Zone-dependent expression of estrogen receptors alpha and beta in human benign prostatic hyperplasia

Estrogen, which acts through estrogen receptors (ERs) alpha and beta, has been implicated in the pathogenesis of benign and malignant human prostatic tumors, i.e. benign prostatic hyperplasia and prostate cancer, thought to originate from different zones of the prostate [the transition zone (TZ) and peripheral zone (PZ), respectively]. Here, we examined the cellular distribution of ERalpha and ERbeta in human normal and hyperplastic prostate tissues, using in situ hybridization and immunohistochemistry. ERalpha expression was restricted to stromal cells of PZ. In contrast, ERbeta was expressed in the stromal cells of PZ as well as TZ. ERbeta-positive epithelial cells were evenly distributed in PZ and TZ of the prostate. Our results suggest that estrogen may play a crucial role in the pathogenesis of benign prostatic hyperplasia through ERbeta.     

A system for studying epithelial-stromal interactions reveals distinct inductive abilities of stromal cells from benign prostatic hyperplasia and prostate cancer

The development of normal and abnormal glandular structures in the prostate is controlled at the endocrine and paracrine levels by reciprocal interactions between epithelium and stroma. To study these processes, it is useful to have an efficient method of tissue acquisition for reproducible isolation of cells from defined histologies. Here we assessed the utility of a standardized system for acquisition and growth of prostatic cells from different regions of the prostate with different pathologies, and we compared the abilities of stromal cells from normal peripheral zone, benign prostatic hyperplasia (BPH-S), and cancer to induce the growth of a human prostatic epithelial cell line (BPH-1) in vivo. Using the tissue recombination method, we showed that grafting stromal cells (from any histology) alone or BPH-1 epithelial cells alone produced no visible grafts. Recombining stromal cells from normal peripheral zone with BPH-1 cells also produced no visible grafts (n = 15). Recombining BPH-S with BPH-1 cells generated small, well-organized, and sharply demarcated grafts approximately 3-4 mm in diameter (n = 9), demonstrating a moderate inductive ability of BPH-S. Recombining stromal cells from cancer with BPH-1 cells generated highly disorganized grafts that completely surrounded the host kidney and invaded into adjacent renal tissue, demonstrating induction of an aggressive phenotype. We conclude that acquisition of tissue from toluidine blue dye-stained specimens is an efficient method to generate high-quality epithelial and/or stromal cultures. Stromal cells derived by this method from areas of BPH and cancer induce epithelial cell growth in vivo, which mimics the natural history of these diseases.     

Symptomatic and asymptomatic benign prostatic hyperplasia: molecular differentiation by using microarrays

Benign prostatic hyperplasia (BPH) is a disease of unknown etiology that significantly affects the quality of life in aging men. Histologic BPH may present itself either as symptomatic or asymptomatic in nature. To elucidate the molecular differences underlying BPH, gene expression profiles from the prostate transition zone tissue have been analyzed by using microarrays. A set of 511 differentially expressed genes distinguished symptomatic and asymptomatic BPH. This genetic signature separates BPH from normal tissue but does not seem to change with age. These data could provide novel approaches for alleviating symptoms and hyperplasia in BPH.     

磁共振波谱成像对中央腺体前列腺癌与良性增生结节的鉴别诊断

目的 探讨磁共振波谱成像(MRS)检查中央腺体前列腺癌代谢特点,与良性增生结节的鉴别诊断价值. 方法 应用3.0T MR成像仪对38例前列腺疾病患者进行前列腺MRI成像,中央腺体前列腺癌11例,良性前列腺增生27例.在MRI常规成像基础上行MRS检查,分析良性前列腺增生(BPH)和前列腺癌的MRS表现,11例前列腺癌中3例局限于中央腺体,8例肿块较大同时累及外周带,测量中央腺体内前列腺癌及BPH的胆碱(Cho)+肌酐(Cr)/枸橼酸盐(Cit)比值,并对前列腺癌与BPH体素的代谢物比值进行比较. 结果 中央腺体内前列腺癌波谱主要表现为Cit峰明显下降1,Cho+Cr峰显著升高,(Cho+Cr)/Cit的均值为1.94±1.43;BPH主要表现为Cit峰高耸,Cho+Cr峰低,(Cho+Cr)/Cit的均值为0.83±0.28(P＜0.01). 结论 联合应用MRI和MRS,有利于中央腺体内前列腺癌和BPH的鉴别,可提高前列腺癌诊断的准确性.     

