madman
Super Moderator
ABSTRACT
Documented male-female differences in the risk of cardiovascular and chronic kidney diseases have been largely attributed to estrogens. The cardiovascular and renal protective effects of estrogens are mediated via the activation of estrogen receptors (ERα and ERβ) and G protein-coupled estrogen receptors and involve interactions with the renin-angiotensin-aldosterone system. Aromatase, also called estrogen synthase, is a cytochrome P-450 enzyme that plays a pivotal role in the conversion of androgens into estrogens. Estrogens are biosynthesized in gonadal and extra-gonadal sites by the action of aromatase. Evidence suggests that aromatase inhibitors, which are used to treat high estrogen–related pathologies, are associated with the development of cardiovascular events. We review the potential role of aromatization in providing cardio-renal protection and highlight several meta-analysis studies on cardiovascular events associated with aromatase inhibitors. Overall, we present the potential of aromatase enzyme as a fundamental contributor to cardio-renal protection.
1. Introduction
1.1. Prevalence of cardiovascular and chronic kidney diseases
1.2. Age and sex factors contributing to cardiovascular health
1.3. Age and sex factors contributing to renal health
2. Estrogens
2.1. Types of estrogens and primary sites of production
Estrogens are steroidal sex hormones that include estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4) [25]. The predominant circulating female hormone is E2, which is commonly referred to as"estrogen", due to its physiological importance and prevalence during the reproductive years [16,25]. E1 is commonly detected at higher levels after menopause, while E3 and E4 are produced only during pregnancy[26].
The ovaries, specifically the granulosa cells, are the primary source of E2 in premenopausal women, acting as a circulating hormone in distal tissues [25,27]. In men, E2 is produced in minute amounts by the testes [28]. Estrogens are also produced in extra-gonadal sites such as adipose tissue, brain, skin, muscles, bones, vascular endothelium, vascular smooth muscles, intestine, liver, and adrenal glands, where they act locally in a paracrine or intracrine manner [27,29]. In a study investigating the source of elevated estrogen after menopause, an increase in the expression of aromatase (the enzyme catalyzing estrogen biosynthesis) was detected in the subcutaneous abdominal adipose tissue of ovariectomized rats [30]. This finding coincides with another study, which concluded that the conversion of androstenedione to estrogen was higher in obese women [31]. Additionally, a cross-sectional study on postmenopausal women found a link between rising body mass index and circulating estrogens (E1 and E2) [32]. However, the contribution of extra-gonadal E2 biosynthesis in different organ systems to the systemic levels of sex hormones remains debatable.
2.2. Biosynthesis of estrogens
The biosynthesis of estrogen takes place through a series of reactions catalyzed by a number of cytochrome P450 enzymes and different hydroxysteroid dehydrogenases [33]. It starts with the conversion of cholesterol to pregnenolone by cytochrome P450 cholesterol side-chain cleavage enzyme (CYP11A) [33]. Pregnenolone can either be converted to 17-hydroxypregnolone and consequently to dehydroepiandrosterone by 17α-hydroxylase (CYP17), or it can be converted to progesterone by3β-hydroxysteroid dehydrogenase (3β-HSD) [33]. Both dehydroepiandrosterone and progesterone are then converted to androstenedione by 3β-HSD and CYP17, respectively [33]. Afterward, the androstenedione can be either converted to testosterone by 17β-hydroxysteroid dehydrogenase (17β-HSD) or to E1 by the aromatase enzyme (CYP19A1)[33]. Then, 17β-HSD catalyzes the conversion of E1 to E2 [33]. Fig. 1 demonstrates the steps of estrogen biosynthesis.
2.3. Estrogen receptors
Estrogens exhibit a wide range of physiological functions on different body tissues, including the cardiovascular, reproductive, skeletal, adipose, and central nervous systems [34–36]. E2 exerts its functions by acting on the estrogen receptors (ERα and ERβ) which are encoded by the ESR1 and ESR2 genes, respectively [37]. In addition, E2 also binds to a recently discovered G protein-coupled estrogen receptor1 (GPER1) or G protein-coupled receptor 30 (GPER30), also known as the membrane estrogen receptor [25]. Table 1 lists the gene and protein designations for estrogen receptors.
