ORIGINAL ARTICLE Effects of soy phytoestrogens on pituitary-ovarian function in middle-aged female rats Ivana M. Medigovic ´ 1 • Jasmina B. Z ˇ ivanovic ´ 1 • Vladimir Z. Ajdz ˇanovic ´ 1 • Aleksandra L. Nikolic ´-Kokic ´ 2 • Sanja D. Stankovic ´ 3 • Svetlana L. Trifunovic ´ 1 • Verica Lj. Milos ˇevic ´ 1 • Natas ˇa M. Nestorovic ´ 1 Received: 6 April 2015 / Accepted: 13 July 2015 Ó Springer Science+Business Media New York 2015 Abstract The aim of this study was to assess the effects of genistein (G) and daidzein (D) on the histological, hormonal, and functional parameters of the pituitary- ovarian axis in middle-aged female rats, and to compare these effects with the effects of estradiol (E), commonly used in the prevention and treatment of menopausal symptoms. Middle-aged (12 month old) Wistar female rats subcutaneously received 35 mg/kg of G, or 35 mg/kg of D, or 0.625 mg/kg of E every day for 4 weeks. Each of the treated groups had a corresponding control group. An intact control group was also established. G and D did not change the intracellular protein content within gonadotropic and lactotropic cells, but vacuolization was observed in all the cell types. In contrast, E caused an inhibition of gonado- tropic and stimulation of lactotropic cells. Also, ovaries of middle-aged female rats exposed to G or D have more healthy primordial and primary follicles and less atretic follicles. E treatment in the ovaries had a mostly negative effect, which is reflected by the increased number of atretic follicles in all tested classes. G and D provoked decrease in CuZnSOD and CAT activity, while E treatment increased MnSOD and decreased CuZnSOD and GSHPx activity. All the treatments increased serum estradiol and decreased testosterone levels, while D and E increased the serum progesterone level. In conclusion, soy phytoestrogens exhibited beneficial effects on pituitary-ovarian function in middle-aged female rats, as compared to estradiol. Keywords Genistein Á Daidzein Á Estradiol Á Pituitary- ovarian function Introduction Menopause, as the culmination of reproductive aging, is characterized by depletion of ovarian follicles, cessation of ovarian hormone production down to gonadectomy levels, and elevated levels of serum gonadotropins from the pituitary [1]. Normally, menopause is a natural process, but the progressive loss of estrogens leads to typical meno- pausal symptoms like hot flushes, night sweats, vaginal dryness, and/or insomnia, which may seriously compro- mise the quality of life in menopausal women [2]. Many women thus want to extend their reproductive life due to collateral benefits, i.e., in order to delay the uncomfortable menopause-related symptoms. To alleviate these symptoms and to protect women against estrogen deficiency-related ailments like osteoporosis, hormone replacement therapy (HRT) used to be the treatment of choice [3]. Since studies have shown that the benefits of such therapy are out- weighed in the long run due to the increased risk of breast cancer, stroke, thromboembolism, and dementia [4–6], HRT is no longer being prescribed [7]. As a consequence, consumer interest in the effective and preferably safe alternative treatment options is increasing. Therefore, soy phytoestrogens such as genistein and daidzein have been proposed as a possible alternative to treat the menopausal symptoms [8, 9]. & Ivana M. Medigovic ´ ivana84@ibiss.bg.ac.rs 1 Department of Citology, Institute for Biological Research ‘‘Sinis ˇa Stankovic ´’’, University of Belgrade, Belgrade, Serbia 2 Department of Physiology, Institute for Biological Research ‘‘Sinis ˇa Stankovic ´’’, University of Belgrade, Belgrade, Serbia 3 Center for Medical Biochemistry, Clinical Centre of Serbia, School of Pharmacy, University of Belgrade, Belgrade, Serbia 123 Endocrine DOI 10.1007/s12020-015-0691-x