INDEX

Licorice (Glycyrrhiza glabra 2)

Indications

Elevated testosterone and prolactin, metabolic syndrome, polycystic ovary syndrome (PCOS).

Mechanism of Action

Researchers report that Glycyrrhiza helps normalize elevated testosterone by several mechanisms including reducing the synthesis of testosterone1 and blocking the dehydrogenase enzymes2,3 that help synthesize it4,5; blocking 5α-reductase enzymes that convert testosterone to the more active dihydrotestosterone6; enhancing the metabolism of testosterone; and reducing cellular response to testosterone at testosterone receptors.7

Evidence-Based Research

A saponin, a steroid-like molecule in Glycyrrhiza named glycyrrhizic acid, is credited with an ability to improve insulin resistance8 and fat metabolism in animal models of metabolic syndrome.9 Glycyrrhiza reduces inflammation and supports function in animal models of diabetic kidney damage,10 improves insulin sensitivity, reduces fat deposition in tissues,9 and suppresses the accumulation in abdominal fat.11

Animal studies suggest that Glycyrrhiza can reduce elevated androgens,7 and one human study showed Glycyrrhiza to decrease serum testosterone in women as well.1 Glycyrrhiza is a traditional Japanese herbal medicine for infertility and researchers have shown it to promote ovulation and menstruation in amenorrhoeic women12 as well as women with PCOS.13 Glycyrrhiza is often used in Japan combined with peony to treat PCOS in a traditional herbal medicine called Shakuyaku-Kanzo-To, which is reported to reduce elevated testosterone.14 One early study reported Shakuyaku-Kanzo-To to be more effective in women with generalized diffuse cysts than with peripheral cysts, a finding that has not been further investigated.13

Glycyrrhiza may also reduce elevated prolactin. An undesirable side effect of some drugs, particularly antipsychotics, is prolactin elevation and the resulting cessation of menses. The combination of peony and Glycyrrhiza has been shown to reduce elevated prolactin in women with hyperprolactinemia induced by the antipsychotic medication risperidone.15

One clinical study evaluated the effects of Glycyrrhiza in women with PCOS taking spironolactone, a synthetic drug capable of blocking androgen receptors and thereby reducing elevated testosterone and other androgens, but also impairing the regulation of body minerals via mineralocorticoid receptor agonism. Glycyrrhiza was found to reduce such side effects and support regular menses.16 Glycyrrhiza may be an effective alternative to spironolactone therapy, as licorice itself may reduce elevated testosterone.

Safety in Pregnancy and Breastfeeding

Glycyrrhiza is not considered to have the risk of inducing miscarriage or acting as an abortifacient, but it has been associated with an increased risk of preterm delivery. In general, Glycyrrhiza is demonstrated to have a spasmolytic action on the uterus.17 Tissue studies suggest licorice to possibly inhibit oxytocin, prostaglandin, and KCl-induced uterine contractions18 as well as those induced by calcium channel activation, nitric-oxide synthase, or cyclooxygenase.19 However, several outcome studies have reported a higher incidence of threatened miscarriages and preterm labors among regular users of Glycyrrhiza compared with those women not exposed to these herbs during pregnancy, although the sample size was small and the confounding factors numerous and complex.20 “Heavy” Glycyrrhiza exposure (>500 mg of glycyrrhizin per week) was associated with a greater risk of preterm delivery in one outcome study,21 without evidence of effects on birth weight or maternal blood pressure.22 Another outcome study reviewed data on 185 pregnant women who used Glycyrrhiza-containing cough and cold formulas with a maximum dose of 2104 mg/day, anywhere between the 4th day and 25th week of gestation. The rate of stillbirths was marginally higher among women who took Glycyrrhiza compared with those who did not, and there was no evidence of teratogenic effects.23

Synthetic glucocorticoids administered during pregnancy to improve fetal lung maturity in threatened preterm birth have been shown to reduce birth weight and head circumference, but they have not been linked to gross changes in long-term health to date. 11β-Hydroxysteroid dehydrogenase type 2 enzymes (11β-HSD2), discussed above, are also active in the placenta and may become up-regulated during pregnancy if a woman is exposed to stress, as these enzymes promote glucocorticoid production.

