madman
Super Moderator
Aromatase inhibitors in male: A literature review (2022)
Mohsen Korania
Abstract
Aromatase (CYP19A1) is a monooxygenase from the family of cytochrome P450 that plays role in the androgens to estrogens conversion. Aromatase inhibitors prohibit the aromatase enzyme function. This study reviewed the different usages of aromatase inhibitors in the male gender. In this review study, all articles related to the effect of aromatase inhibitors in males were evaluated through databases such as PubMed, Web of Science, Scopus, Science Direct, Google Scholar, and Cochrane Library using the keywords “aromatase inhibitors”, “infertility”, “bone metabolism”, “Breast cancer”, “obesity”, “men” and “male”. Estrogen excess in males shows a correlation with premature closure of the epiphyses. Aromatase inhibitors reduce estrogen by preventing the testosterone to estrogen conversion and have thus been used in patients with short stature or with a delay of puberty. The breast cancer cells show aromatase activity, a probable source of local estrogen for the tumor cells. The inhibition of aromatase suppresses the amounts of serum estrogen and reduces cancer cell proliferation mediated by estrogen in hormone receptor-positive breast cancer. Aromatase inhibitors have also been used in late-onset hypogonadism by lowering the levels of estrogen which are correlated with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and testosterone increase. In obese males, an augmented androgen-to-estrogen conversion happens in the adipose tissue, resulting in raised estrogen levels. Aromatase inhibitors by reducing this conversion lead to a reduction of estrogen and elevation of testosterone and FSH in males with obesity-associated hypogonadotropic hypogonadism. Furthermore, aromatase inhibitor therapy reduced the breast size in males with gynecomastia. They may affect bone metabolism.
Introduction
Aromatase is a member of the cytochrome P450 superfamily, a large family of enzymes that catalyzes the incorporation of oxygen into an organic molecule, titled hydroxylases.1 A single copy of the CYP19A1 gene placed on the short arm of chromosome 15 (15q21) encoding aromatase.2 Numerous tissue-specific promoters under the influence of various hormones and growth factors like gonadotropins, interleukin-6, interleukin-11, and tumor necrosis factor-a regulate the transcription of the aromatase gene.3 Human aromatase is a 58 kDa protein that converts androgens (C19), including testosterone and androstenedione, to estrogens (C18), estradiol, and estrone, in an enzymatic complex with flavoprotein, NADPH-cytochrome P450 reductase.4–6 Aromatase expresses by various cell types such as granulosa cells, neurons, placental cells, preadipocytes and fibroblasts, osteoblasts, Leydig and Sertoli cells, vasculature smooth muscle cells, and chondrocytes.4
Aromatase inhibitors
Aromatase inhibitors are a group of drugs that can stop the construction of estrogens by preventing their conversion from androgens.7 Aminoglutethimide and Testolactone are first-generation aromatase inhibitors. Aminoglutethimide usage for breast cancer was restricted due to many side effects.8 Testolactone is another first-generation aromatase inhibitor that was used for the treatment of progressive breast cancer.9 Formestane was the first selective steroidal inhibitor in the second generation of aromatase inhibitors. Formestane was used as second-line therapy after tamoxifen, it was confirmed to be effective with fewer side effects compared to the first-generation.10 Fadrozole was another second generation and classified as a type 2 inhibitor but due to its rapid clearance and inhibition of aldosterone synthesis in required doses, its use was limited.11,12 The highly selective third-generation aromatase inhibitors were discovered in the 1990s that are including exemestane, anastrozole, and letrozole.7 They were shown to have higher efficacy, specificity, greater potency, and less toxicity than the first and second generations.12,13
Aromatase inhibitors have another classification, steroidal (type 1) and nonsteroidal (type 2). Steroidal aromatase inhibitors such as testolactone, exemestane, and formestane inhibit the activity of aromatase by imitating the substrate androstenedione. They permanently inhibit the aromatase by covalently binding to it. Nonsteroidal aromatase inhibitors, such as aminoglutethimide, anastrozole, fadrozole, vorozole, and letrozole inhibit aromatase activity by binding to the heme iron of the aromatase, leading to competitive inhibition.14
Estradiol has a significant role in gonadotropin secretion, maintaining bone mass, and closing of the epiphyses. The extra estrogen is associated with low gonadotropin and testosterone levels and premature closure of the epiphyses and gynecomastia.15 Therefore, decreasing the levels of estrogen in males has been used as a possible treatment for disorders such as hypogonadism, and gynecomastia. Aromatase is responsible for the conversion of androgens to estrogens. Aromatase inhibitors were defined to be safe and effective for the treatment of hormone-sensitive breast cancer in men and women as well as for other disorders. This review will discuss the different usages of aromatase inhibitors in the male gender.
