of androgen exposure in female rats, suggesting a cardiometabolic androgenic memory in female rats. Interestingly, in the kidney medulla, AGTN and AT1R were still elevated after six months of DHT withdrawal [65]. AT1R blockers or ACE inhibitors are widely used as antihypertensive drugs. Women should be advised about the potential teratogenic and fetotoxic risks of ACE inhibitors or AT1R blockers if they become pregnant. ACE inhibitors and AT1R blockers use in the first trimester of pregnancy may not present significant risks for malformations in live births but a high risk of miscarriage [66]. Novel and tissue-selective RAAS inhibitors that do not cross the placental barrier are warranted to ameliorate the increases in BP in women with PCOS in the future.
In the US, a frequent finding in PCOS patients is an increase in body mass index (BMI), with up to 80% being either overweight or obese [67]. There is a strong link between adiposity and hypertension, with multiple mechanisms being suggested [68]. Hypertrophy of adipocytes is associated with local hypoxia, leading to increased oxidative stress and inflammatory cytokines, followed by capillary rarefaction [69, 70]. These processes can lead to a positive feedback loop, ultimately releasing more inflammatory cytokines and reactive oxidative species into the systemic circulation. Chronic inflammation can ultimately lead to increased BP. In HAF rats, there is increased fat mass and BP coupled with increased plasma tumor necrosis factor-alpha and renal mRNA expression of NADPH oxidase 4 [46, 71]. Increased adiposity is also associated with increased circulating adipokines, such as leptin [69]. Chronic hyperleptinemia is known to stimulate the sympathetic nervous system [72], which could lead to vasoconstriction. It has been reported that in women with PCOS, leptin levels can be elevated [73]. Furthermore, using heart rate variability as a measure of autonomic dysfunction, women with PCOS have increased sympathetic activity compared to control women matched for body mass index, systolic and diastolic BP [74]. Additionally, leptin is linked to activation of the RAAS via the renal sympathetic nervous system [72]. All the findings mentioned above suggest that BP control is complex and depends on multiples pathways in women with PCOS.
Endothelial dysfunction refers to the impaired function in the endothelium, the inner lining of blood vessels, which could lead to inappropriate vasoconstriction and atherosclerosis [75]. Endothelial dysfunction frequently occurs under chronic inflammation conditions or high oxidative stress, which interfere with the nitric oxide production needed for vasodilation [76]. Interestingly, this occurs not just in obese females but also in lean females with PCOS. A recent study found that normotensive lean females with PCOS, even without insulin resistance, had increased endothelial dysfunction compared to controls [77]. One of the major vascular oxygen-derived free radicals is superoxide anion. Superoxide is routinely scavenged by superoxide dismutase (SOD). Superoxide can also combine with nitric oxide (NO), which results in quenching of NO and, theoretically, can induce vasoconstriction. There is an interaction between NO and oxidative stress to maintain endothelial function. We previously showed that an intact NO system is necessary for antioxidants to elicit a BP-lowering effect [78]. Furthermore, Huirliman and colleagues demonstrated that the presence of endothelial dysfunction and IR develops in pair-fed DHT-treated female rats, suggesting an obesity-independent mechanism [79]. Increased endothelial dysfunction has also been found in transgender men compared to cisgender women matched for body mass index [80], suggesting a broader link between endothelial dysfunction and female androgen excess in addition to women with PCOS. Another study with lean females with PCOS also found that they had decreased plasma total antioxidant status [81]. This reduced ability to handle oxidative stress can contribute to the endothelial dysfunction in hyperandrogenic females.
Cardiovascular diseases are the leading cause of death in women. Furthermore, there have been an overall decline in CVD mortality over the past 40 years; however, the mortality in younger women has plateaued since 2000 [82]. Increases in BP is a primary cardiovascular risk factor. The carotid artery intima-media thickness (cIMT) has emerged as an important surrogate marker of target organ damage in hypertensive heart disease. A recent prospective cross-sectional study in PCOS women showed that cIMT was significantly increased in women with PCOS compared to controls, and this increase was independent of BMI, age, and smoking status [83]. Consequenly, the cIMT could be used to determine the cardiovascular risk profile in women with PCOS.
In summary, hyperandrogenemia in females has multiple mechanisms of causing increased BP and impaired vascular function. Pharmacological agents that target multiple pathways could constitute effective therapeutic agents to be used in women with PCOS.
Advertisement
7. Hyperandrogenism is a key factor mediating insulin resistance in PCOS
IR is recognized as a significant contributor to metabolic homeostasis disturbances in women with PCOS, especially in obese individuals, due to increased lipid accumulation in muscle and liver from impaired insulin signaling. Decreased insulin sensitivity and glucose tolerance have been reported in women with PCOS versus healthy individuals in several studies [84]. Additionally, both metabolic syndrome and hyperinsulinemia have a characteristic increase in low-grade inflammation markers [85], which has also been observed in women with PCOS [86]. IR prevalence among women with PCOS is varied between different measurement methods but is reported to be between 40% and 70%, approximately [87]. Women with insulin receptor mutations, and thus high levels of insulin, develop severe hyperandrogenemia [88].
