Perimenopause is one of the most complex and least understood states of a woman's life. Many of the health risks associated with this state were believed to be due to decreases in estrogen levels and that estrogen could protect against health risks faced by perimenopausal women. However, estrogen fluctuates during perimenopause and if at all increases during the premenstrual and follicular phases. Recent clinical trials have shown that chronic administration of estrogenic compounds in postmenopausal women may increase the risk for several diseases. Therefore, it is important to investigate the effects of estrogen exposure on various organ systems. Studies so far indicate that estrogen's effects in the brain are beneficial. These reported effects, however, deal with non-hypothalamic regions of the brain. The effects of chronic estrogen exposure on the hypothalamus which regulates several key body functions have not been investigated. This is critical because women use estrogenic preparations on a prolonged basis and are exposed to endogenous estrogen throughout their adulthood. This proposal focuses on the effects of chronic estrogen exposure on one of the estrogen sensitive neuronal systems of the hypothalamus, namely, the tuberoinfundibular dopaminergic (TIDA) system. Dopamine (DA) released from TIDA neurons inhibits prolactin (PRL) secretion from the anterior pituitary. Age-related reductions in TIDA activity is associated with hyperprolactinemia and appearance of mammary and pitutiary tumors in animal models. The mechanisms behind the loss of TIDA neuronal function is not clear. In this application, we are proposing a novel hypothesis and an interesting model to study how estrogen could affect TIDA neurons and increase PRL levels. This series of studies is important because women not only use estrogen on a long-term basis in HRT but are also exposed to environmental estrogens. Prolonged exposure to estrogen and elevated levels of PRL may promote the risk for breast cancer.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Special Emphasis Panel (ZRG1-EMNR-J (50))
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Mackiewicz, Miroslaw
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Michigan State University
Schools of Veterinary Medicine
East Lansing
United States
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Balasubramanian, Priya; Varde, Pratibha A; Abdallah, Simon Labib et al. (2015) Differential effects of prenatal stress on metabolic programming in diet-induced obese and dietary-resistant rats. Am J Physiol Endocrinol Metab 309:E582-8
Subramanian, Madhan; Hahn-Townsend, Coral; Clark, Kimberly A et al. (2015) Chronic estrogen exposure affects gene expression in the rostral ventrolateral medulla of young and aging rats: Possible role in hypertension. Brain Res 1627:134-42
Gilbreath, Ebony T; MohanKumar, Sheba M J; Balasubramanian, Priya et al. (2014) Chronic exposures to low levels of estradiol and their effects on the ovaries and reproductive hormones: Comparison with aging. Endocr Disruptors (Austin) 2:
Balasubramanian, Priya; Subramanian, Madhan; Nunez, Joseph L et al. (2014) Chronic estradiol treatment decreases brain derived neurotrophic factor (BDNF) expression and monoamine levels in the amygdala--implications for behavioral disorders. Behav Brain Res 261:127-33
Balasubramanian, Priya; Sirivelu, Madhu P; Weiss, Kathryn A et al. (2013) Differential effects of inhalation exposure to PM2.5 on hypothalamic monoamines and corticotrophin releasing hormone in lean and obese rats. Neurotoxicology 36:106-11
Kasturi, Badrinarayanan S; MohanKumar, Sheba M J; Sirivelu, Madhu P et al. (2013) Chronic estradiol-17ýý exposure suppresses hypothalamic norepinephrine release and the steroid-induced luteinizing hormone surge: role of nitration of tyrosine hydroxylase. Brain Res 1493:90-8
Sirivelu, Madhu P; MohanKumar, P S; MohanKumar, Sheba M J (2012) Differential effects of systemic interleukin-1β on gene expression in brainstem noradrenergic nuclei. Life Sci 90:77-81
Balasubramanian, P; Jagannathan, L; Mahaley, Rochell E et al. (2012) High fat diet affects reproductive functions in female diet-induced obese and dietary resistant rats. J Neuroendocrinol 24:748-55
Sirivelu, Madhu P; MohanKumar, P S; MohanKumar, Sheba M J (2012) Interleukin-1 beta simultaneously affects the stress and reproductive axes by modulating norepinephrine levels in different brain areas. Life Sci 91:878-84
Subramanian, Madhan; Balasubramanian, Priya; Garver, Hannah et al. (2011) Chronic estradiol-17ýý exposure increases superoxide production in the rostral ventrolateral medulla and causes hypertension: reversal by resveratrol. Am J Physiol Regul Integr Comp Physiol 300:R1560-8

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