madman
Super Moderator
Androgen Sensitivity: Beyond the Well-Known
© Irina A. Khripun*, Sergey V. Vorobyev
Rostov State Medical University, Rostov-on-Don, Russia
The gonadal and extragonadal effects of testosterone in men have been actively studied in recent years. To date there is no doubt an increased risk of obesity, type 2 diabetes mellitus, hypertension, and atherosclerosis in men with testosterone deficiency. One of the mechanisms by which the action of testosterone is realized is sensitivity to androgens, determined by the length of CAG repeats in the androgen receptor gene. An increase in the number of CAG repeats reduces their activity and is manifested by low sensitivity to testosterone. In contrast, a decrease in the number of trinucleotide repeats is accompanied by an increase in the sensitivity of receptors to androgens. This review reviews data on the effect of androgen receptor gene polymorphism on embryogenesis and differentiation of sex, regulation of spermatogenesis, the progression of cancer and benign prostatic hyperplasia, symptoms of hypogonadism, control of carbohydrate and lipid metabolism, mineral density bone tissue, vascular endothelium, response to testosterone replacement therapy, as well as the psychosocial aspects of male personality. The introduction of the study of androgen receptor gene polymorphism into clinical practice will allow not only to predict male fertility or the risk of prostate cancer but also to select an individual testosterone deficiency therapy.
The action of androgens affects almost everything organs and systems. The formation of sexual characteristics in the process of embryogenesis, the formation and functioning of the reproductive system, and the provision of fertility are only a small part of the effects of testosterone (T) and its metabolites. The extragonadal action of androgens represented by them is a much wider effect on the cardiovascular system, lipid and carbohydrate metabolism, bone mineralization tissue, stimulation of blood formation, formation and functioning of cognitive functions, psychosocial adaptation, and sexuality. One of the most important issues of clinical practice is a different severity of symptoms of hypogonadism, as well as a different response to substitution therapy in patients with the same level of serum T. The answer to this question lies in determining the sensitivity to androgens and is on today, is extremely little studied. The review contains an analysis of the most relevant studies published in peer-reviewed journals of the PubMed and eLibrary databases.
The structure and function of the androgen receptor
The multifaceted action of T is realized through androgen receptors (AR) located intracellularly and structurally related to receptor steroid hormones. ARs are present in the cells of the testes, prostate, skin, nervous system, and other tissues. Genetic activity control of these receptors is carried by the AR gene, which and determines the sensitivity to androgens and the implementation of the action of T. The breadth and versatility effects realized through the AR gene are impressive - from sex differentiation in embryogenesis, regulation of spermatogenesis, cancer progression and benign prostatic hyperplasia (BPH), symptoms of hypogonadism before exposure, carbohydrate and lipid metabolism, mineral bone density, vascular endothelium and even psychosocial aspects of personality.
The AR gene is localized on the long arm of the X chromosome and consists of 8 exons encoding 3 structurally functional protein domains. The N-terminal domain is involved in the homodimerization of the receptor and
binding to co-activators or co-repressors and is represented by exon 1. The second - DNA-binding domain contains a loop region of two “Zinc fingers” (exons 2 and 3). The C-terminal domain provides binding to steroid hormones and is represented by exons 4–8 [1].
In recent years, researchers have especially focused on the study of the first exon AR gene, which is characterized by repeats of the sequence of three nucleotides - cytosine, adenine, and guanine - CAG. The CAG triplet encodes the amino acid glutamine, therefore, the amount of glutamine in the protein depends on the number of trinucleotide repeats. So, a smaller number of CAG repeats correspond to a lower degree of conformational changes in the receptor, which makes the connection of the hormone and receptor stronger and leads to an increase in the transcriptional activity of AR. In contrast, with an increase in the number of CAG repeats, the relationship between androgens and the receptor becoming weaker and transcriptional activity AR is decreasing.
For men of the European population, the number of CAG repeats from 9 to 37 is considered normal. However, there are population differences in this standard. So, the average number of CAG repeats per the AR gene for Europeans is 21, for Africans - 17, for Asians - 23. At the same time, for example 25 CAG repeats though fit into normative values often associated with weakening the action of androgens, manifested by the corresponding clinical symptoms [8].
