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S W Hayward

Publications and source records attributed to S W Hayward.

At least 19 recordsLinked to original sources
PubMed2001

Malignant transformation in a nontumorigenic human prostatic epithelial cell line.

The human prostatic epithelial cell line BPH-1 is normally nontumorigenic in nude mice. The present report demonstrates that this cell line can be permanently transformed by its microenvironment to become tumorigenic. The establishment of a series of tumorigenic sublines based on this parental cell line is described. BPH-1 cells were induced to form tumors either by recombination with human prostatic carcinoma-associated fibroblasts (CAFs) or by exposure to carcinogenic doses of testosterone and estradiol (T+E2) after recombination with rat urogenital sinus mesenchyme. Epithelial cells isolated from these tumors were established as cell strains in culture. When regrafted to nude mouse hosts epithelial cells isolated from CAF- or T+E2-induced tumors were found to be consistently tumorigenic even in the absence of CAF or T+E2. The T+E2-induced cell strains have been designated BPH1(TETD)-A and -B and the CAF-induced strains are designated BPH1(CAFTD)-01 through -08. In vitro, the cells had an epithelial morphology with a less well-defined cobblestone pattern than the parental line. They express SV40 large T antigen, confirming their derivation from the parental BPH-1 line. The BPH1(CAFTD) strains formed colonies in soft agar, whereas the parental BPH-1 cells and the BPH1(TETD) sublines did not. There was no immunocytochemically detectable expression of androgen (AR), alpha-estrogen (ERalpha), or progesterone (PR) receptors by the parental BPH-1 cell line or by any of the tumor-derived cell strains. The cells uniformly coexpressed both basal and luminal cell-type cytokeratins and the basal cell marker p63. When grafted beneath the renal capsule of athymic mouse hosts, all of the tumor-derived cell strains consistently formed tumors. These were predominantly poorly or moderately differentiated squamous or adenosquamous tumors, similar in organization to the primary tumors from which the cell strains were derived. The cell strains continued to express both basal- and luminal-type cytokeratins in vivo. Some of the cell strains also coexpressed vimentin. E-cadherin expression was absent from many of the cells, although patches of cells expressing this marker were seen. The cells continued to express SV40T antigen. These cell strains, which are all derived from a common nontumorigenic progenitor, represent a useful resource for examining genetic and phenotypic changes during carcinogenesis.

Animals↗
PubMed2001

The consequences of chromosomal aneuploidy on gene expression profiles in a cell line model for prostate carcinogenesis.

Here we report the genetic characterization of immortalized prostate epithelial cells before and after conversion to tumorigenicity using molecular cytogenetics and microarray technology. We were particularly interested to analyze the consequences of acquired chromosomal aneuploidies with respect to modifications of gene expression profiles. Compared with nontumorigenic but immortalized prostate epithelium, prostate tumor cell lines showed high levels of chromosomal rearrangements that led to gains of 1p, 5, 11q, 12p, 16q, and 20q and losses of 1pter, 11p, 17, 20p, 21, 22, and Y. Of 5700 unique targets on a 6.5K cDNA microarray, approximately 3% were subject to modification in expression levels; these included GRO-1, -2, IAP-1,- 2, MMP-9, and cyclin D1, which showed increased expression, and TRAIL, BRCA1, and CTNNA, which showed decreased expression. Thirty % of expression changes occurred in regions the genomic copy number of which remained balanced. Of the remainder, 42% of down-regulated and 51% of up-regulated genes mapped to regions present in decreased or increased genomic copy numbers, respectively. A relative gain or loss of a chromosome or chromosomal arm usually resulted in a statistically significant increase or decrease, respectively, in the average expression level of all of the genes on the chromosome. However, of these genes, very few (e.g., 5 of 101 genes on chromosome 11q), and in some instances only two genes (MMP-9 and PROCR on chromosome 20q), were overexpressed by > or =1.7-fold when scored individually. Cluster analysis by gene function suggests that prostate tumorigenesis in these cell line models involves alterations in gene expression that may favor invasion, prevent apoptosis, and promote growth.

Aneuploidy↗
PubMed2001

A human prostatic epithelial model of hormonal carcinogenesis.

