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Chinese Journal of Natural Medicines 2020, 18(7): 526-535 doi: 10.1016/S1875-5364(20)30063-7

•Review•

Advances on hormone-like activity of Panax ginseng and ginsenosides

TIAN Mei, LI Lin-Nan, ZHENG Rui-Rong, YANG Li, WANG Zheng-Tao*

The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China Available online 20 Jul., 2020

[ABSTRACT] Traditional Chinese medicine (TCM) has been paid much attentions due to the prevention and treatment of steroid hor- mone disorders. Ginseng, the root of Panax ginseng C. A. Meyer (Araliaceae), is one of the most valuable herbs in complementary and alternative medicines around the world. A series of dammarane triterpenoid saponins, also known as phytosteroids, were reported as the primary ingredients of Ginseng, and indicated broad spectral pharmacological actions, including anti-cancer, anti-inflammation and anti-fatigue. The skeletons of the dammarane triterpenoid aglycone are structurally similar to the steroid hormones. Both in vitro and in vivo studies showed that Ginseng and its active ingredients have beneficial hormone-like role in hormonal disorders. This review thus summarizes the structural similarities between hormones and dammarane ginsenosides and integrates the analogous effect of Ginseng and ginsenosides on prevention and treatment of hormonal disorders published in recent twenty years (1998–2018). The review may provide convenience for anticipate structure-function relationship between saponins structure and hormone-like effect. [KEY WORDS] Panax ginseng; steroid hormones; triterpenoid saponins; hormone-like activity; molecular signaling [CLC Number] R965 [Document code] A [Article ID] 2095-6975(2020)07-0526-10

Introduction verse effects, a large number of researchers are concentrating on using available and alternative traditional Chinese medi- Steroid hormones play an indispensable role in regulat- cine (TCM). Especially, plant-derived natural products which ing physical and emotional growth, sex differentiation, repro- are similar to synthetic hormones are applied to prevent endo- duction, immune functions, protein synthesis and metabo- [9-13] crine disorder and treat disease . [1] lism . Generally, the steroid hormones can be grouped into Panax ginseng C. A. Meyer, is a perennial plant belongs four main classes by their structural characteristics: progesto- to the genus Panax of Araliaceae family. It is widely used for [2] gens, corticosteroids, androgens and estrogens (Fig. 1A) . curing miscellaneous diseases all over the world. As early as The clinical practice showed that the imbalance of hormone 4000 years ago, P. ginseng was acquainted as “The king of level would directly or indirectly lead to the occurrence of the grass bouquet” by means of nourishing weakness, replen- [3, 4] many physiological and psychological diseases . With the ishing energy, supporting body balance and consolidating ro- increasing environmental pollution and social pressure, the bustness [14, 15]. Nowadays, there are plenty of herbal prepara- disorder of endocrine system is becoming more complicated tions including tablets, capsules, granules that containing gin- [5, 6] and serious . Many diseases caused by hormone imbal- senosides [16, 17]. Triterpenoid saponins are the principal com- ance were treated with synthetic hormones, nevertheless, pro- ponents in Panax species, which refer to a range of dam- longed intake of these artificial drugs might lead to severe ad- marane- or oleanane-type triterpenoid ginsenosides [18-21]. verse effects [7, 8]. Therefore, due to lower cost and minor ad- Ginsenoside Ro belongs to oleanane-type (OA) saponins which has a five-link trans ring [22]. Dammarane-type ginsen- [Received on] 20-Dec.-2019 osides share a four-ring hydrophobic steroid-like structure [Research funding] This work was supported by the National Natur- skeleton, and can be divided into two functional groups based al Science Foundation of China (Nos. 81530096, 81920108033, on their preferred glycosylation sites at C6 position: proto- 81573581) and the Shanghai Sailing Program (No. 19YF 1448800). * panaxadiol (PPD), such as ginsenoside Rb1, Rg3; protopan- [ Corresponding author] Tel: 021-51322507, E-mail: ztwang@shu- [18, 23] tcm.edu.cn axatriol (PPT) such as ginsenoside Rg1, Rh1 (Fig. 2) .

