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@ Asian Journal of Andrology (2014) 16, 248-255 
© 2014 AJA, SIMM & SJTU. All rights reserved 1008-682X 

www.asiaandro.com; www.ajandrology.com 

Open Access 
INVITED REVIEW 

| Androgens and prostate disease 

o 
u 

-§ Lori A Cooper 1 , Stephanie T Page 1 ' 2 

LU 

75 A growing body of literature has established the anabolic benefits of testosterone (T) therapy in hypogonadal men. However, there 
51 remains a paucity of data regarding the risks of exogenous androgen use in older men and the potential for adverse effects on the 
prostate gland. Whether T therapy in older, hypogonadal men might worsen lower urinary tract symptoms or exacerbate, unmask, 
or even incite prostate cancer development has tempered enthusiasm for T therapy, while known prostatic disease has served as a 
relative contraindication to T therapy. Androgens are necessary for the development and maintenance of the prostate gland. However, 
epidemiologic studies do not consistently find a positive relationship between endogenous serum androgen concentrations and 
the risk of prostate disease. Recent data demonstrate that 5a-reductase inhibitors decrease the risk of low-grade prostate cancer, 
suggesting that modifying androgen metabolism may have beneficial effects on prostate health, yet similar reductions in high-grade 
disease have not been observed, thereby questioning the true clinical benefits of these agents for chemoprevention. Knowing how 
to best investigate the relationship between androgens and the development of prostate disease given the lack of large, randomized 
trials is difficult. Accumulating data challenges the assumption that alterations in serum androgens have parallel effects within the 
prostate hormonal environment or change androgen-regulated processes within the gland. Long-term intervention studies are needed 
to truly ascertain the effects of androgen manipulation on prostate tissue and disease risk. However, available data do not support 
the notion that restoring serum androgens to normal physiologic ranges drives prostate disease. 

Asian Journal of Andrology (2014) 16, 248-255; doi: 10.4103/1008-682X.122361; published online: 23 December 2013 
Keywords: androgens; male hypogonadism; prostate; testosterone 




INTRODUCTION 

In 1935, Adolf Butenandt and Leopold Ruzicka independently but 
simultaneously synthesized testosterone (T), leading to their joint 
award of the Nobel Prize in Chemistry in 1939 (although Butenandt 
was forced to decline the honor by the Nazi government). Since the 
availability of synthetic T in the 1940s, worldwide use has grown 
markedly. 1 Despite the fact that prescriptions for T continue to climb, 2 
to date there have been no large, randomized-controlled trials to 
definitively assess the risks and benefits of exogenous androgens in 
older men. While androgens clearly have attractive anabolic effects, 
whether these provide true health benefits remains unclear. Moreover, 
there remain significant concerns regarding the safety of androgens 
for hormone-sensitive tissues, particularly the prostate gland. Here, 
we review our current knowledge regarding the relationship between 
endogenous and exogenous androgens and prostate disease. 

Testosterone replacement and aging: benefits 

T levels are highest in men during their twenties and steadily decline 
1 %-2% per year thereafter. 3 While serum total T concentrations decrease 
with age, prospective longitudinal studies demonstrate that declines 
in free testosterone (fT), the active hormone, may be even greater, 
attributable to the effects of aging and health status. 4 Whether or not this 
decline in T represents pathologic, late-onset hypogonadism or simply 
normal aging is controversial, and current clinical recommendations 
for both the diagnosis and treatment of androgen deficiency rely upon 
a combination of biochemical and clinical criteria. 5 



The differences in reported prevalence of late-onset hypogonadism 
vary in part due to assay variation and methods and are further 
complicated by the differences in cohorts and the definition used 
for diagnosis. Assay heterogeneity in the quantification of serum 
T concentrations makes absolute biochemical criteria unfeasible. 
Particularly at concentrations below the normal range for healthy 
young men, platform assays used by some commercial laboratories to 
measure total T concentrations are inaccurate and lack reproducibility. 6 
Currently, quantification of serum T concentrations by liquid 
chromatography-tandem mass spectrometry is optimal. The Centers 
for Disease Control has recently offered a program to certify 
laboratories for T quantification, 7 an effort that should greatly improve 
assay quality for those laboratories that elect to participate. Using data 
from the European Male Ageing Study, Wu et al., s consider late-onset 
hypogonadism to be defined as a total T level <320 ng ml" 1 and free T 
level <64 pg ml" 1 , in conjunction with at least three sexual symptoms. 
In this cohort, 2.1% of men from age 40 to 79 years fit this definition. 
In contrast, in the Massachusetts Male Aging Study, the prevalence of 
men age 30-79 having a total T level <300 ng ml" 1 , fT <50 pg ml" 1 , and 
symptoms consistent with androgen deficiency was 5.6%. 9 

The administration of T therapy to older, hypogonadal men to 
reach serum concentrations consistent with those of young, healthy 
men has been shown in randomized controlled trials to consistently 
offer several benefits. These include improvements in muscle mass and 
strength, favorable changes in body composition, and improvements 



