Effects of Long‐Term Hormone Treatment and of Tibolone on Monoamines and Monoamine Metabolites in the Brains of Ovariectomised, Cynomologous Monkeys

Abstract

The effects of long-term hormone treatment on monoamines and monoamine metabolites in different regions of the primate brain were examined and compared. Ovariectomised Cynomologous monkeys received daily oral administration of either conjugated equine oestrogens (CEE), CEE + medroxyprogesterone acetate (MPA), or a low or high dose of tibolone, for a period of 2 years. Tissue punches collected from frozen sections through various regions of the forebrain, midbrain, and hindbrain were assayed for levels of dopamine, dihydroxyphenylacetic acid (DOPAC), serotonin, 5-hydroxyindole acetic acid (5-HIAA), and norepinephrine by high-performance liquid chromatography. Few differences between hormone-treated animals and ovariectomised controls were observed. No statistically significant effects of CEE relative to controls were detected in any of the seven brain regions analysed. Animals treated with CEE + MPA showed significant reductions in 5-HIAA in the dorsal raphe nucleus, a significant reduction in dopamine in the hypothalamus, and a significant reduction in serotonin (5-HT) levels in area 8AD of the frontal cortex. Similar to CEE, no significant effects of tibolone relative to controls were detected; however, animals treated with high-dose tibolone showed a decrease in 5-HT levels in the frontal cortex that approached significance and was similar to the effect of CEE + MPA. Collectively, the findings suggest that long-term oral administration of these compounds has relatively few effects on the levels of dopamine, serotonin, and their primary metabolites in the primate brain. This differs from the significant effects on serotonergic and dopaminergic systems detected following parenteral treatment with oestradiol and progesterone, and likely reflects differences between the effects of treating with CEE + MPA versus oestradiol and progesterone on brain monoaminergic systems.

Effect of injectable medroxyprogesterone acetate and etonogestrel implants on GABA-A and serotonin receptors in white and gray matter of the brain: experimental study in rats

“…In some previous studies evaluating the relationship between MPA and serotonin, it has been argued that serotonin levels decreased in brain tissues when MPA was applied [23,24]. Blocking the stimulator effect on tryptophan hydroxylase of MPA, estrogen resulted in a negative effect on serotonin levels [25].…”

Tibolone reverses the cognitive effects caused by leuprolide acetate administration, improving mood and quality of life in patients with symptomatic uterine leiomyomas

“…In particular, both 3a-and 3b-hydroxytibolone metabolites, which bind only to estrogen receptors (52), could be responsible for the estrogenic activity on the CNS. In addition, we also can hypothesize an indirect effect of tibolone administration on cerebral vascular reactivity (53)(54)(55)(56). On the contrary, D 4 -tibolone metabolite could exert its androgenic activity without the progestogenic negative action on cognition (52).…”

Metabolism of exogenous sex steroids and effect on brain functions with a focus on tibolone

“…Small doses of testosterone propionate implanted in the hypothalamus restored sexual desire of rhesus monkeys [14], suggesting direct androgenic effects on the brain. Longterm CEE + MPA or tibolone treatments of ovariectomized cynomolgus monkeys reduced the activities of choline acetyltransferase and acetylcholinesterase in the brain [65] and had no effects on the brain levels of dopamine, serotonin, norepinephrine and metabolites [56] suggesting that these treatments exert their effects on mood, well-being, sexual functioning and libido through other mechanisms. Tibolone has also been shown to increase central and peripheral levels of allopregnanolone and ␤-endorphin in preclinical models [57], the latter hormone associated with the improvement of mood [17].…”