Hyperandrogenism and or hyperandrogenemia is present in about 80% of women with PCOS [89]. Both circulating testosterone and its precursor androstenedione have been shown in positive association with the severity of metabolic dysfunction in women with PCOS [90]. The prevalence of type 2 Diabetes Mellitus (T2DM) in the US is 10-times higher among young women with PCOS compared to age-matched, normal-cycling women [91]. Insulin and insulin signaling can influence androgens in women with PCOS. Insulin can stimulate the ovaries of theca cells to produce androgens. This dysfunctional androgen stimulation is suggested to induce hyperandrogenism in women with PCOS in a positive feedback mechanism with hyperinsulinemia. Specifically, the P450c17 (CYP17A1) enzyme in the theca cells has been addressed as having modulated activity in response to insulin and IGF. This is specifically relevant to PCOS because the enzyme is necessary for the production of androgens [92]. Additionally, high circulating plasma insulin may itself influence androgen availability due to its suppression of sex hormone-binding globulin (SHBG) synthesis, a steroid transport protein, and subsequent increase in the bioavailability of unbound testosterone [93]. PCOS patients have been shown to have reduced SHBG level [94], that could lead to increases in free T. In addition to its role in glucose homeostasis and metabolism, in the central nervous system insulin can effectively modulate food intake and signal satiety. Insulin has also been shown to influence gonadotropin-releasing hormone (GnRH) in the hypothalamic neurons by increasing its expression and activity [95]. In PCOS, GnRH pulse frequency modifications and subsequent LH timing alterations have been suggested as another potential trigger to prevent inhibition of androgens and lead to their increased biosynthesis [96, 97]. This relationship illustrates the importance of the interplay between the neuroendocrine system, insulin, and androgen production in women with PCOS. Clinically, in a randomized controlled trial, women with PCOS treated for three months with Resveratrol, a natural polyphenol able to reduce androgen production via CYP17A1, showed a 30% reduction in fasting insulin and increased insulin sensitivity [98]. Together, these findings suggest the potential therapeutic importance of androgen targeted drugs to treat IR in PCOS patients.
The main target tissues of insulin action and subsequent insulin resistance and dysfunction include white adipose tissue, skeletal muscle, and the liver. Androgens play a significant role in each of these insulin-responsive target tissues in women.
7.1 Androgen actions on the adipose tissue
Androgens regulate several different aspects of adipose cell function and lipid accumulation and are themselves synthesized by the adipose tissue. Adipose tissue is known to play a role in whole-body insulin sensitivity, inflammation, and intracellular stress. The adipose tissue is crucial for the storage of lipids, and adipocytes are the primary storage cells to serve this purpose. The adipose tissue can also release adipokines, like leptin and adiponectin, which may directly influence insulin sensitivity, inflammatory response, fatty acid oxidation, sex steroids, and even energy expenditure. Several adipokines are dysregulated in PCOS [99]. Women with high androgens have been shown to display a fat distribution pattern more similar to men, with increased abdominal visceral adipose accumulation [100]. Although the expansion of the subcutaneous adipose depot is also associated with PCOS [101]. Additionally, after administration of androgen antagonists, women with PCOS were shown to lose visceral adiposity, which suggests that androgens have a role in fat distribution [102]. This increased adiposity is considered to be due to a hypertrophic adipocyte expansion compared to a hyperplasic response, which is more highly indicative of metabolic syndrome. Hypertrophy of adipocytes is influenced by androgens directly by increasing visceral adipocyte mass. Women with PCOS have an increase in adipocyte size [103]. Androgens influence adipogenesis by limiting the differentiation of preadipocytes. In preadipocytes taken from the subcutaneous adipose depots of healthy women were shown to have impaired insulin-induced glucose uptake in response to testosterone [104]. This study suggests that androgens, via the androgen receptor, mediate insulin resistance in adipocytes. Interestingly, the relationship between circulating testosterone and elevated fasting insulin in PCOS is independent of adiposity [105], supporting that insulin resistance is intrinsic to PCOS and may be mediated by hyperandrogenemia independently of obesity.
7.2 Androgens actions on the skeletal muscle
Glucose can be used as a primary fuel source in the skeletal muscle when insulin is high, instead of fatty acids, or can be stored in the form of glycogen for future periods of exercise. Glucose may enter the skeletal muscle in response to insulin by the specific cell surface transporter GLUT4. Skeletal muscle alone may show insulin resistance, which is defined as a reduced ability for glucose uptake and glycogen storage in response to insulin. Skeletal muscle serves as a primary organ for glucose disposal [87].
Several studies suggest that adiponectin and lower AMPK phosphorylation may be important in skeletal muscle-specific insulin resistance in PCOS [106], even in non-obese hyperandrogenic women. Adiponectin is an adipokine that has an inverse relationship with a degree of adiposity. Adiponectin has both insulin-sensitizing properties, including skeletal muscle, and is decreased by androgens [107].
Androgens have been shown to alter lean muscle mass. Both healthy and women with PCOS who exercised using resistance strength training, which focuses on skeletal muscle contractions, along with aerobic training showed reduced fasting glucose concentration and serum testosterone profiles [108]. Together, this suggests the potential to target the skeletal muscle to improve insulin-sensitive tissue sensitivity and improve hyperandrogenemia.
7.3 Androgens actions on the liver
Of crucial importance following a meal, glucose is allowed entry into the liver and stored as glycogen in the liver due to the effects of insulin. In a healthy adult, storage is especially important to help varying energy levels in the body to prevent blood glucose from changing rapidly between meals and allow it to be released when energy is needed.
Hyperandrogenemia in PCOS has been associated with several different disturbances of the liver. Alanine aminotransferase (ALT), often used as a clinical biomarker of liver injury, has been shown in positive association to androgen levels in young women with PCOS [109]. Women with PCOS with high androgens display a distinct metabolic phenotype different than women with normal levels of androgens. There is evidence that women with PCOS are at an increased risk of developing a spectrum of nonalcoholic fatty liver disease, the most common liver disease. Women with PCOS and obesity have an increased risk for NAFLD [110]. Interestingly, even after adjusting for BMI, other PCOS cohorts have shown that hyperandrogenemic women with PCOS have a significantly higher liver fat than women with normal levels of androgens [111]. Those findings suggest that androgens may be an independent risk factor for steatosis and the development of NAFLD.