Animal studies show that long-term stress alters the hypothalamic–pituitary–adrenal axis and that Glycyrrhiza-like synthetic glucocorticoids can increase the occurrence of behavioral problems as a result.24 Glycyrrhizin, a natural constituent of Glycyrrhiza, potently inhibits 11β-HSD2, thereby reducing the fetoplacental barrier to the higher maternal cortisol levels. Maternal consumption of glycyrrhizin was shown to correlate to increased salivary cortisol levels in newborns, compared with newborns whose mother had zero exposure during pregnancy.25 Another human outcome study reported that prenatal exposure to Glycyrrhiza exerted detrimental effects on cognitive performance, as determined by standardized neuropsychological assessment tests and the report of psychiatric symptoms. Those with zero to low exposure (0–249 mg/week) scored better than those with high exposure (≥500 mg/week).26

One rat study reported Glycyrrhiza gavage at a dose of 100 mg/kg for 7 days to significantly increase the teratogenicity of cyclophosphamide by inducing cytochrome p450 enzyme conversion of the compound into toxic metabolites.27 Other human outcome studies however have not observed licorice to have teratogenic activity.

Thus, it may be concluded that Glycyrrhiza should be avoided in pregnancy in anything greater than an occasional cup of tea. High doses, concentrated products, and daily consumption of Glycyrrhiza should be avoided during pregnancy.

General Safety

There have been widely publicized reports that Glycyrrhiza may lead to an increase in blood pressure, although the actual occurrence of this side effect is quite rare. Nonetheless, high blood pressure is a concern for some women with metabolic syndrome. Studies are now indicating that Glycyrrhiza may aggravate high blood pressure more often in those with a preexisting complex adrenal disorder involving altered potassium levels28,29,30,31,32 or in those with a particular isoform of the 11β-DHS enzymes. Defects in the 11β-HSD2 enzyme contribute to hypertension and may make some people more sensitive to the hypertensive effects of salt and Glycyrrhiza because the kidneys express high levels 11β-HSD2 and are the principal source of cortisone in humans.33

Interestingly, Glycyrrhiza has in fact been reported to reduce blood pressure in animal models with metabolic syndrome.34 However, the side effect of elevated blood pressure remains unpredictable, so people using Glycyrrhiza supplements regularly should monitor their blood pressure. People with abnormally low potassium levels should avoid Glycyrrhiza because of the possibility of serious muscle weakness and high blood pressure. Do not consume more than 2 or 3 cups of Glycyrrhiza tea per day unless under a physician’s guidance. One clinical study investigating the benefits of Glycyrrhiza on mineralocorticoids in women taking spironolactone reported no subjects to experience hypertension as a side effect.16 There has been one anecdotal case report of acute urinary retention associated with severe hypokalemia possibly associated with licorice use in a pregnant woman.35 Various genotoxic studies have indicated that glycyrrhizin is neither teratogenic nor mutagenic and may possess antigenotoxic properties under certain conditions.36

Glycyrrhizin/glycyrrhizic acid may induce edema, hypertension, and hypokalemia in patients treated with higher doses and long-term administration, all as a side effect of pseudoaldosteronism caused by the 11β-HSD inhibition. There are cases of Glycyrrhiza aggravating pseudohyperaldosteronism.37 Hypokalemic periodic paralysis, a rare disorder consisting of sudden episodes of muscle weakness with areflexia involving all four limbs that spontaneously resolves in several hours to several days, may be associated with heavy Glycyrrhiza ingestion in some people.38

Dosage

Traditional medicines include teas, syrups, and powders at a wide variety of dosages, depending on whether it is being used as a lead or supportive herb within the formula.

