INDEX

Kudzu (Pueraria mirifica, Pueraria lobata)

Indications

Menopausal symptoms; general female reproductive health; support of bone, hair, and fingernails; sexual longevity including vaginal lubrication; and enhanced breast size.

Mechanism of Action

Pueraria contains numerous isoflavones that are phytosterols, plant compounds with steroid-like effects. The phytosterols include β-sitosterol, coumestrol, genistein, daidzein, formononetin, puerarin, and miroesterol.1,2,3,4 Miroesterol is a stable phytosterol credited with many tissue-rejuvenating effects, and it may be used as a biomarker for kudzu quality.

Pueraria has been shown to act on both alpha (ERα) and beta (ERβ) estrogen receptors.5 In general, ERα receptors direct cellular proliferation, whereas the ERβ subtype directs differentiation and apoptosis. ERα are more active early in the fetal and neonatal periods, whereas ERβ subtype dominates in puberty and adulthood. When the balance between ERα and ERβ receptors is disrupted, reproductive health may be impaired. The phytoestrogens miroestrol and coumestrol act on both ERα and ERβ receptors, whereas daidzein and genistein are more active on ERβ receptors.5,6 Miroestrol blocks excessive stimulation of ER receptors in cases of breast or endometrial cancer, yet acts as an estrogen agonist to support cardiovascular health and alleviate menopausal symptoms. Deoxymiroestrol, which is probably more active than miroestrol, has similar cellular and clinical effects.7

The phytosterol formononetin up-regulates the expression of ERβ without stimulating ERα in endometrial and vaginal cells of ovarectomized rats.8 Formononetin has intramembranous ossification effects in traumatized mice bones.9 This effect is comparable to that of parathyroid hormone administration. Formononetin decreases metabolic activity in osteoarthritic osteoblasts while markedly increasing metabolic activities in normal osteoblasts. Formononetin has a greater remodeling effect on osteogenic markers and inflammatory cytokines in osteoarthritic bone than in normal bone.10

Although one study reported puerarin to have little to no binding of ERα and ERβ receptors in bone,11 other studies have reported ER agonism that contribute to Pueraria’s bone-building effects.12,13 In one study, puerarin stimulated osteoprotegerin, inhibited receptor activator of nuclear factor-κB ligand, and suppressed interleukin-6 production by human osteoblastic cells via agonism at both ERα and ERβ.12 Pueraria retards bone absorption without interfering with overall bone metabolism and stimulates bone regeneration without having proliferative effects on the endometrium.14 Pueraria promotes alkaline phosphatase and osteoprotegerin, decreases osteoclastogenic factors, inhibits bone absorption by osteoclasts, and stimulates proliferation and especially differentiation of osteoblasts. In total, these mechanisms promote bone gain. Formononetin also improves trabecular microarchitecture, collagen synthesis, and osteoprotegerin activation without exerting proliferative effects on the endometrium,15 and it has only weak proliferative effects on the breast epithelia.13

Puerarin prevents the increase in β-amyloid caused by estrogen deficiency. In the hippocampus, puerarin increases choline acetyltransferase activity and expression.16

Pueraria extracts have been used topically to treat postmenopausal vaginal atrophy and in skin products for cosmetic effects. One study on postmenopausal macaques has shown kudzu to significantly mature the vaginal epithelium without causing systemic side effects.17 A 12-week randomized controlled study of postmenopausal women significantly improved the vaginal maturation index, decreased adverse vaginal symptoms, and was comparable to conjugated equine estrogen cream.18

Evidence-Based Research

Numerous animal and human clinical trials as well as many molecular and tissue culture studies support the use of Pueraria for menopausal symptoms and to support the skin, vaginal mucosa, bones, brain, and cardiovascular system in the postmenopausal decades. One double-blind, placebo controlled clinical trial found Pueraria to retard or prevent the development of gray hair.19 Pueraria may reduce the risk of cerebrovascular disease that accelerates in postmenopausal women.16 Animal studies have shown that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels decrease with Pueraria supplementation, suggesting negative feedback from increased hormonal status of the tissues. Several small clinical studies dosed symptomatic perimenopausal women with either 50 or 100 mg of Pueraria mirifica for 6 months and reported improvements in the Greene climacteric scale of menopausal symptoms associated with slight increases in serum estradiol.20,21

