Testosterone stimulates growth and secretory activity of the female prostate in the adult gerbil (Meriones unguiculatus)

The prostate of the female gerbil (Meriones unguiculatus) is similar to the human female prostate (Skene gland) and, despite its reduced size, it is functional and shows secretory activity. However, virtually nothing is known about its physiological regulation. This study was thus undertaken to evaluate the behavior of the gerbil female prostate in a hyperandrogenic condition. Adult females received subcutaneous injections of testosterone cypionate (1 mg/kg body weight every 48 h) up to 21 days. Circulating levels of testosterone and estradiol were monitored, and the prostate and ovaries subjected to structural and immunocytochemical analyses. The treatment resulted in sustained high levels of circulating testosterone, and caused a transient increase in estradiol. There was an increase in epithelial cell proliferation accompanied by significant reorganization of the epithelium and an apparent reduction in secretory activity, followed by a progressive increase in luminal volume density and accumulation of secretory products. Immunocytochemistry identified the expression of androgen receptor and a prostate-specific antigen (PSA)-related antigen in prostatic epithelial cells. A circulating PSA-related antigen was also found, and its concentration showed strong negative correlation with circulating estrogen. Epithelial dysplasia was detected in the prostate of treated females. Analysis of the ovaries showed the occurrence of a polycystic condition and stromal cell hyperplasia. The results indicate that testosterone has a stimulatory effect on the female prostate, inducing epithelial cell proliferation, differentiation, secretory activity, and dysplasia. The results also suggest that prostatic growth and activity, polycystic ovaries, and ovarian stromal cell hyperplasia are related to a hyperandrogenic condition in females.     

Hormonal oscillations during the estrous cycle influence the morphophysiology of the gerbil (Meriones unguiculatus) female prostate (skene paraurethral glands)

The hormonal oscillations that occur during the female reproductive cycle influence the morphophysiology of several organs of the reproductive system. The female prostate is a functional organ sensitive to the action of steroidal hormones, but it is not known whether the hormonal oscillations that occur during the reproductive cycle can alter the biology of this gland. Thus, the present work aims to evaluate the morphofunctional aspects of the female prostate during the gerbil estrous cycle. For this purpose, morphological, morphometric-stereological, serological, and immunocytochemical analyses were carried out. The results of the present study show that the hormonal oscillations that occurred during the estrous cycle altered both the structure and functionality of the gerbil female prostate. These alterations include increased prostatic growth and augmented secretory activity during the proestrus and estrus phases and a gradual decrease of the secretory activity and glandular development in the diestrus I and II phases. These cyclical oscillations appear to be determined by the hormonal peaks of estrogen in diestrus II and by the high levels of progesterone during estrus, since the androgen levels remained constant throughout the estrous cycle.     

Experimental endocrine therapies promote epithelial cytodifferentiation and ciliogenesis in the gerbil female prostate

The incidence of ciliated cells in the prostate gland of the female gerbil (Meriones unguiculatus) is uncommon and apparently becomes more frequent during androgen (testosterone cypionate) and anti-estrogen (letrozole) endocrine therapies. To evaluate the effects of such drug therapies on the induction of ciliogenesis in the glandular epithelium of female prostate glands, adult female gerbils aged 90 days were treated for 14 days with testosterone and letrozole after which their prostate glands were removed for histological, ultrastructural, and serological analyses. The cytodifferentiation of the ciliated phenotype in the alveolar epithelium became more frequent after both the testosterone and the letrozole treatments. The ciliogenesis phenomenon of the epithelial cells in the prostate gland of female gerbils thus appears to be induced by variations in the increase of androgen levels.     

