Progesterone increased β-endorphin innervation of the locus coeruleus , but ovarian steroids had no effect on noradrenergic neurodegeneration

Abstract

With the decline of ovarian steroids levels at menopause, many women experience an increase in anxiety and stress sensitivity. The locus coeruleus (LC), a central source of noradrenaline (NE), is activated by stress and is inhibited by β-endorphin. Moreover, increased NE has been implicated in pathological anxiety syndromes. Hormone replacement therapy (HRT) in menopause appears to decrease anxiety and vulnerability to stress. Therefore, we questioned the effect of HRT on the inhibitory β–endorphin innervation of the LC. In addition, we found that progesterone protects serotoninergic neurons in monkeys, leading us to question whether ovarian steroids are also neuroprotective in LC neurons in monkeys. Adult Rhesus monkeys (Macaca mulatta) were ovariectomized, and either treated with Silastic capsules that contained estradiol, estratiol + progesterone, progesterone alone or that were empty (ovariectomized;control). After 1 month, the LC was obtained and processed for immunohistochemistry for β-endorphin and terminal deoxynucleotidyl transferase -mediated dUTP-biotin nick end-labeling (TUNEL). The density of β–endorphin axons was determined with image analysis using ImageJ. The TUNEL-positive neurons were counted in the entire LC. progesterone-alone significantly increased the density of the β-endorphin axons in the LC (p<0.01). No significant differences between groups in the number of TUNEL-positive cells in the LC were found. In conclusion, we found that HRT increases the inhibitory influence of β–endorphin in the LC, which could, in turn, contribute to reduce anxiety and increase stress resilience. In addition, we did not find compelling evidence of neurodegeneration or neuroprotection by HRT in the LC of Rhesus monkeys.

Hormonal and neural responses to restraint stress in an animal model of perimenopause in female rats

“…It is likely that the lower amount of opiatergic afferents to LC is a result of the lower levels of plasma progesterone systematically observed during the transition period in reproductive life, both in women and in animals. Indeed, we have shown in rhesus monkeys that progesterone, but not oestradiol, increased the density of the BE axons in the LC 27 . Therefore, it is plausible that the low levels of progesterone in the VCD‐treated rats have decreased the levels of BE in the LC, resulting in the disinhibition of these neurones and, consequently, the longer recovery period of the stress response.…”

“…These fibres are one of the main inhibitory systems of the noradrenergic stress response and they modulate this response by decreasing autonomic and neuroendocrine responses induced by stress 26 . We have shown that progesterone increases the density of the β‐endorphin axons in the LC 27 and that, in this perimenopausal rat model, progesterone levels are lower 15‐17 . Thus, it is possible that, during perimenopause, the lower levels of progesterone result in a lower inhibition of LC neurones by BE and exacerbate stress responses.…”

“…Indeed, we have shown in rhesus monkeys that progesterone, but not oestradiol, increased the density of the BE axons in the LC. 27 Therefore, it is plausible that the low levels of progesterone in the VCD-treated rats have decreased the levels of BE in the LC, resulting in the disinhibition of these neurones and, consequently, the longer recovery period of the stress response.…”

Distribution of alpha‐neoendorphin, ACTH (18–39) and beta‐endorphin (1–27) in the alpaca brainstem

“…Here, we have reported a moderate/low density of immunoreactive fibres containing beta‐endorphin (1–27) in the area postrema, locus coeruleus, reticular formation, nucleus of the solitary tract, dorsal nucleus of the raphe and the periaqueductal gray. This means that the peptide could be involved in the control of pain transmission, sleep–waking cycle, taste, feeding, respiratory, cardiovascular, vigilance and stress mechanisms (Cerritelli, Hirschberg, Hill, Balthasar, & Pickering, ; de Freitas, Medeiros, & Khan, ; Li et al., ; Lima, Leite, Bethea, & Anselmo‐Franci, ).…”

Efeitos da terapia hormonal na resposta ao estresse em modelo animal de perimenopausa

“…Durante a fase lútea, quando as concentrações deste hormônio encontram-se mais elevadas que as do estradiol, foi observado que a frequência cardíaca, o débito cardíaco e a pressão arterial sistólica foram menores em resposta ao estresse pscicossocial e por frio (SITA, MILLER, 1996). Nós também já demonstramos em macacas que o tratamento crônico com progesterona aumenta as aferências β-endorfinérgicas no LC, as quais, por sua vez, inibem a atividade deste núcleo (LIMA et al, 2017).…”