Embryogenesis and sex differentiation
Cell cascade of normal differentiation in the male is also modeled by the molecular interaction of T and dihydrotestosterone (DHT) with AR in androgen-dependent target tissues. The correct formation of the male depends on this interaction as early as the 7-8th week of embryogenesis gender. The most striking example of the involvement of AR in sex formation is testicular syndrome feminization resulting from mutations AR gene with the development of insensitivity to androgens [1]. In the embryo with genotype 46, XY, when the effects of T and DHT occur, bipotential bookmarks internal and external genitalia develop along the base path with the formation of a female phenotype. Such patients in the post-pubertal period often have well-developed mammary glands and a female-type distribution of adipose tissue, which is associated with aromatization of androgens synthesized in the testes into estrogens.
Prostate
One of the most androgen-sensitive organs is the prostate, which has a large number of androgen receptors. It is assumed that the AR gene polymorphism with its ability to model the effects of androgens affects the proportion of malignant cells in the prostate gland [9]. According to a meta-analysis of many studies [10], the ratio of the chances of pancreatic cancer with a decrease in the frequency of trinucleotide repeats is 1.19.
A possible link between BPH and CAG polymorphism of the AR gene also has another aspect: BPH is an overgrowth of transitional tissue zones and periurethral areas of the pancreas (epithelial and fibromuscular hyperplasia). In 2 large studies compared comparable cohorts healthy volunteers and patients with BPH. The ratio of the chances of enlarging the prostate to necessary surgical intervention in the group with a CAG repeat frequency of <20 and >24 was 1.92. Moreover, with a decrease in the length of CAG repeats, the frequency of medium and heavy obstructive symptoms of the lower urinary tract. An inverse correlation was also found between the frequency of adenomas and the size of the prostate, on the one hand, and the length of CAG repeats, on the other [11, 12]. In addition, a polymorphism relationship was identified MA of the AR gene with sexual activity in men with BPH [13].
Fertility
The relationship between the number of CAG repeats in the AR gene was established with oligozoospermia [14, 15]. It is well known that spermatogenesis requires stimulation of Sertoli cells by follicle-stimulating hormone (FSH). So, the intratesticular activity of androgens is mediated by an important cofactor, positively affecting Sertoli cell function. A negative relationship between the number of CAG repeats and the effectiveness of spermatogenesis has been established [16]. The most severe forms of spermatogenesis disorders are observed in patients with spinobulbar Kennedy atrophy - a rare hereditary disease characterized by vivid neurological symptoms combined with hypogonadism and infertility. The number of trinucleotide repeats in the AR gene reaches 36 or more [17].
Clinical manifestations of hypogonadism and psychosocial aspects of personality
Analyzing the clinical manifestations of androgen deficiency, we must emphasize their close relationship with AR gene polymorphism. So, among patients with normal T concentrations in men with a large number of CAG repeats increased the risk of developing symptoms of androgen deficiency [18, 19]. A regression analysis of the data from the international Aging Males ’Symptoms questionnaire revealed an increase in symptoms of T deficiency on two scales (psychological and somatic) as the length of CAG repeats in the AR gene increases, while symptoms of sexual scales were directly related to the level of endogenous T [18]. An Asian study of 702 men with no association between T level and distribution of AR gene polymorphism in a population, showed that at a T level above 340 ng/dl, patients with a CAG repeat count of more than 25 had a significantly higher risk of developing andropause symptoms than individuals with a trinucleotide repeat value of less than 22 [19]. In other words, men with long-term normotestosterone CAG repeats in the AR gene are at higher risk for androgen symptoms deficit. In addition, a connection between the length CAG repeats in the AR gene with non-specific manifestations of androgen deficiency, such as anxiety and depression [20, 21]. Regression analysis revealed a positive relationship between the number of CAG repeats and the severity of depression in men older than 50 years. This demonstrates an increase in symptoms of depression in sync with the increase in the length of trinucleotide repeats as the receptors weaken for androgens, regardless of the level of endogenous T [21]. It has also been shown that genetically determined lengthening of CAG repeats in the AR gene is an independent risk factor for high anxiety, panic attacks, and phobic disorders [20].
Surprising seems the data on the relationship of AR gene polymorphism with intellectual giftedness boys [22]. Thus, it was found that a high level of intelligence (IQ over 130) in boys is associated with a short length of CAG repeats in the AR gene, even at pre-tuberculously low levels of T. In other words, high sensitivity to androgens is a factor predisposing to intellectual giftedness regardless of the level of T.
