Despite a lack of evidence, there have been stated concerns that testosterone replacement therapy (TRT) can pose a risk to men suffering with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). TRT may improve components of the metabolic syndrome, which is associated with worsening LUTS. Furthermore, the evidence suggests that TRT may decrease prostatic inflammation, which is also associated with worsening LUTS. The data on the relationship between TRT and LUTS have never shown worsening of LUTS, often show no change in LUTS, and occasionally show improvement.
Key points
- •
Despite a lack of evidence, there have been stated concerns that testosterone replacement therapy (TRT) can pose a risk to men suffering with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH).
- •
TRT may improve components of the metabolic syndrome, which is associated with worsening LUTS. Furthermore, the evidence suggests that TRT may decrease prostatic inflammation, which is also associated with worsening LUTS.
- •
The data on the relationship between TRT and LUTS have never shown worsening of LUTS, often show no change in LUTS, and occasionally show improvement.
Introduction
As men age, they tend to become burdened with an increasing number of medical illnesses. Many of these illnesses tend to be urologic. Two of these conditions frequently seen by urologist are hypogonadism and benign prostatic hyperplasia (BPH) with its associated lower urinary tract symptoms (LUTS). Testosterone levels begin decline to in men’s middle 30s. Shortly thereafter, many men begin to become bothered by LUTS associated with BPH. Understanding the relationship between LUTS/BPH and hypogonadism is increasingly important, as more aging men inquire about testosterone replacement therapy (TRT).
Several safety concerns have been raised about TRT. In 2015, the FDA required a black box warning regarding a possible increased risk for myocardial infarction and cerebrovascular events. Methods from the studies leading to this conclusion have been called into question. Additionally, the US Food and Drug Administration (FDA) issued a black box warning regarding TRT in men with BPH. The warning regarding topical androgens included the following statement:
“Patients with BPH treated with androgens are at an increased risk of worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms. Patients treated with androgens may be at an increased risk for prostate cancer. Evaluation of patients for prostate cancer prior to initiating and during treatment is appropriate.”
The data for these recommendations are unclear, and this article will examine the evidence relating to TRT in men with BPH.
Both hypogonadism and BPH become more prevalent with increasing age in men. This article will examine the pathophysiology leading to both processes and the potential impact of TRT in patients suffering from BPH.
Introduction
As men age, they tend to become burdened with an increasing number of medical illnesses. Many of these illnesses tend to be urologic. Two of these conditions frequently seen by urologist are hypogonadism and benign prostatic hyperplasia (BPH) with its associated lower urinary tract symptoms (LUTS). Testosterone levels begin decline to in men’s middle 30s. Shortly thereafter, many men begin to become bothered by LUTS associated with BPH. Understanding the relationship between LUTS/BPH and hypogonadism is increasingly important, as more aging men inquire about testosterone replacement therapy (TRT).
Several safety concerns have been raised about TRT. In 2015, the FDA required a black box warning regarding a possible increased risk for myocardial infarction and cerebrovascular events. Methods from the studies leading to this conclusion have been called into question. Additionally, the US Food and Drug Administration (FDA) issued a black box warning regarding TRT in men with BPH. The warning regarding topical androgens included the following statement:
“Patients with BPH treated with androgens are at an increased risk of worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms. Patients treated with androgens may be at an increased risk for prostate cancer. Evaluation of patients for prostate cancer prior to initiating and during treatment is appropriate.”
The data for these recommendations are unclear, and this article will examine the evidence relating to TRT in men with BPH.
Both hypogonadism and BPH become more prevalent with increasing age in men. This article will examine the pathophysiology leading to both processes and the potential impact of TRT in patients suffering from BPH.
Natural history of testosterone/hypogonadism
Testosterone is the major hormone responsible for male sexual differentiation. It has a short half-life at 12 minutes. Its secretion begins in utero. It is a cholesterol derivative produced in the adrenal and testes that is 98% bound in the blood. It is loosely bound to albumin and binds tightly to sex hormone-binding globulin. Testosterone that is bound to albumin and testosterone that is free is bioavailable. Its release is pulsatile, and its level fluctuates during the day after peaking in the morning. It appears that these fluctuations become less predominant in men over 45 years of age. Peripheral aromatization results in the conversion of androgens to estrogens. Testosterone binds the androgen receptor (AR), which is translocated to the cell nucleus, and results in the production and secretion of peptide growth factors.
