The Morpho-Functional Parameters of Rat Pituitary Hormone Producing Cells After Genistein Treatment

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Phytoestrogens are a diverse group of steroid–like compounds that occur naturally in many plants. There are various types of phytoestrogens, including the best-researched isoflavones which are commonly found in soy. The consumption of soy products has many health benefits, including protection against breast cancer, prostate cancer, menopausal symptoms, heart disease and osteoporosis. In contrast, use of hormonally active compounds-isoflavones may unfortunately interfere with the endocrine system and can have far-reaching consequences. Genistein, the most abundant soy-bean derived isoflavone, possesses a ring system similar to estrogens and acts through an estrogen receptor (ER)-mediated mechanism, by increasing or decreasing the transcription of ER-dependent target genes. Also, genistein can act on cells through ER non-dependent mechanisms, such as tyrosine kinase inhibitor. The neuroendocrine systems are responsible for the control of homeostatic processes in the body, including reproduction, growth, metabolism and energy balance, and stress responsiveness. It is well known, that estrogen is important for development of the neuroendocrine system in both sexes. At the pituitary level, estrogen is known to affect the regulation of all hormone producing (HP) cells, by direct and/or indirect mechanisms. Due to structural and functional resemblance to estrogen, the question may arise of whether and how genistein affects the morphofunctional features of pituitary HP cells. This review deals with the consequences of genistein’s effects on morphological, stereological and hormonal features of HP cells within the anterior pituitary gland. Transparency on this issue is needed because isoflavones are presently highly consumed. Inter alia, genistein as well as other isoflavones, are present in various dietary supplements and generally promoted as an accepted alternative to estrogen replacement therapy. Potential isoflavone biomedical exploitation is not only limited to estrogen replacement therapy, so it should be treated in a wider context of different ageing symptoms remediation.

1. Patisaul, H.B., Jefferson, W. (2010). The pros and cons of phytoestrogens. Front Neuroendocrinol. 31, 400-419. PMid:20347861 PMCid:PMC3074428

2. Setchell, K.D., Borriello, S.P., Hulme, P., Kirk, D.N., Axelson, M. (1984). Nonsteroidal estrogens of dietary origin: possible roles in hormone-dependent disease. Am J Clin Nutr. 40, 569-578. PMid:6383008

3. Wet, L., Birac, P.M., Pratt, D.E. (1978). Separation of the isomeric isoflavones from soybeans by highperformance liquid chromatography. J Chromatogr. 150, 266–268.

4. Cheng, E., Story, C.D., Yoder, L., Hale, W.H., Burrough, W. (1953). Estrogenic activity of isoflavone derivatives extracted and prepared from soybean oil meal. Science 118, 164–165. PMid:13076231

5. Batterham, T.J., Hart, N.K., Lamberton, J.A. (1965). Metabolism of oestrogenic isoflavones in sheep. Nature 4983, 509.

6. Kuiper, G.G., Lemmen, J.G., Carlsson, B., Corton, J.C., Safe, S.H., van der Saag, P.T., van der Burg, B., Gustafsson, J.A. (1998). Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139, 4252-4263. PMid:9751507

7. Lephart, E.D., West, T.W., Weber, K.S., Rhees, R.W., Setchell, K.D., Adlercreutz, H., Lund, T.D. (2002). Neurobehavioral effects of dietary soy phytoestrogens. Neurotoxicol Teratol. 24, 5-16.

8. Kostelac, D., Rechkemmer, G., Briviba, K. (2003). Phytoestrogens modulate binding response of estrogen receptors alpha and beta to the estrogen response element. J Agric Food Chem. 51, 7632-7635. PMid:14664520

9. Patisaul, H.B. (2005). Phytoestrogen action in the adult and developing brain. J Neuroendocrinol. 17, 57-64. PMid:15720476

10. Setchell, K.D., Cassidy, A. (1999). Dietary isoflavones: biological effects and relevance to human health. J Nutr. 129, 758-767.