Of interest are data on polymorphism. AR gene in men with Klinefelter syndrome, having an additional X chromosome, on which the discussed gene is located [23]. The length of trinucleotide repeats had a positive relationship with growth, but at the same time was negatively associated with mineral bone density and the ratio of the span of the hands to growth, which reflects the negative effect of androgens on epiphyseal areas of bone growth. In addition, elongation of CAG repeats contributed to the development of gynecomastia and a decrease in testicle size, while shortening the triplet length was associated with stable partner relationships and professions requiring more high level of education.
It is amazing that sensitivity to androgens can cause a phenomenon such as transsexualism. Chain elongation found CAG repeats in the AR gene are one of three studied genetic causes of male transsexualism [24].
Metabolic status
The number of CAG repeats in the AR gene with the content body adipose tissue, leptin, and insulin levels. A small number of CAG repeats were independently associated with protective parameters (low-fat mass, low plasma insulin levels), but also with undesirable factors (low level of high-density lipoproteins) [25]. Similar data for dyslipidemia were obtained in a study of sugar patients type 2 diabetes [26].
Another interesting aspect of influence AR gene polymorphism is the effectiveness of testosterone replacement therapy (STT) in patients with various forms of hypogonadism. A large TIMES 2 study found that high sensitivity to androgens, modeled by a small number of CAG repeats in the AR gene, independently positively associated with more significant dynamics fasting insulin levels, triglycerides, diastolic blood pressure, and the NOMA insulin resistance index in the presence of STT. However no association of the AR gene polymorphism with the level of glycated hemoglobin, other indicators of lipid profile, obesity, or distribution of adipose tissue was detected [10]. Negative influence elongation of CAG repeats was also found in another study [27], which showed higher blood pressure numbers and worst values lipid patterns on the background of CTT in combination with more low hematocrit located under the control of androgens. Another parameter responsive to STT is the size of the pancreas [28]. A negative relationship between the length of trinucleotide repeats and the change in the volume of the pancreas on the background T therapy [10]. Moreover, 20 triplets of the AR gene and less increase the risk of increasing pancreatic size and the growth rate of the level of prostate-specific antigen(PSA) [27].
Therapy T in patients with Klinefelter syndrome with short triplet repetitions causes a deeper suppression of LH level, expressed an increase in PSA concentration, and increases hemoglobin level [23].
Endothelium
One of the most important points of the application of the extrapulmonary action of T is the endothelium, and this interaction is modeled by polymorphism gene AR. This question is least studied. Healthy volunteers have previously been found to have a low number of CAG repeats in the AR gene with impaired arterial vasoreactivity, regardless of the level of total and free T [29]. Some studies [30, 31] have shown a deterioration in endothelial function in patients with type 2 diabetes. At that however, there is evidence of negative effects deficiency of T on the cardiovascular system in men [32, 33]. In the study of the effect of AR gene polymorphism on the formation of endothelial dysfunction in men with type 2 diabetes type [34] it was found that a larger number CAG repeats in the AR receptor gene through attenuation sensitivity to androgens leads to a decrease in the severity of endothelium-dependent vasodilation during a test with reactive hyperemia simultaneously with an increase in the production of such markers endothelial dysfunctions like P-selectin and resistin. Thus, an increase in the number of CAG repeats in AR gene impairs both the vasomotor and secretory function of the endothelium and can be considered as a predictor of development and progression of cardiovascular lesions in men with diabetes.
Conclusion
The increasing interest of researchers in the study of biochemical and molecular mechanisms of T action dictates the need to decipher the genetic aspects of the functioning of AR. The study of sensitivity to androgens, determined by the length of the trinucleotide repeat CAG in the gene AR, not only explains the phenomenon of a different response to STT in patients with the same level of endogenous T but also is necessary for understanding sexual differentiation, psychological status, sexuality, and reproductive potential, as well as the risks of developing pancreatic cancer and BPH, osteoporosis, disorders of carbohydrate, lipid metabolism and even cardiovascular disease in men. The most important in clinical practice is the ability to predict the patient's response to the STT. In individuals with a low number of CAG repeats in the gene AR due to its high sensitivity to androgens lower doses of T drugs may be used, whereas starting dose inefficiency TRT in men with a large number of trinucleotide repetitions, indicates the need to increase the dose of T. Determination of the CAG polymorphism of the AR gene is not recommended for routine practice, but in the near future it can be used in particular for the selection of individual therapy for androgen deficiency.
