NIH Public Access: Cholesterol and Benign Prostate Disease

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Differentiation. Author manuscript; available in PMC 2014 June 10.
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Differentiation. 2011 ; 82(0): 244–252. doi:10.1016/j.diff.2011.04.005.
Cholesterol and Benign Prostate Disease

Michael R. Freeman1,2,3,* and Keith R. Solomon1,4
1TheUrological Diseases Research Center, Children's Hospital Boston Harvard Medical School
Enders Research Laboratories 300 Longwood Ave. Boston, MA 02115
2Departments of Surgery, Children's Hospital Boston Harvard Medical School Enders Research
Laboratories 300 Longwood Ave. Boston, MA 02115
3Biological
Chemistry and Molecular Pharmacology, Children's Hospital Boston Harvard Medical
School Enders Research Laboratories 300 Longwood Ave. Boston, MA 02115
4Orthopaedic Surgery, Children's Hospital Boston Harvard Medical School Enders Research
Laboratories 300 Longwood Ave. Boston, MA 02115
Abstract
The origins of benign prostatic diseases, such as benign prostatic hyperplasia (BPH) and chronic
prostatitis/chronic pelvic pain syndrome (CP/CPPS), are poorly understood. Patients suffering
from benign prostatic symptoms report a substantially reduced quality of life, and the relationship
between benign prostate conditions and prostate cancer is uncertain. Epidemiologic data for BPH
and CP/CPPS are limited, however an apparent association bet ween BPH symptoms and
cardiovascular disease (CVD) has been consistently reported. The prostate synthesizes and stores
large amounts of cholesterol and prostate tissues may be particularly sensitive to perturbations in
cholesterol metabolism. Hypercholesterolemi, a major risk factor for CVD, is also a risk factor for
BPH. Animal model and clinical trial findings suggest that agents that inhibit cholesterol
absorption from the intestine, such as the class of compounds known as polyene macrolides, can
reduce prostate gland size and improve lower urinary tract symptoms (LUTS). Observational
studies indicate that cholesterol-lowering drugs reduce the risk of aggressive prostate cancer,
while prostate cancer cell growth and survival pathways depend in part on cholesterol-sensitive
biochemical mechanisms. Here we review the evidence that cholesterol metabolism plays a role in
the incidence of benign prostate disease and we highlight possible therapeutic approaches based
on this concept.
Keywords
BPH; CP/CPPS; cholesterol; statins; ezetimibe (Zetia)
© 2011 Interational Society Of Differentition. Published by Elsevier B.V. All rights reserved.
*
Correspondence Michael R. Freeman, PhD: michael.freeman@childrens.harvard.edu Keith R. Solomon, PhD:
keith.solomon@childrens.harvard.edu.
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Freeman and Solomon Page 2
The human prostate is subject to a variety of pathologic conditions and syndromes that are
not well understood. The prevalence of benign prostatic hyperplasia (BPH) and chronic
prostatitis/chronic pelvic pain syndrome (CP/CPPS) greatly exceeds that of prostate cancer,
which is the most common non-cutaneous malignancy among males in the United States.
BPH and CP/CPPS have been documented to reduce quality of life to a similar extent as
hypertension and heart disease.1, 2 Both conditions affect adults of all ages, yet they can co-
exist with prostate cancer, and their mechanistic relationship to prostate cancer, and to other
pre-malignant conditions, such as prostatic inflammatory atrophy (PIA)3, is uncertain.
While prostate cancer has been extensively studied and much is now known about this
disease at the molecular level, there has been comparatively little study of BPH and CP/
CPPS using modern tools, and the etiology and natural history of these conditions are poorly
described in mechanistic terms. These limitations are major obstacles preventing rational,
targeted strategies for new therapeutic interventions. A recent meta-analysis summarizing
the state of the literature on the findings of randomized controlled trials for CP/CPPS4
revealed that no effective therapy currently exists for this condition. Although medical
therapies for BPH have resulted in a substantial decrease in traditional surgical approaches5,
the effectiveness of the current medical treatments, primarily alpha-blockers and 5α-
reductase inhibitors, is difficult to evaluate6. In addition, data are not available on the
percentage of men on medical therapy who go on to more invasive therapy at a later time.
BPH as a clinical condition is not well defined and histologic confirmation of BPH is rarely
attempted. Because objective information about underlying mechanisms in benign prostate
disease is largely lacking, much confusion and inconsistency exists in the literature, and in
clinical practice, on clinical categories, terminology and therapeutic recommendations7.
Prostate health and metabolism