Aromatase inhibitors for male infertility
In adult men, neurons in the preoptic region and the medial basal area of the hypothalamus are responsible for the secretion of gonadotropin-releasing hormone (GnRH), which regulates the secretion pattern of the gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) from the anterior pituitary gland. FSH regulates spermatogenesis via Sertoli cells in the testis while LH produces testosterone by acting on the Leydig cells in the testis. Estradiol is mainly produced through the aromatization of testosterone with the Leydig cells with a contribution of the aromatase enzyme.14,23 Testosterone and estradiol act on the anterior pituitary and the hypothalamus through a negative feedback mechanism. It was shown that estradiol signaling through the hypothalamic-pituitary-gonadal (HPG) axis plays a significant role in regulating GnRH and gonadotropin secretion in males. The hypothalamus and pituitary gland have many estradiol receptors besides testosterone receptors. Aromatase inhibitors decrease the levels of estradiol, which counteract the estradiol’s negative feedback mechanism at the pituitary gland level and consequently increase the levels of gonadotrophins, LH, and FSH, and result in a rise in serum testosterone.24,25
Effect of aromatase inhibition on bone metabolism in Elderly Male
Aging in males is accompanied by loss of bone mass and weakened physical function.26 Estrogens and androgens play significant roles in skeletal development and maintenance in males. Recent data recommended that a threshold level of bioavailable estradiol is required to avoid bone loss, and with aging, in a large number of elderly men, the levels fall below this threshold.27 Aromatase inhibitors reduce estrogen production and raise androgen production in males.28
The effect of aromatase inhibitors in obese males
Adipose tissue is the main estrogen-producing nongonadal tissue. In the adipocyte differentiation process, PPARγ regulates the aromatase expression. During obesity, the rise of pro-inflammatory factors in adipocytes caused by obesity will result in greater transcription of the CYP19 gene encoding aromatase in adipocytes, which in turn results in augmented expression of aromatase in adipocytes.30
In obese males, the amplified expression of the aromatase enzyme in the adipose tissue results in a great conversion of androgens to estrogens which leads to hypogonadotropic hypogonadism.31
Aromatase inhibitor and male breast cancer
Male breast cancer is a scarce incidence. Treatment of male breast cancer is normally inferred from data on the treatment of female breast cancer. Now, first-line use of aromatase inhibitors is a standard strategy in hormone-sensitive metastatic breast cancer in females.36 Aromatase inhibitors are widely used for treating metastatic male breast cancer patients.37
The effects of aromatase inhibitors on short stature in males
In males besides females, estrogen is a critical regulator of the maturation of bone, growth plate fusion, and longitudinal growth cessation. Thus, a rise in predicted adult height (PAH) may be attained in short boys by blocking estrogen biosynthesis.43
Use of aromatase inhibitors as treatment for gynecomastia
Gynecomastia may occur in boys during puberty and in adult males. The main cause of the development of gynecomastia is an imbalance of estrogen to androgen levels. Therefore, most of the treatments have been based on lowering the estrogen level.49
Conclusion
Aromatase, an estrogen synthetase, is the main enzyme in the biosynthesis of estrogen. Estradiol has an essential role in bone mass gaining, gonadotrophin secretion, and closing of the epiphyses. Estrogen increase has been correlated with premature closure of the epiphyses, low levels of gonadotrophin and testosterone, and gynecomastia. Therefore, lowering estrogen levels in males using aromatase inhibitors can be a potential treatment for related disorders. In this study, we assessed the effectiveness of the use of aromatase inhibitors in some male disorders. The study revealed that aromatase inhibitors are effective in the treatment of male infertility by rising the testosterone-to-estradiol ratio accompanied by enhancing the semen parameters. It was determined that aromatase inhibitors can normalize the serum testosterone levels in obese males with obesity-related hypogonadotropic hypogonadism. Aromatase inhibitors are suggested as an effective treatment strategy for hormone receptor-positive metastatic male breast cancer. They were shown to be effective in the treatment of short stature in boys as well. Moreover, aromatase inhibitor therapy reduced the breast size in males with gynecomastia. They may affect bone metabolism.