© Irina A. Khripun*, Sergey V. Vorobyev
Rostov State Medical University, Rostov-on-Don, Russia
The gonadal and extragonadal effects of testosterone in men have been actively studied in recent years. To date there is no doubt an increased risk of obesity, type 2 diabetes mellitus, hypertension, and atherosclerosis in men with testosterone deficiency. One of the mechanisms by which the action of testosterone is realized is sensitivity to androgens, determined by the length of CAG repeats in the androgen receptor gene. An increase in the number of CAG repeats reduces their activity and is manifested by low sensitivity to testosterone. In contrast, a decrease in the number of trinucleotide repeats is accompanied by an increase in the sensitivity of receptors to androgens. This review reviews data on the effect of androgen receptor gene polymorphism on embryogenesis and differentiation of sex, regulation of spermatogenesis, the progression of cancer and benign prostatic hyperplasia, symptoms of hypogonadism, control of carbohydrate and lipid metabolism, mineral density bone tissue, vascular endothelium, response to testosterone replacement therapy, as well as the psychosocial aspects of male personality. The introduction of the study of androgen receptor gene polymorphism into clinical practice will allow not only to predict male fertility or the risk of prostate cancer but also to select an individual testosterone deficiency therapy.
The action of androgens affects almost everything organs and systems. The formation of sexual characteristics in the process of embryogenesis, the formation and functioning of the reproductive system, and the provision of fertility are only a small part of the effects of testosterone (T) and its metabolites. The extragonadal action of androgens represented by them is a much wider effect on the cardiovascular system, lipid and carbohydrate metabolism, bone mineralization tissue, stimulation of blood formation, formation and functioning of cognitive functions, psychosocial adaptation, and sexuality. One of the most important issues of clinical practice is a different severity of symptoms of hypogonadism, as well as a different response to substitution therapy in patients with the same level of serum T. The answer to this question lies in determining the sensitivity to androgens and is on today, is extremely little studied. The review contains an analysis of the most relevant studies published in peer-reviewed journals of the PubMed and eLibrary databases.
The structure and function of the androgen receptor
The multifaceted action of T is realized through androgen receptors (AR) located intracellularly and structurally related to receptor steroid hormones. ARs are present in the cells of the testes, prostate, skin, nervous system, and other tissues. Genetic activity control of these receptors is carried by the AR gene, which and determines the sensitivity to androgens and the implementation of the action of T. The breadth and versatility effects realized through the AR gene are impressive - from sex differentiation in embryogenesis, regulation of spermatogenesis, cancer progression and benign prostatic hyperplasia (BPH), symptoms of hypogonadism before exposure, carbohydrate and lipid metabolism, mineral bone density, vascular endothelium and even psychosocial aspects of personality.
The AR gene is localized on the long arm of the X chromosome and consists of 8 exons encoding 3 structurally functional protein domains. The N-terminal domain is involved in the homodimerization of the receptor and
binding to co-activators or co-repressors and is represented by exon 1. The second - DNA-binding domain contains a loop region of two “Zinc fingers” (exons 2 and 3). The C-terminal domain provides binding to steroid hormones and is represented by exons 4–8 [1].
In recent years, researchers have especially focused on the study of the first exon AR gene, which is characterized by repeats of the sequence of three nucleotides - cytosine, adenine, and guanine - CAG. The CAG triplet encodes the amino acid glutamine, therefore, the amount of glutamine in the protein depends on the number of trinucleotide repeats. So, a smaller number of CAG repeats correspond to a lower degree of conformational changes in the receptor, which makes the connection of the hormone and receptor stronger and leads to an increase in the transcriptional activity of AR. In contrast, with an increase in the number of CAG repeats, the relationship between androgens and the receptor becoming weaker and transcriptional activity AR is decreasing.
For men of the European population, the number of CAG repeats from 9 to 37 is considered normal. However, there are population differences in this standard. So, the average number of CAG repeats per the AR gene for Europeans is 21, for Africans - 17, for Asians - 23. At the same time, for example 25 CAG repeats though fit into normative values often associated with weakening the action of androgens, manifested by the corresponding clinical symptoms [8].