In target organs, testosterone undergoes conversion to 5α-dihydrotestosterone (DHT), a more potent androgen, by the enzyme 5α-reductase. There are 3 isoforms of this enzyme. The 5α-reductase inhibitors (5-ARIs) include finasteride and dutasteride. The type 1 isoenzyme exists primarily in the skin and to a lesser extent the prostate. The type 2 isoenzyme is the dominant form in the prostate although present to a lesser extend in the skin and liver. Finasteride inhibits type 2 5-ARI, with dutasteride inhibiting both type 1 and 2 5-ARI. Dutasteride lowers DHT levels to a greater extent than finasteride. These medications have been used to reduce prostatic volume and LUTS.
Increasing awareness of late-onset hypogonadism has made it a frequent subject of discussion among physicians and between physicians and their patients. After a plateau in men in their 20s, testosterone levels begin to decline. Additionally, there is an age-related increase in sex hormone-binding globulin decreasing the bioavailable testosterone. In a large cross-sectional study, the European Male Aging Study (EMAS), annually there was a 0.4% decline in serum testosterone and a 1.3% decline in free testosterone. There is controversy concerning whether this decline is physiologic or a pathologic process necessitating treatment. Regardless, there has been a global increase in the prescribing of TRT.
The diagnosis of hypogonadism requires a combination of clinical symptoms and biochemical evidence. There are specific and nonspecific symptoms. Signs and symptoms include: low libido, decrease in muscle mass, anemia, fatigue, decrease in erections, low bone mineral density, and dysthymia. The Androgen Deficiency in Aging Males (ADAM) questionnaire can be helpful in ascertaining this information. The Endocrine Society Guidelines published in 2010 do not recommend routine screening. Testing for hypogonadism should consist of a morning total testosterone. A patient with a total testosterone less than 250 is likely to have hypogonadism and should be treated accordingly. Patients with a total T between 250 and 400 should undergo further testing for a free testosterone. Patients with a total testosterone of more than 400 are unlikely to have hypogonadism.
There is no causal link between testosterone therapy and an increased incidence of prostate cancer or LUTS associated with BPH; however, both the International Society of Andrology and the Endocrine society recommend against exogenous testosterone therapy in men who have significant LUTS prior to a urologic evaluation.
Natural history of benign prostatic hyperplasia
BPH is a technically a histologic diagnosis characterized by the proliferation of prostatic epithelial and stromal cells in the transition zone. Most commonly the diagnosis is made based on clinical symptoms and less commonly radiographic images. Androgen stimulation is required for fetal prostate development. The prostate is small at birth, approximately 1.5 g, and remains stable at this size until puberty. At puberty the gland reaches approximately 10 g. Typically, a prostate reaches its normal weight of 20 g between 21 and 30 years of age. In autopsy studies, the incidence of histologic BPH increases with age, being present in 8% of men 31 to 40 years of age, 42% of those 51 to 60 years of age, and 90% of those older than 90. BPH itself is associated with both erectile and ejaculatory dysfunction. Although contributory, the obstructive effect of hyperplastic nodules does not provide sufficient explanation for the LUTS associated with BPH.
Androgens are necessary but not sufficient for the development of BPH. Animal studies have helped elucidate this role. In a canine study, young castrated dogs only developed BPH after testosterone replacement. BPH regressed in older dogs after the castration but returned following exogenous testosterone administration. Men with primary hypogonadism, who normally do not develop BPH, can now develop BPH after TRT.
Obesity and the metabolic syndrome are both risk factors for LUTS associated with BPH. Obesity is a risk factor for hypogonadism as well. A cross-sectional study examining 100 men with moderate and severe obesity found a negative correlation between androgens (both testosterone/free testosterone) and insulin resistance. It is also interesting to note that multiple studies have demonstrated improvement in hypogonadism after weight loss secondary to bariatric surgery. TRT also is conducive to weight loss. Hyperinsulinemia is associated with increased sympathetic nervous system activity, which may affect smooth muscle tone in the prostate and thus worsen LUTS independent of the obstruction associated with macronodular hyperplasia. The metabolic syndrome also creates a proinflammatory milieu within the prostate, which ultimately leads to epithelial and stromal proliferation. In addition patients with the metabolic syndrome have increased amounts of body fat, which leads to the aromatization of androgens into estrogens, further worsening hypogonadism. Studies have established that in conjunction with DHT, estrogen leads to an increase in prostate weight.