Despite the lack of basic information and well-defined clinical data, most investigators have
concluded that prostate health is highly susceptible to lifestyle and stage-of-life influences8.
This association with lifestyle likely reflects a complex interplay between genetic,
epigenetic, biochemical and metabolic processes. In the last two decades in Western
countries it has become clear that interactions between the genome and lifestyle are rapidly
changing the incidence of human disease in unpredictable ways. This is particularly evident
in the US where sedentary habits, a high calorie diet and obesity are now widespread. Tissue
homeostasis is regulated in part by dietary components that mediate reactions to oxidative
stress and inflammation9. For example, type 2 diabetes, which is now appearing for the first
time at significant rates in children, is driven by a sedentary lifestyle in combination with
dietary behaviors that lead to obesity10. The epidemiologic associations seen in diabetes are
partly understood to reflect alterations in the phenotype and endocrine function of adipose
tissue, which secretes a number of adipokines that exert potent effects throughout the body,
including the promotion of a chronic state of low-level inflammation11. Effects of lifestyle
or dietary regimen are likely to emerge in distinctive ways in different organ systems as
metabolic and endocrine processes intersect with the genetic and epigenetic programming of
specialized cells and tissues.

Cholesterol, signal transduction and gene expression

Our laboratory has focused for a number of years on the role of the neutral lipid, cholesterol,
in signal transduction in tissues and cells of the urogenital system. In vertebrate cells,
cholesterol represents about one third of the plasma membrane lipids and its concentration in
membranes is tightly regulated, even in the face of wide swings in bioavailability.
Cholesterol is one of the key regulators of membrane dynamics by its tendency to closely
pack the acyl chains of membrane phospholipids, thereby stabilizing local membrane
structure12. The effect of cholesterol on membrane lipid packing serves to partition
membranes into cholesterol-rich, “liquid-ordered” and cholesterol-poor, “liquid-disordered”
microdomains. Liquid-ordered microdomains have been termed “lipid rafts” to evoke the
image of relatively stable membrane patches floating in a more dynamic “lipid sea.”13 The
membrane segmentation provided by cholesterol, in association with other lipids, exerts
major influences on signal transduction. Along with glycosphingolipids and lipidated
signaling proteins, such as caveolins, cholesterol facilitates the three-dimensional assembly
of multi-protein signaling complexes within cholesterol-rich subcompartments14. This
membrane partitioning promotes interactions between potential protein binding partners by
segregating protein subunits with—and away from—interacting proteins that process
discrete classes of signals. The lipid raft model of membrane organization posits that
cholesterol-rich microdomains channel extracellular stimuli down discrete biochemical
pathways to the nucleus15.
In addition to the formation of lipid raft complexes, cholesterol can also affect signal
transduction and gene expression in other ways. Certain signaling proteins, such as Sonic
hedgehog (SHH), a secreted cytokine, are post-translationally modified by covalent addition
of cholesterolcholesterol. SHH has been linked to fetal prostate development16-18 as well as
prostate cancer19,20, and the cholesterol modification may be involved in formation of
bioactive gradients across tissue spaces21. Cholesterol also serves as a metabolic precursor
for synthesis of steroid hormones, such as androgen, which are the primary activators of
transcription by their cognate nuclear receptors. Many studies using cultured cells have
identified substantial effects on gene and protein expression by depleting or adding
cholesterol to cellular membranes22-25. Certain signaling proteins, which show sensitivity to
manipulations of membrane cholesterol at the level of the plasma membrane, also directly
regulate cholesterol and/ or lipid metabolism. An example is the serine theonine kinase,
AKT, which localizes to lipid rafts and whose activity can be altered by manipulating
membrane cholesterol26, 27. AKT is an important regulator of cell growth and survival and
indirectly controls, at the transcriptional level, a large suite of genes involved in cholesterol
and lipid biosynthesis28.
Cholesterol and prostate cancer

Recent epidemiologic studies from a number of groups have shown that cholesterol-
lowering drugs (primarily 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
inhibitors, known generically as “statins”) may lower prostate cancer risk, and in particular,
the risk of advanced disease29-35. However, this literature is complicated to interpret and
littered with confusing claims and counter-claims. There are four types of epidemiological

studies that shed light on the relationship between prostate cancer and cholesterol: (1) large
population studies of cholesterol and mortality, (2) population studies specifically focused
on cholesterol and prostate cancer incidence/mortality, (3) randomized studies examining
cholesterol-lowering drugs (mostly statins) and cancer risk, and (4) observational studies
either examining cholesterol level or cholesterol-lowering drugs and prostate cancer risk.
These four study types tend to paint different pictures of the cholesterol-prostate cancer
relationship.
Population studies of cholesterol and cancer mortality tend to show that low cholesterol is
associated with cancer risk in general, a finding that is almost certainly due to the metabolic
activity of tumors, including tumors not yet clinically detected3637, 38. This metabolic effect
of pre-existing tumors on cholesterol levels can confound attempts to address the question of
whether high circulating cholesterol might increase risk of specific cancer types. Population
studies with a specific focus on prostate cancer have shown that low cholesterol is
associated with less aggressive prostate cancer, or an overall reduced risk of prostate cancer-
specific mortality3940-42. Randomized placebo controlled trials of statins that report on
cancer of many kinds show no relationship with statin drug use and prostate cancer434445.
Finally, as of this writing, many observational studies of prostate cancer and statin use have
demonstrated an apparent chemopreventive effect of statin drugs on either overall prostate

