Azmy, Abeer M.; Abdallah, Maha A.
Prolactin (PRL) is a pituitary-derived peptide hormone that is mainly synthesized and secreted by the lactotrophs. Although the large majority of circulating PRL is of pituitary origin, extrapituitary PRL production in several peripheral tissues including the mammary gland, placenta, uterus, ovaries, prostate, skin fibroblasts, and immune cells, especially lymphocytes, is well established [1–3].
PRL secretion is under dual regulation by hypothalamic hormones through the pituitary portal circulation. The predominant regulatory signal is the inhibition of PRL secretion by the dopamine neurotransmitter from the neurons in the hypothalamus. The stimulatory signal is mediated by the hypothalamic thyrotropin-releasing hormone [4,5].
PRL affects many physiological processes such as the regulation of mammary gland development, initiation and maintenance of lactation, osmoregulation, immune modulation, and behavior. It has mitogenic, morphogenic, or secretory activities at the cellular level. Furthermore, PRL influences male reproduction by acting as a physiological regulator of prostate activities. It plays an important role in prostate growth, development, proliferation, and function [2,6,7].
A circulating PRL level ranging from 3 to 15ng/l is considered necessary for maintaining normal reproductive function. PRL displays a variable serum level during the day (circadian rhythm). Furthermore, the amount cleared by the kidneys influences its concentration in the blood [4,8].
Hyperprolactinemia is one of the most common endocrinological disorders affecting the hypothalamic-pituitary axis. It occurs when circulating PRL levels increase beyond the normal range. It can occur in physiological and pathological conditions. Physiological hyperprolactinemia occurs during pregnancy, lactation, sleep, stress, sexual activity, and in men after 60 years of age. The most common causes of pathological hyperprolactinemia are pituitary adenomas, hypothalamic diseases, primary hypothyroidism, and also chronic renal diseases. Drug-induced hyperprolactinemia may represent a side effect of certain medications such as antipsychotics, antidepressants, antihypertensive, and drugs that increase bowel motility [9–12].
The prostate is a key gland in the sexual physiology of male mammals. Its location in the reproductive tract influences several vital functions such as those related to micturition, seminal emission, and ejaculation . The general pattern of the prostate gland is common to all rodents and human. Rat prostate has an evident lobular structure. It is divided into distinct ventral, dorsal, andlateral lobe pairs according to the relative position to the urinary bladder. Human prostate shows lobes only during early development. Then, connective tissue joins lobes in one solid gland. The dorsal lobe as well as the lateral lobe of rat prostate is the most homologous to human prostate, although the lateral one is an essential target for PRL [7,10].
It has been established that the growth, differentiation, and programmed cell death of prostate cells are mainly regulated by androgens. For this reason, the main treatment for benign prostate hyperplasia (BPH) and prostate cancer includes inhibition of cell growth by suppressing the action or the production of endogenous androgens. However, despite this treatment, almost all tumors continue to progress. Paradoxically, testosterone levels decrease with age in men, whereas prostate diseases increase markedly. Therefore, it is clear that other nonandrogenic factors may be involved in the regulation of prostate cell growth such as PRL, which is one of the nonsteroidal factors considered to be involved in the proliferation of prostate cells. Moreover, it has been suggested that beyond its role as an enhancer of androgen action, it exerts androgen-independent effects [13–15]. Hence, this study was carried out to determine the influence of experimental hyperprolactinemia on the structure of the prostate lateral lobe in adult albino rats.
Materials and methods
Twenty healthy adult male albino rats (4–6 months) weighing 180–200g were included in this study. They were housed in stainless-steel cages and were maintained in room temperature at 23°C. They were allowed water ad libitum and were fed a standard diet. They were divided equally into two groups: a control group and an experimental group. The animals of the experimental group were injected intraperitoneally with metoclopramide at a dose of 2.2mg/kg for 14 successive days to induce hyperprolactinemia. Animals of the control group were injected with saline in the same manner .
At the end of the experiment before scarification, blood samples from the tails of all animals were collected for the determination of serum PRL and testosterone levels. Then, rats of both the groups were anesthetized by ether inhalation and then intracardiac perfusion was carried out by 2.5% glutaraldehyde buffered with 0.1M phosphate buffer at pH 7.4 for partial fixation of the prostate. The prostate of each animal was dissected out carefully and its lateral lobes were processed for light and electron microscopic examinations. Specimens for light microscope examination were fixed in Bouin's solution for 48 h and were processed to prepare 5-μm thick paraffin sections for H&E stains .
