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

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.

Environmental control of biological rhythms: effects on development, fertility and metabolism.

Internal temporal organisation properly synchronised to the environment is crucial for health maintenance. This organisation is provided at the cellular level by the molecular clock, a macromolecular transcription-based oscillator formed by the clock and the clock-controlled genes that is present in both central and peripheral tissues. In mammals, melanopsin in light-sensitive retinal ganglion cells plays a considerable role in the synchronisation of the circadian timing system to the daily light/dark cycle. Melatonin, a hormone synthesised in the pineal gland exclusively at night and an output of the central clock, has a fundamental role in regulating/timing several physiological functions, including glucose homeostasis, insulin secretion and energy metabolism. As such, metabolism is severely impaired after a reduction in melatonin production. Furthermore, light pollution during the night and shift work schedules can abrogate melatonin synthesis and impair homeostasis. Chronodisruption during pregnancy has deleterious effects on the health of progeny, including metabolic, cardiovascular and cognitive dysfunction. Developmental programming by steroids or steroid-mimetic compounds also produces internal circadian disorganisation that may be a significant factor in the aetiology of fertility disorders such as polycystic ovary syndrome. Thus, both early and late in life, pernicious alterations of the endogenous temporal order by environmental factors can disrupt the homeostatic function of the circadian timing system, leading to pathophysiology and/or disease.

Ovarian steroids but not the locus coeruleus regulate stress-induced prolactin secretion in female rats.

Stress has been proposed to stimulate prolactin release if its prestress levels are low, or to inhibit it if they are elevated, but the role of ovarian-steroid fluctuations in the prolactin stress response is not yet clearly understood. Because the noradrenergic nucleus locus coeruleus has been implicated in stress responses and generation of prolactin surges in female rats, the present study aimed to evaluate stress-induced prolactin secretion under different hormonal conditions, determining the effect of locus coeruleus lesion on each response. Blood samples were withdrawn from a jugular vein catheter 5 and 2 min before and 2, 5, 10, 15 and 30 min after ether stress in male rats, female rats during the oestrous cycle and ovariectomised rats treated with oil (OVX), oestradiol (OVE) or oestradiol plus progesterone (OVEP). Increased Fos immunoreactivity demonstrated locus coeruleus activation following ether stress. Ether stress increased both low (at 16.00 h in males, in OVX and on dioestrous and at 11.00 h on pro-oestrous and oestrous) and high plasma prolactin (at 16.00 h on oestrous and in OVE), but it decreased elevated prolactin levels during the afternoon on pro-oestrous and in OVEP. Locus coeruleus lesion prevented prolactin surges during the afternoon on pro-oestrous, oestrous, OVE and OVEP but did not modify either pattern (i.e. increase or decrease) or degree of prolactin stress response under any condition studied. The present data therefore suggest that oestradiol and progesterone modulate stress-induced prolactin secretion, regardless of its prestress levels. Moreover, the locus coeruleus is probably not involved in prolactin response to stress and most likely has a specific role in prolactin surges induced by ovarian steroids.