Pueraria has supportive effects on bone density and reduces postmenopausal thinning of the bones.14 Formononetin has been shown to prevent ovarectomy-induced osteopenia in rats as well as having therapeutic and restorative effects on osteopenia15,22 Formononetin may be a safe hormone-like therapy for osteoporosis. One human randomized clinical trial found Pueraria extracts of 20, 30, or 50 mg to exert estrogen-like effects on bones without exerting a proliferative effect on the endometrium, as evidenced by a decrease in bone-specific alkaline phosphatase compared with placebo.23

Pueraria has positive effects on blood lipids. A recent study on ovarectomized rats showed that isoflavones from Pueraria roots inhibited loss of bone density and lipid elevation.24 Both animal and human studies have shown kudzu isoflavones to reduce lipid elevations and accumulation of abdominal fat that may follow rapid declines in estrogen levels.25,26 A small clinical trial compared Pueraria to placebo on serum lipids of postmenopausal women. After 2 months, high-density lipoprotein was 34% higher and low-density lipoprotein was 17% lower in the group receiving Pueraria.5

A double-blind, placebo controlled human trial examined the effects of Pueraria on blood lipids, bone alkaline phosphatase, and endometrial thickness and breast parameters in postmenopausal women aged 45–60 years. After 6 months, the groups receiving Pueraria showed a significant decrease in bone alkaline phosphatase, suggesting a reduction in bone resorption and turnover. No measurable changes were seen in the breasts or the endometrium, suggesting that it does not have a proliferating effect on the uterine lining or breasts.23

A phase III clinical trial compared Pueraria to conjugated equine estrogen on perimenopausal symptoms and serum hormone levels. All groups showed comparable relief of vasomotor, urogenital, and psychological symptoms. No significant differences in FSH, LH, or serum estradiol levels were seen between the groups. Thus, Pueraria was as effective as conventional pharmaceutical therapy.27

Safety in Pregnancy and Breastfeeding

Pueraria has a folk lore reputation as an emmenagogue and a contraceptive agent and therefore should be avoided during pregnancy unless clinical trials prove otherwise. Puerarin crosses the placental barrier and has endocrine-disrupting effects in rats.28 Significant antifertility activity of Pueraria has been demonstrated in laboratory animals. Puerarin at ≥300  mg/kg/day for days 1–2 postcoitus results in complete implantation failure because of effects on endometrial ERα and ERβ and disrupted implantation in rats.29,30 Pueraria seems to have no impact on male fertility or the hypothalamus–pituitary–testis axis, although in mice doses of 100 mg/kg have been shown to reduce epididymis and seminal vesicle weights and to reduce the sperm motility and viability.31 A study on isolated sperm showed that using puerarin reduced the spontaneous acrosome reaction of spermatozoa, whereas Pueraria reduced sperm motility.32 Sprague–Dawley rats were given testosterone to induce prostate hyperplasia and then daidzein and genistein for 30 days with finasteride as the positive control. The Pueraria extract reduced the size of the hyperplasia-induced prostate and significantly improved the architecture of the prostate cells.33

General Safety

A mouse and rat toxicity study evaluated the acute and subchronic toxicity effects of 5 g/kg body weight of Pueraria flower extract and reported no mortality or toxicological changes during the experimental period.34 There was one anecdotal report from Seoul, South Korea, of a middle-aged female who developed acute interstitial nephritis diagnosed by renal biopsy after the ingestion of Pueraria root juice for 10 days. After discontinuing the juice, symptoms completely resolved.35

Current evidence suggests that Pueraria is safe for women with existing or a history of breast and uterine cancer. Puerarin, the major isoflavone, has been shown to decrease the overexpression of ERs.