These authors have no conflict of interest to declare. Triterpenoid saponins are considered to be the main pharma-

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A O O OH O O SCC 3β-HSD1/2 CYP21/CYP11β2 HO H H H H H HH H H H H H HO HO O Cholesterol Pregnenolone Progesterone O Aldosterone

OH OH CYP19 H H

H H H H HO O Testosterone Estradiol

B 21 HO 20 22 OH 24 20 17 23 25 27 17 2324 11 25 26 6 3 HO 3 OH Steroid scaffold Dammarane ginsenoside skeleton Fig. 1 (A) The main steroidal structure of the four categories of hormones from cholesterol. The steroid hormones are divided into the progestogens, corticosteroids, androgens and estrogens are shown in purple, green, blue and red respectively. (B) Car- bon numbering of a typical steroid scaffold and common functionalized positions (C3, 11, 17, 20, and 21); Carbon numbering of dammarane ginsenoside skeleton, the common functionalized positions at C17, 23, 24 and 25, the typical glycosylation group sites at C3, 6, 20 for these aglycone are labeled in green

R2 OH 20

R2 28

3 6 R1

R1 3 R3

Dammarane ginsenosides Oleanane ginsenosides

Fig. 2 Classification and chemical structure of dammarane ginsenosides and oleanane ginsenosides. PPD, Protopanaxadiol; PPT, Protopanaxatriol; Glc, β-D-glucopyranosyl; GlcA, β-D-glucuropyronosyl; OA, Oleanane acid

cological bioactive ingredients. They can boost immunity idant, cardiovascular system protection, anti-inflammatory, from diseases and enhance physical functions, such as antiox- and anti-tumor [24-28]. More to the point, the study also showed