Embryogenesis and sex differentiation
Cell cascade of normal differentiation in the male is also modeled by the molecular interaction of T and dihydrotestosterone (DHT) with AR in androgen-dependent target tissues. The correct formation of the male depends on this interaction as early as the 7-8th week of embryogenesis gender. The most striking example of the involvement of AR in sex formation is testicular syndrome feminization resulting from mutations AR gene with the development of insensitivity to androgens [1]. In the embryo with genotype 46, XY, when the effects of T and DHT occur, bipotential bookmarks internal and external genitalia develop along the base path with the formation of a female phenotype. Such patients in the post-pubertal period often have well-developed mammary glands and a female-type distribution of adipose tissue, which is associated with aromatization of androgens synthesized in the testes into estrogens.
Prostate
One of the most androgen-sensitive organs is the prostate, which has a large number of androgen receptors. It is assumed that the AR gene polymorphism with its ability to model the effects of androgens affects the proportion of malignant cells in the prostate gland [9]. According to a meta-analysis of many studies [10], the ratio of the chances of pancreatic cancer with a decrease in the frequency of trinucleotide repeats is 1.19.
A possible link between BPH and CAG polymorphism of the AR gene also has another aspect: BPH is an overgrowth of transitional tissue zones and periurethral areas of the pancreas (epithelial and fibromuscular hyperplasia). In 2 large studies compared comparable cohorts healthy volunteers and patients with BPH. The ratio of the chances of enlarging the prostate to necessary surgical intervention in the group with a CAG repeat frequency of <20 and >24 was 1.92. Moreover, with a decrease in the length of CAG repeats, the frequency of medium and heavy obstructive symptoms of the lower urinary tract. An inverse correlation was also found between the frequency of adenomas and the size of the prostate, on the one hand, and the length of CAG repeats, on the other [11, 12]. In addition, a polymorphism relationship was identified MA of the AR gene with sexual activity in men with BPH [13].
Fertility
The relationship between the number of CAG repeats in the AR gene was established with oligozoospermia [14, 15]. It is well known that spermatogenesis requires stimulation of Sertoli cells by follicle-stimulating hormone (FSH). So, the intratesticular activity of androgens is mediated by an important cofactor, positively affecting Sertoli cell function. A negative relationship between the number of CAG repeats and the effectiveness of spermatogenesis has been established [16]. The most severe forms of spermatogenesis disorders are observed in patients with spinobulbar Kennedy atrophy - a rare hereditary disease characterized by vivid neurological symptoms combined with hypogonadism and infertility. The number of trinucleotide repeats in the AR gene reaches 36 or more [17].
Clinical manifestations of hypogonadism and psychosocial aspects of personality
Analyzing the clinical manifestations of androgen deficiency, we must emphasize their close relationship with AR gene polymorphism. So, among patients with normal T concentrations in men with a large number of CAG repeats increased the risk of developing symptoms of androgen deficiency [18, 19]. A regression analysis of the data from the international Aging Males ’Symptoms questionnaire revealed an increase in symptoms of T deficiency on two scales (psychological and somatic) as the length of CAG repeats in the AR gene increases, while symptoms of sexual scales were directly related to the level of endogenous T [18]. An Asian study of 702 men with no association between T level and distribution of AR gene polymorphism in a population, showed that at a T level above 340 ng/dl, patients with a CAG repeat count of more than 25 had a significantly higher risk of developing andropause symptoms than individuals with a trinucleotide repeat value of less than 22 [19]. In other words, men with long-term normotestosterone CAG repeats in the AR gene are at higher risk for androgen symptoms deficit. In addition, a connection between the length CAG repeats in the AR gene with non-specific manifestations of androgen deficiency, such as anxiety and depression [20, 21]. Regression analysis revealed a positive relationship between the number of CAG repeats and the severity of depression in men older than 50 years. This demonstrates an increase in symptoms of depression in sync with the increase in the length of trinucleotide repeats as the receptors weaken for androgens, regardless of the level of endogenous T [21]. It has also been shown that genetically determined lengthening of CAG repeats in the AR gene is an independent risk factor for high anxiety, panic attacks, and phobic disorders [20].
Surprising seems the data on the relationship of AR gene polymorphism with intellectual giftedness boys [22]. Thus, it was found that a high level of intelligence (IQ over 130) in boys is associated with a short length of CAG repeats in the AR gene, even at pre-tuberculously low levels of T. In other words, high sensitivity to androgens is a factor predisposing to intellectual giftedness regardless of the level of T.
