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a Department of Medicine, DO2, University of Sydney, Sydney, New South Wales 2006, Australia
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-reductase deficiency develop only a rudimentary prostate [3] that does not develop late-life prostate disease. Prostatic development and hormonal sensitivity in rodents are determined both by neonatal imprinting and by subsequent exposure to testicular androgens [4]. A perinatal androgen surge in males results in adult levels of testosterone (T) that permanently alter the androgen sensitivity [5] or histological structure and function of the prostate at adulthood [6]. While exposure to T neonatally is essential for normal development of sex accessory organs [7], high neonatal T levels reduce weights and induce persistent biochemical defects in adult accessory organs of rats [8, 9] and mice [10]. Similarly, anti-androgen exposure in neonatal male mice affects the functional development of accessory organs and fertility [11] as well as androgen responsiveness at adulthood [12].
Besides androgens, estrogens have also been reported to contribute significantly to the regulation of sex accessory organs [13]. For example, neonatal estrogens induce abnormal growth of testes and ventral prostate [4] and alter prostatic androgen receptor expression [14] in adult rats. Studies reporting synergistic effects of estrogens with androgens on prostate growth in intact [15] and castrated dogs [16] suggest the involvement of estrogens in prostate development as well as in the origin of benign prostatic hyperplasia. However, the long-range effects of sex steroids as well as the hormonal synergy between estrogens and androgens on prostate function and morphology are poorly understood.
The interaction of exogenous and endogenous sex steroids in a normal mouse make it difficult to dissociate direct effects on the prostate from indirect ones due to negative feedback inhibition of endogenous androgen production. Hence, we aimed to utilize the hypogonadal (hpg) mouse model to define the molecular requirements of androgen imprinting. This mouse is congenitally androgen deficient but has an inherently normal reproductive system capable of full development when exposed to appropriate hormonal stimuli. In this study, we aimed to determine whether aromatization or 5-reduction is required for hormonal imprinting of the mouse prostate and to investigate whether combined administration of estrogens and androgens played a synergistic role on the ultimate mature prostate structure.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The hypogonadal (hpg) colony is maintained at the University of Sydney by breeding from fertile heterozygotes originally from F1 hybrids of two inbred strains C3H/HeH and 101/H [17]. Genotyping is performed by polymerase chain reaction of DNA isolated from tail snips and amplification of a region of genomic DNA using three oligonucleotide primers placed strategically around the large deletion in the GnRH gene. The products are separated by agarose gel electrophoresis and three genotypes (homozygous hypogonadals [hpg/hpg], heterozygotes [N/hpg], and homozygous normal [N/N]) are distinguished based on the size of the bands. Heterozygous and homozygous normal mice of this strain (designated as non-hpg) are fertile and phenotypically identical. The mutant hpg is characterized by a sterile phenotype due to functional gonadotropin deficiency.
In the present study, male mice were housed in groups of three to four in standard plastic mouse cages, maintained under controlled conditions (lights-on 0700–1900 h; temperature 20–24°C), and fed ad libitum. All operative procedures were performed under anesthesia administered by an injection (0.01 ml/g BW, i.p.) of a solution containing 5 mg/ml each of ketamine (Parke-Davis, Caringbah, NSW, Australia) and xylazine (Bayer Australia Ltd., Botany, NSW, Australia). All procedures were carried out under approval by the University of Sydney Animal Care and Ethics Committee within the NH&MRC guidelines for animal experimentation.
Chemicals
T propionate was purchased from Sigma Chemical Co. (St. Louis, MO), dihydrotestosterone (DHT) from Merck (Darmstadt, Germany), and estradiol benzoate (EB) and nandrolone decanoate (N) from Steraloids Inc. (Wilton, NH). Collagenase was purchased from Worthington Biochemical Corporation (Lakewood, NJ), arachis oil from Sigma, and heparin from Delta West (Perth, Australia). Tri Reagent for DNA extraction was obtained from Sigma, chloroform (biotechnology grade) from Amresco (Solon, OH), ethanol from Analar (Merck Pty Ltd., Kilsyth, Victoria, Australia), and sodium citrate from BDH Lab Supplies (Poole, England).