The expression of ERs has been identified in a wide range of cells and tissues. ERα is primarily found in the mammary glands, uterus, ovary (thecal cells), bones, male reproductive organs (testes and epididymis), prostate (stroma), liver, and adipose tissue [37,38]. ERβ is present in the prostate (epithelium), bladder, ovary (granulosa cells), colon, adipose tissue, and immune system [37,38]. In addition, both ERα and ERβ are markedly expressed in the cardiovascular and central nervous systems [37,38]. Within the cardiovascular system, ERα and ERβ are expressed in endothelial cells, vascular smooth muscle cells, and a variety of cardiac tissue, including cardiomyocytes, and cardiac fibroblasts [18,28]. Stained human renal biopsies showed that ERα is mainly expressed the renal glomeruli and tubules [39], while both ERα and ERβ are expressed in the kidney proximal tubule [40]. According to several studies on rodents and humans, GPER1 is ubiquitously expressed within the reproductive system [41], cardiovascular system [42], renal system[43], brain [44], adrenal glands [45], adipocytes [46], and bones [47].
2.4. The cardio-renal protective effect of estrogen
2.5. The RAAS-estrogen interactions
2.6. Estrogen in aging
3. Aromatase enzyme
The aromatase enzyme, alternatively known as estrogen synthase, is a mono-oxygenase that belongs to the cytochrome P450 family and is encoded by the CYP19A1 gene [33]. This enzyme catalyzes the demethylation of carbon 19 in androgens causing their aromatization into 18-carbon estrogens [110]. Androstenedione, testosterone, and 16-hydroxytestosterone are the physiological substrates of aromatase which are then transformed into E1, E2, and E3, respectively [111]. Collectively, the synthesis of estrogen is catalyzed by the aromatase enzyme, which converts endogenous androgens into estrogens [111].
3.1. The mechanism of aromatization
The aromatization process advances through a number of steps elaborated in Fig. 3. First, the methyl group at C19 in androstenedione is hydroxylated to produce 19-hydroxy androstenedione, which is then followed by a second hydroxylation reaction to produce 19-dihydroxyandrostenedione [112,113]. The latter is then dehydrated to 19-oxoandrostenedione [112,113]. Finally, the steroid ring-A is subjected to oxidative cleavage of the C10-C19 bond followed by the release of formic acid, leading to the formation of estrogen [112,113].
3.2. Distribution of aromatase
Estrogens are produced by gonadal and extragonadal sites. Gonadally and extragonadally-driven estrogens share the same chemical structure and biological activity but differ in their metabolic pathway of synthesis [29]. Extra-gonadal estrogens are produced when C19 precursors are supplied to any tissue that expresses aromatase [29]. Noteworthy, aromatase is primarily produced by ovarian granulosa cells in premenopausal women and adipose cells in postmenopausal women[114].
On the gonadal level, aromatase is expressed in both ovaries and testis. In the ovaries, aromatase expression is limited to differentiated perovulatory granulosa cells and luteal cells, and it is not expressed by differentiated granulosa cells in preantral follicles [115]. The follicle-stimulating hormone stimulates the growth and maturation of preantral follicles to the preovulatory stage, and the differentiation of granulosa cells, inducing the activation of aromatase [115]. Aromatase is downregulated after ovulation as granulosa cells develop into luteal cells [115]. Meanwhile, the detection of high amounts of estrogens in the male semen can be explained by the expression of aromatase in different testicular cells. Carreau et al. reported the presence of physiologically active aromatase in Leydig cells, Sertoli cells, spermatocytes, spermatids, and ejaculated spermatozoa in males [116].
