REVIEW ARTICLE

Intrinsic and Extrinsic Factors ControllingBenign Prostatic Growth

Chung Lee,* James M. Kozlowski, and John T. Grayhack

Department of Urology, Northwestern University Medical School, Chicago, Illinois

ABSTRACT: This review will present a new concept on the etiology of the developmentof benign prostatic hyperplasia (BPH). Conventionally, two known etiological factors for thedevelopment of BPH have been aging and the presence of functional testes. Assignment ofthese two factors, although reasonable, has not been conducive to aid the research communityto identify and isolate the patho-physiological agents that are directly responsible for thedevelopment of this disease. In the present review, we proposed a broadened concept ofintrinsic and extrinsic factors for BPH. This concept offers identifiable research opportunitiesthat will facilitate our quest in search for etiological agents for BPH. A brief description ofvarious intrinsic and extrinsic factors and justifications for their selection will be discussed.Prostate 31:131–138, 1997. © 1997 Wiley-Liss, Inc.

KEY WORDS: stromal-epithelial interaction; testicular factors; non-testicular factors;genetic factors; environmental factors

INTRODUCTION

The prostate is a male accessory sex organ that isthe site of frequent benign and malignant growths thatconstitute a major health concern. The present reviewis confined to a discussion of etiological factors thatcontribute to benign growth of the prostate.

For over a century, the two known etiological fac-tors for the development of benign prostatic hyperpla-sia (BPH) have been aging and the presence of func-tional testes [1,2]. BPH is an age-associated diseasethat does not develop in men whose testes have beenremoved at a young age [3,4]. Assignment of these twofactors as the basis for BPH development is reasonablebut somewhat empirical. Their acceptance has servedas the basis for numerous research projects attemptingto identify and isolate the pathophysiological agentsdirectly responsible for the development of this dis-ease. Despite decades of intensive research efforts,progress has been slow, and information regardingthe precise factors responsible for the pathogenesis ofBPH remains incomplete. Progress in this area hasbeen hampered in part by the necessary and dominantrole of androgens in stimulating and maintainingprostatic growth, by the lack of identical pathologicBPH models in animals, and by a failure to generateinnovative concepts and approaches to evaluate the

problem. In the present review, a broadened conceptregarding etiological factors for BPH is proposed.While retaining our conventional concept that agingand the presence of functional testes are known nec-essary factors for the development of BPH, the pro-posed concept suggests possible roles for both intrin-sic and extrinsic factors in excessive benign prostaticgrowth. This concept offers identifiable research op-portunities which hopefully will facilitate our questfor etiological factors for BPH.

PROPOSED INTRINSIC ANDEXTRINSIC FACTORS

Table I summarizes intrinsic and extrinsic factorsthat may play a continuing or episodic role in normaland/or pathologic prostatic growth. Although the cel-lular makeup of the stroma and epithelium maychange with age in response to stimuli, the signaledinteraction between stromal and epithelial compo-

Contract Grant sponsor: National Institutes of Health/NIDDK;Contract Grant number: DK 39250.*Correspondence to: Chung Lee, Ph.D., Department of Urology,Northwestern University Medical School, Tarry Building 11-715,303 East Chicago Avenue, Chicago IL 60611-3009.Received 14 February 1996; Accepted 13 March 1996

The Prostate 31:131–138 (1997)

© 1997 Wiley-Liss, Inc.

nents represents the predominant, and very possiblythe only, basic end organ growth mechanism withinthe prostate. Extrinsic factors consist of testicular,other systemic, environmental, and genetic factors.Most, if not all, extrinsic factors for prostatic growthare mediated through intrinsic factors by modifyingthe relationship between prostatic stromal and epithe-lial cells. The aging factor in BPH development may beviewed as a cumulative event resulting from a con-tinuing interaction between extrinsic and intrinsic fac-tors. The interactions of extrinsic and intrinsic factorsare proposed with the intention that they be tested byscientific methodologies.

