Curr Urol Rep (2015) 16:51 DOI 10.1007/s11934-015-0526-6
BENIGN PROSTATIC HYPERPLASIA (K MCVARY, SECTION EDITOR)
Testosterone Replacement Therapy on the Natural History of Prostate Disease Aaron Moore 1,3 & Michael J. Butcher 2,3 & Tobias S. Köhler 2,3
# Springer Science+Business Media New York 2015
Abstract The physiology of testosterone production and action are closely related to prostatic disease. An understanding of the natural history of testosterone and prostate growth and development is needed in order to understand this complex relationship. Lower urinary tract symptoms (LUTS), benign prostatic hyperplasia (BPH), prostate cancer, and sexual function are common disorders for which testosterone is thought to play a role. Proposed in this review are some theories as to how testosterone interacts to potentially ameliorate these conditions. Further research is needed, but we feel our proposed points are valid given the review of the literature.
Keywords Testosterone . Prostate cancer . Benign prostatic hyperplasia . Lower urinary tract symptoms . Sexual medicine . Prostate
This article is part of the Topical Collection on Benign Prostatic Hyperplasia * Michael J. Butcher [email protected] Aaron Moore [email protected] Tobias S. Köhler [email protected] 1
School of Medicine, Southern Illinois University, 801 North Rutledge St., Springfield, IL 62702, USA
2
The Pavilion at St. John’s Hospital, 301 North Eighth Street, Springfield, IL 62701, USA
3
Division of Urology, Illinois University School of Medicine, Springfield, IL, USA
Introduction As men age, they become plagued with more disease. Some of these diseases and symptoms arise from male specific organs like the prostate. Indeed, urinary troubles begin shortly after endogenous testosterone levels begin to decline in the mid 30s to 40s. Some of the most common bothersome signs are lower urinary tract symptoms (LUTS) which can often be related to bladder outlet obstruction from benign prostatic hyperplasia (BPH). Exploring the physiology of testosterone and LUTS/ BPH and how they interrelate is an important part of medical practice especially due to recent concerns over safety risks of testosterone supplementation. All testosterone products legally must include a safety warnings and black box warning about the product. Specific sections of the warning related to prostate include the following: BPatients with BPH treated with androgens are at an increased risk for worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms. Patients treated with androgens may be at increased risk for prostate cancer. Evaluation of patients for prostate cancer prior to initiating and during treatment with androgens is appropriate.^ The black box warning is only applicable for topical testosterone gels which states, BVirilization has been reported in children who were secondarily exposed to testosterone gel. Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel. Healthcare provider’s should advise patients to strictly adhere to recommended instructions for use.^ [1] It is unclear what evidence these recommendation are based upon except for the clinical data pertaining to gels (the black box warning). This paper will describe the most recent and rigorous literature on these interactions.
51
Page 2 of 10
In addition, as people age, testosterone decreases and prostate-specific diseases increase. This manuscript seeks to answer questions pertaining to the relationship of testosterone use and sexual function, obstructive uropathy and LUTS, and prostate cancer risk in the context of increasing age. A solid foundation of testosterone physiology and separate prostate pathologies is essential to answer these questions and help theorize how testosterone works in concert with other organ systems.
Natural History of Testosterone and Hypogonadism Testosterone is an important hormone that is first secreted in utero and plays an important role in sexual differentiation. Testosterone is a lipophilic molecule that is 98 % protein bound in the blood. Albumin and sex hormone binding globulin (SHBG) are the two serum proteins to which testosterone is bound. Free testosterone and testosterone bound to albumin are biologically active throughout the body. Testosterone exerts the majority of its action by binding a nuclear receptor resulting in transcription and protein synthesis, which accounts for much of the difference between men and women. Testosterone is released in a pulsatile manner causing the serum concentration to fluctuate throughout the day, but it generally peaks early in the morning [2]. This age attenuation seems to be most relevant in men less than age 45 [3] In addition to the diurnal variation of testosterone, there are age-related changes in serum testosterone concentration. This differentiation of the male reproductive tract occurs at 12– 18 weeks of gestation with neonatal imprinting of androgendependent tissues around 2 months of age, and then again at puberty. After the pubertal increase in serum testosterone, testosterone reaches peak level and plateaus during the 2nd to 3rd decade of life. From this point, there is a slow decline in serum levels [4–10]. Whether the decrease in androgens with age is physiologic, pathologic or confounded by comorbid conditions remains controversial [11]. The leading theory for decreasing androgen concentration with age is due to an altered feed-forward and feedback link between LH and testosterone [12]. In the body, testosterone can be converted to a more potent androgen from metabolization of bioactive testosterone via 5-alpha reductase to dihydrotestosterone (DHT). This more potent form of testosterone concentrated in the prostate has been the premise behind the proposed pathophysiology of BPH via activation of prostatic androgen receptors [13••]. Increases in DHT equate to increased prostate volume resulting in LUTS. Medications focusing on blocking 5-alpha reductase have been used to help inhibit this conversion and decrease the symptoms and volume of the prostate by about 25 % [14]. However, more recent research has
Curr Urol Rep (2015) 16:51
proposed a different mechanism of DHT; one that is protective rather than pathologic when sufficient levels of testosterone is present [15] (see Fig. 1 for physiologic effects of DHT) Late onset hypogonadism is a burgeoning health topic because of the aging population and due to increased awareness. With the steady age-related decline of serum testosterone, the prevalence of hypogonadism increases [4, 16]. SHBG also increases with age which limits the bioavailable testosterone [9]. Using the Boston Area Community Health survey in 2007, Araujo et al. estimated that 5.6 % of men between the ages of 30 to 79 met the criteria for symptomatic androgen deficiency defined by one specific symptom for androgen deficiency or two non-specific symptoms and total T
BENIGN PROSTATIC HYPERPLASIA (K MCVARY, SECTION EDITOR)
Testosterone Replacement Therapy on the Natural History of Prostate Disease Aaron Moore 1,3 & Michael J. Butcher 2,3 & Tobias S. Köhler 2,3
# Springer Science+Business Media New York 2015
Abstract The physiology of testosterone production and action are closely related to prostatic disease. An understanding of the natural history of testosterone and prostate growth and development is needed in order to understand this complex relationship. Lower urinary tract symptoms (LUTS), benign prostatic hyperplasia (BPH), prostate cancer, and sexual function are common disorders for which testosterone is thought to play a role. Proposed in this review are some theories as to how testosterone interacts to potentially ameliorate these conditions. Further research is needed, but we feel our proposed points are valid given the review of the literature.