'Departments of Medicine, Division of Endocrinology and Metabolism, University of Washington, Seattle; 2 University of Washington and Harborview Medical Center, Seattle, 
Washington, USA. 
Correspondence: Prof. ST Page (page@uw.edu) 

Received: 13 June 2013; Revised: 23 July 2013; Accepted: 23 July 2013 



Androgens and prostate disease 

LA Cooper and ST Page 



in libido and sexual health. Snyder et al. w demonstrated in a group 
of hypogonadal men >65 years old that those randomized to a 
6 mg per day T patch for 36 months had significant reductions in fat 
mass and increased lean muscle mass compared with placebo-treated 
men. Similarly, in a study of 70 men >65 years old with low T levels, 
Page et al. n randomized subjects to receive either T enanthate 200 mg 
IM every 2 weeks, T enanthate plus finasteride (F) [to block conversion 
of T to dihydrotestosterone (DHT)], or placebo for 36 months. 
Compared to baseline assessments, those in the T and T plus F groups 
had improvements in timed functional tests and handgrip strength. 
Similar to the study by Snyder, there were also significant decreases in 
fat mass and increases in lean body mass in both groups treated with 
T compared to those on placebo. Favorable effects of T and T + F were 
also seen on total cholesterol and low-density lipoprotein, and there 
were significant benefits of T on bone mineral density at both the spine 
and hip in these older, community dwelling men with low T. 12 

While Wu et al. s found that sexual symptoms are the most sensitive 
indicator of hypogonadism in older men (European Male Ageing Study) , 
the effects of T therapy on libido and sexual function, while generally 
positive, are somewhat mixed. Cumulatively, the data points to the 
greatest response in men with the lowest baseline T levels and does 
not show a consistent dose response. A meta-analysis of 656 subjects 
treated with T or placebo for a median study length of 3 months showed 
T moderately improved sexual desire and function in men with baseline 
T levels <12 nmol l" 1 , but these benefits were not seen in eugonadal 
men. 13 Gray et al. u examined T dose-response relationships on sexual 
function in older, healthy men. A significant dose effect of T on libido 
was observed in men who were sexually active at the start of the study, 
as well as a dose effect on the frequency of morning erections, which 
differs from effects seen in younger, healthy men. The reasons for the 
age-related differences on sexual function in response to T are unknown. 

Positive effects of T on mood, 1516 cognitive function, 17 and quality 
of life (QoL) have been noted in some studies but are not consistently 
observed. Cross-sectional data, such as the Longitudinal Aging Study in 
Amsterdam, have reported that symptoms of depression are higher in 
men with low free T levels. 15 Controlled intervention trials examining 
the impact of T therapy on depression and cognition 18,15 have been 
small and to date insufficient to support the use of T in the treatment 
of cognitive and mood disorders, even in the men with low serum T. 19 
The effect of T therapy on QoL measures is also difficult to discern. 
In a recent placebo-controlled trial of T therapy in frail, elderly men 
with low or low-normal T levels, significant improvements in strength, 
body composition, physical function, and QoL were observed in those 
men receiving T therapy for 6 months compared to placebo. 20 However, 
when this same group was followed-up 6 months post T therapy, 
these effects were not maintained. 21 Improvement in health-related 
QoL measures were also demonstrated in a larger, double-blinded, 
placebo-controlled trail of 362 men with low to low-normal T after 
6 months of therapy. 22 

Perhaps the most compelling rationale to advance our understanding 
of the risks and benefits of T therapy are recent observations linking 
low T levels with increased risk of all-cause mortality in older men. The 
Rancho Bernardo Study followed older, community dwelling men for 
a mean of 1 1.8 years and observed that low serum T (T <241 ng mL 1 ) 
was associated with a 40% greater risk of death compared to 
men with higher T levels. 23 At least two other large, prospective 
studies have reported similar results, 24,25 and the CHIANTI study 
found that low levels of anabolic hormones (T, insulin-like growth 
factor-1, dihydroepiandosterone-sulfate (DHEA-S)) were associated 
with significantly higher 6-year mortality. 26 Although long-term 



249 

intervention data regarding T therapy and mortality are clearly lacking, 
in an observational cohort of over 1000 hypogonadal male veterans, 
Shores etal. 17 observed that those men with low serum T who received 
T replacement had significantly decreased mortality compared with 
those men who had not received T, even after adjusting for multiple 
co-morbidities including age, diabetes, body mass index, and coronary 
artery disease. Together, these observational studies suggest that low T 
levels may predispose men to early mortality and support the possibility 
that T replacement may be beneficial in selected patients. 