Advertisement
8. Pharmacological management of cardiometabolic complications in women with PCOS
Recent studies have shown that women with PCOS frequently report long delays in the syndrome’s diagnosis, dissatisfaction with information and care provided, and distrust in primary care providers’ opinions [112, 113]. Those patients’ concerns with their diagnosis and health care providers are shocking, considering that PCOS is the most common endocrine disorder in reproductive-age women. We described below the current therapeutic options for the management of cardiometabolic complications in women with PCOS.
8.1 Oral contraceptives
Oral contraceptives (OCPs) are the first-line therapy in women with PCOS to improve their irregular menstrual cycles. OCPs reduce circulating androgens by suppression of Luteinizing Hormone and stimulation of sex hormone-binding globulin (SHBG), leading to a decrease in free testosterone plasma levels. In some women, OCPs can exacerbate hypertension and are associated with a 2-fold increase in the risk of cardiovascular diseases in the general female population [114]. Exogenous estrogens can stimulate the production of AGTN by the liver in female rats [115, 116], which theoretically could lead to higher levels of ANG II. OCPs are contraindicated for smokers due to the higher risk of cardiovascular diseases in this population [117]. OCPs do not seem to affect glucose and insulin homeostasis in healthy individuals [118]. However, the effect of OCPs on women with PCOS remains controversial, mainly due to the heterogeneity of the studies, as shown in a recent meta-analysis [119]. Furthermore, several clinical studies have suggested that the use of oral contraceptives may aggravate insulin resistance and worsen hyperglycemia in obese women with PCOS [120, 121, 122, 123]. The long-term impact of OCPs in IR and cardiovascular diseases in women with PCOS remains unknown. Interestingly, previous use of OCPs was associated with an increased risk of development of CVD in PCOS in a Danish study [33]. Prospective randomized long-term clinical trials analyzing the effect of OCPs on cardiovascular morbidity and mortality in women with PCOS, obese and lean, are lacking and desperately needed.
8.2 Androgen receptor blockers
Recommendations from the International evidence-based guideline for the assessment and management of Polycystic Ovary Syndrome [7] recommend that AR blockers be used mostly towards the dermatological manifestations of the syndrome, not the metabolic ones. AR blockers can be used in addition to OCPs and insulin sensitizers to ameliorate excessive hair growth or hirsutism. Antiandrogen monotherapy is not recommended because of its teratogenic potential [124]. In the US, the AR blocker most commonly used in the clinic is spironolactone [124]. Spironolactone is also a progesterone and mineralocorticoid receptor blocker. Blockade of the mineralocorticoid receptor causes a diuretic effect that potentially can cause serious side effects such as hyperkalemia and hypotension [124]. Other potent antiandrogens are flutamide and cyproterone acetate. Cyproterone acetate is not currently available in the US and recently has been linked to an increased risk of meningioma among high dose users [125]. Flutamide use has been associated with severe hepatoxicity, and it is not FDA-approved for use in women with PCOS. Bicalutamide, an androgen receptor blocker, has been used in combination with OCPs in a study where hirsutism was the primary endpoint [126]. Safe, effective, and specific AR blockers are necessary to positively impact the management of the cardiometabolic risk factors in women with PCOS.
8.3 Insulin sensitizers
Metformin is the most frequent insulin sensitizer agent used in women with PCOS [124, 127]. Obesity exacerbates the IR in women with PCOS, and weight loss in women with PCOS ameliorates it. However, weight loss is very difficult to achieve and sustain. Since insulin resistance is present in obese and lean women with PCOS, it has been proposed to be the key factor in mediating the adverse cardiovascular risk profile observed in PCOS subjects. Metformin has been used for years to treat insulin resistance in women with PCOS. The effectiveness of metformin to improve IR and prevent T2DM in women with PCOS is unclear. Metformin reduces the risk of progression from insulin resistance to T2DM in only 30% of patients in the Diabetes Prevention Trial [128]. Metformin can lower testosterone levels; thereby, some of the beneficial effects in women with PCOS may be due to lowering their androgen levels [129]. A recent metanalysis showed no effect of metformin on indexes of fasting insulin, homeostasis model assessment of insulin resistance, sex hormone-binding globulin, high-density lipoprotein cholesterol, total cholesterol, triglycerides, fasting blood glucose, and androstenedione in overweight women with PCOS [130]. Long-term prospective randomized controlled trials assessing the effect of metformin on cardiovascular morbidity and mortality in women with PCOS are not available at present.
8.4 Incretins
Glucagon-like peptide-1 (GLP-1) is an incretin that potentiates the food-mediated release of insulin leading to a decrease in plasma glucose levels and delaying gastric emptying, and exerting satiety effects. Several short-term clinical trials showed that administration of GLP-1 receptor agonists caused significant improvement in metabolic abnormalities and also cause weight loss in women with PCOS [131]. Similar beneficial effects of GLP-1 were observed in hyperandrogenic female rats [132]. In contrast, we recently reported that administration of the GLP-1 receptor agonist (GLP-1 RA) liraglutide to a model of postmenopausal PCOS, elicits several beneficial metabolic effects but the BP-lowering effect of GLP-1 RA was blunted compared with control rats [64]. These results suggest that GLP-1 RA treatment could improve DHT-induced metabolic and BP abnormalities in reproductive-aged PCOS. It is possible to hypothesize that GLP-1 RA’s BP-lowering effect in PCOS animals could be mediated by estrogens, which are significantly decreased in postmenopausal PCOS rodents, leading to the lack of effect in those aging animals. This concept of a role for estrogens in the age-differential effect of GLP-1 RA in BP regulation in PCOS is an exciting hypothesis that needs to be tested.