Of interest are data on polymorphism. AR gene in men with Klinefelter syndrome, having an additional X chromosome, on which the discussed gene is located [23]. The length of trinucleotide repeats had a positive relationship with growth, but at the same time was negatively associated with mineral bone density and the ratio of the span of the hands to growth, which reflects the negative effect of androgens on epiphyseal areas of bone growth. In addition, elongation of CAG repeats contributed to the development of gynecomastia and a decrease in testicle size, while shortening the triplet length was associated with stable partner relationships and professions requiring more high level of education.
It is amazing that sensitivity to androgens can cause a phenomenon such as transsexualism. Chain elongation found CAG repeats in the AR gene are one of three studied genetic causes of male transsexualism [24].
Metabolic status
The number of CAG repeats in the AR gene with the content body adipose tissue, leptin, and insulin levels. A small number of CAG repeats were independently associated with protective parameters (low-fat mass, low plasma insulin levels), but also with undesirable factors (low level of high-density lipoproteins) [25]. Similar data for dyslipidemia were obtained in a study of sugar patients type 2 diabetes [26].
Another interesting aspect of influence AR gene polymorphism is the effectiveness of testosterone replacement therapy (STT) in patients with various forms of hypogonadism. A large TIMES 2 study found that high sensitivity to androgens, modeled by a small number of CAG repeats in the AR gene, independently positively associated with more significant dynamics fasting insulin levels, triglycerides, diastolic blood pressure, and the NOMA insulin resistance index in the presence of STT. However no association of the AR gene polymorphism with the level of glycated hemoglobin, other indicators of lipid profile, obesity, or distribution of adipose tissue was detected [10]. Negative influence elongation of CAG repeats was also found in another study [27], which showed higher blood pressure numbers and worst values lipid patterns on the background of CTT in combination with more low hematocrit located under the control of androgens. Another parameter responsive to STT is the size of the pancreas [28]. A negative relationship between the length of trinucleotide repeats and the change in the volume of the pancreas on the background T therapy [10]. Moreover, 20 triplets of the AR gene and less increase the risk of increasing pancreatic size and the growth rate of the level of prostate-specific antigen(PSA) [27].
Therapy T in patients with Klinefelter syndrome with short triplet repetitions causes a deeper suppression of LH level, expressed an increase in PSA concentration, and increases hemoglobin level [23].
Endothelium
One of the most important points of the application of the extrapulmonary action of T is the endothelium, and this interaction is modeled by polymorphism gene AR. This question is least studied. Healthy volunteers have previously been found to have a low number of CAG repeats in the AR gene with impaired arterial vasoreactivity, regardless of the level of total and free T [29]. Some studies [30, 31] have shown a deterioration in endothelial function in patients with type 2 diabetes. At that however, there is evidence of negative effects deficiency of T on the cardiovascular system in men [32, 33]. In the study of the effect of AR gene polymorphism on the formation of endothelial dysfunction in men with type 2 diabetes type [34] it was found that a larger number CAG repeats in the AR receptor gene through attenuation sensitivity to androgens leads to a decrease in the severity of endothelium-dependent vasodilation during a test with reactive hyperemia simultaneously with an increase in the production of such markers endothelial dysfunctions like P-selectin and resistin. Thus, an increase in the number of CAG repeats in AR gene impairs both the vasomotor and secretory function of the endothelium and can be considered as a predictor of development and progression of cardiovascular lesions in men with diabetes.
Conclusion
The increasing interest of researchers in the study of biochemical and molecular mechanisms of T action dictates the need to decipher the genetic aspects of the functioning of AR. The study of sensitivity to androgens, determined by the length of the trinucleotide repeat CAG in the gene AR, not only explains the phenomenon of a different response to STT in patients with the same level of endogenous T but also is necessary for understanding sexual differentiation, psychological status, sexuality, and reproductive potential, as well as the risks of developing pancreatic cancer and BPH, osteoporosis, disorders of carbohydrate, lipid metabolism and even cardiovascular disease in men. The most important in clinical practice is the ability to predict the patient's response to the STT. In individuals with a low number of CAG repeats in the gene AR due to its high sensitivity to androgens lower doses of T drugs may be used, whereas starting dose inefficiency TRT in men with a large number of trinucleotide repetitions, indicates the need to increase the dose of T. Determination of the CAG polymorphism of the AR gene is not recommended for routine practice, but in the near future it can be used in particular for the selection of individual therapy for androgen deficiency.