Aromatase is also highly expressed in the placenta of both human and non-human primates [117], as well as other extra-gonadal tissues including the thalamus, hypothalamus, and hippocampus, indicating that aromatase is expressed widely in numerous regions of the human brain in both men and women [118]. Aromatase activity has also been reported in stromal cells and adipocytes [119]. In bone tissue, aromatase has been identified within the human fetal osteoblastic cell line(SV-HFO) [120], and human osteoblasts [121]. The human hepatocellular carcinoma cells and HepG2 hepatoma cells showed an increase in estrogen biosynthesis upon treatment with androgen precursors such astestosterone or androstenedione, indicating elevated aromatase activity[122]. Western blotting and immunohistochemistry showed that aromatase is expressed in the adrenal cortex as well as in adrenocortical tumors [123,124]. In addition, aromatase activity was demonstrated by 3[H2O] assay and gas chromatography-mass spectrometry in the parietal cells of the gastric mucosa [125]. It has also been previously reported that aromatase is expressed in epidermal keratinocytes and dermal fibroblasts [126,127]. In situ, hybridization revealed the presence of aromatase in human vascular smooth muscle cells but not in endothelial cells [128]. In men, aromatase is also expressed in the prostate [129]. Although extra-gonadal estrogen is synthesized in small amounts, its concentration is high enough to exert a biological effect locally [29]. Therefore, the disruption of aromatase homeostasis, accompanied by a disturbance in estrogen levels, will result in organ-specific effects.
3.3. Disruption of aromatase homeostasis
Both high and low levels of aromatase, and consequently high and low levels of estrogen, can cause a wide range of diseases and side effects [130]. Aromatase or estrogen excess-driven pathologies include breast, prostate, lung, gastric, and hepatic cancers, polycystic ovary syndrome, endometriosis, obesity, short stature, male hypogonadism, gynecomastia, and testicular hypertrophy [130–132]. Aromatase or estrogen deficiency-induced pathologies include cardiovascular problems [36,133], osteoporosis [36,130], hot flushes [134], vaginal dryness and vaginal atrophy [134], skin aging, thinning and pigmentation [135,136], schizophrenia [130], Alzheimer’s disease [130], depression [137], insomnia [134], neuropathies [36], and elevated aldosterone levels [138,139]. Fig. 4 illustrates the sites of aromatase expression and estrogen disturbance-related effects.
3.4. Regulation of aromatase enzyme
4. Aromatase inhibitors (AIs)
4.1. Discovery of AIs
Historically, oophorectomy and adrenalectomy have been used to treat breast cancer [144]. The anti-epileptic medication, aminoglutethimide, was found to reduce the production of adrenal steroid hormones by blocking cytochrome P450 enzymes [145]. It was then recommended as a potential medical substitute for adrenalectomy for the treatment of breast cancer [146,147]. Later, it was discovered that the key mechanism of aminoglutethimide was the suppression of aromatase enzyme, which subsequently leads to a reduction in estrogen levels[148,149]. Aminoglutethimide was recognized as the first-generation AI [114]. In 1981, the effect of using 4-hydroxy-androstenedione (4-OH-A) against breast cancer in post-menopausal women was reported [150,151]. By the middle of the 1980s, 4-OH-A was named formestane and was recognized as the first selective AI against breast cancer [152]. Formestane is considered as a second-generation AI [114]
Currently used AIs (shown in Fig. 5) are classified into irreversible steroidal inhibitors (exemestane) and reversible non-steroidal inhibitors (anastrozole and letrozole) [153]. These AIs are nominated as third-generation AIs [114]. The third-generation AIs have an advantage over the first and second generations as they are well tolerated and highly selective for the aromatase enzyme [154]. In addition,third-generation AIs outperform first- and second-generation AIs in terms of clinical benefit and near-complete specificity in clinical application [155]. However, long-term adverse effects of these drugs, such as skeletal and cardiovascular problems, must be carefully monitored [155].
