Ginseng & Women's Health - Endometriosis

Long silenced and under-diagnosed, endometriosis is still a little-known pathology that has recently come to the forefront because of its high incidence among modern women. Faced with the lack of effective pharmacological solutions, women suffering from endometriosis are turning to an ever-expanding market of natural products to alleviate the heavy symptoms that accompany it.

On the other hand, research into the health properties of powerful universal remedies like ginseng continues to intensify and brings new potential applications to light, especially in the field of woman’s health.

Could it be that world-renown root of ginseng also holds the potential to relieve the symptoms of endometriosis while meeting the needs of an ever more demanding consumer in terms of naturalness, safety and efficacy ?

In the first and second article of BOTALYS’ Women’s Health series, the promising potential of ginseng to fit into the ever-growing demand for feminine health and well-being nutraceuticals was exposed. A particular emphasis on its potential for the alleviation of menopausal symptoms was highlighted with the support of a significant number of studies.

In this article, we review the key mechanisms of action of ginseng and its bioactive compounds on the symptomatology and development of endometriosis.

1. ENDOMETRIOSIS – INCIDENCE & SYMPTOMS

It is estimated that endometriosis affects 10% of women of childbearing age and between 20 and 50% of patients suffering from chronic pelvic pain and/or infertility [2].

Endometriosis is defined as a proliferation of endometrial tissue outside the uterine cavity. It generally causes significant gynaecological pain (pelvic or abdominal, often chronic), painful menstruation and sexual intercourse, and even infertility in the most severe cases. It may also be asymptomatic and go undetected / undiagnosed for years in certain cases.

Despite the chronic and incapacitating pain (from the first menstrual period), the French endometriosis association EndoFrance estimates that the average diagnosis time is 7 years, as the disease is still little known and largely under-diagnosed by health professionals. This can partially be explained by the existence of only one definitive diagnostic method, laparoscopy, an invasive test which consists in inserting a camera into the pelvic cavity to observe the presence / absence of endometriotic lesions. In addition, the intestinal problems that can accompany the disease can also lead to false diagnoses.

In this context, it seems important that the recent awareness of this problem should be followed by therapeutic solutions to alleviate the inconveniences of endometriosis in the long term.

There is, however, no definitive cure for endometriosis at the moment. The most widespread solution – apart from surgery, which is very invasive and carries a high risk of recurrence – is hormonal treatment. The aim of this treatment is to induce amenorrhea (continuous contraceptive pill) or even an artificial menopause in order to block the production of oestrogens – largely to blame for the pain and the development of endometriotic lesions. Although it can improve the quality of life of affected women, hormonal treatment only reduces the symptoms and can have serious side effects. New avenues of treatment should thus be investigated.

2. GINSENG & ENDOMETRIOSIS

Given the high incidence of endometriosis and the severe impairments it can cause to women’s quality of life and fertility, there is a growing need for non-hormonal alternatives to current drug treatments.

Ginseng has a long history of use and a significant number of health benefits supported by scientific studies. Among those benefits stand promising antitumor, antioxidant, immunomodulating and anti-inflammatory properties, all of which may positively influence the inflammatory state in the context of pathologies like endometriosis. Ginseng and its saponin compounds could therefore appear as a natural solution with great potential for inhibiting the physiopathologies linked to endometriosis and ultimately help its resolution.

2.1. Antiproliferative effects of endometriosis lesions

Several studies demonstrate that treatment with red ginseng saponin extracts – and the individual ginsenosides Rg3, PPD, PPT and Rh2 – significantly reduces the viability of human endometrial stromal cells (HESCs) from patients with endometriosis in a time- and dose-dependent manner [2-40] (i.e., saponins induce apoptosis of endometriotic cells).

Rg3 treatment also significantly reduces the proliferative (Ki67 marker) and invasive (MMP2, MMP9 markers) nature of HESCs [3-4] and induces a reduction of fibrosis markers in-vitro as well as in-vivo (CTGF, Col-1, fibronectin and TGF-β1) [3].

The mechanism of this in-vitro pro-apoptotic effect of ginseng saponins, and in particular Rg3, on endometriosis cells would be notably linked to the modulation of the expression of microRNAs involved in the pathogenesis of the disease and is accompanied by an increase in the expression of caspase 3, a programmed cell death/pro-apoptotic enzyme. Modulation of these miRNAs could therefore constitute a new approach for the treatment of endometriosis.