良性前列腺增生组织中雄激素结合位点和表皮生长因子受体的相关性研究

目的评估雄激素结合位点（ＡＢＳ）和表皮生长因子受体（ＥＧＦＲ）在良性前列腺增生症（ＢＰＨ）中的作用及相互调节关系。方法应用免疫组织化学方法（ＳＰ法）在５０例ＢＰＨ组织和９例正常前列腺组织中对ＡＢＳ和ＥＧＦＲ进行免疫定位、半定量表达。结果前列腺增生组织中ＡＢＳ和ＥＧＦＲ表达均增强，ＡＢＳ主要位于腺上皮细胞和基质细胞，ＥＧＦＲ主要位于基底细胞，ＡＢＳ和ＥＧＦＲ呈显著正相关。结论雄激素的作用部位主要在上皮细胞和基质细胞，表皮生长因子的作用部位在基底细胞，二者的密切相关在ＢＰＨ的发病机理中可能是非常重要的。     

Proliferation of prostate epithelia induced by IL‐6 from stroma reacted with Trichomonas vaginalis

Benign prostatic hyperplasia (BPH) is characterized by the proliferation of stromal and epithelial cell types in the prostate, and interactions between the two types of cells. We demonstrated previously that proliferation of prostate stromal cells was induced by BPH epithelial cells in response to Trichomonas vaginalis (Tv) infection via crosstalk with mast cells. In this study, we investigated whether IL‐6 released by the proliferating stromal cells in turn induce the BPH epithelial cells to multiply. When culture supernatants of the proliferating prostate stromal cells were added to BPH epithelial cells, the latter multiplied, and expression of cyclin D1, FGF2 and Bcl‐2 increased. Blocking the IL‐6 signalling pathway with anti‐IL‐6R antibody or JAK1/2 inhibitor inhibited the proliferation of the BPH epithelial cells and reduced the expression of IL‐6, IL‐6R and STAT3. Also, epithelial‐mesenchymal transition was detected in the proliferating BPH epithelial cells. In conclusion , IL‐6 released from proliferating prostate stromal cells induced by BPH epithelial cells infected with Tv in turn induces multiplication of the BPH epithelial cells. This result provides first evidence that the inflammatory microenvironment of prostate stromal cells resulting from Tv infection induces the proliferation of prostate epithelial cells by stromal‐epithelial interaction.     

Decreased urinary 5 alpha-androstane-3 alpha,17 beta-diol glucuronide excretion in patients with benign prostatic hyperplasia

Urinary testosterone and 3 alpha-androstanediol (3 alpha diol G) glucuronides together with plasma testosterone, 5 alpha-dihydrotestosterone (DHT), and delta 4-androstenedione (delta 4) were measured in 43 normal young men (18-36 yr old), 23 elderly men without clinically evident prostatic pathology (54-89 yr old), 68 elderly men with benign prostatic hyperplasia (BPH group; 54-91 yr old), and 26 elderly men with well differentiated cancer of the prostate (K group; 63-97 yr old). Plasma testosterone decreased slightly with age in all 3 elderly groups (from 591 to 438, 479, and 444 ng/100 ml, respectively). Plasma DHT, on the contrary, was significantly (P less than 0.01) higher in the BPH group than in the other three groups (68 vs. 30, 37, and 32 ng/100 ml, respectively). Plasma delta 4 was significantly lower (P less than 0.01) in the elderly K group than in all other groups (59 vs. 109, 83, and 78 ng/100 ml, respectively). Urinary testosterone glucuronide decreased with age in all 3 elderly groups (from 109 to 55, 38, and 44 micrograms/24 h, respectively) as a result of decreased androgen production rates with age. All 3 elderly groups also had decreased urinary 3 alpha diol G, from 194 to 123, 55, and 118 micrograms/24 h, respectively. The group of elderly patients with BPH had the lowest mean urinary 3 alpha diol G excretion together with the highest mean plasma DHT. This low urinary 3 alpha diol G excretion, which reflects a decrease in both androgen production and DHT metabolism, suggests a decrease in 3 alpha-hydroxysteroid dehydrogenase activity, which, in turn, could explain the increased DHT availability and tissue retention in most target organs. Moreover, the extent of these modifications in androgen metabolism specific to the BPH condition raises the question of an overall alteration of androgen metabolism in patients with BPH which could be the cause of the disease.     

