Physiopathological role of the enzymatic complex 5α-reductase and 3α/β-hydroxysteroid oxidoreductase in the generation of progesterone and testosterone neuroactive metabolites

Giatti, Silvia; Diviccaro, Silvia; Falvo, Eva; García‐Segura, Luis M.; Melcangi, Roberto Cosimo

doi:10.1016/j.yfrne.2020.100836

Cited by 26 publications

(15 citation statements)

References 348 publications

(370 reference statements)

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“…Both steroid hormones and neurosteroids, which are both found in the nervous system, are collectively referred to as neuroactive steroids and are important physiological regulators of nervous system functioning [23]. In particular, DHP controls reproductive functions, as well as glutamatergic and GABAergic neurotransmission [24], whereas isoallopregnanolone influences the lipid bilayer model system containing cholesterol [25,26]. In the brain, androgen molecules have been shown to regulate dendritic spine maturation [27,28], behaviour [29,30], neurite growth [31], neurogenesis and neuronal survival [32], apoptosis [33] and catecholamine production [34].…”

Section: Introductionmentioning

confidence: 99%

Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals

Diviccaro

Caputi

Cioffi

et al. 2021

IJMS

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Steroid hormones are essential biomolecules for human physiology as they modulate the endocrine system, nervous function and behaviour. Recent studies have shown that the gut microbiota is directly involved in the production and metabolism of steroid hormones in the periphery. However, the influence of the gut microbiota on levels of steroids acting and present in the brain (i.e., neuroactive steroids) is not fully understood. Therefore, using liquid chromatography–tandem mass spectrometry, we assessed the levels of several neuroactive steroids in various brain areas and the plasma of germ-free (GF) male mice and conventionally colonized controls. The data obtained indicate an increase in allopregnanolone levels associated with a decrease in those of 5α-androstane-3α, 17β-diol (3α-diol) in the plasma of GF mice. Moreover, an increase of dihydroprogesterone and isoallopregnanolone in the hippocampus, cerebellum, and cerebral cortex was also reported. Changes in dihydrotestosterone and 3α-diol levels were also observed in the hippocampus of GF mice. In addition, an increase in dehydroepiandrosterone was associated with a decrease in testosterone levels in the hypothalamus of GF mice. Our findings suggest that the absence of microbes affects the neuroactive steroids in the periphery and the brain, supporting the evidence of a microbiota-mediated modulation of neuroendocrine pathways involved in preserving host brain functioning.

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Section: Introductionmentioning

confidence: 99%

Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals

Diviccaro

Caputi

Cioffi

et al. 2021

IJMS

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“…Furthermore, gene expression levels for enzymes related to metabolism of DHP and ALLO also appeared to compensate for decreased levels of these steroids as a result of gonadectomy. Indeed, we here reported that the gene expression of the 5-alpha-reductase (i.e., enzyme converting PROG into DHP) [ 68 ] was upregulated in a sexually dimorphic way, depending on the isoforms considered. Gonadectomy induced an increase in the gene expression of type 1 only in females, and of type 2 only in males.…”

Section: Discussionmentioning

confidence: 99%

Gut Steroids and Microbiota: Effect of Gonadectomy and Sex

et al. 2022

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Sex steroids, derived mainly from gonads, can shape microbiota composition; however, the impact of gonadectomy and sex on steroid production in the gut (i.e., gut steroids), and its interaction with microbiota composition, needs to be clarified. In this study, steroid environment and gut steroidogenesis were analysed by liquid chromatography tandem mass spectrometry and expression analyses. Gut microbiota composition as branched- and short-chain fatty acids were determined by 16S rRNA gene sequence analysis and gas chromatography flame ionisation detection, respectively. Here, we first demonstrated that levels of pregnenolone (PREG), progesterone (PROG), and isoallopregnanolone (ISOALLO) were higher in the female rat colon, whereas the level of testosterone (T) was higher in males. Sexual dimorphism on gut steroidogenesis is also reported after gonadectomy. Sex, and more significantly, gonadectomy, affects microbiota composition. We noted that a number of taxa and inferred metabolic pathways were associated with gut steroids, such as positive associations between Blautia with T, dihydroprogesterone (DHP), and allopregnanolone (ALLO), whereas negative associations were noted between Roseburia and T, ALLO, PREG, ISOALLO, DHP, and PROG. In conclusion, this study highlights the novel sex-specific association between microbiota and gut steroids with possible relevance for the gut-brain axis.

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“…Interestingly, we recently observed that rat colon expresses steroidogenic capability and, in particular, an high production of a T metabolite, such as the 3α-diol [ 71 ]. It is important to note that this androgen metabolite, like THP, is able to interact with GABA-A receptors [ 72 ] and its levels are affected in PFS patients as well as in its experimental model [ 14 , 21 , 22 , 28 ]. This may further support the hypothesis of a role of steroids interacting with GABA-A receptors in the pathogenesis of PFS.…”

Section: Discussionmentioning

confidence: 99%

Alterations of gut microbiota composition in post-finasteride patients: a pilot study

Borgo

Macandog

Diviccaro

et al. 2020

J Endocrinol Invest

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Purpose Post-finasteride syndrome (PFS) has been reported in a subset of patients treated with finasteride (an inhibitor of the enzyme 5alpha-reductase) for androgenetic alopecia. These patients showed, despite the suspension of the treatment, a variety of persistent symptoms, like sexual dysfunction and cognitive and psychological disorders, including depression. A growing body of literature highlights the relevance of the gut microbiota-brain axis in human health and disease. For instance, alterations in gut microbiota composition have been reported in patients with major depressive disorder. Therefore, we have here analyzed the gut microbiota composition in PFS patients in comparison with a healthy cohort. Methods Fecal microbiota of 23 PFS patients was analyzed by 16S rRNA gene sequencing and compared with that reported in ten healthy male subjects. Results Sexual dysfunction, psychological and cognitive complaints, muscular problems, and physical alterations symptoms were reported in more than half of the PFS patients at the moment of sample collection. The quality sequence check revealed a low library depth for two fecal samples. Therefore, the gut microbiota analyses were conducted on 21 patients. The α-diversity was significantly lower in PFS group, showing a reduction of richness and diversity of gut microbiota structure. Moreover, when visualizing β-diversity, a clustering effect was found in the gut microbiota of a subset of PFS subjects, which was also characterized by a reduction in Faecalibacterium spp. and Ruminococcaceae UCG-005, while Alloprevotella and Odoribacter spp were increased compared to healthy control. Conclusion Gut microbiota population is altered in PFS patients, suggesting that it might represent a diagnostic marker and a possible therapeutic target for this syndrome.

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Physiopathological role of the enzymatic complex 5α-reductase and 3α/β-hydroxysteroid oxidoreductase in the generation of progesterone and testosterone neuroactive metabolites

Cited by 26 publications

References 348 publications

Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals

Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals

Gut Steroids and Microbiota: Effect of Gonadectomy and Sex

Alterations of gut microbiota composition in post-finasteride patients: a pilot study

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