In summary, both cross- sectional and intervention data suggest 
that T therapy in older men with low serum T has beneficial effects 
on body composition, strength, bone mineral density, and libido. 
However, evidence that T therapy reduces morbidity and mortality 
lacking. Ultimately the benefits of T therapy need to be considered 
against potential risks of therapy. But what are those risks? Similar to 
the issue of beneficial effects, evaluation of the risks of T therapy has 
focused on signs and symptoms rather than on disease endpoints. 
T therapy increases hemoglobin and hematocrit 28 (although this can 
be a benefit in some cases) and may worsen obstructive sleep apnea. 29 
The greatest concerns regarding T therapy and disease are the potential 
to increase cardiovascular disease risk and prostate cancer incidence. 
Exogenous T can mildly reduce total and high-density lipoprotein 
cholesterol concentration, 28 changes that might have negative effects 
on cardiovascular disease risk, and a recent small intervention study 
in frail older men suggested that the cardiovascular event rate might 
be increased by T therapy in select groups of men. 30 In contrast, no 
controlled intervention studies to date have reported an increased 
risk of prostate cancer or prostate disease in men receiving T therapy 
compared with control subjects. But due to issues of study power and 
duration, the relationship between T therapy and prostate disease risk is 
a fundamental and unanswered question in the field. No studies to date 
have been powered to discern the risk, if any, of T therapy and prostate 
disease; moreover, no such trials are currently underway. Thus, data 
regarding T therapy and prostate disease risk are at least a decade away. 
In the interim, however, prescriptions for T have steadily risen. A recent 
examination of prescribing habits in the United Kingdom showed the 
number of prescriptions for T has increased 90% from 2001 to 2010. 31 

Since appropriate evidence from randomized-controlled trials is 
lacking, what is the best evidence available regarding T therapy and 
prostate disease? Conventional teaching has been that pre-existing 
benign prostatic hypertrophy (BPH) and prostate cancer may be 
aggravated by T therapy, given that androgen diminution and 
withdrawal are the mainstays of therapy for these diseases. However, 
the applicability of these observations, accrued in the setting of 
disease, to the physiology of the healthy prostate is unclear. Here, we 
will review both observational data as well as clinical intervention 
trials involving T therapy and prostate responses. In addition, we will 
discuss recent data involving the intraprostatic response to systemic 
androgen manipulation. Further investigation into the hormonal and 
cellular pathways regulating prostate disease processes is crucial to 
our understanding of the relationship between T therapy and prostate 
disease. 

Androgen deprivation and prostate cancer 

Androgens are an absolute requirement for the development and 
maintenance of male reproductive tissues including the prostate. 
The prostate fails to develop in men with mutations in the androgen 
receptor (AR) or the enzyme 5oc-reductase type 2 (5ocR2), which is 
highly expressed in the prostate and converts T to the more potent 
androgen, DHT. 32 BPH results predominantly from expansion of the 




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250 

prostate stroma, under the influence of DHT. 33,34 Prostate cancer, on 
the contrary, is a disease of the prostate epithelium, although stromal 
factors appear to play a role in neoplastic transformation. 35 

In 1941, Huggins and Hodges 36 demonstrated the sensitivity of 
prostate carcinoma to androgens ultimately garnering the Nobel Prize 
in 1966 for their work. Their seminal paper, and hundreds of studies 
that have followed, demonstrate that androgen withdrawal results in 
initial regression of essentially all prostate cancers, albeit for a finite 
period of time, with the ultimate development of castration-resistant 
disease. Thus, androgen deprivation therapy, via either orchidectomy 
or, much more commonly, use of a gonadotropin releasing 
hormone (GnRH) agonist to suppress production of luteinizing 
hormone has become the cornerstone of therapy in the treatment of 
metastatic prostate cancer. Newer agents, such as abiraterone, which 
block androgen synthetic pathways, have added clinical benefit in 
disseminated disease, demonstrating that even in "castration-resistant 
disease" androgens may still be supporting prostate cancer growth. 37 
These data support the notion that prostate cancer, in most cases, is a 
hormone sensitive disease. 

While there is clear evidence that prostate cancers can respond 
to androgen withdrawal, Huggins and Hodges' conclusions regarding 
the sensitivity of prostate cancer to exogenous T are more difficult to 
interpret and have been the subject of recent scrutiny and debate. 38 
Indeed, the extrapolation of their findings in individuals with metastatic 
prostate carcinoma to the natural history of low-grade prostate 
carcinomas, as well as healthy prostate tissue, likely oversimplifies 
the complexity of normal prostate physiology. Similarly, in 1981, a 
retrospective analysis helped to potentiate the notion that exogenous 
T might accelerate prostate cancer. Fowler and Whitmore 40 reported 
a series of 52 men with metastatic prostate cancer who had received 
exogenous T, 45 of whom had reported unfavorable effects (subjective 
symptoms or objective progression of disease), most of which reversed 
again following cessation of T administration. All but four of these 
men had undergone prior androgen deprivation either by castration or 
estrogen administration. Interestingly, only one of the four men who 
did not undergo prior castration had an early, unfavorable response, 
and the remaining three continued to receive T. In this retrospective 
series, it was concluded that T administration resulted in rapid 
disease progression due to the inherent androgen responsiveness of 
prostate cancer, although this effect was less clear in men with normal 
pre-treatment androgen production. 41 

The concept that exogenous T "feeds the fire" of prostate 
cancer has been challenged by subsequent retrospective analyses. 
Morgentaler et aV reported a higher than expected prevalence of 
occult prostate cancer in a retrospective series of 77 men with low 
serum T concentrations, normal prostate-specific antigen (PSA), and 
normal digital rectal exams. This report was followed with additional 
retrospective analyses of men with prostatic intraepithelial neoplasia 
treated with T therapy for 1 year and having no greater increase in PSA 
or significantly increased risk of cancer than men without prostatic 
intraepithelial neoplasia, 42 and a recent case series suggesting the safe 
treatment of men with a history of prostate cancer with T therapy. 43 
Others have also reported retrospective series of men safely treated 
with T therapy, following treatment for prostate cancer, 44 46 suggesting 
that while exogenous T may raise serum PSA concentrations, in 
appropriately selected subjects, T therapy may not increase the risk of 
clinically significant disease recurrence. 

