Pueraria

Scientific Name(s): Pueraria mirifica Airy Shaw et. Suvatabhandu. Family: Fabaceae. 1

Common Name(s): Kwao Krua , White Kwao Krua , Kwao Keur , Kwao Kruea 2 , 3 , 4 , 5

Uses

Most commercial products containing pueraria are available as rejuvenating, antiaging, or skin-lightening creams or gels, as beauty soaps, or as capsules or tablets for increasing appetite, enlarging breasts, modulating hair growth or regrowth, and other rejuvenating purposes. However, there is no literature to support these uses. The medical literature documents the plant's use primarily for menopause, but also for cancer and osteoporosis.

Dosing

Commercial products are available in topical (creams, gels, and soaps) or oral (capsules or tablets) dosage forms. Some clinical studies used 200 to 400 mg (extracted from the root or tuber) by mouth per day. Commercial manufacturers suggest 250 mg (root or tuber) by mouth every morning and evening. For breast enlargement, manufacturers suggest a twice-daily topical application to the breast area for 3 to 5 minutes until fully absorbed.

Contraindications

Avoid use if hypersensitive to any of the components of product. Because of its phytoestrogen-like effects, use pueraria with caution if diagnosed with an estrogen-dependent neoplasia, pulmonary embolism, liver dysfunction or disease, or anemia.

Pregnancy/Lactation

Avoid use during pregnancy and lactation because of the lack of clinical data and the plant's phytoestrogen activity.

Interactions

None well documented.

Adverse Reactions

Because of pueraria's estrogen-like effect, use with caution in patients with asthma, diabetes mellitus, epilepsy, migraine, or systemic lupus erythematosus. Use with caution in patients with abnormal triglycerides or hypercalcemia.

Toxicology

No data.

Botany

The plant species P. mirifica (pueraria) belongs to the Fabaceae, or bean, subfamily, and its tuberous roots contain several phytoestrogens. 4 P. mirifica is a woody vine commonly found in forests throughout Thailand, 6 with 28 cultivars presently documented. The tuberous root varies in size depending on soil condition, but may weigh as much as 100 kg. The plant's palmate-type leaves are simple or ovate and contain 3 leaflets in 1 petiole. The blue-to-purple flowers are composed of 5 petals and bloom from February to March.

History

The plant species is rich in phytoestrogens, and postmenopausal women in Thailand have consumed it for more than 100 years citing its beneficial estrogen effects. 1 In traditional Thai medicine, it is common to use P. mirifica as a skin moisturizer, to improve regrowth of hair, to improve body flexibility and sexual performance, and to firm and enlarge the breasts. 6 Commercial products containing pueraria are continually introduced into the world market 5 and have become popular in Thailand, Korea, and Japan. 6 Most commercial products are available as topical rejuvenating, antiaging, or skin-lightening creams or gels, as beauty soaps, or as capsules or tablets for increasing appetite, enlarging breasts, modulating hair growth or regrowth, and other rejuvenating purposes. 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 Since 1999, domestic and global demand for the raw materials from P. mirifica roots or tubers has increased, resulting in intense harvesting of the plant from the forests of Thailand. 15

Chemistry

Isoflavones, coumestans, and lignans are the 3 main classes of phytoestrogens. The tuberous roots of P. mirifica primarily contain the active component miroestrol and its derivative, deoxymiroestrol. 2 The tuberous roots of P. mirifica also contain daidzin, daidzein, genistin, genistein, puerarin, 16 mirificoumestan, kwakhurin, 17 , 18 coumestrol, 19 mirificin, and 2 steroids, estrone and estriol. 5 , 17 , 20 , 21 The manufacture and synthesis of miroestrol is documented. 22 , 23 Deoxymiroestrol was isolated and identified as the most active phytoestrogen of the plant. 3 , 5 , 24

Thin-layer chromatography analysis has documented varying amounts of phytoestrogens collected from P. mirifica in different locations in Thailand. 6 , 25 One of the challenges of large-scale manufacturing of P. mirifica for drugs and cosmetics is resolving these variations in lots.

