Consequences of steroid-5α-reductase deficiency and inhibition in vertebrates

Abstract

In 1974, a lack of 5α-dihydrotestosterone (5α-DHT), the most potent androgen across species except for fish, was shown to be the origin of a type of pseudohermaphrodism in which boys have female-like external genitalia. This human intersex condition is linked to a mutation in the steroid-5α-reductase type 2 (SRD5α2) gene, which usually produces an important enzyme capable of reducing the Δ4-ene of steroid C-19 and C-21 into a 5α-stereoisomer. Seeing the potential of SRD5α2 as a target for androgen synthesis, pharmaceutical companies developed 5α-reductase inhibitors (5ARIs), such as finasteride (FIN) and dutasteride (DUT) to target SRD5α2 in benign prostatic hyperplasia and androgenic alopecia. In addition to human treatment, the development of 5ARIs also enabled further research of SRD5α functions. Therefore, this review details the morphological, physiological, and molecular effects of the lack of SRD5α activity induced by both SRD5α mutations and inhibitor exposures across species. More specifically, data highlights 1) the role of 5α-DHT in the development of male secondary sexual organs in vertebrates and sex determination in non-mammalian vertebrates, 2) the role of SRD5α1 in the synthesis of the neurosteroid allopregnanolone (ALLO) and 5α-androstane-3α,17β-diol (3α-diol), which are involved in anxiety and sexual behavior, respectively, and 3) the role of SRD5α3 in N-glycosylation. This review also features the lesser known functions of SRD5αs in steroid degradation in the uterus during pregnancy and glucocorticoid clearance in the liver. Additionally, the review describes the regulation of SRD5αs by the receptors of androgens, progesterone, estrogen, and thyroid hormones, as well as their differential DNA methylation. Factors known to be involved in their differential methylation are age, inflammation, and mental stimulation. Overall, this review helps shed light on the various essential functions of SRD5αs across species.

https://www.ncbi.nlm.nih.gov/pubmed/31981690

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Outline

Highlights

Abstract

Keywords

  1. Introduction

  2. History of 5α-reductase inhibitors (5ARIs)

  3. Consequences of a lack of 5α-DHT

3.1. Impacts on male secondary sexual organs
3.1.1. Atrophy of androgen-dependent organs
3.1.2. Developmental defects
3.1.3. Disruption of erectile function
3.1.4. Effects on spermatogenesis and the structure of seminiferous tubules
3.1.5. Effects on sperm maturation and fertilization
3.1.6. Effects on sex determination in non-mammalian vertebrates
3.1.7. Impaired bone development and retention
3.1.8. Effects on the abundance and distribution of body and scalp hair

3.2. Impacts on female reproductive system
3.2.1. Effects in the uterus during gestation
3.2.2. Androgenic and estrogenic effects in female fish

3.3. Brain development and behaviour: role of ALLO
3.3.1. ALLO decreases anxiety-related behaviour
3.3.2. Anticonvulsant effect of ALLO
3.3.3. Neuroprotection of fetal brain during late gestation

3.4. Aggressiveness in males: role of 5α-androstane-3α,17β-diol (3α-diol)

3.5. Effects on weight, steatosis, and insulin resistance

3.6. Role of SRD5α3 in N-Glycosylation

  1. Genomic and non-genomic pathways are involved in the regulation of SRD5α expression

4.1. Androgens drive tissue-specific regulation of SRD5αs

4.2. Progesterone and estrogen regulate SRD5αs in females

4.3. Cholesterol upregulates SRD5α2 levels

4.4. Thyroid hormones and androgens crosstalk

4.5. Age- and tissue-specific methylation patters of SRD5α promoter

  1. Conclusion

Acknowledgements

References

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Transcriptomic profiling in Silurana tropicalis testes exposed to finasteride