While such retrospective reports are provocative, none of these 
analyses directly address the impact of T therapy on healthy prostate 
tissue and on long-term prostate disease risk. The response of prostate 



cancer to androgen deprivation therapy is unequivocal, but whether 
the converse is true, that exogenous T accelerates prostate cancer 
risk, disease, or recurrence has been called into question. Without 
appropriately designed and powered intervention studies, the true 
risk of T therapy on prostate disease is unknown. However, an 
understanding of the relationships between endogenous androgens 
and prostate cancer risk, as well as the prostate response to changes in 
the serum hormonal milieu, may inform current clinical practice and 
the design of future trials. 

Epidemiology linking endogenous androgens and prostate disease 

If increases in exogenous androgens increase prostate disease risk, one 
would expect that higher endogenous androgen concentrations would 
be positively associated with prostate cancer risk. Most studies to date 
have failed to find a strong relationship between serum T levels and 
prostate cancer. However, such longitudinal studies are complicated 
by many uncontrolled variables including the length of follow-up, 
sample acquisition (single versus repeat samples, fasting, time of day, 
etc.), sample storage, assay characteristics, and disease reporting during 
follow-up. The Baltimore Longitudinal Study on Aging 47 has the longest 
such follow-up and includes serial androgen measures performed 
over a period spanning nearly 40 years. In this cohort, Parsons et al. 
found that higher calculated fT levels were positively associated with 
prostate cancer risk (relative risk 2.59), while hypogonadal men had 
49% lower risk of prostate cancer compared to age-matched, eugonadal 
men. Further analysis of men in the Baltimore Longitudinal Study on 
Aging 48 examined the relationship between serum T concentrations 
and high-risk prostate cancer, defined as death from prostate cancer, a 
PSA level >20 ng ml" 1 , or a Gleason score >8. The incidence of high-risk 
prostate cancer among men >65 years was significantly increased for 
those in the highest tertile of fT concentration (hazard ratio 2.07), 
although this was not true for men <65 years. Adding to the concern 
that higher endogenous androgen levels contribute to prostate disease, 
the Rancho Bernardo Study 49 found a positive relationship between 
baseline serum DHT levels and the development of BPH over 8 years 
of follow-up. Of note, however, is that in a subsequent analysis, among 
the 158 surviving participants without prostate cancer in this cohort 
the relationship with serum DHT did not persist, and in fact an inverse 
relationship was noted at 20 years between the development of lower 
urinary tract symptoms and serum bioavailable T. 50 

In contrast to the aforementioned publications, a number of studies 
have failed to find a positive association between endogenous serum 
androgen concentrations and the development of prostate disease. 51,52 
In an effort to resolve these conflicting epidemiologic studies and 
increase the power of the analyses, the Endogenous Sex Hormones and 
Prostate Cancer Collaborative Group pooled data from 18 prospective 
studies of 3886 men with incident prostate cancer and 6438 control 
men. 53 In this collaborative analysis, serum concentrations of T, free 
T, DHT, DHEA-S, androstenedione, androstanediol glucuronide, 
estradiol, and calculated free estradiol, whether high or low, were not 
found to be associated with the risk of prostate cancer. While this 
analysis has some limitations, the pooled data clearly refute the notion 
that endogenous serum androgens are a strong, modifiable driver of 
prostate cancer development. 54 

Although serum androgen concentrations are not clearly 
linked to the development of prostate disease, what about the 
concentration of androgens within the gland itself? Recent data 
from large, randomized-controlled trials 55,56 have demonstrated that 
interference with the intraprostatic hormonal environment may 
reduce the incidence of some prostate cancers. Before abandoning a 



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251 



hormone-driven hypothesis regarding androgens and prostate disease 
altogether, it is important to consider the impact that androgens, and 
the manipulation of androgen metabolism, have on prostate growth 
and the intraprostatic hormone environment. 

