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

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, estradiol + 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.