Estrogen inhibits tuberoinfundibular dopaminergic neurons but does not cause irreversible damage

Abstract

Dopaminergic neurons of the hypothalamic tuberoinfundibular dopaminergic (TIDA) system exert a tonic inhibitory control on prolactin (PRL) secretion whereas estrogen, known to inhibit TIDA neuron function, has been postulated to be toxic to TIDA neurons when it is chronically high. In order to determine whether estrogen in high doses can cause permanent damage to TIDA function, we submitted young female rats to continue high doses of estrogen administered, either centrally (intrahypothalamic estrogen implants) or peripherally (subcutaneous estrogen implants or weekly intramuscular (i.m.) injections for 7 weeks), subsequently withdrawing the steroid and observing the evolution of lactotrophes, serum PRL and TIDA neurons. Serum PRL was measured by radioimmunoassay whereas tyrosine hydroxylase positive (TH+) neurons and PRL cells were morphometrically assessed in sections of fixed hypothalami and pituitaries, respectively. After 30 days, hypothalamic estrogen implants induced a significant increase in serum PRL, whereas TH+ neurons were not detectable in the arcuate-periventricular hypothalamic (ARC) region of estrogenimplanted rats. Removal of implants on day 30 restored TH expression in the ARC and brought serum PRL back to basal levels 30 days after estrogen withdrawal. Subcutaneous or i.m. administration of estrogen for 7 weeks induced a marked hyperprolactinemia. However, 30 weeks after estrogen withdrawal, TH neuron numbers in the ARC were back to normal and serum PRL returned to basal levels. After peripheral but not central estrogen withdrawal, pituitary weight and lactotrophic cell numbers remained slightly increased. Our data suggest that estrogen even at high doses, does not cause permanent damage to TIDA neurons.

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

“…Although estrogens are known to impact DA levels in the hypothalamus (33), the mechanism by which chronic estradiol exposure reduces TIDA neuronal activity is unclear. In this study, we propose a novel hypothesis that involves the induction of the cytokine, interleukin-1␤ (IL-1␤) in the AN after chronic estradiol exposure.…”

Prevention of Mammary Tumor Development through Neuroimmunomodulation in the Spleen and Lymph Nodes of Old Female Sprague-Dawley Rats by <smlcap>L</smlcap>-Deprenyl

“…A similar decline in sympathetic NA innervation and/or NE concentration in the spleen has been observed in aging [9,10,24], arthritis [25,26] and autoimmune diseases [27,28]. Loss of splenic sympathetic NA innervations may result from elevated estrogen and PRL in tumor-bearing rats known to damage hypothalamic dopaminergic neurons [29,30]. Based on preliminary evidence in our laboratory, we propose similar effects of estrogen on the loss of sympathetic NA innervations in the spleens of tumor-bearing rats.…”

Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D2 receptor activation using multi‐biomarker pharmacokinetic/pharmacodynamic modelling

“…In contrast, studies with selective D 2 and D 3 agonists in ovariectomized oestrogen‐primed female rats showed a decrease of TIDA neuron activity and an increase of subsequent prolactin release (Liang and Pan, ; Liang et al ., ). However, the oestrogen‐priming in these studies prevents a direct comparison between these results and our results, since oestrogen interferes with TIDA neuron activity as well as the sensitivity of the pituitary to dopamine (Gudelsky et al ., ; Morel et al ., ). Indeed, our study design is more similar to that of the studies observing activation of TIDA neuron activity and suppression of prolactin release, that is, they studied male rats or diestrous female rats with low oestrogen levels (Eaton et al ., ; Durham et al ., ).…”