– 527 – TIAN Mei, et al. / Chin J Nat Med, 2020, 18(7): 526-535 that ginsenosides act as an estrogen analogue by activating C17, 23, 24 and 25), and glycosyl (Glc, Ara, etc.) group at estrogen receptor (ER) [29, 30]. C3, 6, 20 (Fig. 1B) [46]. In terms of the molecular structure, In the last decades, in vitro and in vivo results have re- ginsenosides is analogous to steroid hormones, and it would vealed that P. ginseng and its active compounds are equipped provide a solid structural basis for the hormone-like effect of with hormone analogous effects. Many studies have demon- dammarane ginsenosides. strated that dammarane ginsenosides possess greater poten- Hormone-like Activity of P. ginseng and Ginsen- tial in hormone-like effects [31, 32]. Therefore, to gather all of osides the literature relevant to hormone-like activities of P. gin- seng and ginsenosides is of great importance. The objective In vitro study on the hormone-like activity of Ginseng and of this review is to provide valuable research results on the ginsenosides roles and mechanisms of the hormone-like activities of P. A few studies have demonstrated that the hormone-like ginseng and ginsenosides between 1998 and 2018 from the effects of P. ginseng and ginsenosides in hormone-associated Web of Science, ScienceDirect and GeenMedical databases. cells. In oestrogen receptor-positive cells, such as human And it may provide insight into opportunity for anticipating breast cancer MCF-7 cells, often used as the preferred cell structure-function relationship of saponins in the activity of line for estrogen assay, exhibited cells proliferation distinctly hormone-like. after treatment with P. ginseng water extract and ginsenoside Rg1 [47]. In glucocorticoid receptor-related cells, like murine Structure of Endogenous Steroid Hormones and macrophagic RAW264.7 cells, ginsenoside Rg1 could en- Dammarane Ginsenosides hance the effect of anti-inflammatory by up-regulating gluco- The structure characterization of endocrine steroid hor- corticoid receptor (GR) expression [48]. These may indicate mones and triterpenoid saponins lead to a better understand- that P. ginseng and ginsenosides regulate the production, con- ing of their semblable biological activities [33]. Eighteen ster- version and metabolism of hormones in different organs and oid hormones are derived from cleavage of the cholesterol cells. side chain by cytochrome P450 cholesterol side-chain cleav- In vivo study on the hormone-like activity of ginseng and gin- age enzyme (SCC) [34, 35]. Cholesterol is converted into pro- senosides gestogens in mammals by SCC, corticosteroids and andro- Except extracorporeal exploration, internal experiments gens are bioconverted from progestogens by enzyme CYP21 also verified the analogous steroid hormone effects of P. gin- and CYP17, respectively. And then enzyme CYP19 turns the seng and ginsenosides in many explorations. In vivo studies, androgen into estrogen (Fig. 1A) [36, 37]. These enzymes play a surgical removal of sexual organs, drinks or drug-induced crucial role in transformation of one hormone into another in hormonal disorders and ageing rats were commonly used as line with indicating arrow [38, 39]. experiment model systems. In a general way, castrated rats or Visually from the structure of ginsenosides and hor- ovariectomized (OVX) rats have been adopted for simulating mones: 1) all steroids share the same basic 17 carbon back- model of testosterone deficiency or estrogen decline in con- bone which are known as the cyclopentanophenanthrene ring. siderable literatures [49, 50]. Chronic alcohol consumption may Three six-carbon cyclohexane rings are designated A, B, and bring about the problem of nervous system and male infertil- C rings and the five-carbon cyclopentane ring is denoted as ity [51]. Cyclosporine A (CsA), which has been reported that the D ring. All of the A ring are lipid rings, except for oestro- the concentration in serum were negatively correlated with gens——the C18 steroids estranges, which A ring is aromat- vitality and motility of sperm [52]. Hence, Pan et al. [53] have ic [40]. The other three main groups of steroids of interest in adopted mice model of cyclosporine-induced damage of sper- clinical endocrinology consist of 21, 19 or 21 carbon atoms, matogenic apoptosis and testosterone synthesis to investigate representing the progestogen, androgen and corticosteroid the potential protective effects of decoction, which contain- skeleton [41, 42]. Similarly, the parent ring of PPD and PPT ing P. ginseng. In addition, using ageing-induced testoster- type ginsenosides have a steroid-like four-link trans ring, and one deficiency or estrogen decline rat model in a natural state the C17 side chains of ginsenosides are similar in structure to is also a good alternative method to perform an exploration, cholesterol [43, 44]. 2) In addition, most of steroids have angu- which could limit the risk of damage to experimental animals lar methyl group in C10 or C13. Similarly, the structure of a and in line with the provisions of the experimental animal saponin comprises a sapogenin moiety and one or two glyc- protection laws [54, 55]. osyl units and/or chains, and the sapogenin has the same an- This is the fact that accumulating evidence have demon- gular methyl group in C10 or C13 as the parent nucleus of the strated P. ginseng or its saponins have a potent steroid hor- hormone. 3) Generally, steroid has shown to possess at least monal activity by evaluating physiological change compared one hydroxy (−OH) or ketone (=O) or methyl (-CH3) group at with placebo control. The regain of estrus cycle, improve- various carbon positions (typically C3, 11, 17, 20, and 21) of ment of target tissue function, reversal of the atrophy of the their scaffold [45]. Besides, there also have structures of gin- vagina and uterus could be regarded as the effective reflec- seng saponins whose genin has a hydroxyl (−OH) or methyl tions of P. ginseng and ginsenosides estrogen-like activity in

(−CH3) group or double bond at some carbon sites (generally OVX rats. Moreover, the balance of steroid hormone levels in

– 528 – TIAN Mei, et al. / Chin J Nat Med, 2020, 18(7): 526-535 serum or plasma is also the expression of effectiveness of dative stress kinase are also common index in functional or- ginsenosides, which were detected by radioimmunoassay gans [64-66]. According to the enzyme-immunoassay (EIA), (RIA) kit or ultra-performance liquid chromatography hy- ginsenoside Rg1 could protect tissue and cell from oxidative phenated with mass spectrometry (UPLC-MS/MS) after treat- stress damage by increasing the activities of superoxide dis- ments [56-58]. In the testosterone decline male rat model, the mutase (SOD) and catalase (CAT) and decreasing the level of number and vitality of fully mature sperm cells at the center malondialdehyde (MDA) [67, 68]. Additionally, observing of the tubules was limited; the number of cells lining the tu- change of rat sex organs weight, like epididymis, testis and bular membrane was decreased; and the tissue around the tu- seminal vesicles, were often considered as a simple and wide- bule was degraded, these symptoms all indicated that cells spread assessment [51, 69]. Table 1 displays the hormone-like was late maturation arrest or premature death in reproduc- activity of Ginseng and ginsenosides in detail. tive organ [59, 60]. Hence, the improvement of symptoms can Mechanism research on the hormone-like activity of Ginseng be analyzed to evaluate the androgen-like effect of P. gin- and ginsenosides seng and ginsenosides [61-63]. The level and activity of oxi- Many studies have shown that the molecular target path-