Androgen-stimulated human prostate epithelial growth mediated by stromal-derived fibroblast growth factor-10.

It has been suggested that prostate homeostasis is regulated indirectly by androgens through stromal-epithelial interactions in part by factors from the stromal cells acting on receptors in epithelial cells. In this report, the role of fibroblast growth factor (FGF)-10 in prostatic epithelial proliferation was investigated. The expression of FGF-10 mRNA was apparent in primary-cultured stromal cells, but not in epithelial cells derived from human tissue from patients with benign prostatic hyperplasia (BPH). The mitogenic activity of human recombinant FGF-10 assessed by 5-bromo-2'-deoxyuridine (BrdU) incorporation was demonstrated in isolated epithelial cells, but not in cultured stromal cells. No mitogenic activity of dihydrotestosterone (DHT) for either epithelial or stromal cells could be demonstrated, but quantitative PCR (real-time PCR) with a double-labeled fluorogenic probe demonstrated that expression of FGF-10 in stromal cells was enhanced 5.3-fold at a DHT concentration of 100 pM. Androgen receptor mRNA levels showed no significant change with DHT at concentrations less than 100 pM, but were reduced to 50% of control levels at a DHT concentration of 10 nM. These results suggest that stromal-derived FGF-10 stimulates human prostatic epithelial growth and its mRNA expression is induced by androgens, without an increase in the androgen receptor mRNA. Moreover, FGF-10 may be involved in the development or support of human BPH.     

Proliferative disorders of the aging human prostate: involvement of protein hormones and their receptors.

The majority of elderly men is affected by benign and malignant diseases of the prostate. Both proliferative disorders, i.e., benign hyperplasia of the prostate (BPH) and prostate cancer (PCa)-which has recently emerged as the most common male malignancy in industrialized countries-seem to be governed by endocrine factors such as sex steroid hormones, but auto/paracrine factors are involved as well. Age-related changes in levels and ratios of endocrine factors as androgens, estrogens, gonadotropins, and prolactin (PRL) and changes in the balance between auto/paracrine growth-stimulatory and growth-inhibitory factors such as insulin-like growth factors (IGFs), epidermal growth factor (EGF), nerve growth factor (NGF), IGF-binding proteins (IGFBPs), and transforming growth factor beta (TGFbeta) are meant to be responsible for abnormal prostatic growth. We investigated the existence of putative local regulatory circuits involving the protein hormones, human growth hormone (hGH), human placental lactogen (hPL), and hPRL, and their corresponding receptors in prostatic tissue specimens (transurethral resections of the prostate, TURP; n = 11), in the prostatic cancer cell lines PC3, Du145, LnCap, a virus-transformed BPH cell line (BPH-1), and in a normal healthy prostate by RT-PCRs and highly specific and sensitive immunofluorometric assays (IFMA). Neither hPRL nor hGH was detected at the mRNA or protein levels in prostatic tissue and cell lines, with the exception of 2 of 11 prostatic TURP-samples, which showed weak expression of the PL-A/B genes. PRL- and GH-receptors were expressed in all normal and pathological prostatic specimens. Surprisingly, PRL-receptor expression was not detectable in prostatic cancer cell lines. The trophic effects of exogenous hGH, hPL, and hPRL were investigated by cell proliferation assays (WST-I) in prostatic primary cell cultures and PCa cell lines. hGH significantly (p < 0.005) increased cell proliferation up to 138+/-3.2% (1 nM hGH), while hPL and hPRL revealed only moderate effects. Our data suggest that local auto/paracrine networks of protein hormone actions are not involved in the pathology of BPH or prostatic cancer. On the other hand, systemic pituitary-derived hGH can increase the proliferative response of BPH and PCa, acting directly on the target organ prostate, via the hGH-R. In this case, envisaged GH substitution in elderly people must be viewed at with caution because age-related declines in GH/IGF-I could act as a protective mechanism against abnormal cell growth.     