Experimental Design
This experiment was designed to study various androgens to investigate the receptor mechanism of androgen imprinting. Since T can undergo aromatization as well as 5-reduction to DHT, it can act via both the androgen and the estrogen receptor. DHT cannot be aromatized; hence any effects observed with DHT treatment will imply action via the androgen receptor. On the other hand, nandrolone undergoes little, if any, aromatization, and its 5-reduced product is inactive as an androgen and hence also acts largely via the androgen receptor [18].
On the first or second day of life, mice (n = 6 per group) were administered a single s.c. injection (100 µg/pup) of androgens (T, DHT, N) or 5 µg of estrogen: estradiol benzoate (EB) alone or in conjunction with DHT (EB+DHT) or arachis oil (vehicle) in 20-µl volume. On Day 21, homozygous hpg male mice neonatally injected with androgen or vehicle were implanted with a 1-cm T pellet subdermally to induce androgen-dependent maturation of sex accessory organs [19]. Untreated homozygous hpg mice (that had never been exposed to androgens neonatally or pubertally), as well as phenotypically normal mice (non-hpg) exposed neonatally to a single s.c. injection of vehicle, were also studied for comparison with treated mice.
Vehicle-treated hpg mice are the mutant mice injected with vehicle at birth followed by T replacement at 3 wk; non-hpg mice are either heterozygous or wild-type homozygous mice with normal reproductive functions and sex accessory organs. For this experiment, non-hpg mice were studied as a positive control for prostate branching morphogenesis.
At 7 wk of age, mice were weighed and killed by cardiac exsanguination under anesthesia; organs (ventral prostate, seminal vesicles, and epididymis) were excised and serum was stored at -20°C for hormone level determinations. Seminal vesicles (SV) were weighed both before and after manual expression of fluid, with the difference defined as SV secretions. Organ weights were corrected for body weights (expressed as mg tissue/g body weight) before data analysis. Mice (n = 4) from each group underwent whole-body perfusion to provide perfusion-fixed tissue for stereological studies.
To evaluate baseline T levels in hpg and normal mice, blood was obtained via cardiac puncture under anesthesia in 1- and 2-wk-old mice. In neonates (Day 1 of birth), anesthesia was administered by cold narcosis. Pups were cooled between ice bags until they became unconscious and blood was obtained via cardiac puncture.
Microdissection
Prostates were excised and weighed; one lobe of ventral prostate (VP) was reserved for microdissection and the other lobe snap frozen in liquid nitrogen for subsequent DNA content measurements. Prior to microdissection, prostatic lobes were dissected free of surrounding fat in calcium- and magnesium-free (CMF) Hanks' solution and then incubated in Hanks' CMF solution containing 0.5% collagenase for 10 min at room temperature [20]. The individual ducts were teased apart on a glass slide under a dissecting microscope using fine forceps and needles. The whole-mount two-dimensional array of ducts was photographed on an inverted microscope equipped with a Polaroid (Cambridge, MA) camera. Ductal tips were counted in the photographs by a single observer with between-day reproducibility (CV) of 3.4% and between-observer CV of 4.5% (n = 8).
Determination of DNA Content
DNA was extracted from VP tissues based on the method of Chomczynski [21]. Frozen VP tissues were weighed and homogenized in 1 ml of Tri Reagent using disposable polypropylene tubes and pestle (Kontes Scientific Instruments, Vineland, NJ). The homogenates were stored at room temperature for 5 min, supplemented with 200 µl of chloroform, and shaken vigorously for 15 sec. After incubation for 15 min at room temperature, the mixture was centrifuged at 14 000 x g for 20 min at 4°C for phase separation. After removal of the aqueous layer, DNA was precipitated from the interphase and organic phase with 300 µl of cold 100% ethanol, incubated at room temperature for 5 min, and centrifuged at 2000 x g for 5 min at 4°C. The phenol-ethanol supernatant was removed and the DNA pellet washed twice in a solution containing 0.1 M sodium citrate in 10% ethanol. At each wash, the DNA pellet was stored in the washing solution for 30 min at room temperature with periodic mixing and centrifuged at 2000 x g for 5 min at 4°C. The DNA pellet was suspended in 75% ethanol, incubated for 20 min at room temperature with intermittent mixing, and centrifuged at 2000 x g for 5 min at 4°C. The pellet was air dried for 1–2 h at room temperature and dissolved in sterile water. Optical density measurements were taken on a spectrophotometer after suitable dilution of the sample. DNA content was calculated assuming that one A260 unit equals 50 µg of double-stranded DNA/ml and multiplying the total amount of DNA per aliquot by the dilution factor.