cancer incidence or the risk of advanced disease30,32,33,46,47.
The reason for the disparate findings in these studies likely originates from study design and
the types of data gathered. We will thoroughly explore the differences between these study
types, the data they have generated, and the reasons underlying the conclusions that can be
drawn from these data sets in an upcoming review of these studies (Solomon and Freeman,
manuscript in preparation). Here we will briefly touch on some of the most prominent
distinctions. Large inclusive population studies on cancer typically include small numbers of
prostate cancers, and few to no prostate cancer deaths. In 52 studies with 7.95 million
individuals, only 1,128 prostate cancer cases are recorded and few of these are deaths.
Population studies of cholesterol level include many more prostate cancer patients (3,273
prostate cancers in 369,206 patients) and more advanced cases or cases leading to death.
Large randomized placebo controlled trials of statins include limited numbers of prostate
cancers. We reviewed 49 trials that included 134,516 individuals and identified only 5
prostate cancer deaths and 1,142 incident prostate cancer cases, and these trials were of
relatively short duration (4.2 years on average). Observational studies of prostate cancer risk
and statin use include many more prostate cancer cases (77,325 in a population of
4,168,049) in studies examining men for up to 14 years. When considered in aggregate, the
current literature is consistent with the view that HMG-CoA-reductase inhibitors exert
moderate protective effects against prostate cancer progression, while the effect on incident
prostate cancer is still uncertain (and given the heterogeneity of the disease, may be
impossible to evaluate).
Our group has provided mechanistic evidence in support of potential chemopreventive

effects of cholesterol-lowering in prostate cancer. In a series of laboratory studies over the
past 9 years, we have shown that a variety of signal transduction mechanisms, including
those propagated by the prosurvival kinase AKT23, 24, 27, androgen receptor48, IL-649,

STAT349, caveolin-150, and other proteins and pathways relevant to prostate cancer involve
constituents that localize to cholesterol-rich microdomains. We and others have shown that
the biochemical activity of lipid raft-associated proteins can be re-directed by targeting
plasma membrane cholesterol in cell culture22, 25, 49. Our studies have also demonstrated
that these membrane-associated proteins, and their functional roles, can be altered by
changes in circulating cholesterol in vivo23, 51. From the point of view of therapy or
chemoprevention, circulating cholesterol can be effectively reduced by widely used, well-
tolerated medications, which also confer additional health benefits. Consistent with
population studies showing evidence of inhibition of disease progression with long-term
statin therapy, our research has demonstrated that high circulating cholesterol promotes,
while cholesterol-lowering retards, the growth of human prostate cancer xenografts in
mice23, 51. Taken together, these data point to the possibility that prostatic cells respond to
the external cholesterol environment in a manner that alters their potential for growth and
possibly other cell activities.
Metabolism and the prostate

Because tumor cells retain programming that reflects the cells and tissues of their origin52,
one implication of the cholesterol-sensitivity of prostate cancer is that the normal prostate
might also be affected in significant ways by changes in cholesterol metabolism. The
prostate synthesizes high levels of cholesterol, at similar rates or in excess of those seen in
the liver, and the prostate accumulates cholesterol deposits with age53. BPH, as defined by
several criteria, including lower urinary tract symptom (LUTS) score and prostate growth
rate, correlates with symptoms of metabolic syndrome, such as low HDL cholesterol levels,
peripheral insulin insensitivity, high body mass index (BMI), high triglyceride levels and
large waist circumference54. A recent community-based cohort study found a four-fold
increased risk of BPH among diabetic men with LDL cholesterol in the highest tertile in
comparison to men in the lowest tertile55. There has been very limited study of the effects of
statins on BPH, with two studies showing no discernable effect56, 57 and one study showing
statin use to be associated with a 6.5-7-year delay in onset of moderate to severe LUTS or
benign prostatic enlargement58. Several studies indicate that heart disease, diabetes and
metabolic syndrome are associated with increased risk or severity of BPH59-62. To date,
there are no reports in humans of the effects of statins on CP/CPPS. These findings are
consistent with data from a number of groups indicating a demonstrable relationship
between LUTS and metabolic syndrome-like symptoms and/or cardiovascular disease. This
potential relationship has led to the suggestion that a healthy heart = a healthy prostate.8
If such a relationship exists, the underlying mechanisms are unknown. Statin drugs inhibit
the bioactivity of HMG-CoA-reductase, a proximal enzyme in the mevalonic acid pathway
that synthesizes cholesterol. However, HMG-Co-reductase inhibitors also reduce the
synthesis of the isoprenoid intermediates, farnesyl pyrophosphate and geranylgeranyl
pyrophosphate, which are involved in a number of biosynthetic processes, including post-
translational modification (isoprenylation) of many signal transduction proteins, such as
RAS and RHO family GTPases13. Inhibition of isoprenoid synthesis by statins can therefore
disrupt many signal transduction cascades relevant to cell turnover, survival and
differentiation. Other complications in interpretation arise from the results of experiments