Puerarin may inhibit hepatic cytochrome P450-mediated drug metabolism in rats and humans, so interactions with some drugs are possible.36 A rat study that administered 4.0 and 2.0 g/kg of Pueraria root decoction with methotrexate caused 57.1% mortality in the 4.0-g group and 14.3% mortality in the 2.0-g group and increased the half-life of methotrexate by 53.9% and slowed the clearance by 47.9%.37 Methotrexate requires CYP450 2E1 for metabolism. A study of Pueraria extract on rabbit and human liver supersomes found an ethanol extract had more effect than puerarain 2E1, 1A2, and 2C9 enzymes, but it concluded that the herb was safe for human consumption.38

Dosage

Dosages of 20 mg to 2.4 g/day have been used in most of the human clinical studies. Topical doses have been 0.5–1.0 g/day.

Traditional Uses

Pueraria species are referred to as kudzu or Japanese arrowroot in North America. The vine is native to southern Japan and southeastern China, but it was introduced to India and North America for erosion control where it now grows prolifically, covering everything in its path. The roots have been used in Oriental medicine for centuries and in classic antiaging and rejuvenation formulas in Thailand. Kwoa khruea is the common name used for rejuvenating herbs in Thailand and white kwao khruea or Pueraria candollei is especially indicated for female rejuvenation; menopausal symptoms; facial rejuvenation; support of the bone, hair, and fingernails, and it is sometimes claimed to support sexual longevity including vaginal lubrication and enhanced breast size.

Pueraria is credited with many medicinal uses including hepatoprotective effects; alcohol protection; reduction in alcohol consumption and craving; neuroprotective, cardioprotective, antidiarrheal, and activity against acute dysentery; and for treatment of deafness, tinnitus, and vertigo. It is also credited with optimizing metabolism and is reported to have antidiabetic, insulin-enhancing, and antiobesity effects.

Pueraria lobata is historically used in combination with Salvia miltiorrhiza and Angelica species for cardiotonic effects including circulatory-enhancing, anti-inflammatory, anti-ischemic, and antiatherogenic effects.

References

1

Zhongguo Zhong Yao Za Zhi. 2010;35(23):3156–60. Chemical constituents from roots of Pueraria lobata. Li G, Zhang Q, Wang Y.

2 Zhongguo Zhong Yao Za Zhi. 2009;34(24):3217–20. Isoflavones from vine of Pueraria lobata. Zhang D, Ren Y, Dai S, Liu W, Li G.

3 Chem Pharm Bull (Tokyo). 2013;61(9):941–51. Simultaneous determination of Isoflavones, Saponins and Flavones in Flos Puerariae by ultra performance Liquid chromatography coupled with Quadrupole time-of-flight mass spectrometry. Lu J, Xie Y, Tan Y, Qu J, Matsuda H, Yoshikawa M, Yuan D.

4 Zhongguo Zhong Yao Za Zhi. 2012;37(16):2388–91. Determination of five components in Pueraria labta decoction with reference extraction method. Xue C, Zhang J, Jing W, Wang Y, Si N, Liu A.

5 Tohoku J Exp Med. 2008;216(4):341–51. Pueraria mirifica phytoestrogens improve dyslipidemia in postmenopausal women probably by activating estrogen receptor subtypes. Okamura S, Sawada Y, Satoh T, Sakamoto H, Saito Y, Sumino H, Takizawa T, Kogure T, Chaichantipyuth C, Higuchi Y, Ishikawa T, Sakamaki T.

6 Biochem Biophys Res Commun. 2009;379(1):139–44. Insight into estrogenicity of phytoestrogens using in silico simulation. Sugiyama H, Kumamoto T, Suganami A, Nakanishi W, Sowa Y, Takiguchi M, Ishikawa T, Tamura Y.

7 J Nat Prod. 2000;63(2):173–5. Identification of deoxymiroestrol as the actual rejuvenating principle of “kwao keur”, Pueraria mirifica. The known miroestrol may be an artifact. Chansakaow S, Ishikawa T, Seki H, Sekine K, Okada M, Chaichantipyuth C.