Specimens for electron microscopic examination were immediately fixed in the same perfusion fixative (2.5% glutaraldehyde) for 2h and postfixed in 1% osmium tetroxide buffered with 0.1M phosphate buffer at pH 7.4 for 1h. Then, they were dehydrated in ascending grades of alcohol and embedded in resin to prepare semithin and ultrathin sections using a Leica ultracut (Glienicker, Berlin, Germany). Semithin sections (1-μm-thick) were stained with 1% toluidine blue for light microscopic examination . Ultrathin sections were stained with uranyl acetate and lead citrate . They were examined using a JEOL JEM 1010 electron microscope (Japan) at the Electron Microscope Research Laboratory of the Histology and Cell Biology Department, Faculty of Medicine, Zagazig University (Egypt).
The epithelial height of the prostatic lateral lobes acini was measured using a Leica Qwin 500 (England) image analyzer computer system in the Histology and Cell Biology Department, Faculty of Medicine, Cairo University. The procedure was performed using H&E-stained sections at a total magnification of × 400 by measuring 10 nonoverlapping fields from each specimen of randomly chosen five rats of each group.
Data obtained from the control and the experimental groups were expressed as mean ± SD (X ± SD). The data obtained from the image analyzer were subjected to SPSS program version 15 (SPSS Inc., Chicago, Illinois, USA). Statistical analysis using Student's t-test was carried out. P values less than 0.05, less than 0.01, and more than 0.05 were considered significant, highly significant, and nonsignificant, respectively.
In rats of the experimental group as compared with the control group, the mean serum PRL concentration was more than two times higher (27.5±5.4 vs. 12.3±3.1ng/ml) whereas the mean testosterone concentration was lower in the experimental group (1.52 ± 0.6ng/ml) as compared with the control group (3.51 ± 1.6ng/ml).
Light microscopic examination of the sections of the prostate gland lateral lobes of the control adult albino rats showed that the prostatic parenchyma was composed of closely packed acini of different sizes. Their epithelium formed folds supported by connective tissue stroma. These acini were separated by narrow interacinar spaces occupied by minimal stroma. Some acini contained homogenous acidophilic secretion (Figs 1 and 2). The acini were lined by pseudostratified columnar epithelium comprising tall columnar cells with basal nuclei and basal cells with flattened nuclei. Flattened smooth muscle cells were observed in close contact to the basement membrane (Fig. 3).
The electron microscopic examination of the ultrathin sections of the prostate gland lateral lobes of the same group showed that the tall columnar secretory cells of the prostatic acini remained in contact with the glandular lumen with obvious apical microvilli and basally located euchromatic nuclei. Their cytoplasm contained parallel flattened cisternae of rough endoplasmic reticulum, well-developed Golgi saccules, and many secretory vesicles with different electron densities. The surface (superficial) vesicles were electron dense. Other deeper vesicles appeared with centrally located flocculent material surrounded by electron-lucent zones. Among the tall columnar cells, there were electron-lucent basal cells. The latter were smaller, had fewer synthesis organelles, and the nucleus occupied most of the cell (Figs 4 and 5).
Light microscopic examination of the sections of the prostate gland lateral lobes of the experimental hyperprolactinemia adult albino rats showed that most of the prostatic acini had a pale acidophilic foamy secretion and poorly infolded mucosa in comparison with that observed in the control group in Figs 1 and 2. Focal areas of epithelial proliferation were obvious in some acini. Noticeable areas of stromal thickening contained cellular infiltration and congested blood vessels were detected in between some acini (Figs 6 and 7). Numerous prostatic acini were lined by multiple layers of epithelial cells with rounded or oval nuclei and prominent nucleoli, with an apparent increase in the basal cells. Desquamated cells were observed within the lumina of some acini (Fig. 8). Epithelial evaginations were also observed. The bases of these acini were surrounded by prominent smooth muscle cells and many connective tissue cells. Mast cells were obvious in the interacinar connective tissue (Fig. 9).
Electron microscopic examination of the ultrathin sections of the prostate gland lateral lobes of the same group showed that acinar epithelium had different ultrastructural features. Some acini were lined by closely related epithelial cells arranged in several layers (hyperplasia). Their cytoplasm contained vacuoles and residual bodies. The nuclei showed a pleomorphic shape, were close together without order, and had a highly infolded nuclear envelope (Fig. 10). Other acinar cells were packed with extensive flat cisternae of rough endoplasmic reticulum and secretory vesicles (Fig. 11). Others showed irregular nuclei, prominent dilated rough endoplasmic reticulum, and dilated Golgi saccules. Their secretory vesicles were few in comparison with that observed in Fig. 3. The majority of the vesicles contained centrally located flocculent material surrounded by electron-lucent zones. Also, the apical microvilli appeared discontinuous and sparse in some acinar cells (Figs 12 and 13). Among the prostatic epithelial cells, many basal cells with a clear electron-lucent cytoplasm were observed. Both secretory and basal cells rested on the irregular thickened basement membrane. Some epithelial cells contained lipofuscin pigments in the perinuclear region (Figs 14 and 15). The prostatic epithelial lining was infiltrated by inflammatory cells with heterochromatic nuclei (Fig. 16). Smooth muscle cells were arranged in several layers around the prostatic acini. Mast cells with their irregular nuclei and prominent electron-dense variable-sized granules were observed in the prostatic stroma (Figs 17 and 18).