Keywords Testosterone . Prostate cancer . Benign prostatic hyperplasia . Lower urinary tract symptoms . Sexual medicine . Prostate
This article is part of the Topical Collection on Benign Prostatic Hyperplasia * Michael J. Butcher [email protected] Aaron Moore [email protected] Tobias S. Köhler [email protected] 1
School of Medicine, Southern Illinois University, 801 North Rutledge St., Springfield, IL 62702, USA
2
The Pavilion at St. John’s Hospital, 301 North Eighth Street, Springfield, IL 62701, USA
3
Division of Urology, Illinois University School of Medicine, Springfield, IL, USA
Introduction As men age, they become plagued with more disease. Some of these diseases and symptoms arise from male specific organs like the prostate. Indeed, urinary troubles begin shortly after endogenous testosterone levels begin to decline in the mid 30s to 40s. Some of the most common bothersome signs are lower urinary tract symptoms (LUTS) which can often be related to bladder outlet obstruction from benign prostatic hyperplasia (BPH). Exploring the physiology of testosterone and LUTS/ BPH and how they interrelate is an important part of medical practice especially due to recent concerns over safety risks of testosterone supplementation. All testosterone products legally must include a safety warnings and black box warning about the product. Specific sections of the warning related to prostate include the following: BPatients with BPH treated with androgens are at an increased risk for worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms. Patients treated with androgens may be at increased risk for prostate cancer. Evaluation of patients for prostate cancer prior to initiating and during treatment with androgens is appropriate.^ The black box warning is only applicable for topical testosterone gels which states, BVirilization has been reported in children who were secondarily exposed to testosterone gel. Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel. Healthcare provider’s should advise patients to strictly adhere to recommended instructions for use.^ [1] It is unclear what evidence these recommendation are based upon except for the clinical data pertaining to gels (the black box warning). This paper will describe the most recent and rigorous literature on these interactions.
51
Page 2 of 10
In addition, as people age, testosterone decreases and prostate-specific diseases increase. This manuscript seeks to answer questions pertaining to the relationship of testosterone use and sexual function, obstructive uropathy and LUTS, and prostate cancer risk in the context of increasing age. A solid foundation of testosterone physiology and separate prostate pathologies is essential to answer these questions and help theorize how testosterone works in concert with other organ systems.
Natural History of Testosterone and Hypogonadism Testosterone is an important hormone that is first secreted in utero and plays an important role in sexual differentiation. Testosterone is a lipophilic molecule that is 98 % protein bound in the blood. Albumin and sex hormone binding globulin (SHBG) are the two serum proteins to which testosterone is bound. Free testosterone and testosterone bound to albumin are biologically active throughout the body. Testosterone exerts the majority of its action by binding a nuclear receptor resulting in transcription and protein synthesis, which accounts for much of the difference between men and women. Testosterone is released in a pulsatile manner causing the serum concentration to fluctuate throughout the day, but it generally peaks early in the morning [2]. This age attenuation seems to be most relevant in men less than age 45 [3] In addition to the diurnal variation of testosterone, there are age-related changes in serum testosterone concentration. This differentiation of the male reproductive tract occurs at 12– 18 weeks of gestation with neonatal imprinting of androgendependent tissues around 2 months of age, and then again at puberty. After the pubertal increase in serum testosterone, testosterone reaches peak level and plateaus during the 2nd to 3rd decade of life. From this point, there is a slow decline in serum levels [4–10]. Whether the decrease in androgens with age is physiologic, pathologic or confounded by comorbid conditions remains controversial [11]. The leading theory for decreasing androgen concentration with age is due to an altered feed-forward and feedback link between LH and testosterone [12]. In the body, testosterone can be converted to a more potent androgen from metabolization of bioactive testosterone via 5-alpha reductase to dihydrotestosterone (DHT). This more potent form of testosterone concentrated in the prostate has been the premise behind the proposed pathophysiology of BPH via activation of prostatic androgen receptors [13••]. Increases in DHT equate to increased prostate volume resulting in LUTS. Medications focusing on blocking 5-alpha reductase have been used to help inhibit this conversion and decrease the symptoms and volume of the prostate by about 25 % [14]. However, more recent research has
Curr Urol Rep (2015) 16:51
proposed a different mechanism of DHT; one that is protective rather than pathologic when sufficient levels of testosterone is present [15] (see Fig. 1 for physiologic effects of DHT) Late onset hypogonadism is a burgeoning health topic because of the aging population and due to increased awareness. With the steady age-related decline of serum testosterone, the prevalence of hypogonadism increases [4, 16]. SHBG also increases with age which limits the bioavailable testosterone [9]. Using the Boston Area Community Health survey in 2007, Araujo et al. estimated that 5.6 % of men between the ages of 30 to 79 met the criteria for symptomatic androgen deficiency defined by one specific symptom for androgen deficiency or two non-specific symptoms and total T