11. Adlercreutz, H., Mazur, W. (1997). Phyto-oestrogens and Western diseases. Ann Med. 29, 95-120. PMid:9187225

12. Shemesh, M., Lindner, H. R., Ayalaoan, N. (1972). Affinity of rabbit uterine oestradiol receptor for phyto-oestrogens and its use in a competitive protein-binding radioassay for plasma coumestrol. J Reprod Fertil. 29, 1–9. PMid:5017011

13. Piontek, M., Hangels, K.J., Porschen, R., Strohmeyer, G. (1993). Anti-proliferative effect of tyrosine kinase inhibitors in epidermal growth factor stimulated growth of human gastric cancer cells. Anticancer Res. 13, 2119–2123. PMid:8297123

14. Boutin, J.A. (1994). Tyrosine protein kinase inhibition and cancer. Int J Biochem Cell Bio. 26, 1203–1226.

15. Kurzer, M.S., Xia, X. (1997). Dietary Phytoestrogens Annu Rev Nutr. 17, 353–381. PMid:9240932

16. Okura, A., Arakawa, H., Oka, H., Yoshinari, T., Monden, Y. (1988). Effect of genistein on topoisomerase activity and on the growth of [Val 12] Ha-ras-transformed NIH 3T3 cells. Biochem Biophys Res Commun. 157, 183–189.

17. Hu, G., X, Zhao, B.H., Chu, Y.H., Zhou, H.Y., Akingbemi, B.T., Zheng, Z.Q, Ge, R.S. (2010). Effects of genistein and equol on human and rat testicular 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase 3 activities. Asian J Androl. 12(4): 519-526. PMid:20453869 PMCid:PMC3739362

18. Adlercreutz, H. (1990). Western diet and Western diseases: some hormonal and biochemical mechanisms and associations. Scand J Clin Lab Invest Suppl. 201, 3-23. PMid:2173856

19. Wang, H., Li, J., Gao, Y., Xu, Y., Pan, Y., Tsuji, I., Sun, Z.J., Li, X.M. (2010). Xeno-oestrogens and phyto-oestrogens are alternative ligands for the androgen receptor. Asian J Androl. 12, 535-547. PMid:20436506 PMCid:PMC3739360

20. Lee, H.P., Gourley, L., Duffy, S.W., Estève, J., Lee, J., Day, N.E. (1991). Dietary effects on breast-cancer risk in Singapore. Lancet 337, 1197–1200.

21. Adlercreutz, H., Honjo, H., Higashi, A., Fotsis, T., Hämäläinen, E., Hasegawa, T., Okada, H. (1991). Urinary excretion of lignans and isoflavonoid phytoestrogens in Japanese men and women consuming a traditional Japanese diet. Am J Clin Nutr. 54, 1093–1100. PMid:1659780

22. Ingram, D., Sanders, K., Kolybaba, M., Lopez, D. (1997). Case-control study of phyto-oestrogens and breast cancer. Lancet 350, 990-994.

23. Shimizu, H., Ross, R.K., Bernstein, L., Yatani, R., Henderson, B.E., Mack, T.M. (1991). Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer. 63, 963-966. PMid:2069852 PMCid:PMC1972548

24. Watanabe, S., Koessel, S (1993). Colon cancer: an approach from molecular epidemiology. J Epidemiol. 3, 47-61.

25. Severson, R.K., Nomura, A.M., Grove, J.S., Stemmermann, G.N. (1989). A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res. 49, 1857-1860. PMid:2924323

26. Anthony, M.S., Clarkson, T.B., Hughes, C.L.Jr., Morgan, T.M., Burke, G.L. (1996). Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys. J Nutr. 126, 43-50. PMid:8558324

27. Tikkanen, M.J., Wahala, K., Ojala, S., Vihma, V., Adlercreutz, H. (1998). Effect of soybean phytoestrogen intake on low density lipoprotein oxidation resistance. Proc Natl Acad Sci USA 95, 3106-3110. PMid:9501223 PMCid:PMC19702

28. Raines, E.W., Ross, R. (1995). Biology of atherosclerotic plaque formation: possible role of growth factors in lesion development and the potential impact of soy. J Nutr. 125, 624-630.

