Echinacoside Increases Sperm Quantity in Rats by Targeting the Hypothalamic Androgen Receptor

Zhihui Jiang,Xiaoying Zhang,Xinping Li,Gordon M Kirby,Bo Zhou

doi:10.1038/s41598-018-22211-1

Zhihui Jiang, Xiaoying Zhang + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-22211-1

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Abstract

Male infertility is a major health issue with an estimated prevalence of 4.2% of male infertility worldwide. Our early work demonstrated that Cistanche extracts protect against sperm damage in mice and that echinacoside (ECH) is one of the major active components. Here we report an essential role for ECH, a natural product that reverses or protects against oligoasthenospermia in rats. ECH was assayed by HPLC, the quantity and quality of sperm was evaluated and hormone levels were determined by radioimmunosorbent assay. ECH reduced levels of androgen receptor (AR) and key steroidogenic-related genes as determined by Western blot and qPCR analysis. The interaction between ECH and AR were evaluated by indirect ELISA and molecular docking. The results show that ECH combined with hypothalamic AR in the pocket of Met-894 and Val-713 to inhibit transfer of AR from the cytoplasm to nuclei in the hypothalamus. While negative feedback of sex hormone regulation was inhibited, positive feedback was stimulated to increase the secretion of luteinizing hormone and testosterone subsequently enhancing the quantity of sperm. Taken together, these data demonstrate that ECH blocks AR activity in the hypothalamus to increase the quantity of sperm and protect against oligoasthenospermia in rats.

Highlights

The effect of testosterone on the HPG axis feedback loop occurs by binding to the androgen receptor (AR), found in both the hypothalamus and the pituitary gland[5]
We demonstrated that ECH was distributed to the hypothalamus instead of the testes suggesting an indirect effect of ECH on the testes
In studies of human gonadotrophin production, sex hormone levels are tightly regulated by the HPG-axis and a negative feedback loop[21]

Summary

Introduction

The effect of testosterone on the HPG axis feedback loop occurs by binding to the androgen receptor (AR), found in both the hypothalamus and the pituitary gland[5]. The classical genomic mechanism of testosterone signaling occurs when testosterone diffuses into the cell and binds to the AR. This ligand-receptor complex translocates to the nucleus where it binds to androgen response elements (AREs) in the regulatory regions of testosterone-responsive genes to modify their translocation. Cistanche extracts and ECH have been traditionally used as a tonic agent to cure reproductive dysfunction and to boost male sexual activity in traditional Chinese medicine[10]. We investigate the effects of ECH on the sperm quality and hormone levels. BPA was chosen as a sperm injury model agent to further study the protective effect of ECH against poor sperm quality

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