with statins in animal models. In contrast to humans, circulating cholesterol in rodents is

largely in the form of HDL, not LDL;63 moreover, statins are ineffective at lowering serum
cholesterol in rats and mice,64 the conventional subjects of pre-clinical studies. Thus, reports
of statin effects in these species65, 66 are largely due to inhibition of isoprenoid synthesis,
most often from typically large, supraphysiologic doses, or from methods of application that
bypass the liver, and not from cholesterol lowering. Similarly, while statins potently lower
cholesterol levels in humans, their multiple effects complicate attempts to translate
epidemiologic findings into mechanistic conclusions.
Cholesterol and inflammation

Pathologic effects of high circulating cholesterol are prominently seen in the formation of
atherosclerotic lesions. Accumulation of cholesterol-rich lipid deposits in arterial walls
precipitates and sustains inflammatory processes of the innate and adaptive immune
systems. In humans, under conditions of high circulating cholesterol, LDL particles
accumulate in the arterial intima, where they are enzymatically modified to become
stimulants of sustained inflammation. This involves a complex web of interactions between
endothelial cells, smooth muscle cells, monocytes, macrophages, lymphocytes, mast cells
and neutrophils67. Atherosclerotic changes are progressive, move through successive phases,
and develop slowly over decades. Importantly, clinical manifestations of advanced

atherosclerotic lesions can be reversed 20-40% by prolonged treatment with HMG-CoA-
reductase inhibitors68. Relative reductions in risk are proportional to the extent of LDL
cholesterol lowering across a broad range of LDL concentrations. These and other pre-
clinical data have identified cholesterol, and its byproducts (such as cholesteryl esters), as
principal mediators of local inflammatory changes in the cardiovascular system67.
Many human cancers (~20%) are believed to arise from chronic inflammatory or infectious
conditions69. Accumulating evidence now links pathologic or premalignant changes in the
prostate, as well as prostate adenocarcinoma, with inflammatory mechanisms3. Most BPH
tissues show evidence of an inflammatory reaction. In one study, only 23% of prostate
biopsies from 284 patients were free of infiltrating inflammatory cells70. The presence of
inflammatory infiltrates in BPH tissues obtained from patients in the Medical Therapy of
Prostatic Symptoms (MTOPs) study has been associated with increased rates of disease
progression and elevated risk of acute urinary retention5. Human BPH stromal cells isolated
from surgical specimens express all of the toll-like receptors (TLRs) of the innate immune
system and the TLRs expressed by these cells respond to bacterial or viral agonists by
secreting proinflammatory cytokines71. In addition, BPH stromal cells can act as antigen
presenting cells (APCs) by activating alloantigen-specific CD4+ T cells to secrete IFN-γ and
IL-1771. Our group recently published the results of an unbiased DNA microarray study of
BPH-like histomorphologic changes in the rat induced by chronic α(1)-adrenergic receptor
activation72. In this report, we used informatics tools to objectively construct a signaling
network that identified inflammatory pathways as the most significant gene ontology (GO)
processes associated with the experimental treatment, daily phenylephrine injection. We
verified aspects of this proposed BPH network in vivo by demonstrating elevated TGFβ
signaling, a classical inflammatory mechanism, and by confirming the informatics findings

that the signaling protein clusterin, which has been linked to anti-inflammatory
mechanisms73, is a prominent node in the network.
The origin of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is essentially

