Double-edged sword of gonadotropin-releasing hormone (GnRH): A novel role of GnRH in the multiple beneficial functions of endometrial stem cells

Se-Ra Park,In-Sun Hong,Chan Hum Park,Hwa-Yong Lee,Mirim Jin,Sung Taek Park,Ara Cho,Soyi Lim

doi:10.1038/s41419-018-0892-3

Abstract

Gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of gonadotropins, which induce estrogen production and subsequent ovulation. Therefore, long-term GnRH exposure to regulate ovarian hyperstimulation is recognized as the gold standard for most in vitro fertilization (IVF) strategies. However, one of the most disappointing aspects of current IVF technology is relatively low rate (between 35 and 50%) of positive pregnancy outcomes, and the major reason for this high cancellation rate has not yet been revealed. Previous studies have demonstrated that resident stem cell deficiency limits the cyclic regenerative capacity of the endometrium and subsequently increases pregnancy failure rates. Therefore, we hypothesized that long-term GnRH exposure directly damages endometrial stem cells and consequently negatively affects pregnancy outcomes in GnRH-based IVF. In addition to their well-known roles in regulating the hypothalamus-pituitary-gonadal axis, GnRH and its receptors also localize in the extra-hypothalamic endometrium, suggesting a possible non-canonical role in endometrial stem cells. Consistent with our hypothesis, we show for the first time that GnRH suppresses the multiple beneficial functions of endometrial stem cells via the PI3K/Akt signaling pathway in vitro and in vivo. To the best of our knowledge, this is the first study to focus on the direct effects of GnRH on the regenerative potential of stem cells, and the findings will facilitate the development of more promising IVF strategies.

Highlights

Gonadotropin-releasing hormone (GnRH) is the central neuroendocrine regulator of reproductive function in vertebrates[1,2]
Consistent with our hypothesis, we show for the first time that the GnRH receptor (GnRH-R) is more highly expressed in endometrial stem cells than in terminally differentiated fibroblasts and that GnRH acts as a potent inhibitory factor for multiple endometrial stem cell functions, such as proliferation differentiation, and migration in vitro and in vivo
As GnRH might play a role as an exogenous factor that damages the endometrium, we investigated whether GnRH inhibits the various beneficial functions of endometrial stem cells in vitro

Summary

Introduction

GnRH is the central neuroendocrine regulator of reproductive function in vertebrates[1,2]. This decapeptide is secreted by neurons within the hypothalamus and delivered to the anterior pituitary. The physiological features or responses of endometrial cells to exogenous stimuli vary depending on the phase of menstrual cycle as well as the status of menopause. Like many other human tissues, resident stem cells are responsible for this cyclic regeneration of endometrial function and tissue repair[11,12]. Recent work revealed that stem cell deficiency limits the cyclic regenerative capacity of the endometrium and subsequently increases pregnancy failure rates[13]

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Results

Conclusion