29. Šošić-Jurjević, B., Filipović, B., Ajdžanović, V., Brkić, D., Ristić, N., Stojanoski, M.M., Nestorović, N., Trifunović, S., Sekulić. M (2007). Subcutaneously administrated genistein and daidzein decrease serum cholesterol and increase triglyceride levels in male middle-aged rats. Exp Biol Med. 232, 1222-1227. PMid:17895530

30. Filipović, B., Šošić-Jurjević, B., Ajdžanović, V., Brkić, D., Manojlović-Stojanoski, M., Milošević, V., Sekulić, M. (2010). Daidzein administration positively affects thyroid C cells and bone structure in orchidectomized middle-aged rats. Osteoporos Int. 21, 1609-1616. PMid:19859640

31. Messina, M., Ho, S., Alekel, D.L. (2004) Skeletal benefits of soy isoflavones: a review of the clinical trial and epidemiologic data. Curr Opin Clin Nutr Metab Care. 7(6): 649-658.

32. Dalais, F.S., Rice, G.E., Wahlqvist, M.L., Grehan, M., Murkies, A.L., Medley, G., Ayton, R., Strauss, B.J. (1998). Effects of dietary phytoestrogens in postmenopausal women. Climacteric 1, 124-129. PMid:11907915

33. Miao Q., Li J., Miao S., Hu N., Zhang J., Zhang S., Xie Y., Wang J., Wang S. (2012). The bone-protective effect of genistein in the animal model of bilateral ovariectomy: Roles of phytoestrogens and PTH/PTHR1 against post-menopausal osteoporosis. Int J Mol Sci. 13(1): 56–70. PMid:22312238

34. Adlercreutz, C.H., Goldin, B.R., Gorbach, S.L., Hockerstedt, K.A., Watanabe, S., Hamalainen, E.K., Markkanen, M.H., Makela, T.H., Wahala, K.T., Adlercreutz, T. (1995). Soybean phytoestrogen intake and cancer risk. J Nutr. 125, 757-770.

35. Ajdžanović, V., Šosić-Jurjević, B., Filipović, B., Trifunović, S., Manojlović-Stojanoski, M., Sekulić, M., Milosević, V. (2009). Genistein-induced histomorphometric and hormone secreting changes in the adrenal cortex in middle-aged rats. Exp Biol Med (Maywood). 234, 148-156. PMid:19064942

36. Banerje, S., Li, Y., Wang, Z., Sarkar, F.H. (2008) Multi-target therapy of cancer by genistein Cancer Lett. 269(2): 226–242. PMid:18492603 PMCid:PMC2575691

37. Jefferson, W.N., Couse, J.F., Padilla-Banks, E., Korach, K.S., Newbold, R.R. (2002). Neonatal exposure to genistein induces estrogen receptor (ER) alpha expression and multioocyte follicles in the maturing mouse ovary: evidence for ER betamediated and nonestrogenic actions. Biol Reprod. 67, 1285-1296. PMid:12297547

38. Jefferson, W.N., Padilla-Banks, E., Newbold, R.R. (2007). Disruption of the developing female reproductive system by phytoestrogens: genistein as an example. Mol Nutr Food Res. 51, 832-844. PMid:17604387

39. Medigović, I.M., Živanović, J.B., Ajdžanović, V.Z., Nikolić-Kokić, A.L., Stanković, S.D., Trifunović, S.L., Milošević, V.Lj., Nestorović, N.M. (2015). Effects of soy phytoestrogens on pituitary-ovarian function in middle-aged female rats. Endocrine 50, 764-776. PMid:26215277

40. Lindner, H.R. (1976). Occurrence of anabolic agents in plants and their importance. Environ Qual Safety Suppl. pp. 151–158.

