Clinical Research

Obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland

Abstract

Background and objective

Our patient cohort revealed that obesity is strongly associated with steroid-5α reductase type 2 (SRD5A2) promoter methylation and reduced protein expression. The underlying mechanism of prostatic growth in this population is poorly understood. Here we addressed the question of how obesity, inflammation, and steroid hormones affect the development of benign prostatic hyperplasia (BPH).

Material and methods

We used preadipocytes, macrophages, primary human prostatic stromal cells, prostate tissues from high-fat diet-induced obese mice, and 35 prostate specimens that were collected from patients who underwent transurethral resection of the prostate (TURP). RNA was isolated and quantified with RT-PCR. Genome DNA was extracted and SRD5A2 promoter methylation was determined. Sex hormones were determined by high-performance liquid chromatography–tandem mass spectrometry. Protein was extracted and determined by ELISA test.

Results

In prostatic tissues with obesity, the levels of inflammatory mediators were elevated. SRD5A2 promoter methylation was promoted, but SRD5A2 expression was inhibited. Inflammatory mediators and saturated fatty acid synergistically regulated aromatase activity. Obesity promoted an androgenic to estrogenic switch in the prostate.

Conclusions

Our findings suggest that obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland, which may serve as an effective strategy for alternative therapies for management of lower urinary tract symptoms associated with BPH in select individuals.

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Fig. 1: Increased level of inflammatory mediators in prostatic tissues with obesity.
Fig. 2: SRD5A2 promoter methylation and expression are regulated by inflammatory mediators in human prostatic stromal cells.
Fig. 3: TNF-α and myristic acid synergistically regulate aromatase activity in prostatic stromal cells.
Fig. 4: Prostatic estrogen receptor-α (ESR1) and estradiol are elevated with adipocyte and inflammatory mediator exposure.
Fig. 5: Alteration of androgen and estrogen levels in prostate tissue of obese vs. lean BPH patients upon treatment with 5-α reductase inhibitors (5ARIs).

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Acknowledgements

AFO gratefully acknowledges financial support from NIH/NIDDK (NIH/R01 DK091353). ZW was supported by the Urology Care Foundation/American Urological Association Research Scholar Award. We gratefully thank Dr Li Xin at University of Washington for supplying prostate tissues of mice fed with HFD or RFD.

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Correspondence to Zongwei Wang.

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Xue, B., Wu, S., Sharkey, C. et al. Obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland. Prostate Cancer Prostatic Dis (2020). https://doi.org/10.1038/s41391-020-0208-4

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