completely obscure, however evidence for an autoimmune origin is beginning to emerge.
Human CD4+ and CD8+ T cells recognize determinants present in prostate specific antigen
(PSA)74, suggesting the possibility that prostatic secretory products, some of which are
produced in large amounts, can elicit an autoimmune reaction. Peripheral blood
mononuclear cells (PBMC) and CD4+ T cells from CP/CPPS patients proliferate in the
presence of seminal plasma and in response to prostate antigens75, 76, indicating that the
immune system might identify components of the prostatic secretion as foreign. Consistent
with this hypothesis, seminal plasma from CP/CPPS patients has been reported to contain
high levels of proinflammatory cytokines, including IL-6, IL-8, IL-1β and TNFα77, 78 IL-8
has been proposed as a biomarker for CP/CPPS as well as BPH79. IL-6 and IL-8, in addition
to their roles in inflammatory cell recruitment, are mitogens for prostate cells80, 81,
suggesting the possibility that locally elevated concentrations of these inflammatory
mediators can alter the balance between cell growth and cell death required to maintain
tissue homeostasis.
In human prostate tissues, focal areas of epithelial atrophy can be recognized. These atrophic
regions are often accompanied by increased infiltration of inflammatory cells, leading De
Marzo and colleagues to propose the term “proliferative inflammatory atrophy” (PIA) for
this histologic feature3. Frequent transitions have been reported between areas of PIA, or
proliferative atrophy without inflammatory infiltrate, and high-grade prostatic intraepithelial
neoplasia (PIN)3. Inflammatory reactions preceding malignant changes are also observed in
animal models. For example, neonatal estrogen imprinting of the prostate results in lobe-
specific inflammation, hyperplasia, and PIN-like lesions in adult animals82. Genomic
searches for prostate cancer susceptibility genes have identified a number of loci involved in
innate or acquired immunity, including RNASEL, which encodes a ribonuclease expressed
by lymphocytes83; MSR1, encoding macrophage scavenger receptor 1, a homotrimeric
protein complex expressed largely by macrophages84; and TLR4, encoding a toll like
receptor and a mediator of innate and adaptive immunity85. Other loci that mediate
inflammatory processes have also been associated with increased prostate cancer risk85, 86.
Although the data are still limited, collectively, these observations suggest that the prostate
is susceptible to several types of inflammatory disruptions, particularly with age, and that
these reactions lead to pathology. Anti-inflammatory actions of statins (HMG-CoA-
reductase inhibitors) could potentially account for reported clinical efficacy of these drugs
on benign prostatic enlargement and LUTS58.
Cholesterol targeting and prostate health

Polyene macrolides, such as amphotericin B, candicidin, nystatin and filipin, are antifungal
agents that alter membrane permeability and structure. They are extremely effective as
antifungals because of their potency, broad spectrum of activity, and because the emergence
of resistant fungal strains is infrequent. However, when administered i ntravenously, they
are also toxic, causing serious side effects such as renal failure, hypokalemia and

thrombophlebitis. Using Mycoplasm a laidlawii grown in either the presence or absence of

cholesterol (the organism does not synthesize its own cholesterol), Weber and Kinsky87
demonstrated that sensitivity to filipin required cholesterol, a result that suggested that the
bioactivity of polyene macrolides was sterol-dependent. Subsequent s tudies demonstrated

that structural requirements of sterols necessary for their optimal interaction with polyenes
include the presence of a cholestane ring structure, a Δ 22 double bond, which allows for a
more favorable interaction with ergosterol than with cholesterol, and a 3β-OH on the steroid
nucleus, likely for membrane orientation88. These studies established that polyene
macrolides interact predominantly or specifically with sterols.
Later studies by Gordon and Schaffner,89 which were designed to determine the oral toxicity
of several polyene macrolides in a canine model, noted a surprising finding. The prostates of
dogs 7-15 years of age regressed after treatment with the compounds below at 5-20 mg/kg
day for 30 days. The change in prostate volumes was substantial, with the following average
reductions: candicidin 42.1% (100-300 mg/day), nystatin 20.9% (200-400 mg/day),
amphotericin B 37.2% (200-500 mg/day), filipin 39.3% (dose 200-400 mg/day) and
fungimycin 29.9% (100 mg/day). These same authors also noted that polyenes delivered
orally reduced serum cholesterol levels in beagle dogs by 36-50%, depending on the specific
polyene and the degree of hypercholesterolemia present. In these experiments, candicidin

exhibited the greatest hypocholesterolemic activity, with up to a 36% reduction dependent
on dose. Nystatin was the least potent agent, with a maximum 18% reduction in serum
cholesterol, including at higher doses,90. Notably, the authors observed no toxicity with any
of the compounds. Because polyenes are not absorbed to any significant extent from the
gastrointestinal tract, and because their bioavailability is low, the authors suggested that the
mechanism of prostatic regression was intimately related to the drug's hypocholesterolemic
properties. Results in a hamster model of spontaneous, age-dependent BPH confirmed the
candicidin effect and demonstrated that treatment with another hypocholesterolemic
compound, the bile-acid binding resin colestipol, also reduced prostate size91. Together
these reports provided compelling evidence that the cholesterol-reducing properties of oral
polyene macrolides were responsible for the drugs' surprising effects on the prostate.
The pre-clinical studies on the effect of polyenes on the canine prostate led to 10 clinical
BPH trials 1982, in 4 countries (US, Soviet Union, Denmark and Japan), from
1970-198292-101. Aalkaer92 tested nystatin in 18 patients for 2 months, and reported an
improvement in subjective symptoms in 50% of the subjects, with diminished nocturia and a
decrease in residual urine in 29%. However, the effect of nystatin on circulating cholesterol
levels was inconsistent. Nystatin was the least potent polyene in the dog studies reported by
Gordon and Schaffner89, suggesting that an alternative choice of drug would have produced
a more pronounced effect in this trial. Theodorides et al.99 also used nystatin vs. placebo for
a 6 week BPH trial and reported that nystatin was ineffective; given the duration of the trial
and the drug tested, this may not be surprising. Keshin96 treated 92 patients with candicidin
at 300 mg/day for at least 5 months, with up to 18 months of total follow up and observed no
toxicity. Moreover, in the patients that were candidates for surgery, 73% improved to the
extent that surgery was unnecessary, and improvements were evident using both subjective
and objective endpoints. Yamamoto et al.100 treated a small cohort (10 patients) with