In vivo, supplementation with ginsenoside Rg3 in a mouse model of endometriosis has been shown to significantly inhibit the size, growth and fibrotic nature of endometriotic lesions [3, 40].

2.2. Restoration of HESC autophagy

In addition to their increased proliferative (tumor-like) capacity and low apoptotic capacity, hESCs are characterized by a low level of autophagy.

Rg3 and PPD ginsenosides have been shown to down-regulate serum oestradiol levels in rats, resulting in a significant inhibitory action on the development of endometriotic lesions [5-6]. In particular, the anti-endometriosis activity of ginsenoside PPD relies on 3 mechanisms of suppression of autophagy inhibition mediated by oestradiol [5] mediated by autophagy-related proteins (CXCL12/CXCR4, Beclin-1, LC38).

The reduction of autophagy – and thus the efficient removal of ectopic endometriosis tissue – is furthermore involved in the impairment of NK cell cytotoxicity.  PPD ginsenoside has been shown to have the potential to directly activate Natural Killer (NK) cells by treatment or indirectly in coculture with PPD-pre-treated ectopic HESCs [5]. The mechanism is thought to be based on increased activation of natural cytotoxicity receptors.

Restoration of autophagic function of HESCs by Rg3 and PPD ginsenosides therefore also presents a therapeutic pathway of interest for the treatment of endometriosis.

2.3. Anti-angiogenic effect

The growth of fibrotic tissues (ectopic HESC) in endometriosis is accompanied by the generation of blood vessels (angiogenesis) from pre-existing networks. Blocking this process would therefore slow down the development/progression of the disease and promote apoptosis of ectopic HESCs [6].

Two mechanisms could be involved in the anti-angiogenic potential of ginsenoside Rg3 in the context of endometriosis: the NF-kB signalling pathway [4] and the PI3K/Akt/mTOR signalling pathway [6].

The anti-angiogenic approach, widely used in oncology, would also have a high therapeutic potential in the treatment of endometriosis.

CONCLUSION

In conclusion, ginseng saponins – and their noble bioactive forms – demonstrate a multi-target action on various development factors of endometriosis as well as significant alleviation of its symptoms and potential risks for fertility. Ginseng and its active compounds could therefore constitute an effective, natural, and non-hormonal alternative to improve the existing Nutraceutical offer in terms of women’s health and well-being. A new applicative potential for ginseng that deserves further investigation to ensure safe and free of side effects in a clinical context.

REFERENCES

[1] Actif’s Mag n°75, Printemps 2021 (p.20-21).

[2] Park, J. H., Lee, S. K., Kim, M. K., Lee, J. H., Yun, B. H., Park, J. H., … & Choi, Y. S. (2018)“Saponin extracts induced apoptosis of endometrial cells from women with endometriosis through modulation of miR-21-5p.” Reproductive Sciences, 25(2), 292-301.

[3] Kim, M. K., Lee, S. K., Park, J. H., Lee, J. H., Yun, B. H., Park, J. H., … & Choi, Y. S. (2017)“Ginsenoside Rg3 decreases fibrotic and invasive nature of endometriosis by modulating miRNA-27b: in vitro and in vivo studies.” Scientific reports, 7(1), 1-14.

[4] Huang, R., Chen, S., Zhao, M., Li, Z., & Zhu, L. (2020)“Ginsenoside Rg3 attenuates endometriosis by inhibiting the viability of human ectopic endometrial stromal cells through the nuclear factor-kappaB signaling pathway.” Journal of gynecology obstetrics and human reproduction, 49(1), 101642.

[5] Zhang, B., Zhou, W. J., Gu, C. J., Wu, K., Yang, H. L., Mei, J., … & Li, M. Q. (2018) – “The ginsenoside PPD exerts anti-endometriosis effects by suppressing estrogen receptor-mediated inhibition of endometrial stromal cell autophagy and NK cell cytotoxicity.” Cell death & disease, 9(5), 1-13. 

[6] Cao, Y., Ye, Q., Zhuang, M., Xie, S., Zhong, R., Cui, J., … & Cao, L. (2017)“Ginsenoside Rg3 inhibits angiogenesis in a rat model of endometriosis through the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway.” PloS one12(11), e0186520.

[7] Jie, Z. O. U., Zheng, G. U. A. N., Zhang, W. Y., Wei, X. I. A. O., & Ya-Li, L. I. (2013) “Beneficial effects of the Chinese herbal medicine Sanjie Zhentong Capsule on experimental endometriosis in rats.” Chinese journal of natural medicines, 11(6), 666-672.