Fernanda C. A. Santos

Testosterone Stimulates Growth and Secretory Activity of the Female Prostate in the Adult Gerbil (Meriones unguiculatus)

Abstract Theprostate 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.

Antiestrogen Therapies Affect Tissue Homeostasis of the Gerbil (Meriones unguiculatus) Female Prostate and Ovaries

Abstract 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.

Microscopic comparative study of the exposure effects of testosterone cypionate and ethinylestradiol during prenatal life on the prostatic tissue of adult gerbils

There is an increasing variety of endocrine disrupting chemicals (EDCs) either with (anti)estrogenic or (anti)androgenic potential widely present in the environment. These xenosteroids may mimic endogenous steroid hormones disrupting the homeostasis of physiological pathways and leading to several disturbances, especially in tissues highly dependent on steroid hormones such as the prostate. Taking this into account, this comparative study aimed to verify the potential of ethinylestradiol (EE) and testosterone acting as ECDs on the prostate of both male and female adult gerbils exposed to these agents during the embryonic phase. Consequently, pregnant gerbils were treated either with 10 μg/kg/day of EE or with a single dose of 1 mg of testosterone cypionate. The pups that were born 6–8 days after testosterone exposure and the pups that were born after 3 days of EE exposure were allowed to grow but were sacrificed within 4 months. Serological, morphological, stereological, and immunohistochemical analyses were used. Overall, the results showed that both sexes exposed to testosterone and EE during gestation had a prostatic gland with an increased stromal and epithelial and a reduced luminal compartment. Moreover, we observed that glands affected with prostatic intraepithelial neoplasia showed intense stromal reshuffling. In conclusion, although these alterations were observed in both sexes, more relevant to this study was the differential responsiveness of males and females exposed to these different drugs. Whereas the EE affected males more, the testosterone was more harmful to the females. Microsc. Res. Tech. 75:1084–1092, 2012.

Prenatal exposure to testosterone masculinises the female gerbil and promotes the development of lesions in the prostate (Skene’s gland)

Androgenic imbalance may disrupt prostate development, leading to morphological alterations in adulthood and predisposing this gland to develop diseases during ageing. However, little is known about the endocrine disruption of the prostate that is caused by androgenic compounds, especially in female experimental models. Therefore, this study aimed to evaluate the prostates of aged female gerbils exposed to testosterone at certain periods in intrauterine and postnatal life, to determine whether exposure at a particular age increases susceptibility to prostatic lesions in these animals. To this end, morphological, stereological, immunohistochemical and immunofluorescence analyses were employed. It was found that females exposed to testosterone during intrauterine life were masculinised, showing increased anogenital distance, absence of the vaginal opening and ectopic development of prostatic tissue. Several areas of adenomatous hyperplasia, generally associated with inflammatory foci and mainly located in the ectopic prostatic tissue around the vaginal wall, were also observed. In conclusion, the results showed that abnormal prenatal exposure to testosterone severely affects the reproductive systems of female animals by disrupting normal prostate morphogenesis and increasing susceptibility to the development of prostatic diseases during ageing.

Progesterone as a morphological regulatory factor of the male and female gerbil prostate

Testosterone (T) and oestrogen are the main active steroid hormones in the male and female reproductive system respectively. In female rodents progesterone (P4), together with testosterone and oestrogen, has an essential role in the regulation of the oestrous cycle, which influences the prostate physiology through their oscillations. In this work we investigated how the male and female prostate gland of Mongolian gerbils responds to surgical castration at the start of puberty and what are the effects of T, oestradiol (E2) and P4 replacement, using both quantitative and qualitative methods. We also examined the location of the main steroid receptors present in the prostate. In the castrated animals of both sexes an intense glandular regression, along with disorganization of the stromal compartment, and abundant hyperplasia was observed. The replacement of P4 secured a mild recovery of the glandular morphology, inducing the growth of secretory cells and restoring the androgen receptor (AR) cells. The administration of P4 and E2 eliminated epithelial hyperplasia and intensified gland hypertrophy, favouring the emergence of prostatic intraepithelial neoplasia (PIN). In animals treated with T and P4, even though there are some inflammatory foci and other lesions, the prostate gland revealed morphology closer to that of control animals. In summary, through the administration of P4, we could demonstrate that this hormone has anabolic characteristics, promoting hyperplasia and hypertrophy, mainly in the epithelial compartment. When combined with E2 and T, there is an accentuation of glandular hypertrophy that interrupts the development of hyperplasia and ensures the presence of a less dysplastic glandular morphology.

Testosterone Promotes an Anabolic Increase in the Rat Female Prostate (Skene's Paraurethral Gland) Which Acquires a Male Ventral Prostate Phenotype

The female prostate (Skenes paraurethral gland) in the rat is morphologically similar to the ventral lobe of male adults and has been described in other rodent species and humans. Previous studies on prostate morphogenesis suggest that female Wistar rats (Rattus norvegicus) do not develop this gland due to the absence of testosterone during the embryonic and neonatal periods. On the other hand, studies conducted in our laboratory have shown that some females of this species can present an undeveloped but functional prostate. Recent studies on this gland have caused scientific interest because, besides being active in the processes of synthesis and secretion of prostatic material, it is also targeted by both malignant and benign lesions, mainly during senescence. Thus, this work aims to evaluate the structure of female prostate of adult rats (Rattus norvegicus) under normal conditions and under the effect of testosterone treatment and carry out comparative studies on the ventral prostate of young and adult male rats. Morphological and morphometric stereological analyses and immunocytochemical and ultrastructural studies were conducted. The results have shown that the prostate gland of rats exposed to androgen therapy have experienced intense growth, becoming more active in relation to synthesis and secretion. It may be concluded that the prostate in control adult female rats is morphologically very similar to the prostatic ventral lobe of young male rats. Besides, under androgenic action, the female prostate grows considerably and becomes similar to the prostatic ventral lobe in male adults. Anat Rec, 2010.