Testosterone effect on immature prostate gland development associated with suppression of transforming growth factor-beta

The aim of this study was to evaluate the effect of testosterone treatment on the pattern of prostate cell proliferation and differentiation and their correlation with the expression of transforming growth factor-beta (TGF-beta). Prostate gland development was compared in intact immature dogs with one-month testosterone-treated immature dogs. Testosterone treatment resulted in a tenfold increase in prostate gland weight compared to untreated dogs, with a typical organization of the gland into a structure similar to that observed in mature dogs. The narrow acini which contain flat basal cells in immature glands were transformed into tubuloacinar structures containing columnar secretory cells and basal cells. The stromal compartments showed an increase in the muscular component as evidenced by the high reactivity to alpha-actin with no remarkable changes in the vimentin expression. In addition, testosterone treatment induced a significant reduction in the proliferation capacity of stromal cells but with no noticeable changes in the proliferation pattern of epithelial cells. These changes in the prostate are associated with a twofold decrease in TGF-beta mRNA expression as assessed by Real-Time PCR. However, the immunolocalization of TGF-beta was shifted slightly from the epithelial cells in untreated animals to the stromal cells of treated animals. Based on these results it appears that testosterone acts to coordinate prostatic cell proliferation and differentiation and direct their organization into a structure resembling that of the mature gland. The testosterone regulation of the prostate gland appears to involve the regulation of TGF-beta gene expression.     

Neonatal exposure to aluminum chloride disrupts branching morphogenesis and hormonal signaling of the ventral male prostate and female prostate of gerbils

BackgroungExposure to environmental pollutants in critical developmental windows may predispose the prostate to permanent changes in its homeostasis. Thus, it is essential to know the effects that environmental toxics, such as aluminum, can cause during the development of this gland. The aim of this study was to evaluate the effects of neonatal aluminum exposure on the ventral male prostate and the female prostate of 15 days old gerbils.MethodsMale and female gerbils were exposed orally to 10 mg/kg/day of aluminum chloride from the 1st to the 14th postnatal day life. At 15 days of life, gerbils were euthanized and their prostates were collected for biometric, morphological, morphometric, immunohistochemical and three-dimensional reconstruction analyzes.ResultsAl exposure caused a reduction in body weight in males and a significant increase in serum testosterone levels in females. Prostate branching morphogenesis was intensified in males, who had greater length, number and area of prostatic epithelial buds. Additionally, Al altered the prostate hormonal regulation of males and females, causing up regulation of the androgen receptor and estrogen receptor alpha in the female prostate, and increased immunostaining of the androgen receptor in the ventral male prostate. These changes were associated with an increased rate of epithelial and stromal cell proliferation in both sexes.ConclusionTogether, these results indicate that Al altered the neonatal development of the prostate and that this metal acted as an endocrine disruptor in this gland.     

Structure, histochemistry, and ultrastructure of the epithelium and stroma in the gerbil (Meriones unguiculatus) female prostate

The female prostate has aroused scientific interest because it is subjected to the same diseases compromising the male prostate during aging. The objective of this work was to characterize structurally, cytochemically, and ultrastructurally the tissue compartments of the normal adult female prostate of Meriones unguiculatus gerbils. The morphological analyses showed that the gerbil's female prostate is constituted of a cluster of glands and ducts inserted in a musculofibrous stroma. The alveolar epithelium is differentiated and consisted of basal proliferating cells, intermediary cells, and secretory cells. The secretory cells are the most numerous cell type and continuously secrete glycoproteins. The basal cells are the source of the secretory cells and they are then responsible for the alveolus renovation. The prostatic stroma is abundant and rich in elastic and collagen fibers, which are closely associated with smooth muscle cells and fibroblasts. The results showed that the gerbil's female prostate shows morphological and ultrastructural homology to the human female prostate (Skene's gland), and despite being a small organ, it is a mature and physiologically active gland.     

