Estrogen exposure is known to cause hyperprolactinemia which can lead to the development of mammary and pituitary tumors. This hyperprolactinemia is associated with a decrease in the activity of tuberoinfundibular dopaminergic (TIDA) neurons of the hypothalamus. Perikarya of TIDA neurons are located in the arcuate nucleus (AN) of the hypothalamus and their axon terminals extend to the median eminence (ME). Here, dopamine is secreted into the hypophyseoportal circulation and acts on lactotrophs in the anterior pituitary gland to provide tonic inhibition of prolactin release. Therefore, if the activity of TIDA neuronal function is inhibited by estrogen, there is a decrease in dopamine (DA) levels, prolactin is no longer inhibited and a state of hyperprolactinemia ensues. Though it has been established that estrogens inhibit TIDA function, the mechanism by which estrogen exerts this effect has not been clearly elucidated. We hypothesized that a low dose of estradiol17-â (E2) would cause an increase in IL-1â and nitrate levels within the arcuate nucleus (AN), and that this local proinflammatory environment would damage TIDA neurons through nitration of tyrosine hydroxylase, which is the rate-limiting enzyme in DA synthesis. To test this hypothesis, we exposed reproductivelyintact and ovariectomized female Sprague-Dawley rats to E2 by subcutaneously implanting them with slow-release E2 pellets which release E2 at 20ng per day for 90 days. After 90 days of exposure, the animals were sacrificed and serum was collected for hormonal analysis, brain sections were microdissected to analyze IL-1â and nitrate levels in the AN via ELISA and modified Griess assay, respectively, the ME was microdissected and analyzed for the neurotransmitter DA using high performance liquid chromatography (HPLC), and western blot was performed to measure tyrosine hydroxylase (TH) and nitration of TH (nT) in the ME. Our results demonstrate that indeed, chronic exposure to a low dose of E2 increased serum prolactin, decreased DA levels in the ME, increased IL-1â and nitrate concentrations in the AN and increased the ratio of nT to TH in the ME. These findings provide strong evidence that chronic exposure to a low level of E2 induces a proinflammatory state within the AN and this may be a possible mechanism by which E2 exposure causes inhibition of TIDA activity and hyperprolactinemia.Additionally, estrogen exposure is known to affect the reproductive axis and to induce ovarian follicular cysts. Exposure to estrogen has been implicated as a model for polycystic ovary syndrome (PCOS) in women. However, most studies claiming this association, have primarily focused on the ovarian morphologic phenotype and have not thoroughly assessed the other clinical parameters that would correlate with those seen in women with PCOS. We explored whether our paradigm of chronic exposure to low levels E2 could cause changes in ovarian morphology and hormonal profiles similar to that of PCOS. Adult female rats were sham-implanted (control) or implanted with slow-release E2 (20 ng/day) pellets for 30 (E-30), 60 (E-60), or 90 (E-90) days. Old constant estrous (OCE) rats were used for comparison. At the end oftreatment, ovaries were collected and subjected to histological examination and Mullerian inhibiting substance (MIS) immunohistochemistry. We found that follicular size increased with E2 exposure and the number of corpora lutea (CL) decreased in a exposure-dependent manner indicating failure of ovulation. Estradiol treatment was associated with a decrease of MIS immunolabeling in follicles. Serum testosterone (T) levels decreased in a duration dependent manner with E2 treatment. Also, the ratio of serum LH to FSH remained unaffected in different groups. While ovarian changes observed in this model are similar to that seen in PCOS, the hormonal profiles are very different from that observed in PCOS and we therefore determined that this may not be a true model for this condition.
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