Intervention trials of testosterone replacement and effects on prostate 
volume and prostate-specific antigen 

Small trials of androgen replacement in T deficient men have been 
reassuring regarding prostate health. While underpowered to look at 
hard clinical endpoints, numerous trials of T therapy have included 
clinical surrogates of prostate effects including prostate volume, PSA, 
and lower urinary tract symptoms and obstruction. Correction of 
biochemical hypogonadism can be associated with mild increases in 
prostate volume and PSA. Behre et al. 51 compared prostate volume, 
serum PSA, and uroflow parameters in three groups of age-matched 
men with either newly diagnosed hypogonadism (never been on T 
therapy), hypogonadal men with at least 6 months of T therapy, or 
healthy, eugonadal men. Untreated hypogonadal men had significantly 
lower prostate volumes and PS A in comparison to hypogonadal men on 
T therapy and eugonadal, age-matched controls. However, there were no 
significant differences in prostate volume, PSA, or uroflow parameters 
between hypogonadal men on T therapy and healthy controls. Further, 
studies 58 looking at the effects of T therapy on PSA also demonstrated 
only minor elevations in PS A in hypogonadal men treated with T over a 
period of 30 months, and these changes were manifested largely within 
the first 6 months of therapy. Consistent with these results, Bhasin et al. 59 
showed that in 60 older men treated with a GnRH agonist to suppress 
endogenous T and then given back T in dosages ranging from 25 to 
600 mg weekly for 20 weeks, there was a dose-dependent correlation 
with T and free fat mass and muscle strength, but not with PSA. Together 
these studies support the concept that correction of hypogonadism to 
eugonadal levels has mild prostate effects, but that these effects are not 
cumulative over time or with dose, but rather result in a new equilibrium 
akin to that of eugonadal, age-matched men. 

An initial meta-analyses of randomized, controlled trials of 
androgen replacement in older hypogonadal men found no overall 
increase in the incidence of prostate cancer, symptoms associated 
with BPH, clinically significant PSA increases, PSA levels prompting 
biopsy, or prostate biopsies performed in the combined treatment 
group compared to placebo. 60 More recently, Fernandez-Balsells et al. 1 " 
looked in further detail at compiled data from 51 studies of T therapy 
ranging from 3 months to 3 years in duration. While significant effects 
of T were seen on hematocrit and high-density lipoprotein cholesterol, 
there were no significant increases in prostate-related adverse events in 
those on treatment versus controls (including PSA, need for prostate 
biopsy, incidence of prostate cancer, or changes in lower urinary tract 
symptoms) . While the quality of evidence included in the meta-analysis 
was influenced by the short duration of exposure in the studies 
included, it nevertheless is reassuring that no large effect on prostate 
health has been overlooked in the trials of T therapy conducted to date. 

Although limited intervention trials have not demonstrated 
an increase in prostate-related adverse events in men receiving 
testosterone replacement therapy, determining how to best monitor 
men for prostate health while on T-therapy is difficult, and current 
guidelines are not evidence-based. Unfortunately, simply following 
a PSA in men at baseline and following initiation of T therapy is not 
sufficient, as PSA is an androgen-responsive gene likely to modestly 
increase when serum T levels rise, potentially leading to unnecessary 
prostate biopies. Moreover, the routine use of PSA to screen for prostate 
cancer is no longer recommended, 61 since large trials have failed to 



show a mortality benefit in low-risk individuals. 62,63 We believe these 
new recommendations should influence clinical decisions regarding 
obtaining a baseline PSA in many men being considered for T therapy. 
In an effort to minimize the potential for invasive testing and the 
overdiagnosis of prostate cancer in men on T therapy, the Endocrine 
Society, in their 2010 guidelines, recommend following the PSA in 
those individuals >40 years of age who have a baseline PSA value, 
and using a rise in > 1 .4 ng ml" 1 per year as a trigger for more invasive 
testing, noting that the average increase in PSA for men on T therapy 
is approximately 0.5 ng ml" 1 . 5 Given the recent shift away from PSA 
screening in most men, and the lack of data linking T therapy and 
prostate cancer, we suggest that in men with a known, organic cause 
of primary or secondary hypogonadism (i.e., genetic abnormality, 
pituitary surgery or defect, drug effect such as long-term opiates, etc.), 
who receive T therapy targeted to the normal range for healthy men, 
consensus guidelines for use of PSA screening be followed. For these 
men, a baseline PSA should only be obtained after a full discussion 
with the patient regarding the pros and cons of PSA screening and 
not be offered to men <55 years of age. In men with risk factors for 
prostate cancer, those treated for late-onset hypogonadism, and all 
men initiating T therapy ages >55 and <70 years of age we follow the 
Endocrine Society guidelines as outlined above, obtaining a baseline 
PSA and then monitor PSA after 4-6 months and then annually 
thereafter, and recommend a prostate biopsy if we observe a PSA 
increase of > 1 .4 ng ml" 1 per year. The critical issue in all cases is having 
an informed and documented communication process surrounding the 
pros and cons of PSA screening to ensure that each individual realizes 
the risk of biopsies, overdiagnosis, and the lack of clarity regarding the 
relationship between T therapy and prostate cancer risk. Hopefully, 
with the results of the ongoing large, randomized trial of T therapy in 
older men 64 becoming available over the next few years, the approach 
to monitoring prostate health on T therapy can be further refined. 

