madman
Super Moderator
Testosterone and prostate health: Have the paradigms truly shifted?
The concept that testosterone (T) promotes the growth of prostate cancer (PCa) was firmly established around the middle of the last century, based initially on animal and human studies entirely appropriate for the post-World War II state-of-the art. Since then, a great deal of progress has been made in our appreciation of the relationships between T and prostate health. Original concepts have been revised and firmly held opinions have been challenged following clinical observations and discoveries in the fields of biochemistry, genetics, and immunology. More recent developments in the understanding of the interactions between androgens and the androgen receptor 1-3 and the concept of the prostate being an endocrine organ within the hypothalamus-pituitary-gonadal (HPG) axis domain 4,5 has shed new insights on the relations and clinical significance of hormones and prostate health. By a wide margin, urologists treat most men with a current or remote diagnosis of PCa and are consulted and increasingly asked to take primary responsibility for managing those who are also affected by testosterone deficiency (TD). This brings into focus the need to provide a succinct view of the common situations faced by clinicians about the confusing and often controversial issues involving androgens and androgen administration to men. Therefore, following a brief introduction to the fundamentals of T and prostate tissue interactions, we will discuss four scenarios that are of most relevance in clinical practice.
A primer on the prostate and the androgen receptor
A fundamental participant in the translation of androgen action is the androgen receptor (AR), a nuclear transcription factor that binds to androgens and acts through differential DNA targeting and genetic control on the relevant organ systems.6 The effects of androgens on the prostate gland are unquestionable and, although there has been a significant improvement in our understanding of the cellular and molecular mechanisms, they are not yet fully figured out. In the prostate, T acts mostly as a prohormone. The effective androgen is the more potent dihydrotestosterone (DHT), which is converted from T through the action of 5α reductase. Different organs have variable amounts of 5α reductase enzymes 1 and 2. 5α reductase 2 is more prominent in the prostate, external genitalia, and skin, and its deficiency translates into minimal prostate growth and the presence of ambiguous external genitalia in boys who at puberty, however, exhibit the anticipated increase in muscle mass and male habitus. The glandular epithelium and a subset of endothelial cells are the primary androgen target structures within the prostate. DHT acts on the ARs of these tissues to generate a variety of androgen-induced stromal peptide growth factors or andromedins (e.g., prosurvival protein bcl-2, vascular endothelial growth factor) leading to androgen-mediated mitogenic effects and survival signaling. Androgen deprivation, on the other hand, results in insufficient production of andromedins, which in turn, upregulates the production of transforming growth factor β1 (TGF β1 ) that signals the apoptotic cascade in the secretory compartment of the prostatic epithelium.7 Understanding the mechanisms of androgen-dependent prostate cells’ growth, differentiation, and death is important because their manipulation has major consequences in the treatment of prostate neoplasms.8
Relevant clinical settings
*Endogenous T levels and risk of developing PCa
*Testosterone therapy (TTh) and prostate health
*TTh in hypogonadal men successfully treated for PCa
*TTh in men with PCa
Conclusions
There is increasing evidence that symptomatic hypogonadal men successfully treated for PCa can safely receive TTh under certain circumstances. 24,30,45 The innovative idea of using androgen supplementation in men with T deficiency and untreated or unsuccessfully treated PCa is worth exploring. It should be done, however, with a great deal of caution. We should now define which men have prostate cancers that do not progress during T administration and who would experience a benefit in quality of life from such treatment. The issue needs to be addressed from the scientific, medical, ethical, and legal perspectives. The establishment of a global registry would address some of these issues and provide reliable answers in the most expeditious manner. As the validity and universal clinical applicability of the saturation becomes increasingly questioned, 46 the need for persuasive studies acquires an urgent dimension.
The concept that testosterone (T) promotes the growth of prostate cancer (PCa) was firmly established around the middle of the last century, based initially on animal and human studies entirely appropriate for the post-World War II state-of-the art. Since then, a great deal of progress has been made in our appreciation of the relationships between T and prostate health. Original concepts have been revised and firmly held opinions have been challenged following clinical observations and discoveries in the fields of biochemistry, genetics, and immunology. More recent developments in the understanding of the interactions between androgens and the androgen receptor 1-3 and the concept of the prostate being an endocrine organ within the hypothalamus-pituitary-gonadal (HPG) axis domain 4,5 has shed new insights on the relations and clinical significance of hormones and prostate health. By a wide margin, urologists treat most men with a current or remote diagnosis of PCa and are consulted and increasingly asked to take primary responsibility for managing those who are also affected by testosterone deficiency (TD). This brings into focus the need to provide a succinct view of the common situations faced by clinicians about the confusing and often controversial issues involving androgens and androgen administration to men. Therefore, following a brief introduction to the fundamentals of T and prostate tissue interactions, we will discuss four scenarios that are of most relevance in clinical practice.
A primer on the prostate and the androgen receptor
A fundamental participant in the translation of androgen action is the androgen receptor (AR), a nuclear transcription factor that binds to androgens and acts through differential DNA targeting and genetic control on the relevant organ systems.6 The effects of androgens on the prostate gland are unquestionable and, although there has been a significant improvement in our understanding of the cellular and molecular mechanisms, they are not yet fully figured out. In the prostate, T acts mostly as a prohormone. The effective androgen is the more potent dihydrotestosterone (DHT), which is converted from T through the action of 5α reductase. Different organs have variable amounts of 5α reductase enzymes 1 and 2. 5α reductase 2 is more prominent in the prostate, external genitalia, and skin, and its deficiency translates into minimal prostate growth and the presence of ambiguous external genitalia in boys who at puberty, however, exhibit the anticipated increase in muscle mass and male habitus. The glandular epithelium and a subset of endothelial cells are the primary androgen target structures within the prostate. DHT acts on the ARs of these tissues to generate a variety of androgen-induced stromal peptide growth factors or andromedins (e.g., prosurvival protein bcl-2, vascular endothelial growth factor) leading to androgen-mediated mitogenic effects and survival signaling. Androgen deprivation, on the other hand, results in insufficient production of andromedins, which in turn, upregulates the production of transforming growth factor β1 (TGF β1 ) that signals the apoptotic cascade in the secretory compartment of the prostatic epithelium.7 Understanding the mechanisms of androgen-dependent prostate cells’ growth, differentiation, and death is important because their manipulation has major consequences in the treatment of prostate neoplasms.8
Relevant clinical settings
*Endogenous T levels and risk of developing PCa
*Testosterone therapy (TTh) and prostate health
*TTh in hypogonadal men successfully treated for PCa
*TTh in men with PCa
Conclusions
There is increasing evidence that symptomatic hypogonadal men successfully treated for PCa can safely receive TTh under certain circumstances. 24,30,45 The innovative idea of using androgen supplementation in men with T deficiency and untreated or unsuccessfully treated PCa is worth exploring. It should be done, however, with a great deal of caution. We should now define which men have prostate cancers that do not progress during T administration and who would experience a benefit in quality of life from such treatment. The issue needs to be addressed from the scientific, medical, ethical, and legal perspectives. The establishment of a global registry would address some of these issues and provide reliable answers in the most expeditious manner. As the validity and universal clinical applicability of the saturation becomes increasingly questioned, 46 the need for persuasive studies acquires an urgent dimension.
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