THE INTRINSIC FACTOR

The importance of the role of stromal-epithelial in-teraction in prostatic morphogenesis and develop-ment has been recognized since the reports of Cunha[5,6], Chung and Cunha [7], and Chung et al. [8] morethan two decades ago. Our recent studies demon-strated that prostatic epithelial proliferation, differen-tiation, and cell death are all subjected to controllingfactors derived from adjacent stromal cells [9,10]. Ob-servations during these studies indicated that rat pros-tatic stromal cells consist of (besides endothelial cells,nerve cells, and blood-borne cells) predominantly fi-broblast-like cells which contain vimentin and smoothmuscle-like cells which contain alpha-smooth muscleactin [11]. Two important growth factors, keratinocytegrowth factor (KGF) and transforming growth factorbeta (TGF-b), are produced by prostatic stromal cells[12,13]. Prostatic epithelial cells contain receptor pro-teins for these growth factors [14,15]; KGF is growth-

promoting [12,16–20], and TGF-b is inhibitory to thesecells [21,22]. Paracrine signals originating from the ad-jacent prostatic stromal cells, and resulting in growthstimulation or inhibition, are thought to be the funda-mental step in the sequence of events resulting in be-nign growth in the prostate.

At least three cell types have been observed in theepithelial compartment of the prostate: luminal, basal,and neuroendocrine [23–26]. With the exception of lu-minal cells, research in basal and neuroendocrine cellshas been mainly confined to the development ofmeans to identify these cells. Although the fate andfunctions of these two latter cell types remain un-known, all epithelial cells in the prostate are likely toproduce unique signals impacting on one another andon the adjacent stromal cells in a paracrine fashion.Stromal proliferative and functional status is at leastpartially controlled by signals originating in the adja-cent epithelial cells [27]; the development of fibroblast-like or smooth muscle-like cells in the prostatic stromamay be regulated by the type of growth factors re-leased from the adjacent prostatic epithelial cells. Thislatter mechanism, possibly coupled with stromal cellautocrine and/or systemic factors, may be the basisfor stromal overgrowth in certain BPH tissues.

Since both prostatic epithelial and stromal cells areintegral components of the normal prostate, interac-tions between these two cell types are considered basicintrinsic mechanisms generated within the prostate.Secretions, organic or inorganic substances, and cells,derived from outside of the prostate, are consideredextrinsic factors. The present concept proposes thatextrinsic factors primarily produce their end organ ef-fect on prostatic growth, indirectly, by altering the in-teraction between prostate stromal and epithelial cells.Our hypotheses can be tested using current technolo-gies in cellular and molecular biology.

THE EXTRINSIC FACTORS

The prostate is constantly under the influence ofsignals from external sources. Of these, the testis is themost prominent. The testis, functioning as an endo-crine organ, is able to secrete a variety of hormonalfactors which are potent mitogens to the prostate. Sys-temic factors other than those derived from the testiscan also reach the prostate through the circulation, theurine, or the neuronal network, providing stimulationto the prostate. Endocrine organs, such as the pitu-itary, the hypothalamus, the adrenal gland, etc., allbelong to the second class of extrinsic factors whichcan stimulate prostatic growth. Finally, epidemiologi-cal studies indicate that genetic and environmental

TABLE I. Etiological Factors in BPH

Extrinsic factors Intrinsic factors

Testicular factorsAndrogen Stromal-epithelial interactionEstrogen Stromal effect on epitheliaNonandrogenic factors Epithelial effect on stroma

Other somatic factorsNontesticular hormonesNeurotransmittersLymphocytes,

macrophagesEnvironmental factors

Dietary factorsMicroorganisms

(immune response)Genetic predisposition

132 Lee et al.

factors are also important to prostatic growth [28]. Inthe following sections, the impact of each of the abovefactors will be briefly discussed, especially regardingtheir relationship with the intrinsic factor.

THE TESTIS

The role of the testis in prostatic growth has beenrecognized for over a century [1–4]. Of the many sub-stances secreted by the testis, androgen is by far themost important factor as far as prostatic growth isconcerned. The prostate is an androgen-dependent or-gan, in that growth and maintenance of its functionaland structural integrity require the constant supportof an adequate level of circulating androgen [29,30].Depletion of this androgenic support, as by bilateralorchiectomy in the host, results in drastic chemicaland cellular changes in the prostate, leading to tissueatrophy [31–33]. Subsequent replacement of exog-enous androgen in castrated hosts reactivates prostaticgrowth [29]. Without question, androgen is the mostpotent mitogen to the prostate. Despite advancesmade in understanding the biochemical action of an-drogen, the mechanism of androgen action in prostaticgrowth at the cellular level remains incomplete. Al-though androgen is mitogenic to the prostate in vivo,it has no mitogenic effect on prostatic epithelial cells inculture [34]. In contrast, a host of growth factors candirectly stimulate proliferation in prostatic epithelialcells. These observations suggest that androgen maynot be the proximal mitogen to prostatic growth. It isnow well-established that stromal-epithelial cell inter-action in the prostate plays an important role in an-drogen action [5–8].