4.2. Uses and side effects of AIs
4.3. Controversies regarding the cardiotoxicity of AIs
4.3.1. Meta-analyses showing significant increase of CVD with AIs
4.3.2. Meta-analyses showing non-significant increase of CVD with AIs
4.4. AIs and renal toxicity
5. Extra-gonadal aromatase and cardio-renal protection
A unique feature of extra-gonadally synthesized estrogens is being produced locally in concentrations high enough to exert local biological effects with limited systematic effects [29]. Despite the documented cardioprotective effects of estrogen, the use of estrogen-replacement therapy as a cardioprotective agent is still controversial [16]. This is due to the fact that estrogens have major off-target effects which include increased risks of breast and endometrial cancer, as well as thromboembolisms and strokes [186]. However, evidence suggests that the regulation of aromatase enzyme activity and expression protects against cardiac and vascular damage [187]. The aromatase enzyme was found to be expressed in the coronary endothelium and has an effect on the cardiac function and structural modeling as a result of the localized conversion of androgens to E2 in an acute MI male mouse model [187]. Bayard et al. also demonstrated the activity of aromatase enzyme using female rat arterial smooth muscle cells and bovine coronary endothelial cells in in-vitro models [188,189]. Another research revealed that aromatase activity is demonstrated in human arterial smooth muscle cells and therefore hypothesized that E2 produced in vascular smooth muscle cells regulates cardiac contractility and vascular tone (autocrine activity) while stimulating nitric oxide production and angiogenesis in endothelial cells (paracrine activity) [128]. In order to investigate whether upregulation of cardiac aromatase expression could improve ischemic resilience, Bell et al. conducted a study on hearts from male transgenic aromatase-overexpressing mice (AROM+), using an expression vector for human P-450 aromatase [190]. The male AROM+ mice have lower testosterone and higher E2 levels than wild-type male mice. Interestingly, ischemic contractures are attenuated in AROM+ hearts, suggesting that aromatase regulation modulates cardiac performance after ischemia [190]. Another recent study found that HF is associated with local deficiency of cardiac estrogen and downregulation of aromatase, thus suggesting that restoring the transcript level of cardiac aromatase can protect against HF [191]. Taken together, the above-mentioned information indicates a need for more investigation into the potential role of extra-gonadal aromatization and the importance of restoring cardiac aromatase and enhancing estrogen signaling in conferring cardio-renal protection.
6. Conclusion and future prospects
Aromatase is localized in gonadal and extra-gonadal sites in the human body and plays a pivotal role in estrogen biosynthesis. For instance, it is established now that the brain can synthesize estrogen, and that brain aromatase is crucial for neuroprotection [192]. In this context, we propose that estrogens within the cardiovascular and renal systems may function to provide cardio-renal protection as well. We argue that aromatase has a fundamental effect on cardio-renal protection through increasing the level of estrogen. In other words, aromatase can function as a component of androgen metabolism that directly supplies estrogen to cardiovascular tissues. Future studies are required to properly understand this complex relationship and identify the role of aromatization in preserving cardiovascular and renal health.
Documented male-female differences in the risk of cardiovascular and chronic kidney diseases have been largely attributed to estrogens. The cardiovascular and renal protective effects of estrogens are mediated via the activation of estrogen receptors (ERα and ERβ) and G protein-coupled estrogen receptors and involve interactions with the renin-angiotensin-aldosterone system. Aromatase, also called estrogen synthase, is a cytochrome P-450 enzyme that plays a pivotal role in the conversion of androgens into estrogens. Estrogens are biosynthesized in gonadal and extra-gonadal sites by the action of aromatase. Evidence suggests that aromatase inhibitors, which are used to treat high estrogen–related pathologies, are associated with the development of cardiovascular events. We review the potential role of aromatization in providing cardio-renal protection and highlight several meta-analysis studies on cardiovascular events associated with aromatase inhibitors. Overall, we present the potential of aromatase enzyme as a fundamental contributor to cardio-renal protection.
1. Introduction
1.1. Prevalence of cardiovascular and chronic kidney diseases
1.2. Age and sex factors contributing to cardiovascular health
1.3. Age and sex factors contributing to renal health
2. Estrogens
2.1. Types of estrogens and primary sites of production
Estrogens are steroidal sex hormones that include estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4) [25]. The predominant circulating female hormone is E2, which is commonly referred to as"estrogen", due to its physiological importance and prevalence during the reproductive years [16,25]. E1 is commonly detected at higher levels after menopause, while E3 and E4 are produced only during pregnancy[26].
The ovaries, specifically the granulosa cells, are the primary source of E2 in premenopausal women, acting as a circulating hormone in distal tissues [25,27]. In men, E2 is produced in minute amounts by the testes [28]. Estrogens are also produced in extra-gonadal sites such as adipose tissue, brain, skin, muscles, bones, vascular endothelium, vascular smooth muscles, intestine, liver, and adrenal glands, where they act locally in a paracrine or intracrine manner [27,29]. In a study investigating the source of elevated estrogen after menopause, an increase in the expression of aromatase (the enzyme catalyzing estrogen biosynthesis) was detected in the subcutaneous abdominal adipose tissue of ovariectomized rats [30]. This finding coincides with another study, which concluded that the conversion of androstenedione to estrogen was higher in obese women [31]. Additionally, a cross-sectional study on postmenopausal women found a link between rising body mass index and circulating estrogens (E1 and E2) [32]. However, the contribution of extra-gonadal E2 biosynthesis in different organ systems to the systemic levels of sex hormones remains debatable.