Table 1 Preclinical studies of Ginseng and ginsenosides for hormone-like activities compared with placebo control

Active substance Experimental Treatment Steroidal Dose (mg·kg−1) Treatment activities Ref. material model duration (weeks) activity P. ginseng water Nile tilapia Improved: testes and spleen somatic indexes; Oral, 400 12 Androgen [69] extract fingerlings plasma T level Korean red Ageing -induced Improved: body and testis weights; serum T ginseng water testicular Oral, 200 24 Androgen level; cell numbers; the process of [54] extract dysfunction rat spermatogenesis Korean red Improved: apoptosis of prostate epithelial T-inducedprostate ginseng water IP, 100 or 200 4 Androgen cells.Decreased: epithelial layer thickness; [117] hyperplasia rat extract prostate cells proliferation Improved: estrous stage; uterine weight index; P. ginseng water OVX rat Oral, 6000 8 Estrogen serum E2 level.Decreased: body weight; serum [50] extract LH level P. ginseng water Immature and Improved: serum E2 level; uterus and vagina Oral, 24000 4 Estrogen [118] extract OVX mice weights.Decreased: LH and FSH level P. ginseng water MCF-7 cells 0.1–100 μg·mL−1 - Estrogen Improved: cells Proliferation [118] extract Ginsenoside Rc Human sperm 1 and 10 μg·mL−1 - Androgen Improved: sperm motility; sperm progression [119] Improved: 5-HT concentration; HTP Ginsenoside Rb1 OVX mice IP, 10 1 Estrogen [120] accumulations.Decreased: MAO activity Improved: apoptosis of ectopic endometrial Allotransplantatio Ginsenoside Rg3 Oral, 10 4 Estrogen cells.Decreased: serum E2 level; volume and [120] n- induced EM rat height of ectopic endometrial lesions Improved: epididymis, testis and seminal vesicles weights; the count, viability, and Ethanol-induced Ginsenoside Rg1 Oral, 20 and 40 4 Androgen motility of testicular sperm; serum T level; [51] infertility rat SOD and CAT activities.Decreased: MDA levels Gonadectomized Improved: sleep disruption; AR protein rat level.Decreased: serum CORT level Androgen; Ginsenoside Rg1 Chronic Oral, 20 4 [122] corticosteroid Improved: serum T level; GR protein unpredictable level.Decreased: serum CORT level stress rat ALD-induced Improved: T-SOD activity. Decreased: Ginsenoside Rg1 MPC5 mouse 0.08 μg·mL−1 - Corticosteroid oxidative stress; autophagy; MDA level; ROS [123] podocyte cells production Protopanaxatriol ACTH-stimulated Decreased: corticosteroid generation; the saponins and bovine adrenal 9.53 μg·mL−1 - Corticosteroid [113] conversion from cholesterol to pregnenolone metabolites fasciculata cells T, testosterone; IP, Intraperitoneal; E2, estradiol; LH, luteinizing hormone; LHR, luteinizing hormone receptor; FSH, follicle-stimulating hormone; CORT, corticosterone; HPA axis, The hypothalamic-pituitary-adrenal axis; HPG axis, The hypothalamus- pituitary-gonadal axis; VEGF, Vascular endothelial growth factor; 5-HT, 5-hydroxytryptamine; HTP, tryptophan hydroxylase; MAO, monoamine oxidase; EM, endometriosis; ALD, Aldosterone; ROS, reactive oxygen species