In considering etiological factors for BPH, althoughit is clear that androgen is the most important mitogento prostate growth, the fact that circulating androgenis declining at the time of onset of BPH developmentsuggests that androgen alone cannot serve as the solecausative factor for BPH [35,36]. It is most likely thatother factors are participating in concert with the ac-tion of androgen to promote the further enlargementof the prostate after adulthood. Estrogen has been im-plicated in the pathogenesis of BPH, since the estrogenreceptor is predominantly localized in the stromal el-ements of the human prostate [37,38]. It is well-knownthat in studies of canine and rat prostate there is asynergistic effect on prostatic growth by a combina-tion of estrogen and androgen treatment when com-pared with androgen treatment alone [39–41]. Resultsof a recent study indicated that estrogen, but not an-drogen, acting in association with steroid hormonebinding globulin (SHBG), produced an 8-fold increasein the intracellular levels of cyclic Adenosine mono-

phosphate (AMP) in human BPH tissues [42,43]. Cy-clic AMP has been considered an important step insignal transduction pathways in androgen action [44].The above SHBG-cyclic AMP mediated process hasbeen localized primarily in the stroma. In addition,estrogen may also stimulate epithelial cell prolifera-tion through insulin-like growth factor-I [43]. The pre-sent hypothesis provides an opportunity to testwhether or not these factors exert their effect througha modification of stromal-epithelial interaction in theprostate.

NONANDROGENIC TESTICULAR FACTORS

A widely held view is that the role of the testis inprostatic growth is through its ability to secrete an-drogen, and to some extent estrogen. As a result,many investigators centered their hypothesis of BPHdevelopment on the action of androgen or the inter-action between androgen and estrogen. However, itremains difficult to reconcile the middle-age reawak-ening of prostatic growth [45] at a time when circulat-ing testosterone is declining and the androgenic effectto target organs is also declining [46]. This paradox ofcontinuing prostatic growth in the face of decliningandrogenic activity has led to questioning whether ornot the testis has the ability to produce substancesother than androgen that can either stimulate prostaticgrowth directly or enhance the sensitivity of the pros-tate to respond to androgen. The concept of a nonan-drogenic role of the testis in prostatic growth offers apossible explanation to resolve the above paradox.

The concept of the testis having a nonandrogenicrole in BPH development is supported by the demon-stration that irradiation of the testis in dogs with BPHyielded a decrease in prostatic size and degree of pros-tatic hyperplasia [47]. Histology of the irradiated testisshowed germ-cell degeneration, but Leydig cell mor-phology remained normal. Serum levels of testoster-one and estradiol were not significantly different be-tween irradiated dogs and those in the control group.These observations suggest that a testicular factor, un-related to steroid production but possibly related tospermatogenesis, promoted prostatic growth.

In another experiment, castrated rats and rats withintact testes were treated with a supraphysiologicdose of exogenous androgen (either testosterone ordihydrotestosterone (DHT)), which resulted in a maxi-mum degree of prostatic growth. Results indicatedthat the ventral prostate of rats with intact testes washeavier than that of castrated rats receiving the sameamount of exogenous androgen. Thus, the presence oftestes was able to induce an additional prostaticgrowth beyond what could be accomplished by the

Benign Prostate Growth 133

supraphysiologic dose of androgen [48,49]. A similarstudy was conducted by Juniewicz et al. [50], usingcastrated and testis-intact dogs supplemented with anexogenous testosterone and estradiol combination tomaintain physiological serum levels. Results also in-dicated that the incidence of BPH development wassignificantly higher in those dogs with intact testes.These results provide strong evidence that the testiscontributed to prostatic growth in addition to its abil-ity to produce androgen.