Multiple studies have demonstrated an increase in the severity of LUTS in men with the metabolic syndrome. The NHANES III study, an observational study with 2732 men, found an 80% increase in the incidence of LUTS in those with 3 or more components MetS compared to those with none.
The Baltimore Longitudinal Study on Aging demonstrated that for each 1 kg/m 2 increase in body mass index (BMI) there was a 0.41 mL increase in prostatic volume; thus in this study obese men had a 3.5-fold increased risk for an enlarged prostate compared with non-obese men. This is further corroborated by a subsequent paper from this study showing that in radical prostatectomy specimens there was a 0.45 g increase in weight for each additional 1 kg/m 2 increase in BMI.
Androgens and their interaction with benign prostatic hyperplasia
Significant LUTS/BPH is often considered a relative contraindication to TRT. This is based on the pathophysiology connecting androgens to prostatic development and growth. There has been some controversy concerning the impact of TRT on LUTS and related quality of life. This continues to generate concern. There are multiple reasons to suspect that TRT would not have an adverse effect on LUTS and BPH. The first is that the prostate’s androgen receptor appears to saturate above a testosterone level of 50 ng/mL; therefore changes in testosterone levels after TRT would not affect the majority of hypogonadal men. Second the intraprostatic levels of androgens do not appear to mirror serum levels. In a double-blind, placebo-controlled randomized controlled trial (RCT) by Page and colleagues, patients were randomized to either transdermal DHT or placebo. At 4 weeks of follow-up, there was no difference in either DHT or testosterone between the 2 arms.
The decline of testosterone levels and growth of prostatic tissue are often concurrent processes in the aging man. Prostate growth increases over time, while testosterone levels decline. Data from the Olmsted County study have shown that lower bioavailable testosterone and rapidly declining testosterone levels are associated with prostatic growth.
There are several questions regarding the impact of TRT on patients with BPH. Principally, does TRT have an impact on prostate volume? To answer this question a randomized control (44 hypogonadal men with moderate-to-severe LUTS) was treated with injectable testosterone enthanate for 6 months. This study did not demonstrate any significant change in prostate volume as measured by magnetic resonance imaging. Additionally, prostate biopsies did not demonstrate a change in tissue testosterone levels. Another randomized double-blind, placebo-controlled trial from the Netherlands with 237 men randomized to either testosterone undeconoate versus placebo showed no change in prostate volume as measured by transrectal ultrasound after 6 months with a similar study from Moscow demonstrating similar findings. It is important to note that changes in prostate volume were not the primary end point in these trials, and thus they may not have been adequately powered to detect a difference.
Multiple cohort studies of hypogonadal men undergoing TRT did not demonstrate an increase in prostate volume. A prospective cohort of 25 patients receiving testosterone undeconoate showed a statistically significant increase, although modest, in prostate volume after 12 months of therapy going from a mean of 19.7 to 22 mL. It is worth noting that there was no further increase in prostate volume after a total of 4 years of follow up.
Secondary, how does TRT affect LUTS in those with BPH? In the double blind-placebo controlled trial by Emmelot-Von and colleagues men treated testosterone undeconoate did not show any change in International Prostate Symptom Score (IPSS) at 6 months of follow up. Another randomized trial with transdermal testosterone showed no statistically significant change in IPSS after 12 months of therapy. A randomized study by Tan and colleagues with patients receiving injectable testosterone showed a trend towards improvement in IPSS that did not reach statistical significance. A randomized nonblinded study by Shigehara and colleagues even showed a statistically significant improvement in IPSS and maximal flow rate in those treated with injectable testosterone. Multiple open-label observation studies have shown improvement in IPSS scores after treatment with TRT. Consistent with this treatment of hypogonadism of improved voiding status in a trial by Karazindiyanoglu and colleagues which showed improved bladder compliance and capacity in hypogonadal men receiving TRT. It appears that it is quite possible that TRT may improve LUTS. Table 1 demonstrates outcomes of studies assessing the effect of TRT on the prostate/LUTS.
Related posts:
The Epidemiology of Benign Prostatic Hyperplasia Associated with Lower Urinary Tract Symptoms
Diagnostic Work-Up of Lower Urinary Tract Symptoms
Alpha-blockers for the Treatment of Benign Prostatic Hyperplasia
Convective Water Vapor Energy for Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia
Bipolar, Monopolar, Photovaporization of the Prostate, or Holmium Laser Enucleation of the Prostate
Robotic-Assisted Simple Prostatectomy
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
