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).
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.
There is no conflict of interest to declare.
Bole Feysot C, Goffin V, Edery M, Binart N, Kelly PA. Prolactin (PRL) and its receptor: Actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev. 1998;19:225–268
Kindblom J, Dillner K, Sahlin L, Robertson F, Ormandy C, Törnell J, Wennbo H. Prostate hyperplasia in a transgenic mouse with prostate-specific expression of prolactin. Endocrinology. 2003;144:2269–278
Hernandez ME, Soto Cid A, Rojas F, Pascual LI, Aranda Abreu GE, Toledo R, et al. Prostate response to prolactin in sexually active male rats. Reprod Biol Endocrinol. 2006;4:28–33
Serri O, Chik CL, Ur E, Ezzat S. Diagnosis and management of hyperprolactinemia. CMAJ. 2003;169:575–581
Bachelot A, Binart N. Reproductive role of prolactin. Reproduction. 2007;133:361–369
Ben Jonathan N, Mershon JL, Allen DL, Steinmetz RW. Extrapituitary prolactin: distribution, regulation, functions and clinical aspects. Endocr Rev. 1996;17:639–669
Sluczanowska Glabowska S, Laszczynska M, Wylot M, Glabowski W, Piasecka M, Gacarzewicz D. Morphological and immunohistochemical compare of three rat prostate lobes (lateral, dorsal and ventral) in experimental hyperprolactinemia. Folia Histochem Cytobiol. 2010;48:447–454
Egli M, Leeners B, Kruger THC. Prolactin secretion patterns: basic mechanisms and clinical implications for reproduction. Reproduction. 2010;140:643–654
Wylot M, Laszczynska M, Sluczanowska Glabowska S, Piasecka M. Aging process of epithelial cells of the rat prostate lateral lobe in experimental hyperprolactinemia induced by haloperidol. Rocz Akad Med Bialymst. 2004;49(Suppl 1):111–113
Sluczanowska Glabowska S, Laszczynska M, Glabowski W, Wylot M. Morphology of the epithelial cells and expression of androgen receptor in rat prostate dorsal lobe in experimental hyperprolactinemia. Folia Histochem Cytobiol. 2006;44:25–30
Molitch ME. Drugs and prolactin. Pituitary. 2008;11:209–218
Kostrazk A, Meczekalski B. Macroprolactinemia. Pol Merkur Lekarski. 2010;29:47–56
Reiter E, Lardinois S, Klug M, Sente B, Hennuy B, Bruyninx M, et al. Androgen-independent effects of prolactin on the different lobes of the immature rat prostate. Mol Cell Endocrinol. 1995;112:113–122
Reiter E, Hennuy B, Bruyninx M, Cornet A, Klug M, McNamara M, et al. Effects of pituitary hormones on the prostate. Prostate. 1999;38:159–165
Van Coppenolle F, Slomianny C, Carpentier F, Le Bourhis X, Ahidouch A, Croix D, et al. Effects of hyperprolactinemia on rat prostate growth: evidence of androgeno-dependence. Am J Physiol Endocrinol Metab. 2001;280:E120–E129
Bancroft JD, Gamble M Theory and practice of histological techniques. 20025th ed. London Churchill Livingstone
Glauert AM, Lewis PR Biological specimen preparation for transmission electron microscopy. 19981st ed. London Princeton Univ. Press
Anguiano B, López A, Delgado G, Romero C, Aceves C. Deiodinase type 1 activity is expressed in the prostate of pubescent rats and is modulated by thyroid hormones, prolactin and sex hormones. J Endocrinol. 2006;190:363–371
Gunasekar PG, Kumaran B, Govindarajulu P. Role of prolactin on Leydig, Sertoli and germ cellular neutral lipids in bonnet monkeys, Macaca radiata
. Endocrinol Jpn. 1991;38:1–8
Amiri Z, Katz Y, Weizman A, Bidder M, Snyder SH, Gavish M. Adrenal mitochondrial benzodiazepine receptors are sensitive to agents active at the dopamine receptor. Biochem Pharmacol. 1993;45:999–1002
Sanford LM, Baker SJ. Prolactin regulation of testosterone secretion and testes growth in DLS rams at the onset of seasonal testicular recrudescence. Reproduction. 2010;139:197–207
Bosland MC, Tuomari DL, Elwell M, Shirai T, Ward JM, McConnell RF. Proliferative lesions of the prostate and other accessory sex gland in male rats. URG. 4 Guides for toxicologic pathology: STP/ARP/AFIP. 1998 Washington, DC:1–20
Fávaro WJ, Cagnon VH. Morphometric and morphological features of the ventral prostate in rats submitted to chronic nicotine and alcohol treatment. Tissue Cell. 2006;38:311–323