amphotericin (800-1,200 mg/day) in a short trial (2-10 weeks) and observed a marked effect
in one patient, and observable effects in 6 others. Klijucharev et al.97 tested lavorin, which is
structurally identical to candicidin,102 on 14 patients with BPH in a 3 month trial and
demonstrated a complete resolution of dysuria in 93% and a reduction in prostate size in

57% of the patients. They reported no side effects. Orkin101 performed a placebo controlled
trial of 300 mg/day candicidin for ≥ 3 months and reported that 89% of the experimental
group had improved subjective symptoms vs. 18% in the placebo group. Residual urine was
decreased in 86% of the patients, 89% had improved urine flow rate in the active drug
cohort, and >33% had reduced prostate size, based on digital rectal exam, in comparison to
none in the placebo cohort. Sporer et al.98 ran a double-blind placebo controlled trial of
candicidin (300 mg/day) for 7 months in patients with BPH and demonstrated marked
improvement in subjective symptoms (intermittency, dribbling, force of stream, stream size,
nocturia, and diurinal frequency) as well as objective symptoms including residual urine. No
alteration of serum steroid levels or prostate Abrams93 noted. also performed a placebo
controlled randomized trial of candicidin (300 mg/day for 6 months) and found that both the
treatment and placebo groups demonstrated improved subjective symptoms. Urodynamic
data indicated that the maximum urine flow rate improved in the candicidin group but not in
the placebo cohort (p=0.06), as did maximum flow pressure. Residual urine decreased in the
treatment group by 24%, while in the placebo group a decrease of 12% was noted. Jensen
and Hammen95 also ran a placebo controlled trial of candicidin (300 mg/day for 12 months)
and found no statistical difference in subjective symptoms between the candicidin and
placebo cohorts, which improved in both groups. Interestingly, the authors confirm the
hypocholesterolemic properties of candicidin taken orally by demonstrating a serum
cholesterol level drop of≈10% in the candicidin cohort, while the control group
demonstrated an increase of approximately 5%. Similarly, Jensen and Madsen94 performed
a double blind placebo controlled trial of candicidin (300 mg/day 6 months). Most measures
in the treatment group, which included subjective symptoms and urodynamics, improved
significantly over pre-treatment values but the differences between the treatment and control
cohorts were not significant, except for residual urine and bladder volume, likely owing to a
strong placebo effect (some symptoms significantly improved in the placebo group).
The last of these clinical trials of polyene macrolide therapy for BPH were conducted almost
30 years ago. To our knowledge, there have been no trials of these agents in recent times in
the context of BPH. Given the promising outcomes of these prospective experiments in
humans, one wonders why one or more polyenes did not undergo additional clinical
evaluation with the goal of advancing one of them toward standard therapy for BPH. One
possibility is that an insufficient distinction was made between the toxicity of these
compounds when they are given intravenously and the lack of toxicity seen when they are
given orally. In addition, their use as oral agents is not typical because they are poorly
absorbed. Another impediment to clinical translation was that controversy emerged over the
interpretation of the animal and human data. Robb et al103. suggested that animals treated
with polyenes ate less and lost weight; hence the nutritional state of the subjects explained
the effect on the prostate. However, data presented in this report does not establish weight
loss as the principal mechanism of the polyene effect. The experiments on young rats
described in Robb et al.103 are not germane to the study of BPH because they are not a