Estrogen receptors alpha and beta in the normal, hyperplastic and carcinomatous human prostate

Two different estrogen receptors (ER-alpha and ER-beta) have been described, which are differentially involved in regulating the normal function of reproductive tissues. ER-alpha was considered for a long time to be the only estrogen receptor, and it has been detected in the stromal cells of the human prostate but not in the epithelium. To obtain new information about the differential effects of both receptor types, we have investigated their localization in normal prostates, benign prostatic hyperplasia (BPH), and prostatic cancer (PC) by immunohistochemistry, ELISA and Western blot. Epithelial immunostaining was absent in normal prostates and was present in BPH (10% of cells) and PC (80% of cells), whereas about 15% of stromal cells were positively immunostained for ER-alpha in the three types of prostatic specimens studied. Epithelial immunostaining for ER-beta was detected in normal prostates (13% of cells), BPH (30% of cells) and PC (79% of cells), whereas stromal immunostaining for ER-beta was absent in normal and hyperplastic prostates and was present in PC (12% of cells). The complementary presence of both receptor types in the normal prostate (ER-beta in the epithelium and ER-alpha in the stroma) might explain the mechanism of estrogen action in the development of BPH. The increased epithelial immunostaining for both ER-alpha and ER-beta in BPH and PC suggests that the involvement of estrogen receptors in hyperplasia and cancer concerns mainly the epithelium.     

Growth factors in benign prostatic hyperplasia: Basic science implications

Benign prostatic hyperplasia (BPH) is the most common proliferative disease of the prostate of men in the United States. The histopathology of BPH strongly implicates local paracrine and autocrine growth factors and inflammatory cytokines in its pathogenesis. A complex milieu of growth-regulatory proteins includes members of the fibroblast, insulin-like, and transforming growth factor families. It appears that these proteins and downstream effector molecules, in addition to a variety of interleukins, are overexpressed in BPH and, working together, create a landscape of increased stromal and epithelial growth and mesenchymal transdifferentiation that leads to disease progression. Inflammation, commonly present in BPH, may contribute to tissue injury, and cytokines produced by inflammatory cells may serve to drive local growth factor production and angiogenesis in the tissues as a “wound healing” response. As we begin to unravel the precise mechanisms involved, new treatments for BPH aimed at these interacting pathways may emerge.     

Benign prostatic hyperplasia (BPH) epithelial cell line BPH-1 induces aromatase expression in prostatic stromal cells via prostaglandin E2

Estradiol (E2) level in stroma of benign prostatic hyperplasia (BPH) increases with age, and this increase was associated with an elevated expression of aromatase in prostatic stromal cells (PrSCs). Here, we showed that conditioned medium (CM) of BPH-1 (a benign hyperplastic prostatic epithelial cell line), but not of prostate cancer cell lines (LNCaP, DU-145, and PC-3), stimulates aromatase expression in PrSCs. Cyclooxygenase-2 (COX-2) mRNA level in BPH-1, as well as prostaglandin E2 (PGE2) concentration in BPH-1 CM, was significantly higher than that of prostate cancer cell lines. CM of BPH-1 treated with NS-398 (a specific inhibitor of COX-2) failed to stimulate aromatase expression in PrSCs. And PGE2 can stimulate aromatase expression in PrSCs. Our data suggested that BPH-1 induced aromatase expression in PrSCs through the production of PGE2 in a paracrine mechanism.     

Altered metabolism of androgens in elderly men with benign prostatic hyperplasia.

Kinetics of testosterone, dihydrotestosterone (DHT) and 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) were studied in 7 elderly healthy men (ages 61 to 80 years) with benign prostatic hyperplasia (BPH). Clearance rates were determined by the constant infusion technique with labeled testosterone and DHT. Metabolic clearance rate (MCR), conversion ratio (CR), the transfer constants (rho) and production rates (PB) were calculated. Plasma androgens were measured by specific radioimmunoassay. Plasma testosterone was 516 +/- 314 (SD) ng/dl, plasma DHT was 74.6 +/- 19.6 (SD) ng/dl and plasma 3alpha-diol was 16.4 +/- 4.1 (SD) ng/dl. An elevated DHT level in elderly men with BPH wasconfirmed. MCRT was 620 +/- 65 (SD) liter/day and MCRDHT was 393 +/- 50 (SD) liter/day. Both MCRT and MCRDHT in elderly men were significantly lower than in young men. PBT was 3.2 +/- 2.1 (SD) mg/day and PBDHT was 291 +/- 87 (SD)migrogram/day. PBDHT was the same in elderly and young men. DHT production is maintained in elderly men despite reduction of testosterone production. From the data, it was claculated that in contrast to young men where greater than 80% of blood DHT is from secreted testosterone, over 50% in elderly men is derived from secretion or production of DHT by the testis or even more likely the prostate.     

Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells

Progression of benign prostatic hyperplasia (BPH) involves chronic inflammation and immune dysregulation. Preclinical studies have demonstrated that prostate inflammation and tissue remodeling are exacerbated by hypogonadism and prevented by testosterone supplementation. We now investigated whether, in humans, hypogonadism was associated with more severe BPH inflammation and the in vitro effect of the selective androgen receptor agonist dihydrotestosterone (DHT) on cultures of stromal cells derived from BPH patients (hBPH). Histological analysis of inflammatory infiltrates in prostatectomy specimens from a cohort of BPH patients and correlation with serum testosterone level was performed. Even after adjusting for confounding factors, hypogonadism was associated with a fivefold increased risk of intraprostatic inflammation, which was also more severe than that observed in eugonadal BPH patients. Triggering hBPH cells by inflammatory stimuli (tumor necrosis factor α, lipopolysaccharide, or CD4(+)T cells) induced abundant secretion of inflammatory/growth factors (interleukin 6 (IL6), IL8, and basic fibroblast growth factor (bFGF)). Co-culture of CD4(+)T cells with hBPH cells induced secretion of Th1 inducer (IL12), Th1-recruiting chemokine (interferon γ inducible protein 10, IP10), and Th2 (IL9)- and Th17 (IL17)-specific cytokines. Pretreatment with DHT inhibited NF-κB activation and suppressed secretion of several inflammatory/growth factors, with the most pronounced effects on IL8, IL6, and bFGF. Reduced inflammatory cytokine production by T-cells, an increase in IL10, and a significant reduction of T cells proliferation suggested that DHT exerted a broad anti inflammatory effect on testosterone cells [corrected]. In conclusion, our data demonstrate that DHT exerts an immune regulatory role on human prostatic stromal cells, inhibiting their potential to actively induce and/or sustain autoimmune and inflammatory responses.     

Increased expression of CYR61, an extracellular matrix signaling protein, in human benign prostatic hyperplasia and its regulation by lysophosphatidic acid

Lysophosphatidic acid (LPA) is an endogenous lipid growth factor that is thought to play important roles in cell proliferation and antiapoptosis and therefore may have roles in the development and progression of benign prostatic hyperplasia (BPH). CYR61 (CCN1), on the other hand, is a growth factor-inducible immediate early gene that functions in cell proliferation, differentiation, and extracellular matrix synthesis. Here we show the close relationship between LPA-induced expression of CYR61 and prostate enlargement. CYR61 mRNA and protein were dramatically up-regulated by 18:1 LPA (oleoyl-LPA) within 1 and 2 h, respectively, in both stromal and epithelial prostatic cells. G protein-coupled receptors, i.e. Edg-2, Edg-4, and Edg-7, for LPA were also expressed in both stromal and epithelial prostatic cells. Furthermore, on DNA microarray analysis for normal and BPH patients, CYR61 was found to be related to the development and progression of BPH, regardless of symptoms. Although CYR61 mRNA was synthesized in hyperplastic epithelial cells, in many cases of BPH, CYR61 protein was detected in both the epithelial and stromal regions of BPH patient tissues. The functional contribution of CYR61 to prostatic cell growth was demonstrated by recombinant CYR61 protein and anti-CYR61 neutralizing antibodies, which inhibited CYR61-dependent cell spreading and significantly diminished cell proliferation, respectively. In conclusion, these data support the hypothesis that LPAs induce the expression of CYR61 by activating G proteincoupled receptors and that CYR61 acts as a secreted autocrine and/or paracrine mediator in stromal and epithelial hyperplasia, demonstrating the potential importance of this signaling mechanism in the disease.     