8 Br J Nutr. 2017;117(11):1511–22. Formononetin, a methoxy isoflavone, enhances bone regeneration in a mouse model of cortical bone defect. Singh KB, Dixit M, Dev K, Maurya R, Singh D.

9 Zhong Yao Cai. 2010;33(9):1445–9. The estrogenic effect of formononetin and its effect on the expression of rats’ atrium estrogen receptors. Xing DX, Liu XL, Xue CK, et al.

10 Int Immunopharmacol. 2010;10(4):500–7. Biphasic positive effect of formononetin on metabolic activity of human normal and osteoarthritic subchondral osteoblasts. Huh JE, Seo DM, Baek YH, et al.

11 J Nutr Sci Vitaminol (Tokyo). 2012;58(3):202–9. Puerarin exerted anti-osteoporotic action independent of estrogen receptor-mediated pathway. Michihara S, Tanaka T, Uzawa Y, Moriyama T, Kawamura Y.

12 Phytomedicine. 2014;21(8–9):1032–6. Puerarin concurrently stimulates osteoprotegerin and inhibits receptor activator of NF-κB ligand (RANKL) and interleukin-6 production in human osteoblastic MG-63 cells. Wang Y, Yang C, Xie WL, Zhao YW, Li ZM, Sun WJ, Li LZ.

13 Phytomedicine. 2013;20(10):787–96. Puerarin stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. Wang Y, et al.

14 Phytomedicine. 2012;19(13):1147–55. Upregulation of osteoblastic differentiation marker mRNA expression in osteoblast-like UMR106 cells by puerarin and phytoestrogens from Pueraria Pueraria mirifica. Tiyasatkulkovit W, Charoenphandhu N, Wongdee K, et al.

15 Menopause. 2012;19(8):856–63. Formononetin reverses established osteopenia in adult ovariectomized rats. Tyagi AM, Srivastava K, Singh AK, et al.

16 Int J Neurosci. 2013;123(11):783–91. Effects of puerarin on cholinergic enzymes in the brain of ovariectomized guinea pigs. Zhang Y, Chen Y, Shan Y, Wang D, Zhu C, Xu Y.

17 J Reprod Dev. 2014;60(3):238–45. Improvements of vaginal atrophy without systemic side effects after topical application of Pueraria mirifica, a phytoestrogen-rich herb, in postmenopausal cynomolgus macaques. Jaroenporn S, Urasopon N, Watanabe G, Malaivijitnond S.

18 Menopause. 2017;24(2):210–5. Comparision of Pueraria mirifica gel and conjugated equine estrogen cream effects on vaginal health in postmenopausal women. Suwanvesh N, Manonai J, Sophonsritsuk A, Cherdshewasart W.

19 Ann Dermatol. 2013;25(2):218–22. Efficacy and safety of Pueraria lobata extract in gray hair prevention: A randomized, double-blind, placebo-controlled study. Jo SJ, et al.

20 J Med Assoc Thai. 2007;90(7):1274–80. Challenges in the conduct of Thai herbal scientific study: efficacy and safety of phytoestrogen, pueraria mirifica (Kwao Keur Kao), phase I, in the alleviation of climacteric symptoms in perimenopausal women. Chandeying V, Lamlertkittikul S.

21 J Med Assoc Thai. 2004;87(1):33–40. Efficacy and safety of Pueraria mirifica (Kwao Kruea Khao) for the treatment of vasomotor symptoms in perimenopausal women: Phase II Study. Lamlertkittikul S, Chandeying V.

22 Evid Based Complement Alternat Med. 2013;2013:457052. Effect of formononetin on mechanical properties and chemical composition of bones in rats with ovariectomy-induced osteoporosis. Kaczmarczyk-Sedlak I, et al.