8.5 SGLT2 inhibitors
Among therapies in clinical trials for women with PCOS are the sodium-glucose cotransporter-2 inhibitors (SGLT2i), which are antidiabetic agents. SGLT2i has recently been shown to be superior to metformin for weight loss in women with PCOS [133]. Additionally, SGLT2i is cardioprotective in patients with T2DM or with heart failure [134]. For example, in the EMPA-REG trial, SGLT2i reduced the relative risk of cardiovascular death by 38% in patients with T2DM on the background of the blockade of the renin-angiotensin system (RAS) [135]. A possible mechanism to explain why SGLT2i has dramatic cardiovascular protection includes its interactions with the RAS, which is affected by sex steroids and is a major regulator of BP [45, 136].
Advertisement
9. Conclusions
PCOS, the most common endocrine disorder in reproductive-aged women, is associated with increases in BP and IR. Excess of androgens, a cardinal feature of the syndrome, may underlie those cardiovascular risk factors in PCOS. Effective and safe pharmacological agents that target the androgen excess and the androgen receptor are desperately needed to treat the cardiometabolic abnormalities found in women with PCOS.
Advertisement
Acknowledgments
This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM121334 (L.L.Y.C. and D.G.R.), and National Institute of Diabetes and Digestive and Kidney Diseases under Award Number R21DK113500 (D.G.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflict of interest
The authors declare no conflict of interest.
References
- 1.
Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2016;31(12):2841-2855 - 2.
Azziz R, Sanchez LA, Knochenhauer ES, Moran C, Lazenby J, Stephens KC, et al. Androgen excess in women: experience with over 1000 consecutive patients. J Clin Endocrinol Metab. 2004;89(2):453-462 - 3.
Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. 2006;91(11):4237-4245 - 4.
Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merrian GR, editors. Polycystic Ovary Syndrome. Boston: Blackwell Scientific Publications; 1992. p. 377-384 - 5.
Rotterdam EA-SPCWG. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19-25 - 6.
National Institutes of Health. Evidence-based Methodology Workshop on Polycystic Ovary Syndrome. Bethesda, MD2012 - 7.
Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364-379 - 8.
Paradisi G, Steinberg HO, Hempfling A, Cronin J, Hook G, Shepard MK, et al. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation. 2001;103(10):1410-1415 - 9.
Rizzo M, Berneis K, Spinas G, Rini GB, Carmina E. Long-term consequences of polycystic ovary syndrome on cardiovascular risk. Fertil Steril. 2009;91(4 Suppl):1563-1567 - 10.
Tock L, Carneiro G, Togeiro SM, Hachul H, Pereira AZ, Tufik S, et al. Obstructive sleep apnea predisposes to nonalcoholic Fatty liver disease in patients with polycystic ovary syndrome. Endocr Pract. 2014;20(3):244-251 - 11.
Kargili A, Karakurt F, Kasapoglu B, Derbent A, Koca C, Selcoki Y. Association of polycystic ovary syndrome and a non-dipping blood pressure pattern in young women. Clinics (Sao Paulo). 2010;65(5):475-479 - 12.
Moghetti P, Tosi F, Tosti A, Negri C, Misciali C, Perrone F, et al. Comparison of spironolactone, flutamide, and finasteride efficacy in the treatment of hirsutism: a randomized, double blind, placebo-controlled trial. J Clin Endocrinol Metab. 2000;85(1):89-94 - 13.
Burger HG. Androgen production in women. Fertil Steril. 2002;77 Suppl 4:S3–S5 - 14.
Huang A, Brennan K, Azziz R. Prevalence of hyperandrogenemia in the polycystic ovary syndrome diagnosed by the National Institutes of Health 1990 criteria. Fertil Steril. 2010;93(6):1938-1941 - 15.
Kirschner MA, Bardin CW. Androgen production and metabolism in normal and virilized women. Metabolism. 1972;21(7):667-688 - 16.
Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016;106(1):6-15 - 17.
O'Reilly MW, Kempegowda P, Jenkinson C, Taylor AE, Quanson JL, Storbeck KH, et al. 11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2017;102(3):840-848 - 18.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-419 - 19.
DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237(3):E214–E223 - 20.
Quinkler M, Sinha B, Tomlinson JW, Bujalska IJ, Stewart PM, Arlt W. Androgen generation in adipose tissue in women with simple obesity--a site-specific role for 17beta-hydroxysteroid dehydrogenase type 5. J Endocrinol. 2004;183(2):331-342 - 21.
O'Reilly M, Gathercole L, Capper F, Arlt W, Tomlinson J. Effect of insulin on AKR1C3 expression in female adipose tissue: in-vivo and in-vitro study of adipose androgen generation in polycystic ovary syndrome. Lancet. 2015;385 Suppl 1:S16 - 22.
Grino PB, Griffin JE, Wilson JD. Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone. Endocrinology. 1990;126(2):1165-1172 - 23.
Tan MH, Li J, Xu HE, Melcher K, Yong EL. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin. 2015;36(1):3-23 - 24.
Pratt WB, Toft DO. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev. 1997;18(3):306-360 - 25.
Lucas-Herald AK, Alves-Lopes R, Montezano AC, Ahmed SF, Touyz RM. Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications. Clin Sci (Lond). 2017;131(13):1405-1418 - 26.
Giovannucci E, Platz EA, Stampfer MJ, Chan A, Krithivas K, Kawachi I, et al. The CAG repeat within the androgen receptor gene and benign prostatic hyperplasia. Urology. 1999;53(1):121-125 - 27.