Hormone Assays
T was measured in serum samples after hexane-ethyl-acetate extraction, reconstituted in PBS, and assayed in duplicate using the SGT-1 antiserum, tritiated tracer, and a standard curve of 0.5–1000 pg/tube with an incubation of 16 h at 4°C and charcoal separation [19].
Histology
Whole-body perfusion was performed for 4 mice per group under anesthesia. Briefly, 20 ml physiological saline containing 10 IU/ml heparin was pumped manually through the left ventricle, while the right ventricle was incised to allow efflux of perfusate. This was followed by 20 ml of fixative consisting of 2% glutaraldehyde, 2% paraformaldehyde, and 0.1% picric acid buffered in 0.2 M sodium phosphate (pH 7.4). After perfusion, well-perfused lobes of the VP were excised, further fixed for 2–3 h, rinsed in 0.2 M phosphate buffer (pH 7.4), dehydrated in graded concentrations of ethanol, and embedded in Spurr's resin. Semithin sections (1 µm) were cut by an ultramicrotome, stained with 1% toluidine blue, and studied under a light microscope.
Stereology
All stereological estimations were done on 1-µm-thick histological sections using an image analyzer (Kontron Electronik Imaging System KS-400, Munchen, Germany). Images were captured live onto the screen from sections under a light microscope with an affixed video camera (Sony, DXC 3000P, Chiba, Japan) and observed under x20 objective. Calibration of images was done using a stage micrometer. Binary images, for measurement, were generated by color thresholding (for stroma) or by interactive contour drawing (for glandular epithelium and lumen). The final stage of analysis was the extraction of quantitative information from images.
The following parameters were evaluated on the basis of area measurement: volume densities (percentage of tissue volume occupied by the defined tissue compartment) [22–24] of glandular epithelium, stroma, and lumen. The diameters of glands, their lumen, and epithelial width were estimated by measuring the diameter of the circle with equivalent area.
Data Analysis
Results are presented as mean ± SEM. The presence of statistically significant differences among the various treatment groups was determined using one-way ANOVA with suitable post hoc linear contrasts. Analysis of stereological data was done using JMP statistical software (SAS Institute Inc., Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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At Day 49, terminal body weights were increased by 20% with neonatal N and by 15% with T compared with those of hpg+vehicle-injected mice (p < 0.05), while other treatments had no effects (Table 1). Terminal body weights in untreated homozygous hpg mice were 19.7 ± 1.0 g.
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Epididymal weights were unaffected by any hormonal treatment compared with hpg+vehicle injection (p > 0.05) and were 54–60% of non-hpg control values (p < 0.0001) (Table 1). At Day 49, epididymal weight in untreated homozygous hpg male mice was 0.21 ± 0.02 mg/g BW, which was significantly different from values in all other treatments (p < 0.0001).
Weights of intact SV decreased significantly (p < 0.05) in EB-treated mice compared with vehicle-treated hpg mice but were unaffected by other treatments. In untreated hpg mice, SV were 0.12 ± 0.02 mg/g BW.
Empty SV weights were increased by 60% and 56% with DHT and N treatment, respectively, compared to hpg+vehicle (p = 0.0002), while other treatments had no significant effects (Table 1).
SV fluid (difference between intact and empty SV) decreased (p < 0.05) with EB treatment, while mice receiving other treatments showed no significant effects compared with vehicle-treated hpg mice (Table 1).