Uses and Pharmacology

Cancer

Spinasterol, an active cytotoxic component of P. mirifica , was active against certain gynecological cancer cell lines and activates estrogen receptors ER-alpha and ER-beta. The ethanol extract had antiproliferative effects on breast cancer cell lines MCF-7, ZR-75-1, MDA-MB-231, SK-BR-3, and Hs578T. Another component, known as PE-D, affected the growth in a dose-dependent and time-dependent manner on some breast cancer cell lines (MCF-7, MDAMB-231), and on the growth of ovarian (2774) and cervical cancer cells (HeLa). 26 , 27 The estrogenic effect of some components in P. mirifica has been compared with estradiol, a major estrogen in humans. 27 , 28 The rank order of phytoestrogen potency is: deoxymiroestrol; miroestrol; 8-prenylnaringenin; coumestrol; genistein/equol; daidzein; resveratrol. 29 P. mirifica also had an estrogenic effect on a human HepG2 hepatoma cell line that contained an estrogen receptor and a luciferase reporter gene; this evidence indicates that metabolic activation of P. mirifica promotes estrogenic activity. 30 Another study also documents that estrogenic activity may result from metabolic activation of liver enzymes. 31

Animal data

The proposed mechanism of action involves strong competitive binding of the plant's phytoestrogens to ER-alpha and/or synthesis suppressor of ER-alpha. 32

Pretreatment of rats with P. mirifica (1,000 mg/kg body weight per day tuberous root powder) resulted in decreased virulence of rat mammary tumor development from 7,12-dimethylbenz( a )anthracene (7,12-DMBA). Histopathological analysis of the mammary tumor tissues revealed lower ER-alpha, ER-beta, and ER-alpha/ER-beta profile. 32

Menopause
Animal data

In rabbits, P. mirifica improved endothelial function through a nitric oxide pathway, decreased contractile responses to norepinephrine, and increased responses to estradiol. The plant caused no changes in lipid profile or liver enzymes. 33 In male and female gonadectomized rats, P. mirifica had estrogen-like activity and affected accessory sex organs. It increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in both sexes. 34 The mechanism of action involved direct stimulation of the accessory sex organs and suppression of the hypothalamic-pituitary-gonadal axis. Overall activity was more potent in female rats than in male rats. Studies in mice found that P. mirifica does not affect male fertility or the hypothalamus-pituitary-testis axis. 35 The testis, epididymis, and seminal vesicle all had normal histopathology in P. mirifica -treated male mice.

P. mirifica may greatly alter the length of menstrual cycles and suppress ovulation by reducing serum levels of gonadotropins. The length of the menstrual cycle increased in monkeys treated with P. mirifica 10 and 100 mg/day of root extract and disappeared completely in monkeys treated with root extract 1,000 mg/day. Serum FSH, LH, estradiol, progesterone, and immunoreactive-irinhibin were lower in a dose-dependent manner during treatment. During the posttreatment period, only monkeys treated with P. mirifica 10 and 100 mg/day of extract recovered from the changes in menstrual cycle length and hormone levels. 36 Other studies document similar activity for the P. mirifica 1,000 mg/day dose of 37 root extract and the direct correlation in dose with gonadotrophin levels. 38

The plant had a dose-dependent estrogenic effect on rat vaginal cornification. 39 P. mirifica phytoestrogens at a dose of root extract 1,000 mg/day decreased serum parathyroid hormone and calcium levels in aged menopausal monkeys and, thus, may be beneficial in treating bone loss caused by estrogen deficiency. 40 P. mirifica had an estrogenic action in aged menopausal monkeys by changing the sexual skin area around the perineum to the base of the tail to a reddish pigmentation. 41 FSH may be a candidate marker for the study of P. mirifica 's estrogenic effects in female monkeys if changes in urinary hormones are used as an indicator. 42 , 43