Belsham DD, Yee WC, Greenberg CR, Wrogemann K. Analysis of the CAG repeat region of the androgen receptor gene in a kindred with X-linked spinal and bulbar muscular atrophy. J Neurol Sci. 1992;112(1-2):133-138 - 28.
Yoshida KI, Yano M, Chiba K, Honda M, Kitahara S. CAG repeat length in the androgen receptor gene is enhanced in patients with idiopathic azoospermia. Urology. 1999;54(6):1078-1081 - 29.
Jaaskelainen J, Korhonen S, Voutilainen R, Hippelainen M, Heinonen S. Androgen receptor gene CAG length polymorphism in women with polycystic ovary syndrome. Fertil Steril. 2005;83(6):1724-1728 - 30.
Dasgupta S, Sirisha PV, Neelaveni K, Anuradha K, Reddy AG, Thangaraj K, et al. Androgen receptor CAG repeat polymorphism and epigenetic influence among the south Indian women with Polycystic Ovary Syndrome. PLoS One. 2010;5(8):e12401 - 31.
Caldwell ASL, Edwards MC, Desai R, Jimenez M, Gilchrist RB, Handelsman DJ, et al. Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome. Proc Natl Acad Sci U S A. 2017;114(16):E3334-E3E43 - 32.
Cox MJ, Edwards MC, Rodriguez Paris V, Aflatounian A, Ledger WL, Gilchrist RB, et al. Androgen Action in Adipose Tissue and the Brain are Key Mediators in the Development of PCOS Traits in a Mouse Model. Endocrinology. 2020;161(7) - 33.
Glintborg D, Rubin KH, Nybo M, Abrahamsen B, Andersen M. Cardiovascular disease in a nationwide population of Danish women with polycystic ovary syndrome. Cardiovasc Diabetol. 2018;17(1):37 - 34.
Zhou Y, Wang X, Jiang Y, Ma H, Chen L, Lai C, et al. Association between polycystic ovary syndrome and the risk of stroke and all-cause mortality: insights from a meta-analysis. Gynecol Endocrinol. 2017;33(12):904-910 - 35.
de Groot PC, Dekkers OM, Romijn JA, Dieben SW, Helmerhorst FM. PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. Hum Reprod Update. 2011;17(4):495-500 - 36.
Collaborators GBDRF. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1923-1994 - 37.
Chen MJ, Yang WS, Yang JH, Chen CL, Ho HN, Yang YS. Relationship between androgen levels and blood pressure in young women with polycystic ovary syndrome. Hypertension. 2007;49(6):1442-1447 - 38.
Amiri M, Ramezani Tehrani F, Behboudi-Gandevani S, Bidhendi-Yarandi R, Carmina E. Risk of hypertension in women with polycystic ovary syndrome: a systematic review, meta-analysis and meta-regression. Reprod Biol Endocrinol. 2020;18(1):23 - 39.
Khaw KT, Barrett-Connor E. Blood pressure and endogenous testosterone in men: an inverse relationship. J Hypertens. 1988;6(4):329-332 - 40.
Santos RAS, Oudit GY, Verano-Braga T, Canta G, Steckelings UM, Bader M. The renin-angiotensin system: going beyond the classical paradigms. Am J Physiol Heart Circ Physiol. 2019;316(5):H958-HH70 - 41.
Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res. 2017;125(Pt A):21-38 - 42.
Alreja G, Joseph J. Renin and cardiovascular disease: Worn-out path, or new direction. World J Cardiol. 2011;3(3):72-83 - 43.
Diamanti-Kandarakis E, Economou FN, Livadas S, Tantalaki E, Piperi C, Papavassiliou AG, et al. Hyperreninemia characterizing women with polycystic ovary syndrome improves after metformin therapy. Kidney Blood Press Res. 2009;32(1):24-31 - 44.
Jensterle M, Janez A, Vrtovec B, Meden-Vrtovec H, Pfeifer M, Prezelj J, et al. Decreased androgen levels and improved menstrual pattern after angiotensin II receptor antagonist telmisartan treatment in four hypertensive patients with polycystic ovary syndrome: case series. Croat Med J. 2007;48(6):864-870 - 45.
Yanes LL, Sartori-Valinotti JC, Iliescu R, Romero DG, Racusen LC, Zhang H, et al. Testosterone-dependent hypertension and upregulation of intrarenal angiotensinogen in Dahl salt-sensitive rats. Am J Physiol Renal Physiol. 2009;296(4):F771–F779 - 46.
Yanes LL, Romero DG, Moulana M, Lima R, Davis DD, Zhang H, et al. Cardiovascular-renal and metabolic characterization of a rat model of polycystic ovary syndrome. Gend Med. 2011;8(2):103-115 - 47.
Ellison KE, Ingelfinger JR, Pivor M, Dzau VJ. Androgen regulation of rat renal angiotensinogen messenger RNA expression. J Clin Invest. 1989;83(6):1941-1945 - 48.
Chen YF, Naftilan AJ, Oparil S. Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats. Hypertension. 1992;19(5):456-463 - 49.
Quinkler M, Bujalska IJ, Kaur K, Onyimba CU, Buhner S, Allolio B, et al. Androgen receptor-mediated regulation of the alpha-subunit of the epithelial sodium channel in human kidney. Hypertension. 2005;46(4):787-798 - 50.
Torres-Estay V, Carreno DV, San Francisco IF, Sotomayor P, Godoy AS, Smith GJ. Androgen receptor in human endothelial cells. J Endocrinol. 2015;224(3):R131–R137 - 51.