The effects of stromal and hormonal environment on the immortalized but nontumorigenic human prostatic epithelial cell line BPH-1 were investigated in an in vivo model. BPH-1 cells were recombined with rat urogenital sinus mesenchyme (UGM), and the tissue recombinants were grafted to the renal capsule of adult male athymic mouse hosts. BPH-1 + UGM recombinants formed solid branching epithelial cords with a well-defined basement membrane. The cords canalized to form ductal structures. The mesenchymal cells formed thick sheets of well-differentiated smooth muscle surrounding the epithelium, reinforcing the idea that the epithelium dictates the patterning of prostatic stromal cells. When hosts carrying BPH-1 + UGM tissue recombinants were exposed to testosterone propionate and 17-beta-estradiol (T + E2), the tissue recombinants responded by forming invasive carcinomas, demonstrating mixed, predominantly squamous as well as adenocarcinomatous (small acinar and mucinous) differentiation. When either untreated or T + E2-treated hosts were castrated, epithelial apoptosis was observed in the grafts. When tumors were removed and regrafted to fresh hosts they grew rapidly. Tumors were serially regrafted through six generations. Histologically these tumors consisted largely of focally keratinizing squamous cell carcinoma with high-grade malignant cytological features. BPH-1 cells grown in the absence of UGM survived at the graft site but did not form tumors or organized structures. This behavior was not influenced by the presence or absence of T + E2 stimulation. These data show that an immortalized, nontumorigenic human prostatic epithelial cell line can undergo hormonal carcinogenesis in response to T + E2 stimulation. In addition, the data demonstrate that the stromal environment plays an important role in mediating hormonal carcinogenesis.

Animals↗
PubMed2001

Estrogenic effects on prostatic differentiation and carcinogenesis.

Estrogens, alone or in combination with androgens, can induce aberrant growth and/or malignancy of the prostate gland. Squamous metaplasia is an abnormal form of prostatic epithelial differentiation elicited by exogenous estrogen alone. Estrogens elicit their effects via estrogen receptors (ER) in the prostate. Experiments using ERalpha and ERbeta null mice demonstrated that ERalpha, but not ERbeta is essential in the induction of prostatic squamous metaplasia. To determine the respective roles of epithelial versus stromal ERalpha in this response, the following tissue recombinants were constructed with prostatic epithelium (PRE) and stroma (S) from wild-type (wt) and ERalpha knockout (alphaERKO) mice: wt-S + wt-PRE, alphaERKO-S + alphaERKO-PRE, wt-S + alphaERKO-PRE and alphaERKO-S + wt-PRE. A metaplastic response to diethylstilbestrol (DES) was only observed in wt-S + wt-PRE tissue recombinants. Tissue recombinants containing alphaERKO-PRE and/or alphaERKO-S (alphaERKO-S + alphaERKO-PRE, wt-S + alphaERKO-PRE and alphaERKO-S + wt-PRE) failed to respond to DES. Therefore, full and uniform epithelial squamous metaplasia requires ERalpha in both the epithelium and stroma. Estradiol (E2) in combination with testosterone (T) was shown to be effective in inducing prostatic carcinogenesis in a tissue recombinant model composed of rat urogenital sinus mesenchyme plus mouse prostatic epithelium. A particularly efficient model of prostatic carcinogenesis in mice involves T + E2 treatment of mice bearing grafts of wild-type rat urogenital mesenchyme (rUGM) plus retinoblastoma gene (Rb) knockout (Rb-KO) prostatic epithelium (rUGM + Rb-KO-PRE). Such rUGM + Rb-KO-PRE tissue recombinants developed hyperplasia, atypical hyperplasia and invasive prostatic carcinoma with high efficiency. During carcinogenesis in rUGM + Rb-KO-PRE tissue recombinants, epithelial E-cadherin almost totally disappeared and epithelial PCNA labeling was elevated. These epithelial changes were associated with almost total loss of smooth muscle cells in the stroma. The results of this study demonstrate that the absence of the Rb tumor suppressor gene predisposes prostatic epithelial cells to hormonal carcinogenesis.

Animals↗
PubMed2000

Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue.

