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

Verheul, H.A.M.; Kloosterboer, H.J.

doi:10.1016/j.jsbmb.2006.09.037

Cited by 21 publications

(16 citation statements)

References 70 publications

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“…A study performed on ovariectomized cynomolgus monkeys treated orally with 0.5 mg/kg/day tibolone for 36 days showed an increase of estrogenic metabolites in the hypothalamus that was correlated with a reduction in the number and severity of hot flushes and perspirations. The combined effect of tibolone on androgen receptor and ERs is responsible for improving the libido, mood and general well-being [168]. Also, it has been reported in an in vivo study that an increase in antioxidant activity may underlie the neuroprotective effects of tibolone.…”

Section: The Cns As a Target For Neuroprotective Estrogenic Compoundsmentioning

confidence: 99%

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

et al. 2018

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Traumatic brain injury (TBI) is a serious public health problem. It may result in severe neurological disabilities and in a variety of cellular metabolic alterations for which available therapeutic strategies are limited. In the last decade, the use of estrogenic compounds, which activate protective mechanisms in astrocytes, has been explored as a potential experimental therapeutic approach. Previous works have suggested estradiol (E2) as a neuroprotective hormone that acts in the brain by binding to estrogen receptors (ERs). Several steroidal and nonsteroidal estrogenic compounds can imitate the effects of estradiol on ERs. These include hormonal estrogens, phytoestrogens and synthetic estrogens, such as selective ER modulators or tibolone. Current evidence of the role of astrocytes in mediating protective actions of estrogenic compounds after TBI is reviewed in this paper. We conclude that the use of estrogenic compounds to modulate astrocytic properties is a promising therapeutic approach for the treatment of TBI.

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Section: The Cns As a Target For Neuroprotective Estrogenic Compoundsmentioning

confidence: 99%

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

et al. 2018

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“…Tibolone is metabolized in the liver and other tissues, including the brain, in three active steroids: 3α-and 3βhydroxytibolone and Δ4-tibolone. 3α-and 3β-hydroxytibolone have an affinity for estrogen receptors (ERs), while Δ4tibolone binds to androgen and progesterone receptors [17,18]. Previous studies have shown that tibolone 3-hydroxy metabolites activate ERs in human primary astrocytes [19] and that ERs, mainly ERβ, mediate different actions of tibolone on T98G astrocyte-like cells [14,15].…”

Section: Introductionmentioning

confidence: 99%

The synthetic steroid tibolone exerts sex-specific regulation of astrocyte phagocytosis under basal conditions and after an inflammatory challenge

Crespo‐Castrillo

Garcia-Segura

Arévalo

2020

J Neuroinflammation

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Background: Tibolone is a synthetic steroid used in clinical practice for the treatment of climacteric symptoms and osteoporosis. Active metabolites of tibolone, generated in target tissues, have an affinity for estrogen and androgen receptors. Astrocytes are direct targets for estrogenic compounds and previous studies have shown that tibolone protects brain cortical neurons in association with a reduction in reactive astrogliosis in a mouse model of traumatic brain injury. Since phagocytosis is a crucial component of the neuroprotective function exerted by astrocytes, in the present study, we have assessed whether tibolone regulates phagocytosis in primary astrocytes incubated with brain-derived cellular debris. Methods: Male and female astrocyte cell cultures were obtained from newborn (P0-P2) female and male Wistar rats. Astrocytic phagocytosis was first characterized using carboxylate beads, Escherichia coli particles, or brain-derived cellular debris. Then, the effect of tibolone on the phagocytosis of Cy3-conjugated cellular debris was quantified by measuring the intensity of Cy3 dye-emitted fluorescence in a given GFAP immunoreactive area. Before the phagocytosis assays, astrocytes were incubated with tibolone in the presence or absence of estrogen or androgen receptor antagonists or an inhibitor of the enzyme that synthesizes estradiol. The effect of tibolone on phagocytosis was analyzed under basal conditions and after inflammatory stimulation with lipopolysaccharide. Results: Tibolone stimulated phagocytosis of brain-derived cellular debris by male and female astrocytes, with the effect being more pronounced in females. The effect of tibolone in female astrocytes was blocked by a selective estrogen receptor β antagonist and by an androgen receptor antagonist. None of these antagonists affected tibolone-induced phagocytosis in male astrocytes. In addition, the inhibition of estradiol synthesis in the cultures enhanced the stimulatory effect of tibolone on phagocytosis in male astrocytes but blocked the effect of the steroid in female cells under basal conditions. However, after inflammatory stimulation, the inhibition of estradiol synthesis highly potentiated the stimulation of phagocytosis by tibolone, particularly in female astrocytes. Conclusions: Tibolone exerts sex-specific regulation of phagocytosis in astrocytes of both sexes, both under basal conditions and after inflammatory stimulation.

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“…Moreover, the beneficial effects of tibolone on mood and quality of life can be explained not only with the reduction of vasomotor symptoms but also by direct action on the CNS. Different mechanisms by which tibolone acts on the CNS have been hypothesized (58)(59)(60)(61). In fact, in animal and in human models, it has been demonstrated that tibolone's metabolites act on the brain with several site-specific actions (59).…”

Section: Sherwin and Tulandimentioning

confidence: 99%

“…Different mechanisms by which tibolone acts on the CNS have been hypothesized (58)(59)(60)(61). In fact, in animal and in human models, it has been demonstrated that tibolone's metabolites act on the brain with several site-specific actions (59). In particular, estrogenic 3-hydroxitibolone metabolites are predominant in the brain, including the hypothalamus, the area mainly involved in controlling hot flushes.…”

Section: Sherwin and Tulandimentioning

confidence: 99%

“…Furthermore, this last mechanism appears to be insufficient in causing clinically relevant effects on mood, well-being, and libido. Thus, it has been suggested that the decrease in sex hormone-binding globulin that is induced by tibolone administration, increasing the free T levels, could strengthen the androgenic effects on mood and libido (59).…”

Section: Sherwin and Tulandimentioning

confidence: 99%

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

Palomba

Orio

Falbo

et al. 2008

Fertility and Sterility

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

Cited by 21 publications

References 70 publications

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

The synthetic steroid tibolone exerts sex-specific regulation of astrocyte phagocytosis under basal conditions and after an inflammatory challenge

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

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