Hypothalamic Effects of Tamoxifen on Oestrogen Regulation of Luteinising Hormone and Prolactin Secretion in Female Rats

Abstract

Oestradiol (E2) acts in the hypothalamus to regulate luteinising hormone (LH) and prolactin (PRL) secretion. Tamoxifen (TX) has been extensively used as a selective oestrogen receptor modulator, although its neuroendocrine effects remain poorly understood. In the present study, we investigated the hypothalamic effects of TX in rats under low or high circulating E2 levels. Ovariectomised (OVX) rats treated with oil, E2 or TX, or E2 plus TX, were evaluated for hormonal secretion and immunohistochemical analyses in hypothalamic areas. Both E2 and TX reduced LH levels, whereas TX blocked the E2 -induced surges of LH and PRL. TX prevented the E2 -induced expression of progesterone receptor (PR) in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC), although it did not alter PR expression in OVX rats. TX blocked the E2 induction of c-Fos in AVPV neurones, consistent with the suppression of LH surge. However, TX failed to prevent E2 inhibition of kisspeptin expression in the ARC. In association with the blockade of PRL surge, TX increased the phosphorylation of tyrosine hydroxylase (TH) in the median eminence of OVX, E2 -treated rats. TX also precluded the E2 -induced increase in TH expression in the ARC. In all immunohistochemical analyses, TX treatment in OVX rats caused no measurable effect on the hypothalamus. Thus, TX is able to prevent the positive- but not negative-feedback effect of E2 on the hypothalamus. TX also blocks the effects of E2 on tuberoinfundibular dopaminergic neurones and PRL secretion. These findings further characterise the anti-oestrogenic actions of TX in the hypothalamus and provide new information on the oestrogenic regulation of LH and PRL.

Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice

“…We report that tamoxifen treatment affects gene expression in many cell types of the hypothalamus, but most strongly in neurons and ependymal cells. These findings are consistent with previous reports of tamoxifen-induced gene expression changes within neurons (Lopez et al 2006, Aquino et al 2016, Sa et al 2016, and tamoxifen-induced stress in neurons and ependymal cells (Denk et al 2015). Importantly, we detect minor changes in the proportion of different cell types after 28-days of treatment with a clinically relevant dose (0.1 mg/kg) of tamoxifen.…”

“…These cell-type specific effects highlight the additional insights that can be revealed by scRNA-seq compared to overall averages determined by bulk tissue sequencing. Additionally, these results are compatible with the previous findings that tamoxifen can have different effects in different regions of the brain (Wilson et al 2003, Chen et al 2014, Gibbs et al 2014, Aquino et al 2016, Sa et al 2016 and consistent with cell-type-specific effects of tamoxifen within hypothalamic neurons.…”

“…Estrogen receptor alpha (ERα) signaling regulates body temperature (Bowe et al 2006, Musatov et al 2007, Mittelman-Smith et al 2012, Martinez de Morentin et al 2014, physical activity (Musatov et al 2007, Correa et al 2015, van Veen et al 2020, and bone density (Farman et al 2016, Zhang et al 2016, Herber et al 2019 through distinct neuron populations in the hypothalamus. Indeed, the hypothalamus is a demonstrated target of tamoxifen, leading to changes in food intake and body weight (Wade et al 1993, Lopez et al 2006, Lampert et al 2013 and changes in the hypothalamic-pituitary-ovarian (Wilson et al 2003, Aquino et al 2016) and hypothalamic-pituitary-adrenal (Wilson et al 2003) axes. Tamoxifen has also been shown to affect gene expression in the hypothalamus; its administration blocks the estrogen dependent induction of the progesterone receptor (Pgr) in the ventromedial hypothalamus (VMH) and increases the expression of estrogen receptor beta (Esr2) in the paraventricular nucleus of the hypothalamus (PVH) (Patisaul et al 2003, Aquino et al 2016, Sa et al 2016.…”

“…Indeed, the hypothalamus is a demonstrated target of tamoxifen, leading to changes in food intake and body weight (Wade et al 1993, Lopez et al 2006, Lampert et al 2013 and changes in the hypothalamic-pituitary-ovarian (Wilson et al 2003, Aquino et al 2016) and hypothalamic-pituitary-adrenal (Wilson et al 2003) axes. Tamoxifen has also been shown to affect gene expression in the hypothalamus; its administration blocks the estrogen dependent induction of the progesterone receptor (Pgr) in the ventromedial hypothalamus (VMH) and increases the expression of estrogen receptor beta (Esr2) in the paraventricular nucleus of the hypothalamus (PVH) (Patisaul et al 2003, Aquino et al 2016, Sa et al 2016.…”

Controle neuroendócrino da reprodução: fatores que modulam a atividade de neurônios GNRH e kisspetina.

“…Mouse prolactin concentrations were determined using an ELISA kit according to the manufacturer's instructions (Sigma), as was the serum leptin concentration (Crystal Chem). LH levels were determined by double-antibody radioimmunoassay using a kit provided by the National Hormone and Peptide Program (Harbor-University of California at Los Angeles, USA), as previously described (AQUINO et al, 2016; TRASLAVIÑA; FRANCI, 2011). All samples were assayed using the same radioimmunoassay.…”