23 Menopause. 2008;15(3):530–5. Effects and safety of Pueraria mirifica on lipid profiles and biochemical markers of bone turnover rates in healthy postmenopausal women. Manonai J, Chittacharoen A, Udomsubpayakul U, Theppisai H, Theppisai U.

24 Nutrients. 2013;5(7):2734–46. Effects of dietary isoflavones from Puerariae radix on lipid and bone metabolism in ovariectomized rats. Lim DW, Kim JG, Kim.

25 PLoS One. 2011;6(12):e28333. Estrogenic plant extracts reverse weight gain and fat accumulation without causing mammary gland or uterine proliferation. Saunier EF, Vivar OI, Rubenstein A, Zhao X, Olshansky M, Baggett S, Staub RE, Tagliaferri M, Cohen I, Speed TP, Baxter JD, Leitman DC.

26 World J Gastroenterol. 2004;10(13):1967–70. Effects of Radix Puerariae flavones on liver lipid metabolism in ovariectomized rats. Wang JF, Guo YX, Niu JZ, Liu J, Wang LQ, Li PH.

27 J Med Assoc Thai. 2007;90(9):1720–6. Efficacy comparison of Pueraria mirifica (PM) against conjugated equine estrogen (CEE) with/without medroxyprogesterone acetate (MPA) in the treatment of climacteric symptoms in perimenopausal women: phase III study. Chandeying V, Sangthawan M.

28 Fitoterapia. 2013;86:202–7. Pharmacokinetics of puerarin in pregnant rats at different stages of gestation after oral administration. Cao L, Pu J, Cao QR, Chen BW, Lee BJ, Cui JH.

29 Reproduction. 2012;144(5):633–45. Puerarin, a selective oestrogen receptor modulator, disrupts pregnancy in rats at pre-implantation stage. Saha P, Saraswat G, Chakraborty P, Banerjee S, Pal BC, Kabir SN.

30 Acta Eur Fertil. 1985;16(1):59–65. Contraceptive potency of Pueraria tuberosa D.C. and its hormonal status. Prakash AO, Saxena V, Shukla S, Mathur R.

31 Endocrine. 2006;30(1):93–101. Effects of Pueraria mirifica, an herb containing phytoestrogens, on reproductive organs and fertility of adult male mice. Jaroenporn S, Malaivijitnond S, Wattanasirmkit K, Trisomboon H, Watanabe G, Taya K, Cherdshewasart W.

32 Reprod Toxicol. 2015.53:54–62. impact of kudzu and puerarin on sperm function. Gray SL, Lackey BR, Boone WR.

33 Andrologia. 2015;47(10):1153–9. Preventive effect of PUeraria mirifica on testosterone-induced prostatic hyperplasia in Sprague-Dawley rats. Masrudin SS, Mohamad J.

34 J Food Sci. 2013;78(11):T1814–21. Oral toxicological studies of pueraria flower extract: acute toxicity study in mice and subchronic toxicity study in rats. Takano A, Kamiya T, Tsubata M, Ikeguchi M, Takagaki K, Kinjo J.

35 Clin Nephrol. 2013;80(4):298–300. Acute interstitial nephritis following kudzu root juice ingestion. Jung JM, Kwon SH, Noh H, Han DC, Jeon JS, Jin SY.

36 Planta Med. 2014;80(7):561–7. In vitro and in vivo evaluation of the effect of puerarin on hepatic cytochrome p450-mediated drug metabolism. Kim SB, Yoon IS, Kim KS, Cho SJ, Kim YS, Cho HJ, Chung SJ, Chong S, Kim DD.

37 Toxicol Appl Pharmacol. 2005;209(3):263–8. Life-threatening interaction between the root extract of Pueraria lobata and methotrexate in rats. Chiang HM, Fang SH, Wen KC, Hsiu SL, Tsai SY, Hou YC, Chi YC, Chao PD.

38 The Effect of Kudzu, Pueraria lobata, on Various Cytochrome P450s  [Masters Thesis]. Greensboro, NC: University of North Carolina; 2015. p. 64. Zyglocke RK.