The retinoblastoma (Rb) gene product is a prototypic tumor suppressor. Mice lacking the Rb gene are not viable and die in utero at approximately 13 days of gestation. In this study, we have rescued Rb-/- prostates by grafting pelvic organ rudiments from Rb-/- mouse embryos under the renal capsule of adult male nude mouse hosts. Grafts of embryonic pelvic organs developed into functional prostatic tissue. Some of the prostatic tissue generated was further used to construct chimeric prostatic tissue recombinants by combining wild-type rat urogenital mesenchyme (rUGM) with Rb-/- and Rb+/+ prostatic epithelium (PRE). The tissue recombinants were grown as subcapsular renal grafts and treated from the time of grafting with Silastic capsules containing 25 mg of testosterone plus 2.5 mg of estradiol. During 5-8 weeks of hormone treatment, rUGM+Rb+/+PRE tissue recombinants developed prostatic hyperplasia, whereas PRE in rUGM+Rb-/-PRE tissue recombinants developed hyperplasia, atypical hyperplasia, and carcinoma. During carcinogenesis in rUGM+Rb-/-PRE tissue recombinants, prostatic epithelial cells of the basal lineage disappeared, whereas the luminal cells underwent carcinogenesis. Epithelial E-cadherin almost totally disappeared. In all cases, epithelial PCNA labeling was elevated in tissue recombinants containing Rb-/- versus Rb+/+ epithelium. These epithelial changes were associated with almost total loss of smooth muscle cells in the stroma. In contrast, in untreated hosts rUGM+Rb+/+PRE tissue recombinants developed normally, and rUGM+Rb-/-PRE tissue recombinants developed mild epithelial hyperplasia. The results of this study demonstrate that Rb-/- prostatic tissue can be rescued from embryonic lethal mice and used to test its susceptibility to hormonal carcinogenesis. Deletion of the Rb gene predisposes prostatic epithelium to hyperplasia and increases proliferative activity Susceptibility to hormonal carcinogenesis in response to exogenous testosterone + estradiol is manifested in the progression from atypica hyperplasia to carcinoma. Thus, these findings demonstrate that the absence of the Rb tumor suppressor gene may predispose prostatic epithelial cells to carcinogenesis. Rescue of organs from Rb-/- embryos not only provides an opportunity to analyze the Rb gene pathway in the development and progression of prostate cancer but also provides an opportunity for specifically evaluating the role of the Rb pathway in development and carcinogenesis in other organs, such as the mammary gland and colon. Because rUGM greatly stimulates prostatic epithelial proliferation, the tissue recombinant model is a particularly useful tool for assessing the functional role of other genes in prostatic carcinogenesis through use of the appropriate transgenic or gene knockout mice.

Animals↗
PubMed2000

The prostate: development and physiology.

The development of the prostate is controlled by steroid hormones that in turn induce and maintain a complex and little understood cross talk between the various cell types making up the gland. The result of this intercellular communication can be either new growth or growth quiescence, depending upon the differentiation state of the cell type being stimulated. Secretory function of the prostate is dependent upon direct stimulation of fully differentiated prostatic epithelial cells by androgens. The prostate thus seems to be regulated in a similar manner to other organs of the male and female genital tract with proliferative control mediated by cell-cell interactions, whereas differentiated function is determined by direct steroid action on the parenchymal cells.

Androgens↗
PubMed2000

Plasticity of the urothelial phenotype: effects of gastro-intestinal mesenchyme/stroma and implications for urinary tract reconstruction.

The present study tests the hypothesis that heterotypic stromal-epithelial interactions cause phenotypic changes in urothelium. The rational for the experimental design is to simulate heterotypic stromal-epithelial interactions that are created at the anastomotic site of intestinal-bladder augmentations and internal urinary diversions where the urothelium is in direct contact with the gastro-intestinal tract tissues. Tissue recombination experiments were performed by combining 14-day embryonic rat and mouse rectal mesenchyme with urothelium from embryonic, newborn, and adult mice or rats. All tissue recombinants were grown beneath the renal capsule of athymic mouse hosts for 6-16 weeks. Analyses were performed to detect expression of uroplakins, cytokeratin 7, 14, 19 and mucin secreting epithelial cells via Periodic Acid-Schiff (PAS). The phenotype of both mouse and rat urothelium was changed to a glandular morphology under the influence of rectal mesenchyme. Immunohistochemical staining revealed a loss of the urothelial specific uroplakins and cytokeratins 7, 14, and 19 (characteristic of urothelium). Histologic analysis revealed the presence of mucin secreting glandular structures which stained positive for PAS. The urothelial transdifferentiation into glandular epithelium was not a function of epithelial age and occurred in the embryonic, newborn and adult urothelium. Likewise, rectal mesenchyme from embryonic, neonatal, and adult animals was able to induce glandular differentiation in bladder epithelium. Urothelium exhibits the plasticity to change into an intestinal like epithelium as a result of mesenchymal/stromal stimulation from the gastro-intestinal tract. This experimental result is germane to heterotypic stromal-epithelial interactions that are created in patients with urinary tract reconstructions (intestinal augmentations, de-mucosalized urothelial lined bladder patches, and internal urinary diversion such as ureterosigmoidostomies). We propose that heterotypic stromal-epithelial interactions may play a role in determining histodifferentiation of urothelial cells at the anastomotic site between bowel and bladder tissue in patients with gastro-intestinal urothelial reconstructions.