41. Allred, C.D., Allred, K.F., Ju, Y.H., Virant, S.M., Helferich, W.G. (2001). Soy diets containing varying amounts of genistein stimulate growth of estrogendependent (MCF-7) tumors in a dose-dependent manner. Cancer Res. 61, 5045-5050. PMid:11431339

42. Ju, Y.H., Allred, C.D., Allred, K.F., Karko, K.L., Doerge, D.R., Helferich, W.G. (2001). Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent hum and breast cancer (MCF-7) tumors implanted in athymic nude mice. J Nutr. 131, 2957-2962. PMid:11694625

43. Unfer, V., Casini, M.L., Costabile, L., Mignosa, M., Gerli, S., Di Renzo, G.C. (2004). Endometrial effects of long-term treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil Steril. 82, 145-148. PMid:15237003

44. Nohynek, G.J., Borgert, C.J., Dietrich, D., Rozman, K.K. (2013). Endocrine disruption: fact or urban legend? Toxicol Lett. 223, 295-305. PMid:24177261

45. Goldin, B.R., Brauner, E., Adlercreutz, H., Ausman, L.M., Lichtenstein, A.H. (2005). Hormonal response to diets high in soy or animal protein without and with isoflavones in moderately hypercholesterolemic subjects. Nutr Cancer. 51, 1-6. PMid:15749623

46. Jabbar, M.A., Larrea, J., Shaw, R.A. (1997). Abnormal thyroid function tests in infants with congenital hypothyroidism: the influence of soybased formula. J Am Coll Nutr. 16, 280-282. PMid:9176836

47. Divi, R.L., Chang, H.C., Doerge, D.R. (1997). Anti-thyroid isoflavones from soybean: isolation, characterization, and mechanisms of action. Biochem Pharmacol. 54, 1087-1096.

48. Persky, V.W., Turyk, M.E., Wang, L., Freels, S., Chatterton, R.Jr., Barnes, S., Erdman, J.Jr., Sepkovic, D.W., Bradlow, H.L., Potter, S. (2002). Effect of soy protein on endogenous hormones in postmenopausal women. Am J Clin Nutr. 75, 145-153. PMid:11756072

49. Patisaul H., Jefferson W. (2010). The pros and cons of phytoestrogens Front Neuroendocrinol. 31(4): 400–419. PMid:20347861 PMCid:PMC3074428

50. Cone R., Low M., Elmquist J., Cameron J. D. (2011). Anterior pituitary. In: Larsen PR, Kronenberg HM., Melmed S., Plonsky KS, (Eds.), Williams: Text book of Endocrinology. (pp. 81-176). Philadelphia: WB Saunders Company. PMCid:PMC1308188

51. Melmed, S., Kleinberg. (2011). Anterior pituitary. In: Larsen PR, Kronenberg HM., Melmed S., Plonsky KS, (Eds.), Williams: Text book of Endocrinology. (pp. 175-279). Philadelphia: WB Saunders Company.

52. Muller, E.E., Locatelli, V., Cocchi, D. (1999) Neuroendocrine control of growth hormone secretion. Physiol Rev. 79, 511-607. PMid:10221989

53. Whitnall, M.H. (1993). Regulation of the hypothalamic corticotropin-releasing hormone neurosecretory system. Progr Neurobiol. 40, 573–629.

54. Brooks, A. N. (1998). Natural and anthropogenic environmental oestrogens: the scientific basis for risk assessment. Comparative physiology of the reproductive endocrine system in laboratory rodents and humans. Pure Appl Chem. 70, 1633-1646.

55. Horvath, E., Kovacs, K. (1988). Fine structural cytology of the adenohypophysis in rat and man. J Electron Microsc Tech. 8, 401-432. PMid:3058887

56. Dada, M.O., Campbell, G.T., Blake, C.A. (1984). Pars distalis cell quantification in normal adult male and female rats. J Endocrinol. 101, 87-94

57. Milošević, V., Brkić, B., Velkovski, S.D., Sekulić, M., Lovren, M., Starčević, V., Severs W.B. (1998). Morphometric and functional changes of rat pituitary somatotropes and lactotropes after central administration of somatostatin. Pharmacology 57, 28–34. PMid:9670210

58. Milošević, V., Ajdžanović, V. (2014). Pituitary hormone-producing cells after estradiol application in rat models of menopause. Serbian Journal of Experimental and Clinical Research 15, 115-120.

59. Milosević, V., Sekulić, M., Brkić, B., Lovren, M., Starcević, V. (2000). Effect of centrally administered somatostatin on pituitary thyrotropes in male rats. Histochem J. 32, 565-569. PMid:11127978

60. Vankelecom, H. (2007). Non-hormonal cell types in the pituitary candidating for stem cell. Semin Cell Dev Biol. 18, 559-570. PMid:17509912

61. Vankelecom, H., Gremeaux, L. (2010). Stem cells in the pituitary gland: A burgeoning field. Gen Comp Endocrinol. 166, 478-488. PMid:19917287

62. Hauspie, A., Seuntjens, E., Vankelecom, H., Denef, C. (2003). Stimulation of combinatorial expression of prolactin and glycoprotein hormone alpha-subunit genes by gonadotropin-releasing hormone and estradiol-17beta in single rat pituitary cells during aggregate cell culture. Endocrinology 144, 388-399. PMid:12488367

63. Mignot, M., Skinner, D.C. (2005). Colocalization of GH, TSH and prolactin, but not ACTH, with beta LH-immunoreactivity: evidence for pluripotential cells in the ovine pituitary. Cell Tissue Res. 319, 413-421. PMid:15647919

64. Mitchner, N.A., Garlick, C., Ben-Jonathan, N. (1998). Cellular distribution and gene regulation of estrogen receptors alpha and beta in the rat pituitary gland. Endocrinology 139, 3976-3983. PMid:9724053

65. Yin, P., Kawashima, K., Arita, J. (2002). Direct actions of estradiol on the anterior pituitary gland are required for hypothalamus-dependent lactotrope proliferation and secretory surges of luteinizing hormone but not of prolactin in female rats. Neuroendocrinology 75, 392-401. PMid:12065892

66. Milošević, V., Starčević V., Šošić-Jurjević, B., Filipović, B., Trifunović, S., Ristić, N., Nestorović, N., Manojlović, M., Sekulić, M. (2007). Effect of estradiol or calcium treatment on mammotrophs of female middle-aged rats. Acta Vet. 57, 393-402.

67. Trifunović, S., Manojlović-Stojanoski, M., Ajdzanović, V., Nestorović, N., Ristić, N., Medigović, I., Milošević V. (2012). Genistein stimulates the hypothalamo-pituitary-adrenal axis in adult rats: morphological and hormonal study. Histol Histopathol. 27, 627-640. PMid:22419027

68. Trifunović, S., Manojlović-Stojanoski, M., Ajdžanović, V., Nestorović, N., Ristić, N., Medigović, I., Milošević, V. (2014). Effects of genistein on stereological and hormonal characteristics of the pituitary somatotrophs in rats. Endocrine 47, 869-877. PMid:24752394

69. Sekulić, M., Lovren, M., Milosević, V. (1998). Immunoreactive TSH cells in the pituitary of female middle-aged rats after treatment with estradiol or calcium. Acta Histochem. 100, 185-191

70. von Bartheld CS1, Wouters FS, Quantitative techniques for imaging cells and tissues. Cell Tissue Res. 2015 Apr;360(1): 1-4. PMid:25773453 PMCid:PMC4380763

71. Childs, G.V. (2002). Development of gonadotropes may involve cyclic transdifferentiation of growth hormone cells. Arch Physiol Biochem. 110, 42–49. PMid:11935399

72. Trifunović S., Manojlović-Stojanoski M., Ristić N., Nestorović N., Medigović I., Živanović J., Milošević V. (2016). Changes of growth hormone-releasing hormone and somatostatin neurons in the rat hypothalamus induced by genistein: a stereological study. Nutr Neurosci. 19(10): 467-474.

73. Shimizu, T., Kamegai, J., Tamura, H., Ishii, S., Sugihara, H., Oikawa, S. (2005). The estrogen receptor (ER) alpha, but not ER beta, gene is expressed in hypothalamic growth hormonereleasing hormone neurons of the adult female rat. Neurosci Res. 52, 121-125. PMid:15811559

74. Misztal, T., Wańkowska, M., Górski, K., Romanowicz, K. (2007). Central estrogen-like effect of genistein on growth hormone secretion in the ewe. Acta Neurobiol Exp (Wars). 67, 411-419.

75. Ajdžanović, V., Medigović, I., Živanović, J., Šošić-Jurjević B., Trifunović, S., Tanić, N., Miločević, V. (2014). Immunohistomorphometric and fluorescent characteristics of GH cells after treatment with genistein or daidzein in an animal model of andropause. Acta Vet. 64, 93-104.

76. Romanowicz, K., Misztal, T., Barcikowski, B. (2004). Genistein, a phytoestrogen, effectively modulates luteinizing hormone and prolactin secretion in ovariectomized ewes during seasonal anestrus. Neuroendocrinology 79, 73-81. PMid:15004429

77. Gonzalez, M., Reyes, R., Damas, C., Alonso, R., Bello, AR. (2008). Estrogen receptor alpha and beta in female rat pituitary cells, an immunochemical study. Gen Comp Endocrinol. 155, 857–868. PMid:18067893

78. Asnacios, A., Hamant, O. (2012). The mechanics behind cell polarity. Trends Cell Biol. 22, 584–591. PMid:22980034

79. Medigović, I., Ristić, N., Trifunović, S., Manojlović-Stojanoski, M., Milošević, V., Zikić, D., Nestorović, N. (2012). Genistein affects ovarian folliculogenesis: a stereological study. Microsc Res Tech. 75, 1691-1699. PMid:22927040

80. Ohno, S., Nakajima, Y., Inoue, K., Nakazawa, H., Nakajin, S. (2003). Genistein administration decreases serum corticosterone and testosteronelevels in rats. Life Sci. 74, 733–742. PMid:14654166

81. Wójcik-Gładysz, A., Romanowicz, K., Misztal, T., Polkowska, J., Barcikowski, B. (2005). Effects of intracerebroventricular infusion ofgenistein on the secretory activity of the GnRH/LH axis in ovariectomized ewes. Anim Reprod Sci. 86, 221–235. PMid:15766802

82. Polkowska, J., Ridderstråle, Y., Wankowska, M., Romanowicz, K., Misztal, T., Madej, A. (2004). Effects of intracerebroventricular infusion of genistein on gonadotrophin subunit mRNA and immunoreactivity of gonadotrophins and oestrogen receptor-alpha in the pituitary cells of the anoestrous ewe. J Chem Neuroanat. 28, 217–224. PMid:15531133

83. Bliedtner, A., Zierau, O., Albrecht, S., Liebhaber, S., Vollmer, G. (2010). Effects of genistein and estrogen receptor subtype-specific agonists in ArKO mice following different administration routes. Mol Cell Endocrinol. 314, 41–52. PMid:19686804

84. Childs, G.V., Ellison, D.G., Ramaley, J.A. (1982). Storage of anteriorlobe adrenocorticotropin in corticotropes and a subpopulation of gonadotropes during the stress-nonresponsive period in the neonatal male rat. Endocrinology 110, 1676-1692. PMid:6280971

85. Milošević, V., Ajdžanović, V., Sošic-Jurjevic, B., Filipovic, B., Brkic, M., Nestorovic, N., Sekulic, M. (2009). Morphofunctional characteristics of ACTH cells in middle-aged male rats after treatment with genistein. Gen Physiol Biophys 28, 94-97. PMid:19390142

86. Zhang, Q.H., Hu, Y.Z., Zhou, S.S., Wang F.Z. (2001). Inhibitory effect, of, genistein on the proliferation of the anterior pituitary cells of rats. Sheng Li Xue Bao 53, 51-54. PMid:11354798

87. Hauger, R.L., Thrivikraman, K.V. Plotsky, P.M. (1994). Age-related alterations of hypothalamicpituitary-adrenal axis function in male Fischer 344 rats. Endocrinology 134, 1528-1536. PMid:8119195

88. Šošić-Jurjević, B., Filipović, B., Ajdžanović, V., Savin, S., Nestorović, N., Milošević, V., Sekulić, M. (2010). Suppressive effects of genistein and daidzein on pituitary-thyroid axis in orchidectomized middle-aged rats. Exp Biol Med (Maywood). 235, 590-598. PMid:20463299

89. Modaresi, M., Khorrami, H., Asadi-Samani, M. (2014). The effect of feeding with soybean on serum levels of TSH, T3 and T4 in male mice. J Herb Med Pharmacol. 3, 93-96.

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