Clinical data

In a 24-week randomized, double-blind, placebo-controlled trial of 51 postmenopausal women, oral P. mirifica exhibited estrogenicity on vaginal tissue, alleviated vaginal dryness symptoms and dyspareunia, improved signs of vaginal atrophy, and restored atrophic vaginal epithelium. 4 In another clinical trial of 51 postmenopausal women 46 to 60 years of age, P. mirifica tuberous root had an estrogen-like effect on bone turnover rate at a dose of 20, 30, and 50 mg/day for a 24-week period. 1 Phase 1 to 3 trials in Thailand compared the estrogenic effect of P. mirifica to conjugated equine estrogen in relieving climacteric symptoms in perimenopausal women. 44 , 45

In small clinical trials, the administration of P. mirifica crude extract improved hot flushes, frustration, sleep disorder, skin dryness, high blood cholesterol, amenorrhea, and other menopause-related symptoms in women. There was no change in blood cells or liver and renal function. 46 , 47

Other pharmacologic activity
Antioxidant

Some of the isoflavonoids in P. mirifica had antioxidant activity similar to that of alpha tocopherol or vitamin E. 48 P. mirifica decreased neuronal cell death in a time- and dose-dependent manner against neurotoxic agents in an Alzheimer disease model in vitro. 49 , 50 Mechanism of action may be associated with an effect on synaptic density by inducing synaptophysin expression via estrogen receptor. 51

Osteoporosis

In sex-hormone–deficient male rats, treatment with P. mirifica root powder completely inhibited bone loss in long bones and axial bones. At higher doses, it increased bone density without affecting accessory sex organs. 52 In a similar study, P. mirifica completely inhibited bone loss in long bones and axial bones in estrogen-deficient female rats. 53 However, the highest dose of P. mirifica root powder (1,000 mg/kg body weight per day) caused an undesired adverse reaction of increased uterine weight.

Insecticide

The active ingredients from the root of P. mirifica had lethal properties during various growth cycles against the yellow fever mosquito ( Aedes aegypti ) and other mosquito species with disease-spreading abilities. 54

Dosage

Commercial products are available as topical creams, gels, and soaps, or in oral capsule and tablet dosage forms. 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 Some clinical studies used 200 to 400 mg extract from root or tuber orally per day. Commercial manufacturers suggest a dosage of 250 mg of active ingredients from the root orally every morning and evening. For topical products, manufacturers suggest a twice-daily topical application to the breast area for 3 to 5 minutes until fully absorbed.

Pregnancy/Lactation

Avoid use during pregnancy and lactation because of the lack of clinical data and the plant's phytoestrogen activity.

Interactions

Phytoestrogens have estrogen-like effects. Theoretically, drug interactions may occur with the following:

Corticosteroids (eg, prednisone)

May increase pharmacologic and toxicologic effects.

Hydantoins (eg, phenytoin)

May affect concentration of these medications.

Thyroid hormones (eg, levothyroxine)

May decrease serum free thyroxine concentrations.

Drug/Laboratory tests

Increased triglyceride levels may occur. 1

Adverse Reactions

Because of the estrogen-like effect of P. mirifica , use with caution in patients with asthma, diabetes mellitus, epilepsy, migraine, or systemic lupus erythematosus. Also use with caution in patients with abnormal triglycerides 1 or hypercalcemia. 1 , 52 , 53

Toxicology

High doses of P. mirifica caused general and genotoxicity in animals. 55 Rats treated with aqueous and ethanolic root extracts of P. mirifica had significantly lower body weight gain and lower packed red cell volume; the plant also had mutagenic activity. 56 A root extract dosage of 100 mg/kg had adverse effects on mating efficiency and reproduction in female mice. 57 No estrogen hormone activities were found in egg and chicken meat tissue or rats. 58 , 59 The median lethal dose for oral consumption of P. mirifica root powder in mice was 2,000 mg/kg body weight per day. 60

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