Oestrogen and benign prostatic hyperplasia: effects on stromal cell proliferation and local formation from androgen

Oestrogens have been implicated as a cause of benign prostatic hyperplasia (BPH). Previous animal studies led to the hypothesis that oestrogens can stimulate prostate growth, resulting in hyperplasia of the gland. In humans, the precise role of oestrogens in BPH pathogenesis is currently unclear. We investigated the direct effects of oestradiol on the proliferation of BPH-derived prostate cells in culture. Oestradiol (10(-7) and 10(-6) M) moderately increased the proliferation of stromal cells in culture; this stimulation was antagonised by anti-oestrogen ICI 182 780, indicating an oestrogen receptor (ER)-mediated mechanism. By contrast, oestradiol had no effects on the proliferation of epithelial cells in culture. Parameters that can determine the response of stromal cells to oestrogens, including expression of the two ER subtypes and aromatase activity, were investigated. ER beta expression in stromal cells in culture was demonstrated by immunohistochemistry and western blot analysis, and was confirmed by semi-quantitative RT-PCR showing higher expression of ER beta than ER alpha mRNA in stromal cells. Aromatase, the enzyme that converts androgen precursors to oestrogens, was also examined. Aromatase mRNA and activity were detected in stromal, but not epithelial cells in culture, suggesting a mechanism whereby oestrogen concentrations can be regulated in the BPH stroma. Taken together, these findings support the hypothesis that oestrogens play a role in the pathogenesis of BPH, a disease characterised predominantly by stromal overgrowth.     

Update on the use of dutasteride in the management of benign prostatic hypertrophy

Benign prostatic hyperplasia (BPH) is a frequent cause of lower urinary symptoms, with a prevalence of 50% by the sixth decade of life. Hyperplasia of stromal and epithelial prostatic elements that surround the urethra cause lower urinary tract symptoms (LUTS), urinary tract infection, and acute urinary retention. Medical treatments of symptomatic BPH include; 1) the 5α-reductase inhibitors, 2) the α1-adrenergic antagonists, and 3) the combination of a 5α-reductase inhibitor and a α1-adrenergic antagonist. Selective α1-adrenergic antagonists relax the smooth muscle of the prostate and bladder neck without affecting the detrussor muscle of the bladder wall, thus decreasing the resistance to urine flow without compromising bladder contractility. Clinical trials have shown that α1-adrenergic antagonists decrease LUTS and increase urinary flow rates in men with symptomatic BPH, but do not reduce the long-term risk of urinary retention or need for surgical intervention. Inhibitors of 5α-reductase decrease production of dihydrotestosterone within the prostate resulting in decreased prostate volumes, increased peak urinary flow rates, improvement of symptoms, and decreased risk of acute urinary retention and need for surgical intervention. The combination of a 5α-reductase inhibitor and a α1-adrenergic antagonist reduces the clinical progression of BPH over either class of drug alone.     

Insulin-like growth factor (IGF)-I controls prostate fibromuscular development: IGF-I inhibition prevents both fibromuscular and glandular development in eugonadal mice

Although antiandrogen therapy has been shown effective in treating prostatic tumors, it is relatively ineffective in treating benign prostatic hyperplasia (BPH). In an attempt to understand better the role of androgens in the development of the normal prostate and BPH, we studied the relative effects of testosterone and IGF-I on the development of the two compartments of the prostate in castrated IGF-I((-/-)) male mice. Here we report that IGF-I stimulated the development of the fibromuscular compartment, but testosterone inhibited it (stromal epithelial ratio 2.17 vs. 0.83, respectively; P < 0.001). Testosterone also impaired IGF-I induced insulin receptor substrate-1 phosphorylation and cell division, and increased apoptosis in fibromuscular tissue. In sharp contrast IGF-I and testosterone both stimulated the development of the glandular compartment individually and together. The combined effects were either additive or synergistic on compartment size, cell division, insulin receptor substrate-1 phosphorylation, and probasin production. Together they also had a greater inhibitory effect on apoptosis in gland tissue. To determine whether IGF-I inhibition would inhibit both fibromuscular and glandular compartments, we tested the effect of IGF binding protein-1 on prostate development in two different models: castrated Ames dwarf mice and eugonadal normal male mice. IGF binding protein-1 blocked bovine GH-induced fibromuscular and glandular development in both. It also inhibited epithelial cell division and increased apoptosis in both prostate compartments in the eugonadal mice. The observed discordance between IGF-I and testosterone control of prostate compartment development might explain the relative failure of 5alpha-reductase inhibition in BPH and why testosterone inhibition might theoretically reduce gland volume but increase fibromuscular tissue. The work also provides a rationale for considering IGF-I inhibition as therapy for BPH to reduce the size of both prostate compartments.