Female prostate: historical, developmental, and morphological perspectives

The female prostate was first described by Reijnier de Graaf in 1672, and even after several years this gland is still a matter of controversy. Part of this is because the biological function of this female gland is unclear. Moreover, when compared with the male prostate, the existence of this organ in females does not make sense, mainly when we consider that the major function of this gland is to produce a secretion that is responsible for guarantee the sperm survival and assure the reproductive success. However, even under a controversy field, we now have a lot of scientific information which enhances our knowledge of several important biological aspects of this gland. It is clear that this gland is found in some female mammals including humans, rodents, rabbits, bats, and dogs. Several studies with rodents showed that the female prostate is homolog of the male prostate, showing strong macroscopic and microscopic similarities with the ventral lobe of males. Besides these aspects, there are several studies reporting that diseases such as cysts, hyperplasia, and carcinoma may affect the female prostate. Therefore, although diseases involving the female prostate are rare, the susceptibility of this organ to develop lesions must be considered, especially in our recent years in which the exposure to endocrine‐disrupting chemicals has greatly increased. Finally, further studies will be necessary to enhance our understanding about this gland, mainly of the developmental, evolutionary, and biological functions.

Microscopical evaluation of extracellular matrix and its relation to the palatopharyngeal muscle in obstructive sleep apnea

Obstructive sleep apnea hypopnea syndrome (SAHS) is a complex disease of the upper respiratory airways. SAHS physiopathology is multifactorial in which airway compliance is a very important component. To evaluate the tissue changes in the palatopharyngeal muscle by morphometric, histochemical, immunohistochemical, and stereological quantification, with special attention to extracellular matrix associated with this muscle at the structural and ultrastructural levels. Thirty patients with SAHS were divided into groups of 10 according to disease severity: mild, moderate, and severe SAHS. In addition, the control group consisted of 10 patients. Fragments of palatopharyngeal muscle removed from patients with SAHS and tonsillectomies from patients in the control group were histopathologically submitted to light microscopy and transmission electron microscopy. Histopathological evaluations by light and transmission electron microscopes showed differences in analyzed groups, such as reduction of the muscle fiber diameter in patients with SAHS, taking disease severity into consideration. In contrast, stereological analysis showed a gradual increase of the collagen and elastic system fibers relative frequencies, proportionally to SAHS seriousness. MMP‐2 and MMP‐9 immunostaining also showed an increased reaction in the muscle fiber cytoplasm and endomisium during SAHS progression. The ultrastructural analysis showed that palatopharyngeal muscle fibers presented cytoplasmic residual corpuscles, a sign of early cell aging. In conclusion, the increase of tissue compliance in individuals with SAHS can be, in addition to other factors, consequence of diminished contractile activity of the muscle fibers, which exhibited clear signs of early senescence. Moreover, extracellular matrix components changes may contribute to muscle myopathy during SAHS progression. Microsc. Res. Tech., 2011.

MMP-2 and MMP-9 localization and activity in the female prostate during estrous cycle

The gerbil female prostate undergoes morphological and physiological changes resulting from hormonal fluctuations that occur during the reproductive cycle. These repetitive cycles of glandular growth and regression are followed by an extensive reconstruction and remodeling of prostate stroma throughout the reproductive life of the female gerbil. The objective of this study was to evaluate the effect that the hormonal fluctuations of the reproductive cycle have on the stromal remodeling and the expression and activity of matrix metalloproteinases MMP-2 and -9 in the adult female gerbil prostate. For this, serological, ultrastructural, immunohistochemical and biochemical methods were employed. The results showed that the major stromal alteration coincide with the peak of estradiol, which occurs in estrus, and with the peak of progesterone, occurring during diestrus II. MMP-2 and -9 presented a similar pattern of expression and activity during estrous cycle. The estrus was the phase of greater expression and activity of MMP-2 and -9. On the other hand, in DI and DII, the tissue expression and activity of MMP-2 and -9 was very weak. These results are important since they suggest the involvement of estradiol and progesterone in regulating the expression and activity of MMP-2 and -9 in adult gerbil female prostate.

Telocytes play a key role in prostate tissue organisation during the gland morphogenesis

Telocytes are CD34‐positive interstitial cells, known to exert several functions, one of which is a role in tissue organisation, previously demonstrated by telocytes in the myocardium. The existence of telocytes in the prostate has recently been reported, however, there is a lack of information regarding the function of these cells in prostate tissue, and information regarding the possible role of these cells in prostatic development. This study used immunofluorescence techniques in prostate tissue and prostatic telocytes in culture to determine the relationship between telocytes and prostate morphogenesis. Furthermore, immunofluorescent labelling of telocytes was performed on prostate tissue at different stages of early postnatal development. Initially, CD34‐positive cells are found at the periphery of the developing alveoli, later in the same region, c‐kit‐positive cells and cells positive for both factors are verified and CD34‐positive cells were predominantly observed in the interalveolar stroma and the region surrounding the periductal smooth muscle. Fluorescence assays also demonstrated that telocytes secrete TGF‐β1 and are ER‐Beta (ERβ) positive. The results suggest that telocytes play a changing role during development, initially supporting the differentiation of periductal and perialveolar smooth muscle, and later, producing dense networks that separate alveoli groups and form a barrier between the interalveolar region and periurethral smooth muscle. We conclude that telocytes play a relevant role in prostate tissue organisation during postnatal development.