Ibrahim ME, Al Sherif AM, Zaki SM, Al Domairy AF. Effect of estrogen administration on the prostate of the adult albino rat (histological, ultrastructural and immunohistological studies). Aust J Basic Appl Sci. 2011;5:59–73
Pérez Villamil B, Bordiú E, Puente Cueva M. Involvement of physiological prolactin levels in growth and prolactin receptor content of prostate glands and testes in developing male rats. J Endocrinol. 1992;132:449–459
Nevalainen MT, Valve EM, Ingleton PM, Nurmi M, Martikainen PM, Härkönen PL. Prolactin and prolactin receptors are expressed and functioning in human prostate. J Clin Invest. 1997;99:618–627
Leff MA, Buckley DJ, Krumenacker JS, Reed JC, Miyashita T, Buckley AR. Rapid modulation of the apoptosis regulatory genes, bcl-2 and bax by prolactin in rat Nb2 lymphoma cells. Endocrinology. 1996;137:5456–5462
Colombel M, Vacherot F, Gil Diez S, Fontaine E, Buttyan R, Chopin D. Zonal variation of apoptosis and proliferation in the normal prostate and in benign prostatic hyperplasia. Br J Urol. 1998;82:380–385
Perlman H, Zhang X, Chen MW, Walsh K, Buttyan R. An elevated bax/bcl-2 ratio corresponds with the onset of prostate epithelial cell apoptosis. Cell Death Diff. 1999;6:48–54
Jeyaraj DA, Udayakumar TS, Rajalakshmi M, Pal PC, Sharma RS. Effects of long-term administration of androgens and estrogen on rhesus monkey prostate: possible induction of benign prostatic hyperplasia. J Androl. 2000;21:833–841
Belostotskaya LI, Gomon ON, Nikitchenko YV, Chaika LA, Bondar VV, Dzyuba VN. Prooxidant-antioxidant balance in the prostate and blood of rats with sulpyride-induced prostatic hyperplasia corrected with prostatilen. Bull Exp Biol Med. 2005;139:334–336
Andrade Rocha FT. Assessment of exfoliated prostate cells in semen: Relationship with the secretory function of the prostate. Am J Clin Pathol. 2007;128:788–793
Nevalainen MT, Valve EM, Ingleton PM, Härkönen PL. Expression and hormone regulation of prolactin receptors in rat dorsal and lateral prostate. Endocrinology. 1996;137:3078–3088
Lane KE, Leav I, Ziar J, Bridges RS, Rand WM, Ho SM. Suppression of testosterone and estradiol-17beta-induced dysplasia in the dorsolateral prostate of Noble rats by bromocriptine. Carcinogenesis. 1997;18:1505–1510
Härkönen P. Paracrine prolactin may cause prostatic problems. Endocrinology. 2003;144:2266–2268
Tam CC, Wong YC, Tang F. Ultrastructural and cytochemical studies of the effects of prolactin on the lateral prostate and the seminal vesicle of the castrated guinea pig. Cell Tissue Res. 1992;270:105–112
Banerjee PP, Banerjee S, Brown TR. Increased androgen receptor expression correlates with development of age-dependent, lobe-specific spontaneous hyperplasia of the brown Norway rat prostate. Endocrinology. 2001;142:4066–4075
Bonkhoff H, Remberger K. Differentiation pathways and histogenetic aspects of normal and abnormal prostatic growth: a stem cell model. Prostate. 1996;28:98–106
Leav I, Schelling KH, Adams JY, Merk FB, Alroy J. Role of canine basal cells in postnatal prostatic development, induction of hyperplasia and sex hormone-stimulated growth and the ductal origin of carcinoma. Prostate. 2001;48:210–224
Risbridger GP, Taylor RA. Minireview: regulation of prostatic stem cells by stromal niche in health and disease. Endocrinology. 2008;149:4303–4306
Brennick JB, O'Connell JX, Dickersin GR, Young RH. Lipofuscin pigmentation (so-called ‘melanosis’) of the prostate. Am J Surg Pathol. 1994;18:446–454
Mahmoodi M, Zhang S, Salim S, Hou JS, Garcia FU. Lipofuscin pigment can be used as a prognostic marker in prostatic adenocarcinoma. Ann Diagn Pathol. 2006;10:257–262
Wennbo H, Kindblom J, Isaksson OG, Törnell J. Transgenic mice overexpressing the prolactin gene develop dramatic enlargement of the prostate gland. Endocrinology. 1997;138:4410–4415
Stoker TE, Robinette CL, Britt BH, Laws SC, Cooper RL. Prepubertal exposure to compounds that increase prolactin secretion in the male rat: effects on the adult prostate. Biol Reprod. 1999;61:1636–1643