An additional piece of evidence supporting thisconcept was provided by Cooke and Meisami [51],who created transient neonatal hypothyroidism in ratswith propylthiouracil. These animals led a normaladulthood with the exception that the testis showedSertoli cell hyperplasia, which was accompanied by anincrease in spermatogenesis but with a normal circu-lating level of testosterone. The prostate in these pro-pylthiouracil-treated animals was significantly largerthan that of age-matched normal controls. Again, thebigger prostate has been associated with an increase inspermatogenesis and Sertoli cell activity. Larriva-Sahdet al. [52] and Rosner [53] postulated that this Sertolicell factor may be steroid hormone-binding globulin(SHBG), which is produced in rats only by Sertoli cells.SHBG binding has been detected on the cell mem-brane of prostatic epithelial cells, suggesting a possiblerole of SHBG as the testicular factor [52,53].

Finally, in an attempt to identify nonandrogenictesticular factors, Sutkowski et al. [54] collected hu-man spermatocele fluid, which contains secretionsfrom testicular tubules and epididymis [54]. This fluidis mitogenic to both human prostatic epithelial andstromal cells in culture. The factor that promoted ep-ithelial growth was heat-stable but was removed byactivated charcoal. The factor for the stromal cells washeat-liable and persisted after treatment with charcoal.These results are consistent with the concept that thehuman testis produces nonandrogenic substances thatcan promote prostatic growth. Access of these testicu-lar factors to the prostate is postulated to be eitherthrough a systemic route or via a direct exposure tothe urethra. The latter possibility is proposed, sinceperiurethral nodules have been frequently observed inprostatic specimens of symptomatic BPH patients. Thenonhomogenous prostate exposure that could resultfrom urethral access to the prostate has the potential ofplaying a significant role in the regional and nodulargrowth characteristic of the human prostate.

OTHER SOMATIC FACTORS

Among the nontesticular organs, the pituitary-hypothalamus complex, perhaps, is the most influen-tial organ in prostatic growth [55]. It produces a large

number of hormones, e.g., prolactin, growth hormone,gonadotrophin releasing hormone (GnRH), etc.,which have all been demonstrated to have an effect onprostatic growth [56–60]. The effect of these hormonalagents is most likely mediated directly or indirectlythrough their ability to modify the relationship be-tween prostatic stromal and epithelial cells. The pitu-itary-hypothalamus complex can also influence pros-tatic growth indirectly by having an effect on the pro-duction of steroid hormones by the testis and theadrenal gland [61,62].

Neurotransmitters and neurotrophins are anotherclass of prostatic stimulants of nontesticular origin[63–65]. Evidence indicates that nerve growth factor(NGF) mediates its action in the prostate through amechanism of stromal-epithelial interaction [66,67].Neurotransmitters apparently initiate complex intra-cellular signal transduction pathways in prostaticsmooth muscle through their interaction with respec-tive cell surface receptor molecules. Consequently, thetarget smooth muscle cells either undergo contractionwith a potential physiologic effect on voiding [68], orG-protein-induced signal transduction [69], with po-tential impact on adjacent cells leading to prostaticgrowth.

ENVIRONMENTAL FACTORS

Information regarding environmental factors inBPH development remains inadequate, partly due to alack of appropriate working hypotheses. Our presenthypothesis states that the impact of environmental fac-tors on BPH development can be mediated through amodification of either intrinsic or extrinsic factors forprostatic growth. It is now possible to test variousenvironmental factors on the basis of this hypothesis.For the purpose of this review, two environmentalfactors will be discussed briefly: microorganisms anddietary consumption.

The prostate is susceptible to infiltration by lym-phocytes and macrophages with an apparent increasein prevalence with age [70,71]. Infiltration of theseblood-borne cells can take place with or without amicroorganism etiology [72]. In the case of prostaticinflammation in the absence of microorganisms, thepresence of infiltrating lymphocytes should be consid-ered one of the possible somatic factors in the devel-opment and/or growth of BPH. An immune reactionwithin the prostate in response to pronounced lym-phocytic infiltration is most likely to play a role inBPH development [73,74]. The presence of markers oflymphocyte activity suggests a chronic cell-mediatedimmune response in BPH, presumably targeting un-identified antigen(s) of prostatic or microorganism ori-gin. Steiner et al. [74] reported an increase in the num-

134 Lee et al.

ber of infiltrating T-lymphocytes in the interstitium ofBPH tissues. These BPH-associated T-lymphocytes areknown to release factors to stimulate matrix formationthrough collagen synthesis, as well as to promote theproliferation of prostate stromal and epithelial cells,e.g., by the synthesis and secretion of interleukin-6and interleukin-1 [75,76]. They can also exert their ef-fects indirectly, e.g., by promoting neovascularizationby the release of vascular endothelial growth factor.

