Aromatase in the Human Brain

Azcoitia, Íñigo; Méndez, Pablo; Garcia-Segura, Luis Miguel

doi:10.1089/andro.2021.0007

Cited by 17 publications

(17 citation statements)

References 140 publications

(164 reference statements)

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“…Results thus far show that depletion of circulating estrogen via OVX results in a loss of neuroprotection by cytisine. Cells in the brain are steroidogenic and express aromatase (AROM), which is the primary cytochrome P450 enzyme ( CYP19A1) that synthesizes 17-β-estradiol in the brain 28 .…”

Section: Resultsmentioning

confidence: 99%

The smoking cessation drug cytisine requires systemically circulating estrogen for sex-specific neuroprotection in female parkinsonian mice

Zarate,

Garcia,

Pandey

et al. 2024

Preprint

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The smoking cessation drug cytisine exerts neuroprotection in substantia nigra pars compacta (SNc) dopaminergic (DA) neurons of female but not male 6-hydroxydopamine (6-OHDA) lesioned parkinsonian mice. To address the important question of whether circulating estrogen mediates this effect, we employ two mouse models aimed at depleting systemically circulating estrogen: (i) bilateral ovariectomy (OVX), and (ii) aromatase inhibition with systemically administered letrozole. In both models, depleting systemically circulating estrogen in female 6-OHDA lesioned parkinsonian mice results in the loss of cytisine-mediated neuroprotection as measured using apomorphine-induced contralateral rotations and SNc DA neurodegeneration. Our experiments also reveal that OVX alone exerts neuroprotection in SNc DA neurons due to compensatory changes not observed in the letrozole model, which underscores the importance of using independent models of estrogen depletion to study neuroprotection. Taken together, our findings suggest that the smoking cessation drug cytisine is a viable neuroprotective drug for pre-menopausal women with Parkinson disease.

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Section: Resultsmentioning

confidence: 99%

The smoking cessation drug cytisine requires systemically circulating estrogen for sex-specific neuroprotection in female parkinsonian mice

Zarate,

Garcia,

Pandey

et al. 2024

Preprint

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“…Estimates are per 1 standard deviation (SD) increase in the trait. to estrogens in regulating brain functions (Azcoitia et al, 2021). Notably, the epileptogenic effect of estradiol has also been reported.…”

Section: Discussionmentioning

confidence: 98%

“…Among the instrumental variables of estradiol, two (rs3751591, rs7173595) were in the gene CYP19A1 , which encodes the aromatase cytochrome P450 (P450arom) enzyme, or estrogen synthase. The estrogen synthase converts androgens to estrogens, and previous experimental studies in laboratory animals have indicated a prominent role of brain aromatization of androgens to estrogens in regulating brain functions ( Azcoitia et al, 2021 ). Notably, the epileptogenic effect of estradiol has also been reported.…”

Section: Discussionmentioning

confidence: 99%

Sex hormones and risk of epilepsy: A bidirectional Mendelian randomization study

Shang

2023

Front. Mol. Neurosci.

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BackgroundMultiple evidence has suggested complex interaction between sex hormones and epilepsy. However, whether there exists a causal association and the effect direction remains controversial. Here we aimed to examine the causative role of hormones in the risk of epilepsy and vice versa.MethodsWe conducted a bidirectional two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of major sex hormones including testosterone (N = 425,097), estradiol (N = 311,675) and progesterone (N = 2,619), together with epilepsy (N = 44,889). We further performed sex-stratified analysis, and verified the significant results using summary statistics from another study on estradiol in males (N = 206,927).ResultsGenetically determined higher estradiol was associated with a reduced risk of epilepsy (OR: 0.90, 95% CI: 0.83–0.98, P = 9.51E-03). In the sex-stratified analysis, the protective effect was detected in males (OR: 0.92, 95% CI: 0.88–0.97, P = 9.18E-04), but not in females. Such association was further verified in the replication stage (OR: 0.44, 95% CI: 0.23–0.87, P = 0.017). In contrast, no association was identified between testosterone, progesterone and the risk of epilepsy. In the opposite direction, epilepsy was not causally associated with sex hormones.ConclusionThese results demonstrated higher estradiol could reduce the risk of epilepsy, especially in males. Future development of preventive or therapeutic interventions in clinical trials could attach importance to this.

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“…Aromatase inhibitors (AI) are potentially active for the treatment of BCBM as they lower both serum and CSF concentrations of estradiol [ 38 ]. However, the only publications suggesting AI (or tamoxifen) have activity for HR + BCBM are case series and reports [ 39 – 43 ].…”

Section: Discussionmentioning

confidence: 99%

Systematic review of the management of brain metastases from hormone receptor positive breast cancer

2023

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Introduction Brain metastases are a common cause of morbidity and mortality in patients with breast cancer. Local central nervous system (CNS) directed therapies are usually the first line treatment for breast cancer brain metastases (BCBM), but those must be followed by systemic therapies to achieve long-term benefit. Systemic therapy for hormone receptor (HR+) breast cancer has evolved in the last 10 years, but their role when brain metastases occur is uncertain. Methods We performed a systematic review of the literature focused on management of HR+ BCBM by searching Medline/PubMed, EBSCO, and Cochrane databases. The PRISMA guidelines were used for systematic review. Results Out of 807 articles identified, 98 fulfilled the inclusion criteria in their relevance to the management of HR+ BCBM. Conclusions Similar to brain metastases from other neoplasms, local CNS directed therapies are the first line treatment for HR+ BCBM. Although the quality of evidence is low, after local therapies, our review supports the combination of targeted and endocrine therapies for both CNS and systemic management. Upon exhaustion of targeted/endocrine therapies, case series and retrospective reports suggest that certain chemotherapy agents are active against HR+ BCBM. Early phase clinical trials for HR+ BCBM are ongoing, but there is a need for prospective randomized trials to guide management and improve patients’ outcome.

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Aromatase in the Human Brain

Cited by 17 publications

References 140 publications

The smoking cessation drug cytisine requires systemically circulating estrogen for sex-specific neuroprotection in female parkinsonian mice

The smoking cessation drug cytisine requires systemically circulating estrogen for sex-specific neuroprotection in female parkinsonian mice

Sex hormones and risk of epilepsy: A bidirectional Mendelian randomization study

Systematic review of the management of brain metastases from hormone receptor positive breast cancer

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