Doublier S, Lupia E, Catanuto P, Periera-Simon S, Xia X, Korach K, et al. Testosterone and 17beta-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice. Kidney Int. 2011;79(4):404-413 - 52.
Quinkler M, Bumke-Vogt C, Meyer B, Bahr V, Oelkers W, Diederich S. The human kidney is a progesterone-metabolizing and androgen-producing organ. J Clin Endocrinol Metab. 2003;88(6):2803-2809 - 53.
Ivy JR, Bailey MA. Pressure natriuresis and the renal control of arterial blood pressure. J Physiol. 2014;592(18):3955-3967 - 54.
Reckelhoff JF, Zhang H, Granger JP. Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats. Hypertension. 1998;31(1 Pt 2):435-439 - 55.
Loh SY, Giribabu N, Salleh N. Sub-chronic testosterone treatment increases the levels of epithelial sodium channel (ENaC)-alpha, beta and gamma in the kidney of orchidectomized adult male Sprague-Dawley rats. PeerJ. 2016;4:e2145 - 56.
Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, et al. The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7). Physiol Rev. 2018;98(1):505-553 - 57.
Ji H, de Souza AM, Bajaj B, Zheng W, Wu X, Speth RC, et al. Sex-specific modulation of blood pressure and the renin-angiotensin system by ACE (Angiotensin-Converting Enzyme) 2. Hypertension. 2020;76(2):478-487 - 58.
Liu J, Ji H, Zheng W, Wu X, Zhu JJ, Arnold AP, et al. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent. Biology of sex differences. 2010;1(1):6 - 59.
Mishra JS, Hankins GD, Kumar S. Testosterone downregulates angiotensin II type-2 receptor via androgen receptor-mediated ERK1/2 MAP kinase pathway in rat aorta. J Renin Angiotensin Aldosterone Syst. 2016;17(4) - 60.
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-273 - 61.
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-454 - 62.
Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875-879 - 63.
Brandi ML, Giustina A. Sexual Dimorphism of Coronavirus 19 Morbidity and Lethality. Trends Endocrinol Metab. 2020;31(12):918-927 - 64.
Torres Fernandez ED, Huffman AM, Syed M, Romero DG, Yanes Cardozo LL. Effect of GLP-1 Receptor Agonists in the Cardiometabolic Complications in a Rat Model of Postmenopausal PCOS. Endocrinology. 2019;160(12):2787-2799 - 65.
Torres Fernandez ED, Adams KV, Syed M, Maranon RO, Romero DG, Yanes Cardozo LL. Long-Lasting Androgen-Induced Cardiometabolic Effects in Polycystic Ovary Syndrome. J Endocr Soc. 2018;2(8):949-964 - 66.
Moretti ME, Caprara D, Drehuta I, Yeung E, Cheung S, Federico L, et al. The Fetal Safety of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers. Obstet Gynecol Int. 2012;2012:658310 - 67.
Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr Rev. 2015;36(5):487-525 - 68.
Mendoza MF, Kachur SM, Lavie CJ. Hypertension in obesity. Curr Opin Cardiol. 2020;35(4):389-396 - 69.
Choe SS, Huh JY, Hwang IJ, Kim JI, Kim JB. Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders. Front Endocrinol (Lausanne). 2016;7:30 - 70.
Okuno Y, Fukuhara A, Hashimoto E, Kobayashi H, Kobayashi S, Otsuki M, et al. Oxidative Stress Inhibits Healthy Adipose Expansion Through Suppression of SREBF1-Mediated Lipogenic Pathway. Diabetes. 2018;67(6):1113-1127 - 71.
Manneras L, Cajander S, Holmang A, Seleskovic Z, Lystig T, Lonn M, et al. A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology. 2007;148(8):3781-3791 - 72.
Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesity, kidney dysfunction and hypertension: mechanistic links. Nat Rev Nephrol. 2019;15(6):367-385 - 73.
Rojas J, Chavez M, Olivar L, Rojas M, Morillo J, Mejias J, et al. Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth. Int J Reprod Med. 2014;2014:719050 - 74.
Yildirir A, Aybar F, Kabakci G, Yarali H, Oto A. Heart rate variability in young women with polycystic ovary syndrome. Ann Noninvasive Electrocardiol. 2006;11(4):306-312 - 75.
Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag. 2005;1(3):183-198 - 76.
Schulz E, Gori T, Munzel T. Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res. 2011;34(6):665-673 - 77.
Usselman CW, Yarovinsky TO, Steele FE, Leone CA, Taylor HS, Bender JR, et al. Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: role of the endothelin B receptor. J Physiol. 2019;597(11):2853-2865 - 78.
Yanes L, Romero D, Iliescu R, Cucchiarelli VE, Fortepiani LA, Santacruz F, et al. Systemic arterial pressure response to two weeks of Tempol therapy in SHR: involvement of NO, the RAS, and oxidative stress. Am J Physiol Regul Integr Comp Physiol. 2005;288(4):R903–R908 - 79.
Hurliman A, Keller Brown J, Maille N, Mandala M, Casson P, Osol G. Hyperandrogenism and Insulin Resistance, Not Changes in Body Weight, Mediate the Development of Endothelial Dysfunction in a Female Rat Model of Polycystic Ovary Syndrome (PCOS). Endocrinology. 2015;156(11):4071-4080 - 80.
Gulanski BI, Flannery CA, Peter PR, Leone CA, Stachenfeld NS. Compromised endothelial function in transgender men taking testosterone. Clin Endocrinol (Oxf). 2020;92(2):138-144 - 81.
Yilmaz M, Bukan N, Ayvaz G, Karakoc A, Toruner F, Cakir N, et al. The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome. Hum Reprod. 2005;20(12):3333-3340 - 82.