Differences between male and female prostates in terms of physiology,sensitivity to chemicals and pathogenesis—A review in a rodent model

The prostate is a gland that is not exclusively present in males, being also found in females of several mammalian species, including humans. There is evidence that the prostate in both sexes is affected by the same pathologies such as prostatitis, benign alterations and even cancer. In view of the difficulties of manipulating the prostate gland, the Mongolian gerbil (Meriones unguiculatus), a rodent species with high incidence of functional prostates in females, is widely used in studies of the female prostate. However, despite knowing much about the similarities between the female and male prostate, little emphasis has been placed on the differences between them. This review investigates the intersex differences in prostate development, physiology and pathogenesis. The female prostate develops earlier than in males and studies indicate that it is more sensitive to oestrogens than the male prostate, as well as being more sensitive to exposure to xenoestrogens, such as Bisphenol A and methylparaben, with a higher susceptibility to benign lesions in the adult and senile prostate than in males. In addition, the female prostate is impacted by pregnancy and the oestrous cycle, and is also dependent on progesterone. The peculiarities of the female prostate raise concerns about the risk of it undergoing neglected changes as a result of environmental chemicals, since safe dosages are established exclusively for the male prostate.     

Antiestrogen therapies affect tissue homeostasis of the gerbil (Meriones unguiculatus) female prostate and ovaries

The present work aims to evaluate the response of the adult gerbil female prostate (paraurethral glands) and ovaries to short-term exposure to antiestrogenic agents, consisting of daily oral doses of letrozole (1 mg kg(-1) day(-1)) or intradermal doses of tamoxifen (1 mg/kg) every other day for 21 days. The serum levels of testosterone and estradiol were monitored, and the prostates and ovaries collected for structural, ultrastructural, and immunocytochemical analyses. The letrozole treatment resulted in increases of serum testosterone levels and secretory activity as well as in glandular hyperplasia and dysplastic growth, simulating the effects caused by the exogenous androgens. The effects caused by tamoxifen indicate that this endocrine agent acted as an estrogenic agonist on the prostate, causing glandular hypertrophy, secretory activity decrease, and the development of prostatic lesions. Therefore, it is possible to conclude that the letrozole and tamoxifen therapies result in a series of complex effects that endanger the physiology of hormone-dependent organs, including the female prostate and ovaries. The hormonal imbalance caused by administration of these drugs resulted in considerable changes in prostatic morphology, in a manner very similar to what occurs during the development of prostatic lesions in aged postmenopausal women. Thus, these therapies must be chosen carefully since long-term treatments can result in female prostate dysplasic lesions.     

Aromatic esters of progesterone as 5α-reductase and prostate growth inhibitors

The aim of this study was to determine the biological activity of 4 steroidal derivatives (9a, 9b and 10a, 10b) prepared from the commercially available 17α acetoxyprogesterone, where 9a, 9b, have the Δ⁴-3-oxo structure and 10a and 10b an epoxy group at C-4 and C-5.

These steroids were tested as inhibitors of 5α-reductase enzyme, which is present in androgen-dependent tissues and converts testosterone to its more active reduced metabolite dihydrotestosterone.

The pharmacological effect of these steroids was demonstrated by the significant decrease of the weight of the prostate gland of gonadectomized hamsters treated with testosterone plus finasteride or with steroids 10a and 10b. For the studies in vitro the IC₅₀ values were determined by measuring the steroid concentration that inhibits 50% of the activity of-5α-reductase. In this study we also determined the capacity of these steroids to bind to the androgen receptor present in the rat prostate cytosol.

The results from this work indicated that compounds 9a, 9b, 10a, and 10b inhibited the 5α reductase activity with IC₅₀ values of 360, 370, 13 and 4.9 nM respectively. However these steroids did not bind to the androgen receptors since none competed with labeled mibolerone. Steroid 10b, an epoxy steroidal derivative containing bromine atom in the ester moiety, was the most active inhibitor of 5α-reductase enzyme, present in human prostate homogenates with an IC₅₀ value of 4.9 nM and also showed in vivo pharmacological activity since it decreased the weight of the prostate from hamsters treated with testosterone in a similar way as finasteride.     