Animals↗
PubMed1999

Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium.

The present study demonstrates that fibroblasts associated with carcinomas stimulate tumor progression of initiated nontumorigenic epithelial cells both in an in vivo tissue recombination system and in an in vitro coculture system. Human prostatic carcinoma-associated fibroblasts grown with initiated human prostatic epithelial cells dramatically stimulated growth and altered histology of the epithelial population. This effect was not detected when normal prostatic fibroblasts were grown with the initiated epithelial cells under the same experimental conditions. In contrast, carcinoma-associated fibroblasts did not affect growth of normal human prostatic epithelial cells under identical conditions. From these data, we conclude that in this human prostate cancer model, carcinoma-associated fibroblasts stimulate progression of tumorigenesis. Thus, carcinoma-associated fibroblasts can direct tumor progression of an initiated prostate epithelial cell.

Animals↗
PubMed1999

The rat prostatic epithelial cell line NRP-152 can differentiate in vivo in response to its stromal environment.

BACKGROUND: The clonally derived rat prostatic epithelial cell line NRP-152 was examined to determine its ability to differentiate in a tissue recombination model. METHODS: NRP-152 cells alone, or combined with urogenital mesenchyme (UGM) or 10T1/2 fibroblasts, were grafted beneath the renal capsule of athymic rodent hosts. After 1 and 3 months, grafts were examined grossly and immunohistochemically. RESULTS: NRP-152 cells grafted alone formed small (10-25 mg) grafts without recognizable architecture. NRP-152 cells recombined with UGM formed larger grafts (50-100 mg after 28 days) containing glandular epithelium. Columnar luminal cells expressed cytokeratins 8 and 18 and rat prostatic secretory markers (DP-1 and DP-2). The epithelial ducts were surrounded by well-differentiated smooth muscle. The glandular epithelial cells were shown to be of rat origin. NRP-152 + 10T1/2 tissue recombinants formed small grafts (10-40 mg wet weight) after 1 month. The epithelial component of these grafts formed solid unbranched cords expressing cytokeratins 5 and 14; no glandular epithelial structures were observed. The stromal matrix was densely packed with a few cells expressing alpha-actin. CONCLUSIONS: A clonally derived prostatic epithelial cell line can form structurally and functionally normal prostatic tissue. This suggests that prostatic basal and luminal epithelial cells can be derived from a common progenitor.

Animals↗
PubMed1998

Expression of hepatocyte nuclear factor-3alpha in rat prostate, seminal vesicle, and bladder.

Hepatocyte nuclear factor-3alpha (HNF-3alpha), a member of the hepatocyte-forkhead-homolog family of transcription factors, regulates gene expression in the endoderm-derived liver and lung. To determine if HNF-3alpha might also play a role in endodermal derivatives of the urogenital sinus, the expression of HNF-3alpha in male accessory sex organs was assessed by Northern blotting, in situ hybridization, and electrophoretic mobility shift analysis. RNA from the dorsolateral prostate (DP), ventral prostate (VP), anterior prostate (AP), seminal vesicle (SV), and bladder was compared with RNA from the liver and spleen as positive and negative controls, respectively. HNF-3alpha mRNA levels in the DP, VP, AP, and bladder were 20, 14, 5, and 6 times higher than the SV equivalent in the liver. HNF-3alpha mRNA was detected in 8 of 10 prostate epithelial cell lines (rat NRP 152 and 154, mouse Pr14, and human DU-145, PC3, LNCaP, ND-1, and BPH-1) but not in rat Dunning epithelial or mouse Pr12 cells. Addition of testosterone to castrated rats was found to prevent a drastic loss of HNF-3alpha mRNA in the VP. This result suggests that HNF-3alpha mRNA levels are at least indirectly regulated by testosterone. The HNF-3alpha mRNA is expressed in epithelial cells of the urogenital sinus derivatives VP, AP, DP, and bladder and Wolffian duct derivative, the SV. To confirm that functional HNF-3alpha protein is produced in the VP, electrophoretic mobility shift assays were performed with whole-cell extracts and high-affinity oligonucleotide (TTR-S) from the transthyretin promoter. Binding to TTR-S was disrupted when the extract was incubated with HNF-3alpha, but not with HNF-3beta, antibody. Taken together, the results using VP, AP, DP, SV, and bladder suggest that HNF-3alpha may play an important role in development and maintenance of urogenital tract epithelial cells.

Amino Acid Sequence↗
PubMed1998

Interactions between adult human prostatic epithelium and rat urogenital sinus mesenchyme in a tissue recombination model.

Tissue recombinants composed of adult human prostatic epithelium (hPrE) and rat urogenital sinus mesenchyme (rUGM) were grafted beneath the renal capsule of athymic rodent hosts. The pseudostratified human epithelium initially became multilayered, solid epithelial cords emerged, grew into the surrounding mesenchyme and canalized to regenerate a pseudostratified epithelium. Basal cells expressed cytokeratins 5 and 14, while luminal cells expressed cytokeratins 8 and 18, prostate specific antigen and prostatic acid phosphatase. The rat mesenchymal component differentiated into thick sheets of smooth muscle, characteristic of the human but not the rat prostate. These findings indicate that epithelial-mesenchymal interactions were reciprocal. Rat UGM induced adult hPrE to form new ductal-acinar tissue, involving epithelial proliferation, ductal branching morphogenesis and functional cytodifferentiation. Concurrently the epithelium dictated smooth muscle differentiation and patterning. Species-specific reverse transcriptase polymerase chain reaction SC (RT-PCR) analysis of the tissue recombinants was performed to separately examine the expression of epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), epidermal growth factor receptor (EGFR), TGF-beta 1, and TGF-beta 3 in the epithelium, stroma and host components of the graft. All of these genes, except TGF-beta 1, were expressed in all three tissues. Human TGF-beta 1 was not detected, indicating that this gene was not expressed in human prostatic epithelium but was present in stroma.

Adult↗
PubMed1998

Species-specific detection of growth factor gene expression in developing murine prostatic tissue.

The aim of the present study was to develop a method by which the expression of paracrine signaling molecules could be localized to either epithelial or stromal cells of developing prostatic tissue. Heterospecific tissue recombinants composed of mouse urogenital epithelium (mouse UGE) plus rat urogenital mesenchyme (rat UGM) and the reciprocal tissue recombinants, rat urogenital epithelium (rat UGE) plus mouse urogenital mesenchyme (mouse UGM), were grafted under the renal capsule in intact, athymic male mouse and rat hosts. After 2 wk of growth, RNA from the grafts was analyzed by species-specific reverse transcription-polymerase chain reaction for the expression of the mRNA for the following molecules: transforming growth factors beta1, beta3, and alpha; epidermal growth factor; epidermal growth factor receptor; and keratinocyte growth factor. The species of expression of these growth factor and receptor gene products within the heterospecific tissue recombinants was identified, allowing determination of the cell layer in which the genes were expressed. Identification of the tissue-specific expression of the growth factor and growth factor receptor profiles of the epithelium and mesenchyme of this in vivo model provides a basis for understanding the autocrine and paracrine mediators of cell-cell interactions in prostatic development.

Animals↗
PubMed1998

Genetic and epigenetic influences in prostatic carcinogenesis (review).

Prostatic carcinogenesis is a multistep process with well-documented stages. Although prostate cancer is a major cause of mortality many small tumor foci never progress to form clinically significant disease, indicating that the disease process may be regulated at more than one level. Carcinogenesis is accompanied by increasing genetic damage to prostatic epithelial cells, however the pattern of genetic lesions is inconsistent. The differentiation of stromal cells surrounding tumors is more fibroblastic and less muscular than in normal prostate. The present communication reviews the roles of both genetic and, stromally derived, epigenetic effects on prostatic tumorigenesis.

Animals↗
PubMed1997

Cellular signaling in the bladder.

Embryologically, the urinary bladder is formed from endodermally derived epithelial cells and mesenchymal cells from the urogenital sinus and allantois. Experimentally, we have shown that bladder mesenchyme differentiates into bladder smooth muscle via an unknown signaling mechanism that originates from the urothelium. It is hypothesized that this signaling between the cellular types, occurs via growth factors. Evidence supporting this hypothesis is that a number of known growth factors, such as TGF beta 2 and 3, KGF and TGF alpha, as well as their receptors are regulated as a function of bladder development and are also modulated during experimental bladder outlet obstruction. Furthermore, growth factors most likely affect extracellular matrix degradative proteins which play a role in bladder remodeling during development, as well as in partial outlet obstruction. There is certainly impressive cellular communication that occurs during development and also occurs postnatally; such as during bladder injury. We have recently shown that KGF is directly responsible for the proliferation of urothelium during bladder injury. This normally quiescent cell, which in humans turns over once every six months to a year when injured, has the incredible ability to immediately proliferate covering the exposed areas of bladder muscle and submucosa. This proliferation is due to the direct effects of KGF, a classic paracrine growth factor which is secreted by the stromal compartment of the bladder and acts directly on the urothelium which harbors the receptor. The bladder also has an uncanny ability to regenerate. In a model to study the basic science behind bladder regeneration, a partial cystectomy was performed and an acellular tissue matrix devoid of all cellular elements was sutured to the defect. Within four days, the urothelium completely covered the acellular matrix, and within two weeks native smooth muscle was seen streaming into the acellular matrix in association with a new epithelium. It is hypothesized that cellular interactions between the epithelium and the mesenchyme, as we have shown in bladder differentiation, are encouraging the new growth of smooth muscle. For the bladder to be a safe and effective storage chamber the ideal cellular lining should be urothelium. Cells from the gastrointestinal are not optimal for this purpose since they either secrete or absorb electrolytes. We believe that the cellular interactions that occur between the urothelium and the foreign intestinal stroma will in time change the phenotype of the urothelium. Newer strategies for bladder replacement which take into account cellular signaling are critical for our young patients with neurogenic bladder disorders.

Animals↗
PubMed1997

The effect of testosterone on androgen receptors and human penile growth.

PURPOSE: Recent rat studies suggest that early exposure to exogenous testosterone accelerates the loss of androgen receptors and compromises eventual penile length. In humans we hypothesize that down regulation of the androgen receptor is not the mechanism that stops penile growth. To test this hypothesis we investigated the effects of androgen deprivation and supplementation on the developing human penis. MATERIALS AND METHODS: A total of 15 normal human fetal penises at 7 to 19 weeks of gestation (mean plus or minus standard deviation 12 +/- 4.5) was divided in half sagittally. Specimens were grafted beneath the renal capsule of male athymic nude mice or nude rats. Three groups of host animals were prepared, including 10 with no testosterone that were castrated at grafting, 15 with testosterone and 5 with super testosterone in which 50 mg. testosterone propionate pellets were implanted subcutaneously at grafting. Each fetal penile specimen was its own control, since half was implanted into an intact animal and the other into a castrated or super testosterone host. Six weeks after grafting the specimens were analyzed for gross size (length), histology and expression of androgen receptors. RESULTS: All human fetal penile specimens grew from the nadir size and appeared as white exophytic growths on the surface of the host kidneys. Normal grafts were larger than castrate specimens (mean 6.9 +/- 2.1 versus 3.9 +/- 2.1 mm., p = 0.014). Mean length of the super testosterone specimens (7.3 +/- 2.3 mm.) was not significantly greater than that of normal specimens (p = 0.797). Histological analysis revealed that all specimens were composed of viable penile tissue. Cellular density of the castrate penises was approximately 2 times greater than that of the normal and super testosterone specimens (40.6 +/- 5.9 versus 25.1 +/- 2.8 cells per cm.2, p > 0.001), as calculated on enlarged micrographs. Supraphysiological doses of testosterone did not change the histology compared to controls. Immunohistochemical localization revealed androgen receptors expressed throughout the corporeal bodies, surrounding stroma and penile skin with intracellular localization to nucleus. The mean proportion of cells expressing androgen receptors was higher in the castrate (29.4 +/- 5.2 cells per cm.2) than in the normal (24.0 +/- 3.7) and super testosterone (24.7 +/- 4.5) grafts (p = 0.005). However, in regard to growth there was no change in the proportion of androgen receptor positive cells among the groups. CONCLUSIONS: Testosterone influences penile growth, possibly as a result of extracellular stromal expansion. The number of androgen receptor positive cells in the human fetal penis did not change among the castrate, normal and super testosterone hosts. These experiments support the hypothesis that penile growth cessation is mediated by mechanisms other than down regulation of the androgen receptor. Furthermore, these data support the hypothesis that early administration of androgen to prepubertal male individuals does not result in a shorter phallus in adulthood.

Humans↗