In mammals, antiandrogens affect sexual differentiation and development, causing feminization and demasculinization of male offspring dosed in utero during sensitive developmental stages [17,18].
It is generally known that estrogens are synthesized and act on the testis of mammals including humans. The site of estradiol synthesis in the testis switches to Leydig cells during neonatal development, where the aromatase enzyme is present .
The effect on body weight found in this study was in agreement with the result obtained by Bonkhoff and Remberger , who found that flutamide led to reduced weight gain in their experimental animals compared with the control group. The development and activity of the prostate were dependent on stimulation by the testicular hormones. In the absence of the testis, the prostate failed to develop . In our study, early changes in acini were represented by folding of some areas of acini whereas other acini were rudimentary when treated for 2 weeks. Cystic dilatation of acini with a decrease in the epithelial height was observed in acini treated for 4 weeks. Highly dilated and irregular acini with no stroma in between were observed after 6 weeks of treatment and there was an apparent decrease in the cell number with dilated and congested blood vessels because of the separation of the extracellular matrix element.
Some investigators have studied the process of tissue atrophy in the prostates of mice. They found that the height of the epithelium was reduced to one-half after castrations and that the diameter of the glandular acini also increased rapidly . They concluded that the prostatic epithelium was very sensitive to androgen deprivation. Similar results have been obtained by other researchers [22,23].
Another histological finding obtained in this work in subgroup IIb was the increased amount of interacinar fibromuscular tissue; actually, this increase might have been because of the atrophy of the prostatic acini. This reaction of the interacinar tissue was explained by other researcher in which the stromal remodeling following androgen ablation is also variable [3,24]. They observed that the thickness of the interacinar was almost doubled during castration. The same finding was also obtained by Horn and colleagues [25,26].
A weak PAS reaction was observed in the basal laminae of the acinar epithelium and the secretory material with an irregular apparent thick basement membrane, especially in the folded area. This weak reaction in the apical parts of the cells probably resulted from the decreased supranuclear secretory granules, secondary to the antiandrogenic action of flutamide. A similar result was obtained by Ekman , who found that castration resulted in loss of cell polarity accompanied by alterations in all cell organoids. It has been suggested previously that changes in the composition of the basement membrane and other components of connective tissue markedly influence cell proliferation and differentiation in the prostate, and that these alterations may be of fundamental importance in the etiology and progression of pathological processes .
In this study, the prostates of the rats of subgroup IIb and IIc showed the same histological changes as those in subgroup IIa, but the changes in subgroup IIb and IIc were much more exaggerated and much more diffuse in their distribution. The prostatic acini showed cystic changes with a decrease in epithelial height and some acini were in the form of solid cords and rudimentary.
In the sections of prostate in the present study, by light microscopic examination, although the degree AR immunoreactivity seemed to be strongly positive in the acinar epithelial cells of experimental subgroup IIa, the nuclear AR immunoreactivity decreased in the three experimental subgroups (P < 0.001), which was statistically very highly significant compared with the control group. This decrease was most marked in subgroup IIc. It appeared that flutamide as an antiandrogen removed the effect of testosterone away from the ARs, an effect that simulated castration. Many authors have shown that androgen deprivation by castration was associated with a reduction in the immunodetected AR content to the extent that the nuclear immunostaining was completely lost [29,30].
In the sections of prostate in the present study, the ER immunoreactivity was positive in the acinar epithelial cells of experimental subgroups IIa and IIc; the nuclear ER immunoreactivity increased in the three experimental subgroups (P < 0.005), which was statistically significant compared with the control group. This increase was most marked in subgroup IIc. Some researchers have reported that ER in the male genital system have moderate to mild ER values, which is in agreement with our results [31,32]. The blockage of testosterone receptors by flutamide could result in an increase in the amount of free testosterone . Another explanation for the increase in ER could be [34,35] that flutamide, being a competitor for testosterone, inhibits testosterone occupancy of ET, rendering them free for immunoreactivity. Some researchers have reported that ER expression is localized to epithelium and stroma, which is in agreement with our present study [36,37].
There are no conflicts of interest.
Sharpe RM. Pathways of endocrine disruption during male sexual differentiation and masculinization. Best Pract Res Clin Endocrinol Metab. 2006;20:91–110
Metzdorff SB, Dalgaard M, Christiansen S, Axelstad M, Hass U, Kiersgaard MK, et al. Dysgenesis and histological changes of genitals and perturbations of gene expression in male rats after in utero exposure to antiandrogen mixtures. Toxicol Sci. 2007;98:87–98
Beers MH, Berkow R The Merck Manual of Diagnosis and Therapy. 200618th ed. Merck & Co., Inc., Whitehouse Station, NJ, USA. [online] Prostate Cancer.
Miyata K, Yabushita S, Sano M, Miyashita K, Okuno Y, Matsuo M. Effects of perinatal exposure to flutamide on sex hormone responsiveness in F1 male rats. J Toxicol Sci. 2003;28:149–163
Song GS, Seo JT. Relationship between ambient temperature and heat flux in the scrotal skin. Int J Androl. 2009;32:288–294
Song GS, Seo JT. Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses. Int J Androl. 2009;32:288–294
Brandes D, Gyorkey F, Groth DP. Fine structural and histochemical study of the effect of castration on the rat prostatic complex. I. The coagulating gland. Lab Invest. 1962;11:339–350
Williams K, McKinnell C, Saunders PT, Walker M, Fisher JS, Turner KJ, et al. Neonatal exposure to potent and environmental oestrogens and abnormalities of the male reproductive system in the rat: evidence for importance of the androgen-oestrogen balance and assessment of the relevance to man. Hum Reprod Update. 2001;7:236–247
Anderson J. The role of antiandrogen monotherapy in the treatment of prostate cancer. BJU Int. 2003;91:455–461
Zhang M, Latham DE, Delaney MA, Chakravarti A. Survivin mediates resistance to antiandrogen therapy in prostate cancer. Oncogene. 2005;24:2474–2482
Abdelnabi MA, Ottinger MA. Hypothalamic indolamines during embryonic development and effects of steroid exposure. Gen Comp Endocrinol. 2003;130:13–19
Marchlewicz M, Wiszniewska B, Kurzawa R, Wenda Rózewicka L. Possible involvement of microtubules and microfilaments of the epididymal epithelial cells in 17beta-estradiol synthesis. Folia Histochem Cytobiol. 2004;42:19–27
Greco TL, Furlow JD, Duello TM, Gorski J. Immunodetection of estrogen receptors in fetal and neonatal male mouse reproductive tracts. Endocrinology. 1992;130:421–429
Pandini G, Mineo R, Frasca F, Roberts CT Jr, Marcelli M, Vigneri R, Belfiore A. Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells. Cancer Res. 2005;65:1849–1857
Iczkowski KA, Sun EL, Gondos B. Morphometric study of the prepubertal rabbit testis: germ cell numbers and seminiferous tubule dimensions. Am J Anat. 1991;190:266–272
Bancroft JD, Gamble MBancroft JD, Gamble M. The haematoxylin and eosin Theory and practice of histological techniques. 20076th ed. London Churchill Livingstone:99–112 In: , pp.
Drury Wallington SF Histological techniques and their diagnostic applications. 1980 London Churchill Livingstone
Janssen PJ, Brinkmann AO, Boersma WJ, van der Kwast TH. Immunohistochemical detection of the androgen receptor with monoclonal antibody F39.4 in routinely processed, paraffin-embedded human tissues after microwave pre-treatment. J Histochem Cytochem. 1994;42:1169–1175
Bercovich Z, Kahana C. Degradation of antizyme inhibitor, an ornithine decarboxylase homologous protein, is ubiquitin-dependent and is inhibited by antizyme. J Biol Chem. 2004;279:54097–54102
Bonkhoff H, Remberger K. Morphogenetic aspects of normal and abnormal prostatic growth. Pathol Res Pract. 1995;191:833–835
De Carvalho HF, Vilamaior PS, Taboga SR. Elastic system of the rat ventral prostate and its modifications following orchiectomy. Prostate. 1997;32:27–34
Moore RW, Rudy TA, Lin TM, Ko K, Peterson RE. Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer di(2-ethylhexyl) phthalate. Environ Health Perspect. 2001;109:229–237
Chang CS, Kokontis J, Liao ST. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science. 1988;240:324–326
Góes RM, Zanetoni C, Tomiosso TC, Ribeiro DL, Taboga SR. Surgical and chemical castration induce differential histological response in prostate lobes of Mongolian gerbil. Micron. 2007;38:231–236
Horn R, Pastor LM, Moreno E, Calvo A, Ganteras M, Pallares J. Morphological and morphometric study of early changes in the ageing golden hamster testis. J Anat. 1996;188:109–117
Vinggaard AM, Christiansen S, Laier P, Poulsen ME, Breinholt V, Jarfelt K, et al. Perinatal exposure to the fungicide prochloraz feminizes the male rat offspring. Toxicol Sci. 2005;85:886–897
Ekman P. The prostate as an endocrine organ: androgens and estrogens. Prostate Suppl. 2000;10:14–18
Tuxhorn JA, Ayala GE, Rowley DR. Reactive stroma in prostate cancer progression. J Urol. 2001;166:2472–2483
Mylchreest E, Sar M, Cattley RC, Foster PM. Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. Toxicol Appl Pharmacol. 1999;156:81–95
Hotchkiss AK, Ankley GT, Wilson VS, Hartig PC, Durhan EJ, Jensen KM, et al. Of mice and men (and mosquitofish): antiandrogens and androgens in the environment. Bioscience. 2008;58:1037–1050
Carreau S, Delalande C, Silandre D, Bourguiba S, Lambard S. Aromatase and estrogen receptors in male reproduction. Mol Cell Endocrinol. 2006;246:65–68
Fawcett DWFawcett DW. Male reproductive system A textbook of histology. 199412th ed. London Hodder Arnold Publishers:768–815 In: , pp.
Rosenfield RL. Hirsutism. N Engl J Med. 2005;353:2578–2588
Snell RSSnell RS. The abdomen Clinical anatomy for medical students. 20006th ed. London Lippincott Williams & Wilkins:133–183 In: , pp.
Anahara R, Toyama Y, Mori C. Flutamide induces ultrastructural changes in spermatids and the ectoplasmic specialization between the sertoli cell and spermatids in mouse testes. Reprod Toxicol. 2004;18:589–596
Fix C, Jordan C, Cano P, Walker WH. Testosterone activates mitogen-activated protein kinase and the cAMP response element binding protein transcription factor in sertoli cells. Proc Natl Acad Sci USA. 2004;101:10919–10924
Gray LEJ, Wilson VS, Stoker T, Lambright C, Furr J, Noriega N, et al. Adverse effects of environmental antiandrogens and androgens on reproductive development in mammals. Int J Androl. 2006;29:96–104