The limited data available regarding the effects of supraphysiologic 
dosing of androgens on prostate health also do not point toward 
a significant role for circulating androgens in promoting prostate 
hyperplasia or cancer. Young men who chronically abused anabolic 
steroids for athletic purposes had similar prostate volumes and PSA 
levels compared to age- matched controls. 65 Similarly, healthy young 
men who are acutely administered intramuscular T at doses as high 
as 500 mg weekly (fivefold the physiologic replacement dose) for 
1 5 weeks did not have significant changes in PSA or prostate volume. 66 
In two dose-response studies of T administration after GnRH agonist 
treatment, no dose-related increases in PSA or prostate volume were 
reported over 16-20 weeks of treatment. Furthermore, in both of 
these studies PSA levels were reduced when T was decreased below 
baseline but did not increase with increases in T above baseline. 59,67,68 In 
summary, in studies of high-dose T supplementation, prostate-related 
measures do not appear to be dose sensitive to serum T concentrations 
above approximately 300 ng ml" 1 , the lower limit of the normal range 
for healthy young men. 

What about giving androgens to men with known prostate 
enlargement? Arguably, this might be a strategy for unveiling prostate 
effects in a more androgen- sensitive population. Men with symptomatic 
BPH and LUTS have generally been excluded from studies of T therapy 
with concern for symptom exacerbation and even urinary retention 
due to further androgen-induced increases in prostate volume. Several 
recent studies have suggested that this is not a clinically significant 
concern. We recently assessed the effect of T therapy in older men with 
symptomatic BPH who had enlarged prostates (>30 cc by magnetic 




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252 

resonance imaging) and hypogonadism. Subjects were randomized to 
receive T therapy in combination with placebo or the 5ocR inhibitor 
dutasteride (to inhibit the conversion of T to DHT) for 6 months. Despite 
correction of biochemical hypogonadism, neither group experienced an 
increase in prostate volume nor International Prostate Symptom Scores 
with treatment (the latter of which actually improved slightly in both 
groups), and there were no prostate-related adverse events. Moreover, 
the groups receiving T in combination with dutasteride had a significant 
decrease in both PSA and prostate volume compared to baseline. 69 
Overall, these data suggest that the effect of normalization of serum 
T levels in older, hypogonadal men on prostate volume is probably 
clinically safe, even in the setting of pre-existing prostate enlargement, 
and support the hypothesis that the relationship between serum T 
concentrations and prostate growth is likely non-linear. 

5aR inhibitors and prostate disease 

Due to the high levels of expression of 5ocR, the androgen environment 
within the prostate is unique. Three isoforms of 5ocR have been 
described. 70-72 The prostate expresses high levels of the type 2 5ocR 
and is thus capable of in situ conversion of T to DHT. This conversion 
results in intraprostatic DHT concentrations that are ~ 10-fold higher 
than T and 100-fold greater than serum DHT. 33 Conversely, in serum 
T concentrations are 10-fold greater than DHT concentrations. Thus, 
in the healthy human prostate, a gradient of both DHT and T is 
maintained relative to serum. Since DHT binds with higher affinity 
to the AR, the high levels of DHT relative to T in the prostate might 
be considered an amplification of androgen signaling within the tissue 
compared to serum. Thus, inhibition of 5ocR more profoundly affects 
the prostate as compared to other androgen-sensitive tissues that rely 
on T for androgen signaling. Currently, two 5ocR inhibitors are available 
for clinical use. Finasteride, which is specific for the type 2 isoform of 
5ocR, and dutasteride, which inhibits both type 1 and type 2 isoforms. 
Treatment with a 5ocR inhibitor results in very little increase in serum 
T levels, while serum DHT levels are reduced by 70% (finasteride) 
to 95% (dutasteride). 73,74 Large, randomized, controlled trials have 
demonstrated that both F and dutasteride produce significant prostate 
shrinkage and lower serum PSA when taken by men with BPH. 75 " 79 

Recent placebo-controlled trials with 5ocR inhibitors have found 
that long-term treatment with 5ocR inhibitors in older men can reduce 
the incidence of some prostate cancers. The Prostate Cancer Prevention 
Trial (PCPT) demonstrated that administration of F to older men 
results in a 25% reduction in the incidence of prostate cancer compared 
to placebo. 80 Similar risk reduction in prostate cancer incidence was 
reported for dutasteride in the Reduction by Dutasteride of Prostate 
Cancer trial. 55 In the PCPT, the overall reduction in prostate cancer 
incidence resulted from a reduction in the incidence of low-grade 
disease, while higher-grade prostate cancers were paradoxically 
increased in the treatment group. Post hoc analyses of these specimens 
has suggested that this increase in high-grade disease may have been 
the result of ascertainment bias due in part to decreased prostate 
volume, 80,81 but it is conceivable that low androgen levels within the 
gland resulted in a de-differentiation of pre-malignant lesions. 82,83 In 
Reduction by Dutasteride of Prostate Cancer, 6729 men age 50-75 years 
old with PSA levels 2.5-10.0 ng ml" 1 and negative prostate biopsies 
6 months prior to enrollment were randomized to receive either placebo 
or dutasteride over a 4-year period with prostate biopsies performed at 
2 and 4 years. Over the 4-year period of time, dutasteride provided a 
relative risk reduction of 22.8% over placebo, similar to that reported for 
the PCPT. However, like the PCPT, there was a higher risk of high-grade 
disease in those men treated with a 5ocR inhibitor in years 3 and 4 



despite clear reductions in risk of low-grade disease with treatment. 84 
Together, these large trials support the concept that reductions in 
androgens may prevent some prostate cancers in older men. The 
mechanism through which this might occur has not been determined 
but theorectially could result from the impact of reduced intraprostatic 
DHT concentrations on prostate epithelial cell apoptosis. 85,86 