Abstract

Investigations of endocrine disrupting chemicals found in aquatic ecosystems with estrogenic and androgenic modes of action have increased over the past two decades due to a surge of evidence of adverse effects in wildlife. Chemicals that disrupt androgen signalling and steroidogenesis can result in an imbalanced conversion of testosterone (T) into 17β-estradiol (E2) and other androgens such as 5α-dihydrotestosterone (5α-DHT). Therefore, a better understanding of how chemicals perturb these pathways is warranted. In this study, the brain, liver, and testes of Silurana tropicalis were exposed ex vivo to the human drug finasteride, a potent steroid 5α-reductase inhibitor and a model compound to study the inhibition of the conversion of T into 5α-DHT. These experiments were conducted (1) to determine organ specific changes in sex steroid production after treatment, and (2) to elucidate the transcriptomic response to finasteride in testicular tissue. Enzyme-linked immunosorbent assays were used to measure hormone levels in media following finasteride incubation for 6 h. Finasteride significantly increased T levels in the media of liver and testis tissue, but did not induce any changes in E2 and 5α-DHT production. Gene expression analysis was performed in frog testes and data revealed that finasteride treatment significantly altered 1,434 gene probes. Gene networks associated with male reproduction such as meiosis, hormone biosynthesis, sperm entry, gonadotropin releasing hormone were affected by finasteride exposure as well as other pathways such as oxysterol synthesis, apoptosis, and epigenetic regulation. For example, this study suggests that the mode of action by which finasteride induces cellular damage in testicular tissue as reported by others, is via oxidative stress in testes. This data also suggests that 5-reductase inhibition disrupts the expression of genes related to reproduction. It is proposed that androgen-disrupting chemicals may mediate their action via 5-reductases and that the effects of environmental pollutants are not limited to the androgen receptor signalling.

https://www.ncbi.nlm.nih.gov/pubmed/24530632

Full Text on Sci-Hub:
https://sci-hub.tw/10.1016/j.ygcen.2014.01.018

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Steroid 5-reductases are functional during early frog development and are regulated via DNA methylation.

Highlights

Steroid 5-reductases are functional during early anuran development.

Gene regulation of srd5 is based on a positive feedback loop mechanism.

DNA methylation may be involved in regulating srd5α1 and srd5α3.

Steroid metabolites have crucial roles in multiple tissues during early development.

srd5α1 , srd5α2 , srd5α3 , and srd5β show unique expression pattern during embryogenesis.

Abstract

In adulthood, steroid 5-reductases (Srd5) are known to synthesize androgens from testosterone and to play important physiological roles, in particular during reproduction. However, less is known about their regulation and function during early development. To deepen the understanding on Srd5 in amphibian species, we investigated the mechanistic regulation of four important genes ( srd5α1 , srd5α2 , srd5α3 , and srd5β ) via 1) chemical enzymatic inhibition and 2) specific DNA methylation imprinting. Indeed, this is the first study to suggest that Srd5 are functional during the critical early developmental period of vertebrates. Moreover, exposure to Srd5 inhibitors showed that the regulation of srd5 in early development are self-regulated, with decreasing mRNA levels after exposure, consistent to the regulation mechanism in juvenile frog liver. Furthermore, data highlighted a potential novel mechanism of regulation for srd5α1 and srd5α3 , i.e. , through DNA methylation. This opens up important questions regarding the role of a transgenerational effect in the regulation of these crucial genes through maternal transfer. This study also profiled the expression of srd5 throughout early development for the first time in any vertebrate and suggested that steroid metabolites produced by Srd5 have crucial roles in development of the central nervous, sensory, cardiac, respiratory, and detoxifying systems aside from reproduction in early anuran development.

Full Text

Note: The author of papers in this thread, Valerie S. Langlois, specializes in 5a-reductases and their epigenetic regulation. She might be a good person to contact regarding potential future studies.

Valerie S. Langlois
Corresponding author at: Chemistry and Chemical Engineering Department, Royal Military College of Canada, P.O. Box 17 000, Stn Forces, Kingston, ON K7K 7B4, Canada.

valerie.langlois@rmc.ca

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