2.2. Biosynthesis of estrogens
The biosynthesis of estrogen takes place through a series of reactions catalyzed by a number of cytochrome P450 enzymes and different hydroxysteroid dehydrogenases [33]. It starts with the conversion of cholesterol to pregnenolone by cytochrome P450 cholesterol side-chain cleavage enzyme (CYP11A) [33]. Pregnenolone can either be converted to 17-hydroxypregnolone and consequently to dehydroepiandrosterone by 17α-hydroxylase (CYP17), or it can be converted to progesterone by3β-hydroxysteroid dehydrogenase (3β-HSD) [33]. Both dehydroepiandrosterone and progesterone are then converted to androstenedione by 3β-HSD and CYP17, respectively [33]. Afterward, the androstenedione can be either converted to testosterone by 17β-hydroxysteroid dehydrogenase (17β-HSD) or to E1 by the aromatase enzyme (CYP19A1)[33]. Then, 17β-HSD catalyzes the conversion of E1 to E2 [33]. Fig. 1 demonstrates the steps of estrogen biosynthesis.
2.3. Estrogen receptors
Estrogens exhibit a wide range of physiological functions on different body tissues, including the cardiovascular, reproductive, skeletal, adipose, and central nervous systems [34–36]. E2 exerts its functions by acting on the estrogen receptors (ERα and ERβ) which are encoded by the ESR1 and ESR2 genes, respectively [37]. In addition, E2 also binds to a recently discovered G protein-coupled estrogen receptor1 (GPER1) or G protein-coupled receptor 30 (GPER30), also known as the membrane estrogen receptor [25]. Table 1 lists the gene and protein designations for estrogen receptors.
The expression of ERs has been identified in a wide range of cells and tissues. ERα is primarily found in the mammary glands, uterus, ovary (thecal cells), bones, male reproductive organs (testes and epididymis), prostate (stroma), liver, and adipose tissue [37,38]. ERβ is present in the prostate (epithelium), bladder, ovary (granulosa cells), colon, adipose tissue, and immune system [37,38]. In addition, both ERα and ERβ are markedly expressed in the cardiovascular and central nervous systems [37,38]. Within the cardiovascular system, ERα and ERβ are expressed in endothelial cells, vascular smooth muscle cells, and a variety of cardiac tissue, including cardiomyocytes, and cardiac fibroblasts [18,28]. Stained human renal biopsies showed that ERα is mainly expressed the renal glomeruli and tubules [39], while both ERα and ERβ are expressed in the kidney proximal tubule [40]. According to several studies on rodents and humans, GPER1 is ubiquitously expressed within the reproductive system [41], cardiovascular system [42], renal system[43], brain [44], adrenal glands [45], adipocytes [46], and bones [47].
2.4. The cardio-renal protective effect of estrogen
2.5. The RAAS-estrogen interactions
2.6. Estrogen in aging
3. Aromatase enzyme
The aromatase enzyme, alternatively known as estrogen synthase, is a mono-oxygenase that belongs to the cytochrome P450 family and is encoded by the CYP19A1 gene [33]. This enzyme catalyzes the demethylation of carbon 19 in androgens causing their aromatization into 18-carbon estrogens [110]. Androstenedione, testosterone, and 16-hydroxytestosterone are the physiological substrates of aromatase which are then transformed into E1, E2, and E3, respectively [111]. Collectively, the synthesis of estrogen is catalyzed by the aromatase enzyme, which converts endogenous androgens into estrogens [111].
3.1. The mechanism of aromatization
The aromatization process advances through a number of steps elaborated in Fig. 3. First, the methyl group at C19 in androstenedione is hydroxylated to produce 19-hydroxy androstenedione, which is then followed by a second hydroxylation reaction to produce 19-dihydroxyandrostenedione [112,113]. The latter is then dehydrated to 19-oxoandrostenedione [112,113]. Finally, the steroid ring-A is subjected to oxidative cleavage of the C10-C19 bond followed by the release of formic acid, leading to the formation of estrogen [112,113].