model for this disease. Additionally, if canine experiments also presented in Robb et al103.
are analyzed without the lowest (and likely non-therapeutic) dose of candicidin (3 mg/kg/
day) the ratio of prostate weight change (mg)/body weight change (kg) is 1.78 mg/kg. If the
lowest dose of pimaricin (7 mg/kg/day) is also not included, the ratio of prostate weight
change is 4.4 mg/kg body weight. Moreover, even if this interpretation is not compelling,
subsequent studies also demonstrated that the change in prostate size was substantially
greater than the overall weight loss. For example, when 87.20 strain Syrian hamsters, which
exhibit a spontaneous age-dependent prostate enlargement, were treated with candicidin at
40mg/kg/day for 5 months, they exhibited an insignificant body weight loss (124.4 ± 5.0 g
control vs. 117 ± 4.5 g candicidin, 6% change), whereas a substantial change in ventral
prostate weight was observed (138.4 ± 12 mg control vs. 95.6 ± 9.2 mg candicidin, 31%
change)91,101. Prostate weight change in this case was 5.2 mg/kg body weight. In addition,
the effects on weight claimed by Robb et al. were not noted in human patients treated with
candicidin with candicidin101, or in other canine studies104.
Probably the most damaging of the preclinical studies on the effects of oral polyenes, with
respect to the potential for clinical translation of these agents, was one from Texter and
coffey104. These authors reported that oral amphotericin B inhibited testicular function, as
evaluated by serum testosterone levels and spermatogenesis in dogs. The authors reported
74-98% decrease in serum testosterone after treatment for 30 days, less motile spermatozoa
in prostatic secretions, and an absence of spermatogenesis in testicular biopsies taken 1
month after discontinuation of the drug. Notably, these observations were not apparent in
other preclinical experiments on dogs and hamsters89-91. A careful analysis of the data in the
Texter and Coffey report is difficult to reconcile with the biology and physiology of the
systems under investigation. As noted above, polyene macrolides are poorly absorbed from
the intestine and exhibit low bioavailability. Consequently, we are skeptical that a small
amount of the oral agent could elicit such a massive reduction in serum testosterone. This
result also cannot be a function of the cholesterol-lowering properties of polyenes because
the blood-testes barrier prevents changes in the circulation from affecting the testes, and
because cholesterol reduction does not alter serum testosterone levels105. Given that this is
the only study to show a decline in testicular function with oral polyene therapy, we believe
that, in all likelihood the results reported by Texter and Coffey are an artifact106. One clue is
given in the Discussion of this paper “A few of the control dogs have shown transitory
histologic changes in the testes which may be attributed to cage confinement”, but the
authors did not report the testosterone levels for these controls, so a comparison of the
polyene treated dogs vs. untreated controls is not possible. Given the reported loss of
testicular function and the fact that new pharmaceuticals for BPH were soon to become
available, it is likely that the claim that polyenes reduced prostate size by severely
interfering with testicular function reduced enthusiasm for research into the use of polyene
macrolides for the treatment of BPH.
Ezetimibe (Zetia) is an FDA approved hypocholesterolemic drug that blocks cholesterol

absorption from the intestine by interfering with the bona fide gut cholesterol transporter
NPC1L1107-109. Inhibition of cholesterol absorption by ezetimibe also causes LDL receptor
levels to increase, thereby facilitating removal of cholesterol from the circulation. Ezetimibe
is believed to be a highly selective cholesterol antagonist. Because the mechanism of action

of ezetimibe is similar to that of the polyene macrolides, we sought to replicate the

observations made with the polyenes with this new agent that has no apparent toxicity and
for which the mechanism of action is well established.
We recently reported on the effects on the prostate of reducing cholesterol levels in Syrian
87.20 hamsters with ezetimibe110. As mentioned above, the males in this strain exhibit a
substantial, age-dependent prostatic enlargement. In these experiments, we found that
ezetimibe was as effective in reducing prostate size as the 5α-reductase inhibitor,
finasteride, a compound that inhibits the production of the most bioactive intraprostatic
androgen, dihydrotestosterone (DHT) (Figure 1A). Finasteride and other 5α-reductase
inhibitors are widely used to treat BPH in humans. Finasteride and ezetimibe used together
evoked the greatest degree of prostatic regression. Histological analysis of prostate tissue
indicated that finasteride induced widespread epithelial atrophy, consistent with inhibition of
DHT synthesis. Surprisingly, however, normal glandular architecture was preserved in the
ezetimibe cohort, implying a distinct mechanism of action (Figure 1B). Surprisingly, we
found that initiation of prostate enlargement in these animals was dependent on the presence
of cholesterol in the diet, but was no longer required for maintaining the enlargement in
older animals. Because of the increase in prostate size with age, the response to finasteride,
and the epithelial glandular atrophy resembling a similar response to finasteride in

humans111, 112, these studies also confirmed the suitability of the 87.20 strain hamster as a
preclinical model for BPH.
Although we were not the first to use this hamster strain in preclinical experiments on BPH,
the last published studies using this model in this context were reported in the early
1980s106. Our results suggest that ezetimibe might be effective as an alternative to standard
medical BPH therapy and, further, that dysregulation of cholesterol metabolism may be an
important, and neglected, component of disease etiology113. These results also strongly
suggest that the original findings described above with polyene macrolides, published over
30 years ago, were likely correct and that reducing intestinal cholesterol absorption is a
viable approach to controlling LUTS in men. Our preclinical data provide support for
prospective studies on ezetimibe in men as a novel approach to treating BPH.
Conclusions
The mechanism of prostatic enlargement, and accompanying symptoms defined empirically