The effect of castration on the mast cells of the ventral gland of male gerbils (Meriones unguiculatus, Gerbillidae)]

The number of labrocytes increases in male gerbil ventral gland connective tissue, as castration makes epithelial structures enter a resting stage. Inversely, labrocytes number decreases when testosterone injection to castrate males initiates epithelial activity. These variations of mast cells number are not a consequence of changes in gland volume, which only act upon epithelial tissues and do not modify "connective tissue compartment".     

Does Testosterone Therapy Increase the Risk of Prostate Cancer?

ObjectiveTo review factors affecting use of testosterone therapy for hypogonadism including the persistent controversial link between testosterone therapy and prostate cancer.MethodsWe reviewed studies investigating the relationship between testosterone therapy and prostate cancer progression and summarized strategies for hypogonadism management and prostate monitoring.ResultsTrials of up to 36 months in length and longitudinal studies consistently fail to demonstrate an increased prostate cancer risk associated with increased testosterone levels. No evidence of an associated relationship between exogenous testosterone therapy and prostate cancer has emerged from clinical trials or adverse event reports. It does not appear that exogenous testosterone accumulates in the prostate or provokes major biologic change in the prostate gland. In addition, preliminary evidence indicates that low endogenous testosterone may confer an increased risk of prostate cancer.ConclusionsMounting evidence demonstrates that there is a lack of association between testosterone therapy and prostate cancer progression. Testosterone therapy may be prescribed for men for whom it was once not considered. Careful monitoring of patients with hypogonadism who are receiving testosterone therapy is imperative. Well-designed, large-scale prospective clinical trials are necessary to adequately address prostate safety in hypogonadal men receiving testosterone therapy. (Endocr Pract. 2008;14:904-911)     

Impact of the Processes of Total Testicular Regression and Recrudescence on the Epididymal Physiology of the Bat Myotis nigricans (Chiroptera: Vespertilionidae)

Myotis nigricans is a species of vespertilionid bat, whose males show two periods of total testicular regression within the same annual reproductive cycle in the northwest São Paulo State, Brazil. Studies have demonstrated that its epididymis has an elongation of the caudal portion, which stores spermatozoa during the period of testicular regression in July, but that they had no sperm during the regression in November. Thus, the aim of this study was to analyze the impact of the total testicular regression in the epididymal morphophysiology and patterns of its hormonal regulation. The results demonstrate a continuous activity of the epididymis from the Active to the Regressing periods; a morphofunctional regression of the epididymis in the Regressed period; and a slow recrudescence process. Thus, we concluded that the processes of total testicular regression and posterior recrudescence suffered by M. nigricans also impact the physiology of the epididymis, but with a delay in epididymal response. Epididymal physiology is regulated by testosterone and estrogen, through the production and secretion of testosterone by the testes, its conduction to the epididymis (mainly through luminal fluid), conversion of testosterone to dihydrotestosterone by the 5α-reductase enzyme (mainly in epithelial cells) and to estrogen by aromatase; and through the activation/deactivation of the androgen receptor and estrogen receptor α in epithelial cells, which regulate the epithelial cell morphophysiology, prevents cell death and regulates their protein expression and secretion, which ensures the maturation and storage of the spermatozoa.     

Inhibition of 5-alpha-reductase activity induces stromal remodeling and smooth muscle de-differentiation in adult gerbil ventral prostate