Wilmot KA, O'Flaherty M, Capewell S, Ford ES, Vaccarino V. Coronary Heart Disease Mortality Declines in the United States From 1979 Through 2011: Evidence for Stagnation in Young Adults, Especially Women. Circulation. 2015;132(11):997-1002 - 83.
Jabbour R, Ott J, Eppel W, Frigo P. Carotid intima-media thickness in polycystic ovary syndrome and its association with hormone and lipid profiles. PLoS One. 2020;15(4):e0232299 - 84.
Gilbert EW, Tay CT, Hiam DS, Teede HJ, Moran LJ. Comorbidities and complications of polycystic ovary syndrome: An overview of systematic reviews. Clin Endocrinol (Oxf). 2018;89(6):683-699 - 85.
Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care. 2008;31 Suppl 2:S262–S268 - 86.
Peng Z, Sun Y, Lv X, Zhang H, Liu C, Dai S. Interleukin-6 Levels in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis. PLoS One. 2016;11(2):e0148531 - 87.
Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33(6):981-1030 - 88.
Moller DE, Cohen O, Yamaguchi Y, Assiz R, Grigorescu F, Eberle A, et al. Prevalence of mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance. Diabetes. 1994;43(2):247-255 - 89.
Sanchez-Garrido MA, Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies. Mol Metab. 2020;35:100937 - 90.
O'Reilly MW, Taylor AE, Crabtree NJ, Hughes BA, Capper F, Crowley RK, et al. Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione. J Clin Endocrinol Metab. 2014;99(3):1027-1036 - 91.
Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22(1):141-146 - 92.
Rosenfield RL, Ehrmann DA. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocr Rev. 2016;37(5):467-520 - 93.
Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72(1):83-89 - 94.
Deswal R, Yadav A, Dang AS. Sex hormone binding globulin - an important biomarker for predicting PCOS risk: A systematic review and meta-analysis. Syst Biol Reprod Med. 2018;64(1):12-24 - 95.
Gamba M, Pralong FP. Control of GnRH neuronal activity by metabolic factors: the role of leptin and insulin. Mol Cell Endocrinol. 2006;254-255:133-9 - 96.
Chaudhari N, Dawalbhakta M, Nampoothiri L. GnRH dysregulation in polycystic ovarian syndrome (PCOS) is a manifestation of an altered neurotransmitter profile. Reprod Biol Endocrinol. 2018;16(1):37 - 97.
Coutinho EA, Kauffman AS. The Role of the Brain in the Pathogenesis and Physiology of Polycystic Ovary Syndrome (PCOS). Med Sci (Basel). 2019;7(8) - 98.
Banaszewska B, Wrotynska-Barczynska J, Spaczynski RZ, Pawelczyk L, Duleba AJ. Effects of Resveratrol on Polycystic Ovary Syndrome: A Double-blind, Randomized, Placebo-controlled Trial. J Clin Endocrinol Metab. 2016;101(11):4322-4328 - 99.
Spritzer PM, Lecke SB, Satler F, Morsch DM. Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. Reproduction. 2015;149(5):R219–R227 - 100.
Lovejoy JC, Bray GA, Bourgeois MO, Macchiavelli R, Rood JC, Greeson C, et al. Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women--a clinical research center study. J Clin Endocrinol Metab. 1996;81(6):2198-2203 - 101.
Wehr E, Moller R, Horejsi R, Giuliani A, Kopera D, Schweighofer N, et al. Subcutaneous adipose tissue topography and metabolic disturbances in polycystic ovary syndrome. Wien Klin Wochenschr. 2009;121(7-8):262-269 - 102.
Gambineri A, Patton L, Vaccina A, Cacciari M, Morselli-Labate AM, Cavazza C, et al. Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study. J Clin Endocrinol Metab. 2006;91(10):3970-3980 - 103.
Manneras-Holm L, Leonhardt H, Kullberg J, Jennische E, Oden A, Holm G, et al. Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance. J Clin Endocrinol Metab. 2011;96(2):E304–E311 - 104.
Corbould A. Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women. J Endocrinol. 2007;192(3):585-594 - 105.
Luotola K, Piltonen TT, Puurunen J, Morin-Papunen LC, Tapanainen JS. Testosterone is associated with insulin resistance index independently of adiposity in women with polycystic ovary syndrome. Gynecol Endocrinol. 2018;34(1):40-44 - 106.
Hansen SL, Svendsen PF, Jeppesen JF, Hoeg LD, Andersen NR, Kristensen JM, et al. Molecular Mechanisms in Skeletal Muscle Underlying Insulin Resistance in Women Who Are Lean With Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2019;104(5):1841-1854 - 107.
Nishizawa H, Shimomura I, Kishida K, Maeda N, Kuriyama H, Nagaretani H, et al. Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes. 2002;51(9):2734-2741 - 108.
Kogure GS, Miranda-Furtado CL, Silva RC, Melo AS, Ferriani RA, De Sa MF, et al. Resistance Exercise Impacts Lean Muscle Mass in Women with Polycystic Ovary Syndrome. Med Sci Sports Exerc. 2016;48(4):589-598 - 109.
Chen MJ, Chiu HM, Chen CL, Yang WS, Yang YS, Ho HN. Hyperandrogenemia is independently associated with elevated alanine aminotransferase activity in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2010;95(7):3332-3341 - 110.
Gambarin-Gelwan M, Kinkhabwala SV, Schiano TD, Bodian C, Yeh HC, Futterweit W. Prevalence of nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Clin Gastroenterol Hepatol. 2007;5(4):496-501 - 111.
Jones H, Sprung VS, Pugh CJ, Daousi C, Irwin A, Aziz N, et al. Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J Clin Endocrinol Metab. 2012;97(10):3709-3716 - 112.