as LUTS, is poorly understood. We have presented an unusual perspective on benign
prostate health and potential novel treatment strategies. Circulating cholesterol has recently
emerged as a viable target for chemoprevention and adjuvant therapy in prostate cancer. We
have summarized an overview of the literature, going back over 30 years, suggesting that
some of the relevant mechanisms that have been proposed as central to the emergence of
BPH may be susceptible to cholesterol-targeting approaches. In this regard, we have
highlighted a substantial literature on BPH in humans that strongly suggests that cholesterol-
targeting is indeed a viable clinical strategy. The pre-clinical and clinical data on cholesterol
levels in the context of BPH are in substantial agreement, and systems-level analysis of
human BPH tissues and animal models indicate that mechanisms that evoke remodeling of
the prostate are broadly shared across great evolutionary distances72, 114, 115. Inflammatory

mechanisms seem to be a unifying concept resolvable from the published data114, but much
work needs to be undertaken to refine the currently existing models. The literature on
polyene macrolides and BPH is largely unknown among basic science investigators and
medical practitioners in the area. Consequently, we hope this review will stimulate new
research. Phamacologic reductions in cholesterol synthesis or bioavailability may also lower
levels of bioactive sterols, such as pregnenolone, testosterone, and estradiol and the
physiologic consequences of these changes are uncertain. Although our understanding of the
origins of CP/CPPS is even more limited than BPH, we believe the potential for cholesterol-
targeting therapy in this context also deserves experimental attention.
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Figure 1.
A. Effects of ezetimibe (Zetia) and finasteride on prostate size (volume) in the Syrian 87.20
hamster strain, which shows spontaneous, age-dependent prostate enlargement. Data are
presented as mean prostate volume (mm3) vs. drug group ± SD. *p<0.05, **p<0.01
(Students t test) n=4/group. Zetia was as effective as finasteride at reversing prostate
enlargement in this model. B. Representative micrographs of hamster prostate frozen
sections reveal that finasteride induced prostatic epithelial atrophy, while Zetia did not
produce a discernible effect on the prostate epithelium. These data were originally reported
in Pelton et al.110 Used with permission.

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Differentiation. 2011 ; 82(0): 244–252. doi:10.1016/j.diff.2011.04.005.

Cholesterol and Benign Prostate Disease

Prostate health and metabolism

Differentiation. Author manuscript; available in PMC 2014 June 10.

Cholesterol, signal transduction and gene expression

Cholesterol and prostate cancer

Differentiation. Author manuscript; available in PMC 2014 June 10.

demonstrated an apparent chemopreventive effect of statin drugs on either overall prostate

Our group has provided mechanistic evidence in support of potential chemopreventive

Differentiation. Author manuscript; available in PMC 2014 June 10.

Metabolism and the prostate

Differentiation. Author manuscript; available in PMC 2014 June 10.

with statins in animal models. In contrast to humans, circulating cholesterol in rodents is

Cholesterol and inflammation

and develop slowly over decades. Importantly, clinical manifestations of advanced

Differentiation. Author manuscript; available in PMC 2014 June 10.

The origin of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is essentially

Cholesterol targeting and prostate health

Differentiation. Author manuscript; available in PMC 2014 June 10.

thrombophlebitis. Using Mycoplasm a laidlawii grown in either the presence or absence of

bioactivity of polyene macrolides was sterol-dependent. Subsequent s tudies demonstrated

polyene and the degree of hypercholesterolemia present. In these experiments, candicidin

Differentiation. Author manuscript; available in PMC 2014 June 10.

demonstrated a complete resolution of dysuria in 93% and a reduction in prostate size in

Differentiation. Author manuscript; available in PMC 2014 June 10.

Ezetimibe (Zetia) is an FDA approved hypocholesterolemic drug that blocks cholesterol

Differentiation. Author manuscript; available in PMC 2014 June 10.

of ezetimibe is similar to that of the polyene macrolides, we sought to replicate the

and the epithelial glandular atrophy resembling a similar response to finasteride in

The mechanism of prostatic enlargement, and accompanying symptoms defined empirically

Differentiation. Author manuscript; available in PMC 2014 June 10.

Differentiation. Author manuscript; available in PMC 2014 June 10.

Differentiation. Author manuscript; available in PMC 2014 June 10.

Differentiation. Author manuscript; available in PMC 2014 June 10.

Differentiation. Author manuscript; available in PMC 2014 June 10.

71. Penna G, Fibbi B, Amuchastegui S, Cossetti C, Aquilano F, Laverny G, Gacci M, Crescioli C,

72. Kim J, Yanagihara Y, Kikugawa T, Ji M, Tanji N, Masayoshi Y, Freeman MR. A signaling

chronic prostatitis. J Urol. 2000; 164(1):214–8. [PubMed: 10840462]

Differentiation. Author manuscript; available in PMC 2014 June 10.

Differentiation. Author manuscript; available in PMC 2014 June 10.

Differentiation. Author manuscript; available in PMC 2014 June 10.

Differentiation. Author manuscript; available in PMC 2014 June 10.

Differentiation. Author manuscript; available in PMC 2014 June 10.

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