Background and development of aromatase inhibitors

Miller, William R.

doi:10.1007/978-3-7643-8693-1_1

Cited by 5 publications

(2 citation statements)

References 99 publications

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“…Retrodialysis of FAD into NCM increases T levels in the NCM of males (Remage-Healey et al, 2008) and in the left hemisphere of females (de Bournonville et al, 2020). Although nonsteroidal type II aromatase inhibitors such as FAD are effective at inactivating the aromatase enzyme, they are usually reversible and have a relatively short-half life (Buzdar, 2006;Miller R., 2006). FAD effectiveness depends upon the continued presence of the inhibitor (Buzdar, 2006;Miller R., 2006) which was unlikely during this…”

Section: Effects Of Aromatase Inhibition On Neural and Behavioral Aud...mentioning

confidence: 99%

Acute Aromatase Inhibition Impairs Neural and Behavioral Auditory Scene Analysis in Zebra Finches

Fernández-Vargas,

Macedo-Lima,

Remage-Healey

2024

eNeuro

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Auditory perception can be significantly disrupted by noise. To discriminate sounds from noise, auditory scene analysis (ASA) extracts the functionally relevant sounds from acoustic input. The zebra finch communicates in noisy environments. Neurons in their secondary auditory pallial cortex (caudomedial nidopallium; NCM) can encode song from background chorus, or scenes, and this capacity may aid behavioral ASA. Furthermore, song processing is modulated by the rapid synthesis of neuroestrogens when hearing conspecific song. To examine whether neuroestrogens support neural and behavioral ASA in both sexes, we retrodialyzed fadrozole (aromatase inhibitor, FAD) and recordedin vivoawake extracellular NCM responses to songs and scenes. We found that FAD affected neural encoding of songs by decreasing responsiveness and timing reliability in inhibitory (narrow-spiking), but not in excitatory (broad-spiking) neurons. Congruently, FAD decreased neural encoding of songs in scenes for both cell types, particularly in females. Behaviorally, we trained birds using operant conditioning and tested their ability to detect songs in scenes after administering FAD orally or injected bilaterally into NCM. Oral FAD increased response bias and decreased correct rejections in females, but not in males. FAD in NCM did not affect performance. Thus, FAD in the NCM impaired neuronal ASA but that did not lead to behavioral disruption suggesting the existence of resilience or compensatory responses. Moreover, impaired performance after systemic FAD suggests involvement of other aromatase-rich networks outside the auditory pathway in ASA. This work highlights how transient estrogen synthesis disruption can modulate higher-order processing in an animal model of vocal communication.Significance StatementThe ability to extract relevant sounds from a complex acoustic input, or acoustic scene, can decline with age and is often impaired in auditory and neurological disorders. Moreover, hearing decline and speech-in-noise processing have been associated with hormonal changes during perimenopause or menopause in women. However, hormone-dependent hearing impairments are understudied in female animal models. Here, we explore the role of neuroestrogen synthesis in auditory scene analysis (ASA) in a songbird. We found that blocking the synthesis of neuroestrogens with the drug fadrozole (FAD) impaired ASA in auditory neurons. FAD administered orally caused females to decrease correct rejections and respond indiscriminately during behavioral ASA using operant conditioning. These results elucidate potential neural and hormonal mechanisms underlying speech-in-noise impairments in women.

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Section: Effects Of Aromatase Inhibition On Neural and Behavioral Aud...mentioning

confidence: 99%

Acute Aromatase Inhibition Impairs Neural and Behavioral Auditory Scene Analysis in Zebra Finches

Fernández-Vargas,

Macedo-Lima,

Remage-Healey

2024

eNeuro

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“…The ®rst-generation reversible inhibitor, still used clinically, was aminoglutethimide (Shaw at al 1988;Santen 1990); this has been replaced by other more selective and potent non-steroidal inhibitors (Miller 1996). Irreversible steroidal inhibitors which are mechanism-based inactivators of the enzyme have also entered the clinic (Lombardi 1995;Miller 1996). Recently, we have described some non-steroidal mechanism-based inactivators (Saeed et al 1997).…”

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confidence: 99%

Inhibition of Aromatase (P450Arom) by some 1-(Benzofuran-2-ylmethyl)imidazoles

et al. 1999

Journal of Pharmacy and Pharmacology

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Studies of a series of 1-(benzofuran-2-ylmethyl)imidazoles, 1-5, previously proposed as potential agents for prostatic cancer by their inhibition of 17beta-hydroxylase:17,20-lyase (P450 17), have been extended to their selectivity against placental microsomal aromatase (P450(Arom)) in man. The compounds were 3-7-fold more potent than aminoglutethimide and had some selectivity for P450 17 as expressed by the ratio (IC50 P450(Arom))/(IC50 P450) 17)/17.0 (2), 10.3 (3), 34.6 (4) and 42.0 (5), where IC50 is the concentration resulting in 50% inhibition. The lower potency of 1-5 towards P450(Arom) compared with the racemic alpha-phenyl-substituted compounds (6, 80-1000 x aminoglutethimide) and some racemic alpha-methyl (8.5 and 12.2 x aminoglutethimide) and alpha-ethyl (12.1 and 32.9 x aminoglutethimide) analogues has been rationalized. This work selectively extends studies of the P450 17 inhibitor 5, a potential prostatic cancer agent, towards other cytochrome P450 enzymes in the steroidogenic pathway and provides a general method for determining the relative influence of chemical manipulation of a parent inhibitor towards two enzymes in the pathway using additional literature data.

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Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone receptor-positive breast cancer: a systematic review

Ioannides

Barlow

Elwood

et al. 2014

Breast Cancer Res Treat

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Aromatase inhibitors (AIs) decrease the production of oestrogen, decreasing stimulation of hormone receptor-positive breast cancer. Theoretically, AIs may be less effective in obese women, due to the greater quantity of aromatase in peripheral fatty tissue. We performed a systematic review to assess the effect of obesity on AI efficacy in breast cancer treatment. The review followed PRISMA guidelines. Studies included were interventional or observational studies with comparison groups, of postmenopausal women with hormone receptor-positive breast cancer on treatment with an AI, alone or in combination with other drugs, in which body mass index or another measure of obesity was recorded. Studies in all languages were included; if published as an abstract only, authors were contacted for further information. Outcome measures included overall survival, disease-free survival or time to progressive disease, survival from the start of therapy, mortality measures, local or distant recurrence of primary cancer and time to recurrence. Of 2,344 citations identified from five databases, eight studies met the criteria for inclusion; three randomised controlled trials and five retrospective cohort studies. Due to variability in study factors, it was not possible to perform a quantitative meta-analysis. However, the systematic review showed a trend towards a negative effect of obesity on AI efficacy. There is evidence of a negative effect of obesity on AI efficacy in postmenopausal hormone receptor-positive breast cancer, but the size of the effect cannot be assessed. More information is needed before clinical recommendations are made.

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Background and development of aromatase inhibitors

Cited by 5 publications

References 99 publications

Acute Aromatase Inhibition Impairs Neural and Behavioral Auditory Scene Analysis in Zebra Finches

Acute Aromatase Inhibition Impairs Neural and Behavioral Auditory Scene Analysis in Zebra Finches

Inhibition of Aromatase (P450Arom) by some 1-(Benzofuran-2-ylmethyl)imidazoles

Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone receptor-positive breast cancer: a systematic review

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