3.2. Distribution of aromatase
Estrogens are produced by gonadal and extragonadal sites. Gonadally and extragonadally-driven estrogens share the same chemical structure and biological activity but differ in their metabolic pathway of synthesis [29]. Extra-gonadal estrogens are produced when C19 precursors are supplied to any tissue that expresses aromatase [29]. Noteworthy, aromatase is primarily produced by ovarian granulosa cells in premenopausal women and adipose cells in postmenopausal women[114].
On the gonadal level, aromatase is expressed in both ovaries and testis. In the ovaries, aromatase expression is limited to differentiated perovulatory granulosa cells and luteal cells, and it is not expressed by differentiated granulosa cells in preantral follicles [115]. The follicle-stimulating hormone stimulates the growth and maturation of preantral follicles to the preovulatory stage, and the differentiation of granulosa cells, inducing the activation of aromatase [115]. Aromatase is downregulated after ovulation as granulosa cells develop into luteal cells [115]. Meanwhile, the detection of high amounts of estrogens in the male semen can be explained by the expression of aromatase in different testicular cells. Carreau et al. reported the presence of physiologically active aromatase in Leydig cells, Sertoli cells, spermatocytes, spermatids, and ejaculated spermatozoa in males [116].
Aromatase is also highly expressed in the placenta of both human and non-human primates [117], as well as other extra-gonadal tissues including the thalamus, hypothalamus, and hippocampus, indicating that aromatase is expressed widely in numerous regions of the human brain in both men and women [118]. Aromatase activity has also been reported in stromal cells and adipocytes [119]. In bone tissue, aromatase has been identified within the human fetal osteoblastic cell line(SV-HFO) [120], and human osteoblasts [121]. The human hepatocellular carcinoma cells and HepG2 hepatoma cells showed an increase in estrogen biosynthesis upon treatment with androgen precursors such astestosterone or androstenedione, indicating elevated aromatase activity[122]. Western blotting and immunohistochemistry showed that aromatase is expressed in the adrenal cortex as well as in adrenocortical tumors [123,124]. In addition, aromatase activity was demonstrated by 3[H2O] assay and gas chromatography-mass spectrometry in the parietal cells of the gastric mucosa [125]. It has also been previously reported that aromatase is expressed in epidermal keratinocytes and dermal fibroblasts [126,127]. In situ, hybridization revealed the presence of aromatase in human vascular smooth muscle cells but not in endothelial cells [128]. In men, aromatase is also expressed in the prostate [129]. Although extra-gonadal estrogen is synthesized in small amounts, its concentration is high enough to exert a biological effect locally [29]. Therefore, the disruption of aromatase homeostasis, accompanied by a disturbance in estrogen levels, will result in organ-specific effects.
3.3. Disruption of aromatase homeostasis
Both high and low levels of aromatase, and consequently high and low levels of estrogen, can cause a wide range of diseases and side effects [130]. Aromatase or estrogen excess-driven pathologies include breast, prostate, lung, gastric, and hepatic cancers, polycystic ovary syndrome, endometriosis, obesity, short stature, male hypogonadism, gynecomastia, and testicular hypertrophy [130–132]. Aromatase or estrogen deficiency-induced pathologies include cardiovascular problems [36,133], osteoporosis [36,130], hot flushes [134], vaginal dryness and vaginal atrophy [134], skin aging, thinning and pigmentation [135,136], schizophrenia [130], Alzheimer’s disease [130], depression [137], insomnia [134], neuropathies [36], and elevated aldosterone levels [138,139]. Fig. 4 illustrates the sites of aromatase expression and estrogen disturbance-related effects.