One possible strategy for specifically reducing the prostate effects 
of T therapy while retaining the anabolic effects of T in other tissues 
has been to combine T with a 5ocR. Based upon data from PCPT 
and Reduction by Dutasteride of Prostate Cancer, it is possible that 
such a strategy might provide some chemopreventative effects as 
well. Tenover and his colleagues demonstrated this to be an effective 
strategy for T therapy using prostate volume and PSA as markers 
of prostate of response. They demonstrated a neutralizing effect on 
prostate growth when T was combined with F over a 3 year period, 
despite maintaining favorable effects of T replacement on bone, 12 body 
composition, and strength. 11 Bhasin et al. w recently expanded on these 
findings, demonstrating that the addition of dutasteride to T did not 
impact the dose-response-related anabolic endpoints associated with 
T administration. 

In summary, 5ocR inhibitors significantly decrease prostate size, 
PSA, and the incidence of low-grade prostate cancer in older men. 
Small studies conducted during the development of 5ocR inhibitors 
demonstrated that these agents potently alter the intraprostatic 
androgen environment. In men with BPH, administration of a 5aR 
inhibitor markedly reduces intraprostatic concentrations of DHT, 
similar to the effects of these agents on serum concentrations of DHT. 
However, in contrast to the marginal effects observed on serum T 
levels, inhibition of 5ocR results in a marked, compensatory increase in 
intraprostatic T concentrations. 88-91 These alterations in intraprostatic 
androgens are presumed to be the mechanism, whereby 5ocR inhibitors 
exert their clinical benefits. It is of interest, therefore, to examine the 
effects of androgen manipulation in other clinical settings on the 
intraprostatic hormonal milieu, in order to further our understanding 
of both prostate physiology and perhaps aid in the prediction of the 
effects these interventions may have on disease. 

Intraprostatic androgens 

The question of whether alterations in serum androgens are mimicked 
within the intraprostatic hormonal milieu may be relevant when 
considering the risks and benefits of T therapy in older men. Recent 
data suggest that while large decreases in serum androgens, such as in 
the setting of medical castration, also lower intraprostatic androgens, 
the degree of change in each compartment may not be equivalent. 92 94 
Moreover, two recent studies examining the effects of exogenous 
androgens on intraprostatic hormone levels have failed to show parallel 
increases in serum and prostate androgen concentrations. 95,96 

Provocative studies demonstrating high concentrations of 
intraprostatic androgens in castration-resistant, metastatic prostate 
cancers despite longstanding castration 93,94 have complimented the 
growing body of literature examining the impact of 5ocR inhibitors on 
intraprostatic androgen concentrations. In both cases, manipulation 
of serum androgens was not mirrored within the prostate. In an 
observational study, Mohler et al. 93 found high levels of T within 
these prostate tumors, equivalent to levels in non-neoplastic prostate 
tissue, despite serum T levels in the castrate range, suggesting the 
possibility of intratumoral androgen synthesis. Intraprostatic androgen 
synthesis has been postulated by others and a number of groups have 
demonstrated the expression of androgen-synthetic enzymes within 
the prostate. 97 " 99 In the healthy prostate, treatment for 1 month with 



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Androgens and prostate disease 

LA Cooper and ST Page 



a potent GnRH antagonist 92 decreased serum T levels by 94% and 
decreased intraprostatic androgen concentrations, but only by 70%- 
80% compared to controls. Androgen-regulated gene expression, PSA, 
and AR expression were also maintained compared to controls. Thus, 
while medical castration profoundly affects serum androgen levels, 
there is a relative preservation of androgen concentration and action 
within the prostate gland. 

Accumulating data suggest that changes in the intraprostatic 
hormonal milieu resulting from androgen supplementation may not 
be dose-dependent. Studies in rodents suggest that supraphysiologic 
levels of circulating T and DHT in intact rats do not result in prostate 
growth. 100101 In an elegant study by Wright et al. m castrated rats 
were implanted with increasing doses of T or DHT pellets for 7 days. 
Despite a nearly 100-fold increase in serum T or DHT concentrations 
at the maximum dose, intraprostatic DHT increased only 10-fold and 
intraprostatic T was no different compared to placebo-treated castrate 
rats. Of note, when the 5ocR inhibitor F was included with T treatment, 
intraprostatic DHT levels remained near those of placebo-treated, 
castrate controls even at the highest dose of T administered. Moreover, 
measures of prostate androgen response (prostate weight, duct mass, 
and deoxyribonucleic acid content) were twofold to threefold more 
responsive to intraprostatic DHT compared to T, demonstrating the 
greater potency of DHT within prostate tissue. The authors concluded 
that there was a threshold of intraprostatic T and DHT required to 
initiate prostate regrowth in their model. In addition, they postulated 
that the inclusion of a 5ocR inhibitor to T treatment increased the serum 
T level at which these intraprostatic androgen thresholds were reached 
bylO-15-fold by blocking not only conversion of T to DHT, but also by 
inhibiting androgen accumulation within the prostate at low serum T 
concentrations. 102 The mechanism by which this accumulation occurs 
was not elucidated. 