Morphometrical and statistical results
Statistical analysis of the epithelial height of the prostatic lateral lobe acini of the experimental group showed a highly significant increase as compared with the control group (Table 1).
For many years, the development and function of the prostate was believed to be solely dependent on androgens. Although it is still widely accepted that androgens are essential, evidence exists that PRL modulate various aspects of prostate growth, development, and metabolism .
In this study, the mean serum PRL concentration was more than two times higher in the experimental hyperprolactinemic group as compared with the control group (27.5±5.4 vs. 12.3±3.1ng/ml), whereas the mean testosterone concentration was lower in the same group (1.52±0.6ng/ml) as compared with the control group (3.51±1.6ng/ml). Previous studies [19,20] have reported that experimental hyperprolactinemia not only increases the PRL concentration but also reduces cholesterol fractions in Leydig cells, suggesting lower utilization of cholesterol for steroidogenesis. This reduction in testosterone synthesis with hyperprolactinemia may be either because of a direct effect on Leydig cells by the decreased activity of major steroidogenic enzymes  or an indirect effect resulting in an alteration in the sensitivity of Leydig cells to luteinizing hormone . Consequently, the low serum testosterone level causes the prostate lateral lobe to be more sensitive to PRL .
In this search, light microscopic examination of the sections of the prostate gland lateral lobes of the experimental hyperprolactinemia adult albino rats showed that most of the prostatic acini had a pale acidophilic foamy secretion and poorly infolded mucosa. Focal areas of epithelial proliferation were obvious in some acini. Epithelial evaginations were also observed. Certain study  attempted to distinguish between many proliferative lesions of prostate. Two types of nonreactive hyperplasia (functional and atypical) were found. In both types, the lesion can be found focally or multifocally; the amount of intra-acinar secretion is usually decreased in the functional type. In the atypical type, one or more growth patterns that do not obliterate acinar lumen can be seen. Also, epithelial evaginations can be detected as a morphological feature of the prostate of rats exposed to chronic administration of alcohol  and estrogen .
In this study, numerous prostatic acini were lined by multiple layers of epithelial cells with rounded or oval nuclei and prominent nucleoli. Morphometric and statistical analyses of the epithelial height of the prostatic lateral lobe acini showed a highly significant increase as compared with the control group. Several theories have been postulated in an attempt to explain the cause of epithelial prostatic hyperplasia in hyperprolactinemia. It was reported [25,26] that the trophic effect of PRL is mediated by membrane-bound receptors that are present in all three lobes of the rat prostate distributed on the basolateral and apical surfaces. They added that prostatic epithelial cells are able to produce PRL, which may act in an autocrine/paracrine manner in the prostate through apical receptors. Other researchers [27–29] reported that overexpression of the antiapototic protein Bcl-2 led to a marked reduction in apoptosis in the prostatic epithelial cells, which modifies the balance between proliferation and apoptosis, eventually causing hyperplasia. Others have reported that PRL either stimulates RNA and DNA synthesis in all lobes of the gland  or it alters the permeability of the prostate cell membrane to androgen . In agreement with this finding, another study  attributed this hyperplasia to a disturbed prooxidant–antioxidant balance in prostatic tissue and blood toward pro-oxidants, leading to oxidative damage in the prostatic acinar cells.
In our study, desquamated cells were observed within the lumina of some acini. A previous report  found that the prostatic epithelial cells usually exfoliate into the ejaculate and they may be increased with prostate diseases. It is likely that the increase in desquamation of these cells is associated with the disturbance of their secretory patterns.
Ultrastructurally, acinar epithelium had different ultrastructural features. Some acini were lined by closely related epithelial cells arranged in several layers (hyperplasia). Their cytoplasm contained vacuoles and residual bodies. The nuclei had a pleomorphic shape, were close together without order, and had a highly infolded nuclear envelope. Some investigators [33,34] have reported that in the presence of PRL, the epithelial cells were stratified and seemed to have lost their polarized orientation in relation to the basement membrane around the acini. Therefore, the high PRL level plays a direct role in the induction of dysplasia. Furthermore, another study  clarified that the prostatic responses to androgen and PRL were highly similar, but there was one significant difference, which is the capacity to maintain the epithelial integrity. In the presence of androgen alone, the epithelium of the prostate was regular and polarized, whereas in the presence of PRL, the epithelium showed a proliferative and disorganized morphology resembling focal epithelial dysplasia.