Modern encapsulations will use 250–1000 mg in a single dose that is repeated several times a day. As this herb has potential for toxicity symptoms, use caution if exceeding doses greater than 4 g/day continuously.

Based on the in vivo and clinical evidence, an acceptable daily intake of isolated glycyrrhizin, one that will not typically cause sodium retention or hypertension, is 0.015–0.229 mg /kg body weight/day.36

Traditional Uses

Glycyrrhiza is a rhizome that has been used since ancient times in traditional Chinese medicine and in ancient Egyptian, Greek, and Roman healing traditions for numerous medicinal uses. In China, it has been referred to as “the great harmonizer” because of the belief that it can go everywhere in the body and pull together the actions of other herbs in botanical formulas. Licorice seems to deserve this reputation because it can be used for ulcers, allergy, viral infections, fatigue, hepatoprotection, adrenal disorders, infertility, and numerous hormonal problems. Several licorice-based medicines have been introduced including a Japanese glycyrrhizin preparation used clinically as an antiallergic and antihepatitis agent and a remedy for gastric ulcer marketed in the Netherlands in 1940s. Licorice also has a long-standing reputation as an emergency remedy in China for acute pituitary failure such as postpartum Sheehan’s syndrome.39

References

1 Steroids. 2004;69(11–12):763–6. Licorice reduces serum testosterone in healthy women. Armanini D, Mattarello MJ, Fiore C, Bonanni G, Scaroni C, Sartorato P, Palermo M.

2 Mol Cell Endocrinol. 2011;336(1–2):102–9. Liquorice and glycyrrhetinic acid increase DHEA and deoxycorticosterone levels in vivo and in vitro by inhibiting adrenal SULT2A1 activity. Al-Dujaili EA, Kenyon CJ, Nicol MR, Mason JI.

3 J Steroid Biochem Mol Biol. 2007;104(3–5):161–8. Endogenous inhibitors (GALFs) of 11beta-hydroxysteroid dehydrogenase isoforms 1 and 2: derivatives of adrenally produced corticosterone and cortisol. Morris DJ, Latif SA, Hardy MP, Brem AS.

4 Lancet. 2001;358(9293):1613–4. Liquorice consumption and salivary testosterone concentrations. Josephs RA, Guinn JS, Harper ML, Askari F.

5 Toxicology. 2011;285(3):83–9. Environmental inhibitors of 11β-hydroxysteroid dehydrogenase type 2. Ma X, Lian QQ, Dong Q, Ge RS.

6 Int J Endocrinol Metab. 2012;10(2):497–502. An update on plant derived anti-androgens. Grant P, Ramasamy S.

7 Int J Androl. 2009;32(4):417–22. Antiandrogenic activities of Glycyrrhiza glabra in male rats. Zamansoltani F, Nassiri-Asl M, Sarookhani MR, Jahani-Hashemi H, Zangivand AA.

8 Biosci Biotechnol Biochem. 2007;71(6):1452–61. Changes in components, glycyrrhizin and glycyrrhetinic acid, in raw Glycyrrhiza uralensis Fisch, modify insulin sensitizing and insulinotropic actions. Ko BS, Jang JS, Hong SM, Sung SR, Lee JE, Lee MY, Jeon WK, Park S.

9 Lipids Health Dis. 2010;9:81. Glycyrrhizic acid improved lipoprotein lipase expression, insulin sensitivity, serum lipid and lipid deposition in high-fat diet-induced obese rats. Eu CH, Lim WY, Ton SH, bin Abdul Kadir K.

10 Drug Chem Toxicol. 2011;34(2):101–8. Effect of licorice extract on the complications of diabetes nephropathy in rats. Kataya HH, Hamza AA, Ramadan GA, Khasawneh MA.

11 Biol Pharm Bull. 2004;27(11):1775–8. Licorice flavonoids suppress abdominal fat accumulation and increase in blood glucose level in obese diabetic KK-A(y) mice. Nakagawa K, Kishida H, Arai N, Nishiyama T, Mae T.