Serum T Levels
T levels in experimental mice exposed to neonatal hormones are shown in Table 1 and were not significantly different (p = 0.2) between various treatments. T levels in untreated hpg and non-hpg neonates (1 day old) were 2.9 ± 0.5 and 2.8 ± 0.2 nM, respectively. T levels in 1-wk-old untreated hpg and non-hpg were 1.4 ± 0.1 and 2.7 ± 0.8 nM; in 2-wk-old untreated hpg and non-hpg mice, the T levels were 2.4 ± 0.2 and 2.5 ± 0.2 nM, respectively. There were no significant differences in T levels between untreated hpg and non-hpg mice at various ages (p = 0.66). T levels in untreated hpg, non-hpg, and T implant (at 3 wk)-treated hpg mice at weekly intervals (Week 3 to Week 10) were presented in a previous study [25].
VP
Weights and DNA content VP weights were increased by 35%, 53%, and 44% with T, DHT, and N treatments, respectively, over those in vehicle-treated hpg mice and were restored to non-hpg control values. Administration of EB alone had no effect, whereas combined EB+DHT treatment increased VP weights by 22% over those in vehicle-treated hpg controls but had no additive effects on VP weights (Fig. 1). In untreated hpg mice, VP weighed 0.034 ± 0.003 mg/g BW. There were no significant differences in DNA content (p = 0.7) expressed as µg/VP lobe between various treatments (Table 1). In untreated hpg mice, DNA content was 0.87 µg/mg of VP.
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Branching morphogenesis Branch tip numbers (expressed per single lobe of VP) were increased by 52%, 35%, 26%, and 42% with T, DHT, EB+DHT, and N treatments, respectively, compared with values in vehicle-treated hpg mice (p < 0.05). However, compared to non-hpg control values, they were still reduced by 18%, 27%, 32%, and 24%, respectively. EB administration reduced tip numbers nonsignificantly by 17% in comparison to values in hpg+vehicle-injected mice. Combined treatment with EB and DHT had no additive effects on branch tip numbers (Fig. 1).
VP weights in untreated hpg mice were ~1/10 of VP in phenotypically normal mice, and these VP did not appear to have true branches (Fig. 2). Contours of prospective ductal branches were visible under the membranous envelope, and attempts to separate the immature ducts revealed them to be enclosed in a membrane-like sheath. Exogenous T replacement (via implants) in hpg mice induced normal patterns of branching morphogenesis in the VP (Fig. 2).
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Prostate Morphometry
Qualitative Prostate gland in phenotypically normal mice is composed of ducts lined with columnar epithelium with mature nuclei, wide lumen, and stroma. On the other hand, prostate gland in untreated homozygous hpg mice is characterized by small glandular acini lined with tiny lumina embedded in a dense mesenchymal tissue (Fig. 3). The epithelium is undifferentiated and unorganized, with immature nuclei occupying a major portion of the cell. Treatment of homozygous hpg mice with androgens restored the prostate histology to that of normal mice with enlarged acinar and luminal diameters and typical tissue organization of epithelium and stroma. EB administration reduced both the acinar and luminal diameters compared to those in non-hpg mice and increased stromal thickness and cell density. Cotreatment with DHT, however, reversed the effects of EB and restored the histological appearance to that of normal prostate (Fig. 3).
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Quantitative Prostate ductal diameters were significantly increased (p < 0.05) in mice treated with T (by 32%), DHT (by 41%), EB+DHT (by 19.4%), and N (by 34.3%) compared with vehicle-treated hpg mice and were also slightly but nonsignificantly higher than in non-hpg controls (Fig. 4).
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Prostate duct luminal diameters were increased by 55%, 66%, and 53% with T, DHT, and N, respectively, compared with values in hpg+vehicle-injected controls (p < 0.05). Lumen diameter in EB-treated mice was not significantly different (p > 0.05) from that in vehicle-treated hpg mice. Combined EB+DHT administration had no additive effect on epithelial or luminal diameters (Fig. 4).
Epithelial height was slightly but nonsignificantly higher in EB- and EB+DHT-treated mice compared with vehicle-treated hpg mice but remained unchanged with any other treatment (Fig. 4). Prostate ductal and lumen diameter in untreated hpg mice were 45.5 ± 1.52 µm and 10.9 ± 0.97 µm, respectively, and epithelial height was 17.3 ± 0.73 µm.
In proportional as well as absolute terms (mg/g BW of VP), volume of epithelium in the VP of androgen-treated mice was not significantly different (p > 0.05) from values in either vehicle-treated hpg or non-hpg controls. EB treatment slightly but nonsignificantly increased epithelial volume compared with that in vehicle-treated or non-hpg controls. On the other hand, volume density of lumen in androgen-treated mice was 48%, 53%, and 41% greater in mice receiving T, DHT, and N treatment, respectively, than in vehicle-treated hpg mice (p < 0.05) and was slightly but nonsignificantly greater than that in non-hpg controls (Fig. 5). Lumen in EB-treated mice was not significantly different from that in vehicle-treated hpg mice.
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Stroma, expressed as volume percentage or in absolute terms (mg/g BW of VP), was unaffected by any androgen treatment and was nonsignificantly (p > 0.05) different from values in either vehicle-treated hpg or non-hpg controls. However, EB treatment did induce an increase (p < 0.05) in stroma percentage compared with that in androgen- or vehicle-treated hpg mice (Fig. 5). Volume density of epithelium, lumen, and stroma was 28.7 ± 2.8, 2.97 ± 0.28, and 35.5 ± 4.5, respectively, in untreated hpg mice.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In normal male rodents, there is a physiologic surge of T in the peripartum period that controls sexual behavior and promotes functional differentiation of the accessory organs [5, 27]. Neonatal T is required for reversal of reproductive deficiency in mice [28] and for sex accessory organs in intact [7] as well as castrated rats [6, 29–31] to respond to exogenous T at adulthood. This suggests that normal differentiation of the accessory structures may be dependent on androgen imprinting during the neonatal period. However, the biological mechanisms underlying such long-range effects and the molecular basis of such changes in androgen sensitivity are not understood. The present study was therefore undertaken to elucidate some of the mechanisms whereby neonatal exposure to sex steroids induced permanent structural changes in the VP of the hypogonadal (hpg) mouse model.
This mutant mouse strain has a spontaneous, autosomal recessive mutation causing sterility with infantile gonads [17] due to a major deletion in the GnRH gene leading to permanent functional hypothalamic GnRH deficiency [32]. The presence of infantile levels of endogenous sex steroids allows complete modification of lifetime steroid exposure of the prostate while retaining androgen and estrogen sensitivity and without confounding by endogenous hormone secretion. This improves on the previous experimental models, the genetic mutants of androgen (tfm) or estrogen (ERKO) receptors (where resistance to steroid action is permanent and irreversible), and in vitro models (where extrapolation to whole animal is uncertain).
This experiment addressed neonatal androgen effects on VP branching morphogenesis and morphometry at Day 49, at which time sexual maturation and ductal branching were completed in hpg mice. We previously demonstrated that branching morphogenesis in this strain of mice is completed by Day 35 and that further growth of VP is due to increase in its ductal dimensions [33]. Due to regional differences in the morphology and functional activities of epithelial cells lining the ductal system in rat VP [34, 35], it is important to study hormonal effects at a specific region between different experimental groups. It was, therefore, of interest to study the volumetric changes in distal ducts of VP after androgen administration, as they have been shown to be sensitive to androgens and are the site of cell proliferation [34, 36, 37].
A single neonatal dose of androgens significantly increased ductal branching and VP weights compared with those in vehicle-treated hpg mice. On the other hand, neonatal estrogen alone had no effects on VP weights, ductal branch numbers, or luminal diameters compared with values in vehicle-treated hpg mice. Nonaromatizable androgens (DHT and N) increased SV size compared with that in vehicle-treated hpg mice, whereas EB was ineffective. This pattern of response in which all androgens, but not estrogen, have stimulatory effects on organ weights, indicates that the likely mode of androgen action may be via the androgen receptor and that aromatization may not be essential for neonatal androgen imprinting of the prostate.
Exogenous administration of sex steroids elicited cellular proliferation as seen by restoration of DNA content and VP weights to normal levels. Although neonatal androgens restored VP weights to normal, the number of ductal tips remained 20% below non-hpg values despite higher levels of circulating T (due to T implant) in treated mice compared with non-hpg controls. This discrepancy can be partially explained if exogenous androgens increased either stroma or glandular diameters. Stereological evaluation of VP revealed that neonatal androgens had no effect on stromal tissue but increased glandular lumen (in absolute terms), suggesting increased fluid production. Epithelial height was unaffected with any treatment, while neonatal androgens, but not estrogen, increased glandular and luminal diameters. These findings reflect the importance of androgens on the secretory activity of the mature ventral prostatic epithelium.
The lack of treatment effects on epididymis suggests that circulating steroids have relatively little effect on epididymis compared with androgens via tubular fluid. This finding is consistent with earlier studies in which exogenous androgens were unable to fully restore epididymal secretory function [38, 39] owing to their inability to replicate high seminiferous tubular androgen concentrations whereby T and DHT are transported luminally to the initial segment of the epididymis [40].
The lasting effects on body weights with neonatal exogenous N and T reinforce the significance of the postpartum hormone surge, consistent with a recent study in which androgen ablation at birth in male rats resulted in lower body weights at adulthood than in sham-treated males [41]. This surge may promote postmaturation muscle development, since neonatal androgens have been shown to promote somatic growth via imprinting of growth hormone secretory pattern in adult male rats [42].
Exogenously administered androgens restored the undifferentiated hpg prostate to normal mature histology with typical organization of the tissue into epithelial and stromal compartments. On the other hand, EB alone induced regressive effects on the prostate histology with overstimulation of stroma and a marked reduction in glandular and luminal size as well as fluid production. Similar effects upon prostate morphology were reported in earlier studies [43–45] wherein localized hyperplasia and dysplasia at distinct sites of the mouse urethro-prostatic complex were observed with neonatal estrogens. Coexposure to DHT was, however, absolutely essential in order to reverse these regressive effects of EB and to restore normal histology.
Prepubertal T levels were low and remarkably similar in hpg and non-hpg mice, whereas sustained high levels of circulating T were induced with T implants. The T-induced pattern of ductal branching in the VP appeared normal in comparison to the branching network of the non-hpg mice. On the other hand, postpubertal administration of T in neonatally castrated mice resulted in abnormal branching patterns in the dorsolateral prostate [46], perhaps due to a prolonged delay in initiating T replacement.
Some studies suggest that the neonatal period in male mice is characterized by low, constant levels of T up to Day 30 [46–48], followed by a pubertal rise in serum T. Other studies, however, report increased T levels in mice on the day of birth [49] and high perinatal T levels in mice and hamsters [50]. In addition, hormonal patterns studied at different times on or around the day of birth suggest a rapid rise in serum T levels during the first few hours of birth in several male mammals [27, 51], including mice [27, 52], similar to the marked postnatal rise in T levels that occurs in humans [53]. The significance of high perinatal T levels has been examined in many studies and is believed to be important for sexual behavior [54] and imprinting of sex accessory tissues [55–57] and hepatic microsomal drug-metabolizing enzymes in rats [58].
Our model for steroid action in hpg and non-hpg (normal) mice is based on the imprinting of accessory glands by perinatal androgen secretion, which is dependent upon a functional hypothalamic-pituitary-gonadal axis driven by GnRH. In normal mice, a lifelong secretion of GnRH regulates the release of pituitary gonadotropins, which stimulate the release of steroid hormones from the gonads. In turn, these steroids feed back to both the hypothalamus and the pituitary, thus affecting the release of GnRH and its action. On the other hand, hpg mice have a life-long absence of gonadal steroids, including the perinatal surge and the pubertal increase in steroids thereafter, as a result of GnRH deficiency. Administration of neonatal androgens in hpg mice, therefore, aimed to replicate this neonatal surge to imprint the target organs to respond normally to exogenous T administered later in life. This exogenous T acts directly on the accessory organs and results in their T-dependent maturation.
In previous studies, estrogens have been shown to enhance androgen-mediated growth in the canine prostate [15, 16, 59, 60] and in purebred beagles [61]. Similar involvement of estrogens has been implicated in the onset of benign prostatic hyperplasia in men [62], and a more recent study [63] indicates synergism between estrogens and androgens as an important factor in the etiology of prostate cancer. However, the failure to find any experimental evidence of synergism between DHT and EB on any of the parameters in the present study may reflect variability due to differences in animal species, experimental design, or treatment regimen.
Unlike the present study, in which imprinting has been shown to occur in the distal regions of the VP, a previous study [14] has shown that proximal and central but not distal regions of VP demonstrate imprinting at adulthood. Prins and coworkers [14, 36] studied androgen receptor localization in the rat prostate, whereas the present study demonstrated changes in structure and volumetric composition of VP in hpg mice following neonatal sex-steroid administration. Thus, different end points as well as difference in species may account for the variation between the two studies.
The findings in the present study suggest that neonatal androgens produce long-lasting effects on the mature VP structure and secretory function in hpg mice. This imprinting of mouse prostate occurs via the androgen receptor and may not require aromatization. However, this study has its limitations owing to the experimental design. The observed effects of androgens or estrogens were restricted only to ventral prostatic lobes, and the relative roles of aromatization or 5-reduction may be different in other lobes of the prostate.
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FOOTNOTES |
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2 Correspondence. FAX: 61 2 9351 4560; djh{at}med.usyd.edu.au
Accepted: February 24, 1999.
Received: May 7, 1998.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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reductase deficiency. J Clin Endocrinol Metab 1992; 75:1022–1026.[Abstract]-reductase activity along the proximal-distal axis of the rat prostatic duct. Endocrinology 1992; 130:3066–3073.[Abstract]-androgens from birth to adulthood in mice. Endocrinology 1982; 111:1230–1234.[Abstract]This article has been cited by other articles:
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  J. A. Brock, D. J. Handelsman, and J. R. Keast Postnatal androgen deprivation dissociates the development of smooth muscle innervation from functional neurotransmission in mouse vas deferens J. Physiol., June 1, 2007; 581(2): 665 - 678. [Abstract] [Full Text] [PDF]
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 N. A. Sims, K. Brennan, J. Spaliviero, D. J. Handelsman, and M. J. Seibel Perinatal testosterone surge is required for normal adult bone size but not for normal bone remodeling Am J Physiol Endocrinol Metab, March 1, 2006; 290(3): E456 - E462. [Abstract] [Full Text] [PDF]
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 M. W. Leihy, G. Shaw, J. D. Wilson, and M. B. Renfree Penile Development Is Initiated in the Tammar Wallaby Pouch Young during the Period when 5{alpha}-Androstane-3{alpha},17{beta}-Diol Is Secreted by the Testes Endocrinology, July 1, 2004; 145(7): 3346 - 3352. [Abstract] [Full Text] [PDF]
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 P. Y. Liu, A. K. Death, and D. J. Handelsman Androgens and Cardiovascular Disease Endocr. Rev., June 1, 2003; 24(3): 313 - 340. [Abstract] [Full Text] [PDF]
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J. Kindblom, K. Dillner, L. Sahlin, F. Robertson, C. Ormandy, J. Tornell, and H. Wennbo Prostate Hyperplasia in a Transgenic Mouse with Prostate-Specific Expression of Prolactin Endocrinology, June 1, 2003; 144(6): 2269 - 2278. [Abstract] [Full Text] [PDF]
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 J. Singh, L. Young, D. J. Handelsman, and Q. Dong Prostate Epithelial Expression of a Novel Androgen Target Gene J Androl, September 1, 2002; 23(5): 652 - 660. [Abstract] [Full Text] [PDF]
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 O. Putz, C. B. Schwartz, S. Kim, G. A. LeBlanc, R. L. Cooper, and G. S. Prins Neonatal Low- and High-Dose Exposure to Estradiol Benzoate in the Male Rat: I. Effects on the Prostate Gland Biol Reprod, November 1, 2001; 65(5): 1496 - 1505. [Abstract] [Full Text] [PDF]
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S. J. McPherson, H. Wang, M. E. Jones, J. Pedersen, T. P. Iismaa, N. Wreford, E. R. Simpson, and G. P. Risbridger Elevated Androgens and Prolactin in Aromatase-Deficient Mice Cause Enlargement, But Not Malignancy, of the Prostate Gland Endocrinology, June 1, 2001; 142(6): 2458 - 2467. [Abstract] [Full Text] [PDF]
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