– 529 – TIAN Mei, et al. / Chin J Nat Med, 2020, 18(7): 526-535 way of P. ginseng and ginsenosides effect on steroid hor- proving the activities of related hormone enzymes [51, 84-86]. mones by binding or activating intracellular nuclear, cytosol Simultaneously, minor ginsenosides has been shown to re- or cell membrane hormone receptors, such as ER, androgen lieve a high does synthetic hormones-induced sexual dys- receptor (AR), GR, either directly or indirectly, and sub- function in rats through classical signaling pathways [87]. sequently regulating the associated hormone levels [70-74]. Female steroid hormones consist of estrogens secreted Saponins regulate intracellular hormone balance by non-ge- from the ovaries in the body. The cellular response to estro- netic pathways of intracellular signaling molecules [75, 76]. On gen is mediated by the ERα and ERβ isoforms, estrogen re- the other hand, ginsenosides also could active the expression ceptors α and β were differentially exhibited and expressed in of related invertases like endogenous antioxidant enzymes by different tissue distribution patterns. ERβ is mainly ex- regulating intracellular target proteins or genes [77-80]. In many pressed in the ovaries, whereas, ERα is voiced in many or- cases, ginsenosides can cross-talk with multiple signaling gans, like breast, kidney, bone, uterus, ovaries (where ERα pathway at the same time, from enzyme level, protein level to upregulation was stronger than that of ERβ) [67, 88-90]. There is gene level, which directly or indirectly play an important role evidence that ginsenosides Rg1 exert estrogen-like effect via in preventing and treating diseases caused by hormone dis- the activation of ERα, whereas ginsenoside Rb1 have the orders [81]. ability to active ERα and ERβ [81, 91-93]. Ginsenosides not only Androgens play their biological roles predominately in have sex hormone-like activity, but also bind GR to produce binding to the AR whether directly or indirectly [82, 83]. By corticosteroid-like effects. Ginsenosides has been observed to binding to receptors, P. ginseng and ginsenosides have abil- promote the upregulation of cytoplasmic and nuclear GR pro- ity to deeply regulate genes level of hormone metabolism in tein level in the rat liver and lipopolysaccharide (LPS)-stimu- the nucleus [80]. And on the membranes of mitochondria, P. lated RAW264.7 macrophage cells [94]. Table 2 displays the ginseng and ginsenosides play an advantageous role in im- possible pathway of the regulation mechanisms of action of

Table 2 Pathway of the regulation mechanisms of hormone-like effect of Ginseng and ginsenosides Signaling molecules Active substance material Observations Steroidal activity Experimental model Ref. monitored Korean red ginseng Steroids metabolism Androgen; Estrogen Aged male rat testes CYP11a1 [80] water extract improvement and Corticosteroid Korean red ginseng AR transcription suppression Androgen LNCaP cells Kallikrein-3 Mrna, AR [117] water extract Korean red ginseng Spermatogenesis Androgen Aged male rat Inhibin-α, nectin-2, CREB-1 [124] water extract Ginsenoside Ro 5α-reductase inhibitory Androgen Androgenetic alopecia rat 5α reductase [125] Hydrocortisone-induced Ginsenosides Rh4 and Rg5 Endothelial NO production Androgen NO/cGMP/PKGI [87] male mice 20(S)-protopanaxadiol AR protein level diminution Androgen C4-2 xenograft tumors AR [126]

P. ginseng water extract Estrogen-like activity Estrogen OVX mice ERα, ERβ [118] P. ginseng water extract Estrogen-like activity Estrogen Female immature mice ERα, ERβ [127] Ginsenoside Rb1 Estrogen-like activity Estrogen MCF-7 cells ER [128] Endometriosis-associated Allotransplantation- induced Ginsenoside Rg3 Estrogen PI3K-Akt-mTOR [121] angiogenesis rat Ginsenoside Rh1 Estrogen-like activity Estrogen MCF-7 cells ER [129] Ginsenoside Rg1 Estrogen-like activity Estrogen MCF-7 cells ERE-luciferase [47] Ginsenoside Rg1 Estrogen-like activity Estrogen MCF-7 cells pS2 gene expression, ERα [81] Ginsenosides Glucocorticoid-like activity Corticosteroid Hydrocortisone-induced rat GR, TAT, mRNA [94] GR translocation Ginsenoside Rg6 Corticosteroid Human cancer cells GR [130] suppression GR transcription Ginsenoside Rh1 Corticosteroid CIA mice NF-Κb, DUSP1 [131] improvement Ginsenoside Rg1 Glucocorticoid-like activity Corticosteroid RAW 264.7 cells eNOS, TNF-α, GR [48] Human umbilical vein Ginsenoside Rg1 GR activation Corticosteroid GR [132] endothelial cells PI3K/Akt/mTOR, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin; ERE, estrogen response element; CIA, collagen-induced arthritis; NF-κB, nuclear factor kappa B; DUSP1, dual specificity protein phosphatase 1; eNOS, endothelial nitric oxide synthase; NO, Nitric oxide