Mohsen Korania
Abstract
Aromatase (CYP19A1) is a monooxygenase from the family of cytochrome P450 that plays role in the androgens to estrogens conversion. Aromatase inhibitors prohibit the aromatase enzyme function. This study reviewed the different usages of aromatase inhibitors in the male gender. In this review study, all articles related to the effect of aromatase inhibitors in males were evaluated through databases such as PubMed, Web of Science, Scopus, Science Direct, Google Scholar, and Cochrane Library using the keywords “aromatase inhibitors”, “infertility”, “bone metabolism”, “Breast cancer”, “obesity”, “men” and “male”. Estrogen excess in males shows a correlation with premature closure of the epiphyses. Aromatase inhibitors reduce estrogen by preventing the testosterone to estrogen conversion and have thus been used in patients with short stature or with a delay of puberty. The breast cancer cells show aromatase activity, a probable source of local estrogen for the tumor cells. The inhibition of aromatase suppresses the amounts of serum estrogen and reduces cancer cell proliferation mediated by estrogen in hormone receptor-positive breast cancer. Aromatase inhibitors have also been used in late-onset hypogonadism by lowering the levels of estrogen which are correlated with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and testosterone increase. In obese males, an augmented androgen-to-estrogen conversion happens in the adipose tissue, resulting in raised estrogen levels. Aromatase inhibitors by reducing this conversion lead to a reduction of estrogen and elevation of testosterone and FSH in males with obesity-associated hypogonadotropic hypogonadism. Furthermore, aromatase inhibitor therapy reduced the breast size in males with gynecomastia. They may affect bone metabolism.
Introduction
Aromatase is a member of the cytochrome P450 superfamily, a large family of enzymes that catalyzes the incorporation of oxygen into an organic molecule, titled hydroxylases.1 A single copy of the CYP19A1 gene placed on the short arm of chromosome 15 (15q21) encoding aromatase.2 Numerous tissue-specific promoters under the influence of various hormones and growth factors like gonadotropins, interleukin-6, interleukin-11, and tumor necrosis factor-a regulate the transcription of the aromatase gene.3 Human aromatase is a 58 kDa protein that converts androgens (C19), including testosterone and androstenedione, to estrogens (C18), estradiol, and estrone, in an enzymatic complex with flavoprotein, NADPH-cytochrome P450 reductase.4–6 Aromatase expresses by various cell types such as granulosa cells, neurons, placental cells, preadipocytes and fibroblasts, osteoblasts, Leydig and Sertoli cells, vasculature smooth muscle cells, and chondrocytes.4
Aromatase inhibitors
Aromatase inhibitors are a group of drugs that can stop the construction of estrogens by preventing their conversion from androgens.7 Aminoglutethimide and Testolactone are first-generation aromatase inhibitors. Aminoglutethimide usage for breast cancer was restricted due to many side effects.8 Testolactone is another first-generation aromatase inhibitor that was used for the treatment of progressive breast cancer.9 Formestane was the first selective steroidal inhibitor in the second generation of aromatase inhibitors. Formestane was used as second-line therapy after tamoxifen, it was confirmed to be effective with fewer side effects compared to the first-generation.10 Fadrozole was another second generation and classified as a type 2 inhibitor but due to its rapid clearance and inhibition of aldosterone synthesis in required doses, its use was limited.11,12 The highly selective third-generation aromatase inhibitors were discovered in the 1990s that are including exemestane, anastrozole, and letrozole.7 They were shown to have higher efficacy, specificity, greater potency, and less toxicity than the first and second generations.12,13
Aromatase inhibitors have another classification, steroidal (type 1) and nonsteroidal (type 2). Steroidal aromatase inhibitors such as testolactone, exemestane, and formestane inhibit the activity of aromatase by imitating the substrate androstenedione. They permanently inhibit the aromatase by covalently binding to it. Nonsteroidal aromatase inhibitors, such as aminoglutethimide, anastrozole, fadrozole, vorozole, and letrozole inhibit aromatase activity by binding to the heme iron of the aromatase, leading to competitive inhibition.14
Estradiol has a significant role in gonadotropin secretion, maintaining bone mass, and closing of the epiphyses. The extra estrogen is associated with low gonadotropin and testosterone levels and premature closure of the epiphyses and gynecomastia.15 Therefore, decreasing the levels of estrogen in males has been used as a possible treatment for disorders such as hypogonadism, and gynecomastia. Aromatase is responsible for the conversion of androgens to estrogens. Aromatase inhibitors were defined to be safe and effective for the treatment of hormone-sensitive breast cancer in men and women as well as for other disorders. This review will discuss the different usages of aromatase inhibitors in the male gender.
Aromatase inhibitors for male infertility
In adult men, neurons in the preoptic region and the medial basal area of the hypothalamus are responsible for the secretion of gonadotropin-releasing hormone (GnRH), which regulates the secretion pattern of the gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) from the anterior pituitary gland. FSH regulates spermatogenesis via Sertoli cells in the testis while LH produces testosterone by acting on the Leydig cells in the testis. Estradiol is mainly produced through the aromatization of testosterone with the Leydig cells with a contribution of the aromatase enzyme.14,23 Testosterone and estradiol act on the anterior pituitary and the hypothalamus through a negative feedback mechanism. It was shown that estradiol signaling through the hypothalamic-pituitary-gonadal (HPG) axis plays a significant role in regulating GnRH and gonadotropin secretion in males. The hypothalamus and pituitary gland have many estradiol receptors besides testosterone receptors. Aromatase inhibitors decrease the levels of estradiol, which counteract the estradiol’s negative feedback mechanism at the pituitary gland level and consequently increase the levels of gonadotrophins, LH, and FSH, and result in a rise in serum testosterone.24,25
Effect of aromatase inhibition on bone metabolism in Elderly Male
Aging in males is accompanied by loss of bone mass and weakened physical function.26 Estrogens and androgens play significant roles in skeletal development and maintenance in males. Recent data recommended that a threshold level of bioavailable estradiol is required to avoid bone loss, and with aging, in a large number of elderly men, the levels fall below this threshold.27 Aromatase inhibitors reduce estrogen production and raise androgen production in males.28
The effect of aromatase inhibitors in obese males
Adipose tissue is the main estrogen-producing nongonadal tissue. In the adipocyte differentiation process, PPARγ regulates the aromatase expression. During obesity, the rise of pro-inflammatory factors in adipocytes caused by obesity will result in greater transcription of the CYP19 gene encoding aromatase in adipocytes, which in turn results in augmented expression of aromatase in adipocytes.30
In obese males, the amplified expression of the aromatase enzyme in the adipose tissue results in a great conversion of androgens to estrogens which leads to hypogonadotropic hypogonadism.31
Aromatase inhibitor and male breast cancer
Male breast cancer is a scarce incidence. Treatment of male breast cancer is normally inferred from data on the treatment of female breast cancer. Now, first-line use of aromatase inhibitors is a standard strategy in hormone-sensitive metastatic breast cancer in females.36 Aromatase inhibitors are widely used for treating metastatic male breast cancer patients.37
The effects of aromatase inhibitors on short stature in males
In males besides females, estrogen is a critical regulator of the maturation of bone, growth plate fusion, and longitudinal growth cessation. Thus, a rise in predicted adult height (PAH) may be attained in short boys by blocking estrogen biosynthesis.43
Use of aromatase inhibitors as treatment for gynecomastia
Gynecomastia may occur in boys during puberty and in adult males. The main cause of the development of gynecomastia is an imbalance of estrogen to androgen levels. Therefore, most of the treatments have been based on lowering the estrogen level.49
Conclusion
Aromatase, an estrogen synthetase, is the main enzyme in the biosynthesis of estrogen. Estradiol has an essential role in bone mass gaining, gonadotrophin secretion, and closing of the epiphyses. Estrogen increase has been correlated with premature closure of the epiphyses, low levels of gonadotrophin and testosterone, and gynecomastia. Therefore, lowering estrogen levels in males using aromatase inhibitors can be a potential treatment for related disorders. In this study, we assessed the effectiveness of the use of aromatase inhibitors in some male disorders. The study revealed that aromatase inhibitors are effective in the treatment of male infertility by rising the testosterone-to-estradiol ratio accompanied by enhancing the semen parameters. It was determined that aromatase inhibitors can normalize the serum testosterone levels in obese males with obesity-related hypogonadotropic hypogonadism. Aromatase inhibitors are suggested as an effective treatment strategy for hormone receptor-positive metastatic male breast cancer. They were shown to be effective in the treatment of short stature in boys as well. Moreover, aromatase inhibitor therapy reduced the breast size in males with gynecomastia. They may affect bone metabolism.