Also, ultrastructural examination showed that other acinar cells were packed with extensive flat cisternae of rough endoplasmic reticulum and secretory vesicles. Others showed irregular nuclei, prominent dilated rough endoplasmic reticulum, and dilated Golgi saccules. Their secretory vesicles were few in comparison with that observed in the control group. The majority of the vesicles contained centrally located flocculent material surrounded by electron-lucent zones. Also, the apical microvilli appeared discontinuous and sparse in some acinar cells. In a previous study , the PRL treatment after castration clarified that prolactin is capable of stimulating the secretory function of the lateral prostate. This was accompanied by an apparent increase in the number of profiles of granular endoplasmic reticulum, well-developed Golgi complexes with dilated cisternae, and low-contrast electron-dense secretory granules. They added that the action of PRL on the prostate gland could have a direct effect on the thiamine pyrophosphatase enzyme, which is mainly confined to the trans cisternae of the Golgi complex. This enzyme was part of the process of glycosylation, which was inhibited after PRL administration. In contrast, Nevalainen and colleagues [26,37] have reported that rough endoplasmic reticulum, golgi apparatus, and the cell surface are related to the androgen-dependent function of the lateral lobe. Secondary to administration of metoclopramide, the structural abnormalities of these organelles might be caused by a reduced serum testosterone level, which is responsible for the development, maturation, and function of the prostate. This finding has been supported by other investigators [3,7], who added that ultrastructural abnormalities in prostate epithelial cells were mostly restricted in organelles engaged in protein and glycoprotein synthesis or discharge.
Another fundamental finding in this work was an apparent increase in basal cells. These cells had a clear electron-lucent cytoplasm. Both secretory and basal cells were resting on an irregular thickened basement membrane. A previous model study of stem cells  presented for the organization of the prostatic epithelium in an attempt to explain normal and abnormal growth in the human prostate. This model is based on recent data of the three basic cell types found in the prostatic epithelium: secretory, basal, and endocrine paracrine cells. These endocrine paracrine cells are differentiated from the normal epithelial cells and are considered as PRL synthesis cells. They added that the proliferative compartment of the normal and hyperplastic epithelium is located in the basal cell layer as a small stem cell population located in this layer that gives rise to all epithelial cell lineages found in the normal, hyperplastic, and neoplastic prostate. Another study  clarified that basal cells are the major proliferative cell type that can be considered as a key factor in the pathogenesis of prostatic hyperplasia. Some investigators  have proved that the isolation and characterization of prostatic stem cells has received significant attention on the basis of the belief that aberrant regulation of adult stem cells leads to prostate disease including cancer.
Also, some epithelial cells in this study contained lipofuscin pigments in the perinuclear region. These results are in agreement with a previous study of some researchers [41,42] who reported that lipofuscin can be considered as a wear and tear pigment. It probably indicates the slow cellular turnover that developed after androgen deprivation and may be interpreted as a sign of reduced metabolic activity. It is commonly seen in cells undergoing hyperplastic changes and less frequently in those of prostatic intraepithelial neoplasia and adenocarcinoma.
In this work, noticeable areas of stromal thickening were found in between some acini. The bases of these acini were surrounded by prominent smooth muscle cells that were arranged in several layers. Also, congested blood vessels, cellular infiltration, and many connective tissue cells were observed in prostatic stroma. Mast cells were obvious in the interacinar connective tissue with their irregular nuclei and prominent electron-dense variable-sized granules. In addition, the prostatic epithelial lining was infiltrated by inflammatory cells with heterochromatic nuclei. Previous research has reported that the proportion of connective tissue compared with epithelial cells was increased in the PRL transgenic animals, similar to the histological finding in BPH in human . Reiter and colleagues [14,44] found that PRL has been implicated as a cause of inflammation and cellular infiltration defined by cell type (mononuclear or polymorphonuclear) or by location (interstitial or lumen). Furthermore, former studies [9,15] have documented that hyperprolactinemia is sometimes associated with a muscular hyperplasia or thick fibromuscular stroma with inflammatory invasion. Hence, increased stromal component is of particular interest because it evidently resembles the situation in human BPH [2,35].
In conclusion, hyperprolactinemia altered the morphology of epithelium and stroma of the prostate lateral lobe. It played a significant role in inducing a prostatic hyperplasia and an inflammatory response that triggers the abnormal growth of prostate. Therefore, periodic checkup of the serum PRL level is necessary, especially in old age, and with certain medications for early prediction of prostate hyperplastic lesions.
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Conflicts of interest
There is no conflict of interest to declare.
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