Gibson-Helm M, Teede H, Dunaif A, Dokras A. Delayed Diagnosis and a Lack of Information Associated With Dissatisfaction in Women With Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2017;102(2):604-612 - 113.
Lin AW, Bergomi EJ, Dollahite JS, Sobal J, Hoeger KM, Lujan ME. Trust in Physicians and Medical Experience Beliefs Differ Between Women With and Without Polycystic Ovary Syndrome. J Endocr Soc. 2018;2(9):1001-1009 - 114.
Araujo LF, de Matos Soeiro A, Fernandes JL, Pesaro AE, Serrano CV, Jr. Coronary artery disease in women: a review on prevention, pathophysiology, diagnosis, and treatment. Vasc Health Risk Manag. 2006;2(4):465-475 - 115.
Klett C, Hellmann W, Hackenthal E, Ganten D. Modulation of tissue angiotensinogen gene expression by glucocorticoids, estrogens, and androgens in SHR and WKY rats. Clin Exp Hypertens. 1993;15(4):683-708 - 116.
Klett C, Ganten D, Hellmann W, Kaling M, Ryffel GU, Weimar-Ehl T, et al. Regulation of hepatic angiotensinogen synthesis and secretion by steroid hormones. Endocrinology. 1992;130(6):3660-3668 - 117.
Tanis BC, van den Bosch MA, Kemmeren JM, Cats VM, Helmerhorst FM, Algra A, et al. Oral contraceptives and the risk of myocardial infarction. N Engl J Med. 2001;345(25):1787-1793 - 118.
Troisi RJ, Cowie CC, Harris MI. Oral contraceptive use and glucose metabolism in a national sample of women in the united states. Am J Obstet Gynecol. 2000;183(2):389-395 - 119.
Halperin IJ, Kumar SS, Stroup DF, Laredo SE. The association between the combined oral contraceptive pill and insulin resistance, dysglycemia and dyslipidemia in women with polycystic ovary syndrome: a systematic review and meta-analysis of observational studies. Hum Reprod. 2011;26(1):191-201 - 120.
Meyer C, McGrath BP, Teede HJ. Effects of medical therapy on insulin resistance and the cardiovascular system in polycystic ovary syndrome. Diabetes Care. 2007;30(3):471-478 - 121.
Nader S, Riad-Gabriel MG, Saad MF. The effect of a desogestrel-containing oral contraceptive on glucose tolerance and leptin concentrations in hyperandrogenic women. J Clin Endocrinol Metab. 1997;82(9):3074-3077 - 122.
Adeniji AA, Essah PA, Nestler JE, Cheang KI. Metabolic Effects of a Commonly Used Combined Hormonal Oral Contraceptive in Women With and Without Polycystic Ovary Syndrome. J Womens Health (Larchmt). 2016;25(6):638-645 - 123.
Morin-Papunen LC, Vauhkonen I, Koivunen RM, Ruokonen A, Martikainen HK, Tapanainen JS. Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab. 2000;85(9):3161-3168 - 124.
Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E, et al. American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and Pcos Society Disease State Clinical Review: Guide to the Best Practices in the Evaluation and Treatment of Polycystic Ovary Syndrome--Part 1. Endocr Pract. 2015;21(11):1291-1300 - 125.
Gil M, Oliva B, Timoner J, Macia MA, Bryant V, de Abajo FJ. Risk of meningioma among users of high doses of cyproterone acetate as compared with the general population: evidence from a population-based cohort study. Br J Clin Pharmacol. 2011;72(6):965-968 - 126.
Moretti C, Guccione L, Di Giacinto P, Simonelli I, Exacoustos C, Toscano V, et al. Combined Oral Contraception and Bicalutamide in Polycystic Ovary Syndrome and Severe Hirsutism: A Double-Blind Randomized Controlled Trial. J Clin Endocrinol Metab. 2018;103(3):824-838 - 127.
Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E, et al. American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and Pcos Society Disease State Clinical Review: Guide to the Best Practices in the Evaluation and Treatment of Polycystic Ovary Syndrome - Part 2. Endocr Pract. 2015;21(12):1415-1426 - 128.
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403 - 129.
Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med. 1996;335(9):617-623 - 130.
Guan Y, Wang D, Bu H, Zhao T, Wang H. The Effect of Metformin on Polycystic Ovary Syndrome in Overweight Women: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Int J Endocrinol. 2020;2020:5150684 - 131.
Jensterle Sever M, Kocjan T, Pfeifer M, Kravos NA, Janez A. Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin. Eur J Endocrinol. 2014;170(3):451-459 - 132.
Hoang V, Bi J, Mohankumar SM, Vyas AK. Liraglutide improves hypertension and metabolic perturbation in a rat model of polycystic ovarian syndrome. PLoS One. 2015;10(5):e0126119 - 133.
Javed Z, Papageorgiou M, Deshmukh H, Rigby AS, Qamar U, Abbas J, et al. Effects of empagliflozin on metabolic parameters in polycystic ovary syndrome: a randomized controlled study. Clinical endocrinology. 2019;90(6):805-813 - 134.
Butler J, Handelsman Y, Bakris G, Verma S. Use of sodium–glucose co-transporter-2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure. European Journal of Heart Failure. 2020 - 135.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine. 2015;373(22):2117-2128 - 136.
Mompeón A, Lázaro-Franco M, Bueno-Betí C, Pérez-Cremades D, Vidal-Gómez X, Monsalve E, et al. Estradiol, acting through ERα, induces endothelial non-classic renin-angiotensin system increasing angiotensin 1-7 production. Mol Cell Endocrinol. 2016;422:1-8