Prostatic differentiation during embryogenesis and its further homeostatic state maintenance during adult life depend on androgens. Dihydrotestosterone, which is synthesized from testosterone by 5 alpha-reductase (5 alpha-r), is the active molecule triggering androgen action within the prostate. In the present work, we examined the effects of 5 alpha-reductase inhibition by finasteride in the ventral prostate (VP) of the adult gerbil, employing histochemical and electron microscopy techniques to demonstrate the morphological and organizational changes of the organ. After 10 days of finasteride treatment at a dose of 100 mg/kg/day, the prostatic complex (VP and dorsolateral prostate) absolute weight was reduced to about 18%. The epithelial cells became short and cuboidal, with less secretory blebs and reduced acid phosphatase activity. The luminal sectional area diminished, suggestive of decreased secretory activity. The stromal/epithelial ratio increased, the stroma becoming thicker but less cellular. There was a striking accumulation of collagen fibrils, which was accompanied by an increase in deposits of amorphous granular material adjacent to the basal lamina and in the clefts between smooth muscle cells (SMC). Additionally, the periacinar smooth muscle became loosely packed. Some SMC were atrophic and showed a denser array of the cytoskeleton, whereas other SMC had a highly irregular outline with numerous spine-like projections. The present data indicate that 5 alpha-r inhibition causes epithelial and stromal changes by affecting intra-prostatic hormone levels. These alterations are probably the result of an imbalance of the homeostatic interaction between the epithelium and the underlying stroma.     

New Aromatic Esters of Progesterone as Antiandrogens

The in vivo and in vitro antiandrogenic activity of four new progesterone derivatives: 4-bromo-17α-(p-fluorobenzoyloxy)-4-pregnene-3,20-dione 1,4-bromo-17α-(p-chlorobenzoyloxy)-4-pregnene-3,20-dione 2, 4-bromo-17α-(p-bromobenzoyloxy)-4-pregnene-3,20-dione 3 and 4-bromo-17α-(p-toluoyloxy)-4-pregnene-3, 20-dione 4 was determined. These compounds were evaluated as antiandrogens on gonadectomized hamster prostate and reduced the weight of the prostate glands in gonadectomized hamsters treated with testosterone 5 (T) or dihydrotestosterone 6 (DHT) in a similar manner to that of commercially available finasteride, thus indicating a potent in vivo effect. The in vitro studies showed that steroids 1–4 have a weak inhibitory activity on 5α-reductase with IC50 values of: 280 (1), 2.6 (2), 1.6 (3) and 114?μM (4). The presence of Cl and Br atoms in the C-17 benzoyloxy group tends to increase the inhibitory potency of the compounds.

The binding efficiency of the synthesized steroids 1–4 to the androgen receptor of the prostate gland is also evaluated. All compounds form a complex with the receptor and this explains the weight reduction of the seminal vesicles in the animals treated with DHT plus steroids 1–4.     

Antiandrogenic and apoptotic effects of RU-486 on animal prostate

Mifepristone (RU-486) is a potent antagonist of steroid hormone receptors such as glucocoticoid and progesterone receptors. This compound also is a very strong inducer of the interaction between androgen receptors and corepressors NCoR and SMRT and therefore could be used as selective receptor modulator.

In this study we determined the relative binding affinity of RU-486 to androgen receptors (AR) obtained from rat prostate cytosol as well as the in vivo effect of different doses of RU-486 on the prostate weight of hamsters treated with dihydrotestosterone and/or RU-486. We determined also the prostate cell death (apoptosis) in hamster treated with, dihydrotestosterone (DHT) and/or RU-486.

The results of this study indicated that the relative binding affinity of RU-486 for AR is 4.3%. The data from the in vivo experiments also showed that RU-486 inhibited the prostate weight significantly in the highest doses thus indicating the antagonistic action of this compound on hamster prostate.

The immunohistochemistry analysis showed that after 1 month of castration, the hamster prostate was atrophic. Treatment with DHT produced epithelial cell activity (measured by the increase in the prostate weight) and very low rate of apoptosis. When DHT was administered together with RU-486 (10 mg/kg) no change was observed. On the other hand, DHT plus higher doses of RU-486 (40, 80 mg/kg) resulted in an increase of apoptosis in stromal and secretory epithelial cells. In addition to the increase of the prostate cell apoptosis produced by the treatment with high dose of RU-486, other factors could contribute to the decrease of the prostate weight observed. Another possibility could be a reduction in the ductal fluid due to poor epithelial cell secretory activity more than apoptosis itself. Furthermore, in this experiment, RU-486 could have inhibited the growth of the prostate gland produced by DHT in a greater extent than the induction of atrophy and cell death. This fact could depend on the doses used, due to the low affinity of this compound for the androgen receptors.     