The incidence of clinically obstructive BPH in theFar East follows a pattern similar to that observed forprostate cancer when compared with that of the West-ern population. Results of studies tracking immigrantsfrom China and Japan, through Hawaii to the main-land U.S., indicate that they, in a few generations,show an incidence of these diseases that is close to thatof indigenous American people. These observationssuggest that environmental, probably dietary, causesrather than genetic factors are implicated [77,78]. It issuggested that constituents of the Asian diet may re-strain the growth phase in the pathogenesis of clinicalBPH. Attention has been directed to certain vegetable,fruit, whole grain, and soybean constituents that aremetabolized by the normal gut microflora to produceparticular compounds, such as isoflavonoids and lig-nans, in body fluids such as plasma, urine, prostaticfluid, and saliva [79]. These compounds are weak es-trogens capable of modifying the relationship betweenstromal and epithelial cells in the prostate from anendocrine point of view. A large body of literature hasimplicated green tea, which may contain active ingre-dients such as antioxidants, 5a-reductase inhibitors,aromatase inhibitors, and tyrosine-specific protein ki-nase inhibitors [80,81]. The possibility that dietary fac-tors have a role in retarding the development of pros-tatic disease provides an exciting prospect. Much ofthe data relating to the possible relationship of thesedietary constituents to prostatic disease has been ex-tensively reviewed recently [79].

GENETIC PREDISPOSITION

Again, epidemiological studies have pointed out alarge variation in the prevalence of BPH among dif-ferent countries. Determining whether these differ-ences in BPH incidence are due to regional dietaryhabits or genetic factors has been difficult. The conceptthat the ultimate size of the prostate in an individual ispredetermined by genetic programming warrantsconsideration. For example, demonstration in rodentstudies that an alteration in homeobox gene expres-sion leads to a change in prostatic size clearly suggestsa role for genetic factors in determining prostate size[82]. It is now possible to investigate whether or notthese genetic factors control size of the prostate

through regulation mechanisms programmed to uti-lize normal interactions between prostatic stromal andepithelial cells. Men with certain hereditary diseaseshave altered prostate growth. For example, in the Do-minican Republic, patients with male pseudoher-maphroditism, an inherited 5a-reductase deficiencysyndrome, have a rudimentary prostate [83]. Again,this genetic defect alters the androgenic status withinthe prostate and modifies the normal relationship be-tween the stroma and the epithelium of the prostate,leading to a small prostate.

PERSPECTIVES

BPH occurs in aging men with functional testes.Figure 1 summarizes the concept that prostatic growthis the result of a complex interaction of intrinsic andextrinsic cellular control mechanisms. The fundamen-tal intrinsic mechanisms provide potential pathwaysfor a range of variable effects on stromal-epithelialinteraction within the framework of the prostatic duc-tal system. This complex interactive mechanism isconstantly modified by various extrinsic factors. Thepredominant extrinsic factor considered in studyingprostatic growth has been steroid sex hormones de-rived from the testis. It is now clearly demonstratedthat actions of these steroid hormones, i.e., androgensand estrogens, are mediated indirectly through amechanism involving prostatic stromal-epithelial in-teraction. The present concept proposes that other ex-trinsic factors are also likely to produce their effects bymodifying the androgen-regulated prostatic stromal-epithelial interaction. The present review has pro-vided a brief account of the current understanding ofetiologic factors in BPH development on the basis ofthe proposed concept. The hypothesis presented inTable I and in Figure 1 only serves as a concept whichmay be revised at later dates. Experience will un-doubtedly modify the agents and the mechanisms pre-sented for consideration. However, the broad conceptof multifaceted etiologic factors presents a usefulframework that provides an opportunity to identifyand characterize the critical interactions between ex-trinsic and intrinsic factors controlling stromal and ep-ithelial growth during BPH development.

ACKNOWLEDGMENTS

The authors are members of the George O’BrienKidney and Urology Research Center at NorthwesternUniversity, which has been funded by the NIH/NIDDK (grant DK39250). We thank Ms. Lisa-MarieJohnson for her excellent editorial skills.

Benign Prostate Growth 135

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