3.4. Regulation of aromatase enzyme
4. Aromatase inhibitors (AIs)
4.1. Discovery of AIs
Historically, oophorectomy and adrenalectomy have been used to treat breast cancer [144]. The anti-epileptic medication, aminoglutethimide, was found to reduce the production of adrenal steroid hormones by blocking cytochrome P450 enzymes [145]. It was then recommended as a potential medical substitute for adrenalectomy for the treatment of breast cancer [146,147]. Later, it was discovered that the key mechanism of aminoglutethimide was the suppression of aromatase enzyme, which subsequently leads to a reduction in estrogen levels[148,149]. Aminoglutethimide was recognized as the first-generation AI [114]. In 1981, the effect of using 4-hydroxy-androstenedione (4-OH-A) against breast cancer in post-menopausal women was reported [150,151]. By the middle of the 1980s, 4-OH-A was named formestane and was recognized as the first selective AI against breast cancer [152]. Formestane is considered as a second-generation AI [114]
Currently used AIs (shown in Fig. 5) are classified into irreversible steroidal inhibitors (exemestane) and reversible non-steroidal inhibitors (anastrozole and letrozole) [153]. These AIs are nominated as third-generation AIs [114]. The third-generation AIs have an advantage over the first and second generations as they are well tolerated and highly selective for the aromatase enzyme [154]. In addition,third-generation AIs outperform first- and second-generation AIs in terms of clinical benefit and near-complete specificity in clinical application [155]. However, long-term adverse effects of these drugs, such as skeletal and cardiovascular problems, must be carefully monitored [155].
4.2. Uses and side effects of AIs
4.3. Controversies regarding the cardiotoxicity of AIs
4.3.1. Meta-analyses showing significant increase of CVD with AIs
4.3.2. Meta-analyses showing non-significant increase of CVD with AIs
4.4. AIs and renal toxicity
5. Extra-gonadal aromatase and cardio-renal protection
A unique feature of extra-gonadally synthesized estrogens is being produced locally in concentrations high enough to exert local biological effects with limited systematic effects [29]. Despite the documented cardioprotective effects of estrogen, the use of estrogen-replacement therapy as a cardioprotective agent is still controversial [16]. This is due to the fact that estrogens have major off-target effects which include increased risks of breast and endometrial cancer, as well as thromboembolisms and strokes [186]. However, evidence suggests that the regulation of aromatase enzyme activity and expression protects against cardiac and vascular damage [187]. The aromatase enzyme was found to be expressed in the coronary endothelium and has an effect on the cardiac function and structural modeling as a result of the localized conversion of androgens to E2 in an acute MI male mouse model [187]. Bayard et al. also demonstrated the activity of aromatase enzyme using female rat arterial smooth muscle cells and bovine coronary endothelial cells in in-vitro models [188,189]. Another research revealed that aromatase activity is demonstrated in human arterial smooth muscle cells and therefore hypothesized that E2 produced in vascular smooth muscle cells regulates cardiac contractility and vascular tone (autocrine activity) while stimulating nitric oxide production and angiogenesis in endothelial cells (paracrine activity) [128]. In order to investigate whether upregulation of cardiac aromatase expression could improve ischemic resilience, Bell et al. conducted a study on hearts from male transgenic aromatase-overexpressing mice (AROM+), using an expression vector for human P-450 aromatase [190]. The male AROM+ mice have lower testosterone and higher E2 levels than wild-type male mice. Interestingly, ischemic contractures are attenuated in AROM+ hearts, suggesting that aromatase regulation modulates cardiac performance after ischemia [190]. Another recent study found that HF is associated with local deficiency of cardiac estrogen and downregulation of aromatase, thus suggesting that restoring the transcript level of cardiac aromatase can protect against HF [191]. Taken together, the above-mentioned information indicates a need for more investigation into the potential role of extra-gonadal aromatization and the importance of restoring cardiac aromatase and enhancing estrogen signaling in conferring cardio-renal protection.
6. Conclusion and future prospects
Aromatase is localized in gonadal and extra-gonadal sites in the human body and plays a pivotal role in estrogen biosynthesis. For instance, it is established now that the brain can synthesize estrogen, and that brain aromatase is crucial for neuroprotection [192]. In this context, we propose that estrogens within the cardiovascular and renal systems may function to provide cardio-renal protection as well. We argue that aromatase has a fundamental effect on cardio-renal protection through increasing the level of estrogen. In other words, aromatase can function as a component of androgen metabolism that directly supplies estrogen to cardiovascular tissues. Future studies are required to properly understand this complex relationship and identify the role of aromatization in preserving cardiovascular and renal health.