Prenatal and pubertal exposure to 17α-ethinylestradiol cause morphological changes in the prostate of old gerbils

This study evaluated such as exposure to ethinylestradiol during the prenatal (18th–22nd day) and pubertal (42nd–49th day) periods acts on the male ventral prostate and female prostate of 12-month old gerbils. We performed the analysis to serum hormone levels for estradiol and testosterone. The prostates were submitted to morphometric and immunohistochemical analyses. Exposure to ethinylestradiol during these developmental periods decreased the testosterone serum levels in males and increased the estradiol serum levels in females. Morphologically, prostate intraepithelial neoplasia and disorders in the arrangement of the fibrous components were observed in the prostate glands of both sexes of gerbil exposed to ethinylestradiol during development periods. In the male prostate, the ethinylestradiol promoted decreased in the frequency of positive epithelial cell for androgen receptor (AR) and increased the frequency of positive stromal cell for estrogen receptor α. However, in the female prostate, this synthetic estrogen caused AR upregulation and increased cell proliferation. This study shows that the exposure to ethinylestradiol during development phases alters the morphology and the hormonal signaling in the male and female prostates of old gerbils, confirming the action of ethinylestradiol as endocrine disruptor.     

Histology and histochemistry of the accessory reproductive glands in the male hairy-nosed wombat (Lasiorhinus latifrons)

Summary The accessory male reproductive glands of the hairy-nosed wombat, Lasiorhinus latifrons, are a prostate and three pairs of Cowper's glands. Component units of all are branched tubular structures of varying epithelial makeup and secretory content. The prostate has the carrotlike shape and three consecutive regions commonly found in marsupials. The regions differ in their tubular histology and histochemistry: all contain secretory globules in glandular lumina. Cowper's glands A and B are histologically identical except for the absence of interstitial mast cells from gland B: gland C is characterized by narrower tubules and larger epithelial cells. Histochemical tests for protein, carbohydrate and iron indicate that glycogen is a major secretory product of the prostate (largely posterior region), iron is also secreted (mainly posterior region) and a small quantity of acid mucin is produced (mainly central region). Glycogen is a feature also of anterior prostatic glandular epithelium and of the capping cells of the urethral transitional epithelium. Cowper's gland A has considerable protein in its secretion, gland B a neutral glycoprotein and gland C a sialomucin: the latter two also exhibit cytoplasmic glycogen in their secretory cells.     

Acute effects of testosterone on serum PGE2 levels in male dogs

Serum prostaglandin levels are influenced by testosterone. To test the hypothesis that the effect of testosterone is mediated through the prostate gland, testosterone was given acutely to intact and to prostatectomized male dogs. Intact dogs responded to testosterone with an abrupt, transient rise in plasma PGE₂ levels; prostatectomized dogs did not respond. We conclude that testosterone has an acute effect on the prostate gland which results in release of PGE₂ into the blood stream.     

Analysis of regulatory sequences in androgen-responsive genes

We have analysed the effect of androgens on the activity of promoters from MMTV, and the rat prostate C3(1) and mouse secretory protease inhibitor genes. MMTV promoter activity was stimulated by testosterone as well as progesterone and dexamethasone but not by oestradiol. Deletion analysis indicated that the three steroids acted through DNA sequences between nucleotides -201 and -69 upstream of the MMTV cap site. In contrast, the promoters for the C3(1) gene and the protease inhibitor gene were unaffected by testosterone in a number of cell types, including prostate cells, despite the fact that the MMTV promoter was stimulated in such cells.