12 Clin Exp Obstet Gynecol. 2003;30(2–3):95–8. A novel anti-dysmenorrhea therapy with cyclic administration of two Japanese herbal medicines. Tanaka T.

13 Nihon Sanka Fujinka Gakkai Zasshi. 1988;40(6):789–92. Effect of a traditional herbal medicine (shakuyaku-kanzo-to) on testosterone secretion in patients with polycystic ovary syndrome detected by ultrasound. Takahashi K, Yoshino K, Shirai T, Nishigaki A, Araki Y, Kitao M.

14 Am J Chin Med. 1989;17(1–2):35–44. Effect of traditional herbal medicine, shakuyaku-kanzo-to on total and free serum testosterone levels. Takeuchi T, Nishii O, Okamura T, Yaginuma T.

15 J Clin Psychopharmacol. 2008;28(3):264–370. A randomized, crossover comparison of herbal medicine and bromocriptine against risperidone-induced hyperprolactinemia in patients with schizophrenia. Yuan HN, Wang CY, Sze CW, Tong Y, Tan QR, Feng XJ, Liu RM, Zhang JZ, Zhang YB, Zhang ZJ.

16 Eur J Obstet Gynecol Reprod Biol. 2007;131(1):61–7. Treatment of polycystic ovary syndrome with spironolactone plus licorice. Armanini D, Castello R, Scaroni C, Bonanni G, Faccini G, Pellati D, Bertoldo A, Fiore C, Moghetti P.

17 J Obstet Gynaecol Res. 2012;38(7):1004–10. Shakuyaku-kanzo-to inhibits smooth muscle contractions of human pregnant uterine tissue in vitro. Tsuji S, Yasuda K, Sumi G, Cho H, Tsuzuki T, Okada H, Kanzaki H.

18 Pharm Biol. 2013;51(6):744–8. Relaxative effect of core licorice aqueous extract on mouse isolated uterine horns. Jia J, Li Y, Lei Z, Hao Y, Wu Y, Zhao Q, Wang H, Ma L, Liu J, Zhao C, Jiang Y, Wang Y, Tan H, Dai X, Zhang W, Sun T, Yu J.

19 Phytother Res. 2012;26(9):1410–7. Analgesic and uterine relaxant effects of isoliquiritigenin, a flavone from Glycyrrhiza glabra. Shi Y, Wu D, Sun Z, Yang J, Chai H, Tang L, Guo Y.

20 Pharmacoepidemiol Drug Saf. 2010;19(11):1151–8. Use of herbal products among 392 Italian pregnant women: focus on pregnancy outcome. Cuzzolin L, Francini-Pesenti F, Verlato G, Joppi M, Baldelli P, Benoni G.

21 Am J Epidemiol. 2002;156(9):803–5. Preterm birth and licorice consumption during pregnancy. Strandberg TE, Andersson S, Järvenpää AL, McKeigue PM.

22 Am J Epidemiol. 2001;153(11):1085–8. Birth outcome in relation to licorice consumption during pregnancy. Strandberg TE, Järvenpää AL, Vanhanen H, McKeigue PM.

23 Planta Med. 2013;79(2):97–101. Fetal and neonatal outcomes in women reporting ingestion of licorice (Glycyrrhiza uralensis) during pregnancy. Choi JS, Han JY, Ahn HK, Ryu HM, Kim MY, Chung JH, Nava-Ocampo AA, Koren G.

24 Birth Defects Res C Embryo Today. 2012;96(4):315–24. Long-term effects of prenatal stress and glucocorticoid exposure. Painter RC, Roseboom TJ, de Rooij SR.

25 Psychoneuroendocrinology. 2010;35(10):1587–93. Maternal prenatal licorice consumption alters hypothalamic-pituitary-adrenocortical axis function in children. Räikkönen K, Seckl JR, Heinonen K, Pyhälä R, Feldt K, Jones A, Pesonen AK, Phillips DI, Lahti J, Järvenpää AL, Eriksson JG, