Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia

Sheba M.J. MohanKumar, Badrinarayanan S. Kasturi, Andrew C. Shin, Priya Balasubramanian, Ebony T. Gilbreath, Madhan Subramanian, Puliyur S. MohanKumar

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24 Scopus citations

Abstract

Estrogens are known to cause hyperprolactinemia, most probably by acting on the tuberoinfundibular dopaminergic (TIDA) system of the hypothalamus. Dopamine (DA) produced by TIDA neurons directly inhibits prolactin secretion and, therefore, to stimulate prolactin secretion, estrogens inhibit TIDA neurons to decrease DA production. However, the mechanism by which estrogen produces this effect is not clear. In the present study, we used a paradigm involving chronic exposure to low levels of estradiol-17β (E2) to mimic prolonged exposures to environmental and endogenous estrogens. We hypothesized that chronic exposure to low levels of E2 induces oxidative stress in the arcuate nucleus (AN) of the hypothalamus that contains TIDA neurons and causes nitration of tyrosine hydroxylase (TH), the ratelimiting enzyme in the synthesis of DA. This results in a significant decrease in DA and consequently, hyperprolactinemia. To investigate this, adult, intact female cycling rats were implanted with slow-release E2 pellets (20 ng/day) for 30, 60, or 90 days and were compared with old (16-18 mo old) constant estrous (OCE) rats. Chronic E2 exposure significantly increased the expression of glial fibrillary acidic protein and the concentrations of interleukin-1β (IL-1β) and nitrate in the AN that contains perikarya of TIDA neurons and increased nitration of TH in the median eminence (ME) that contains the terminals. These levels were comparable to those seen in OCE rats. We observed a significant decrease in DA concentrations in the ME and hyperprolactinemia in an exposure-dependent manner similar to that seen in OCE rats. It was concluded that chronic exposure to low levels of E2 evokes oxidative stress in the AN to inhibit TIDA neuronal function, most probably leading to hyperprolactinemia.

Original languageEnglish
Pages (from-to)R693-R699
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume300
Issue number3
DOIs
StatePublished - Mar 2011

Keywords

  • Nitration
  • Prolactin
  • Tyrosine hydroxylase

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