In humans, two recent studies have evaluated the effect of exogenous 
androgens on intraprostatic androgen concentrations. Marks et al. 95 
studied 40 elderly men with low serum T who received either placebo 
or low-dose T replacement for 6 months. Prostate core biopsies were 
obtained at baseline and following treatment. T replacement raised 
serum T levels by 2-2.5-fold while keeping them well within the normal 
range for healthy young men, but did not raise intraprostatic T or DHT 
compared to baseline and to the placebo group. Likewise, markers of 
androgen action, including prostate epithelial cell gene expression 
and proliferation, were no different between groups or compared to 
baseline. Only serum PSA, but not prostate volume, increased from 
baseline in the T-treated group, while the percentage of atrophic 
glands tended to decrease with T treatment. While this important trial 
was reassuring regarding the impact of androgen replacement on the 
prostate, it was somewhat limited in terms of both the small number 
of subjects and the modest level of T exposure in the treatment group. 
A second study looked at the shorter-term effects of exogenous DHT on 
intraprostatic hormone levels in healthy men. 96 Consistent with results 
from Marks et al? 5 significant increases in serum DHT concentrations, 
more than seven fold normal serum concentrations, had no impact on 
intraprostatic DHT and T levels, and no significant effects on PSA and 
prostate volume. Together, these studies have led to the proposal that the 
prostate may harbor a "buffering" system which allows for maintenance 
of intraprostatic androgen levels despite fluctuations in serum levels, at 
least within the normal range of serum T concentrations. Both of these 
studies are consistent with the concept that intraprostatic androgens are 
not concomitantly increased when serum androgen levels are raised. 

Morgentaler and Traish 103 have recently proposed a model to 
explain these and other observations wherein the prostate appears to 



253 

be sensitive to low, but not high levels of circulating androgens. The 
"saturation model" proposes that the prostate is sensitive to very low 
concentrations of circulating androgens, but that once maximal AR 
binding is achieved, which occurs at relatively low concentrations of 
circulating T, further increases in serum T have little impact. This 
model is consistent with studies in rodents. 100102 It can also explain the 
ability of low levels of intraprostatic androgens to maintain prostate 
gland size and PSA. 104 It is also consistent with observations by Fowler 
and Whitmore, 40 wherein men with metastatic prostate cancer given 
T who had been previously treated with castration had worsening of 
disease, whereas those without prior castration did not. The saturation 
model, however, does not explain why such saturation responses are 
not observed in other tissues such as muscle and bone, which have 
more linear dose- responses to escalating doses of exogenous T. Further 
studies are needed to substantiate the saturation model before it is used 
as the basis for therapeutic decision making. 

CONCLUSION 

Male hypogonadism has been associated with many comorbidities, and 
T therapy can offer several benefits including improvements in strength, 
bone mass, and some aspects of sexual function. While new evidence 
links low T levels and mortality, there is persistent concern that 
T therapy will stimulate the development of prostate carcinomas. The 
real risk of prostate disease posed by the administration of T therapy 
is unknown. Additionally, more studies are needed to determine the 
differences in serum and intraprostatic androgens and what effects 
long-term manipulation of the intraprostatic hormonal environment 
may cause. Despite the elegant explanation offered by the saturation 
model, its relevance to both normal and neoplastic prostate physiology 
is unproven at this time. 

Currently, a large, multicenter trial looking at 800 hypogonadal 
men on T therapy (The T Trial in Older Men) 64 is underway to assess 
the benefits of T therapy in older men, yet it is not powered to assess 
risk. There is little data to support the withholding of T therapy on the 
basis of concern for precipitating prostate cancer. Both intervention 
data and physiology studies point to minimal effects on the prostate 
gland when serum T levels are increased to the mid- normal range with 
T therapy. However, given the paucity of hard data, current clinical 
guidelines are appropriately conservative 5 in implementing its use 
only in those without a personal history of prostate cancer. Thus, an 
individualized care plan to assess the possible risks and benefits of T 
therapy for each patient is critical to optimizing the use of androgens 
in male health. 

ACKNOWLEDGMENTS 

L.A.C is supported by a grant from the National Institutes of Health, 
T32HL0007028. S.T.P. is supported by NIH/NIA grant 1R01AG037603, NIH/ 
NICHD (U54HD042454), and the Robert B. McMillen Professorship in Lipid 
Research at the University of Washington. We thank Daniel Stone for his editing 
and critical review of this article. 

COMPETING INTERESTS 

S.T.P receives Androgel and placebo gel at no cost from Abbvie Inc. 
for use in investigator-initiated study NCT01327495. 

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How to cite this article: Cooper LA, Page ST. Androgens and prostate 
disease. Asian J Androl 23 December 2013. doi: 10.4103/1008- 
682X.122361. [Epub ahead of print] 




Asian Journal of Andrology