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P. ginseng and ginsenosides. The summarized pathway of the metabolism of ginsenosides revealed that ginsenosides were regulation mechanisms of representative ginsenosides effect transformed via multiple pathways including deglycosylation, on the steroid hormones are shown in Fig. 3. dehydration, oxygenation and hydration both in vitro and in vivo, these transformed ginsenosides further contribute to the Conclusion and Future Perspectives chemical diversity of minor ginsenosides [99]. For example, TCM have attracted considerable concern from the pub- under the conditions of artificial gastric juice, the deglyc- lic, medical community, and governmental agencies, the osylated and dehydrated ginsenosides possessed slightly in- search for lower side effects with a similar endogenous hor- creased than primary ginsenosides [100]. And in vivo studies, mones effect of steroidal constituents like phytohormones in- there have reported that the gut microbiota moieties could de- stead of synthetic hormones has been in full swing [95-97]. In grade ginsenosides via cleavage of the sugar [101-104]. The de- this review, from the perspective of structure-activity rela- graded minor ginsenosides have been proven to traverse tionship, dammarane ginsenosides possess cholesterol-like membrane more efficient than the intact ginsenosides, and four connected trans-ring steroid skeleton with various free or further yield higher bioavailability in cells [104, 105]. Therefore, sugar-bound hydroxyl groups. Meanwhile, there are similarit- lower polar ginsenosides might have great potential to be ab- ies between ligand of saponins and hormones, all the more so sorbed into circulation system [106-109]. For instance, ginsenos- the degraded minor ginsenosides, such as ginsenoside Rg5, ide Rg3, Rg5, Rh1 has been demonstrated to exhibit remark- 25-OH-PPD [98]. Internal studies have manifested that the gin- able anticancer and antioxidant pharmacological activities seng water extract, or individual ginsenosides have activity of than polar ginsenosides [110-112]. Thus, we would be correct to analogous endogenous hormone in mammals. Different from assume that the rare minor ginsenosides may play a more ef- fresh P. ginseng, the main ingredients of Korean Red gin- fective role in keeping regular of hormonal level after treat- seng are the minor ginsenosides. And according to the results, ment with P. ginseng saponins. the minor ginsenosides may have stronger activities than the Current studies speculate that sugar linkage at C-6 was native ginsenosides [87]. Further, ginsenosides could bind and more active than linkage at C-3, total number of sugar mo- activate nuclear hormone receptors to maintain a healthy lecules within a ginsenoside indicated the negative correla- level of physiology in target tissues or cells. In addition, the tion with steroid hormones effect, elimination of glycosyl moderating effect of dammarane saponins on the expression bonds may be consistent with their steroid hormone-like of some invertase proteins also promotes the balanced trans- effects, the steamed red ginseng better than untreated gin- formation and metabolism of hormones. seng [113, 114]. However, whether stereoselectivity, C17 side- To expand structure–activity relationship between gin- chain variation or location of hydroxyl group have a signific- senosides and hormones, thus attention also should be paid to ant impact on the biological activity of ginsenosides still need the structure of ginsenosides after metabolism. Studies on to be further investigated, whether oleanane type saponins

Rb1 PPD Rg1 Rg3

Rg1 Membrane Rb1

P13K Rg3 Rg1 ERα P13K P ERα Akt P Rb1 PPD eNOS ERβ Akt Rg1 AR GR L-Arginine NO MEK mTOR

Regulation Regulation of Nucleus of gene transcription

Fig. 3 A summarized pathway of the regulation mechanisms of representative ginsenosides effect on the steroid hormones via genes and transcriptions pathways. PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; eNOS, endothelial nitric oxide synthase; NO, Nitric oxide; MEK, mitogen-activated protein kinase kinase

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Cite this article as: TIAN Mei, LI Lin-Nan, ZHENG Rui-Rong, YANG Li, WANG Zheng-Tao. Advances on hormone-like activity of Panax ginseng and ginsenosides [J]. Chin J Nat Med, 2020, 18(7): 526-535.

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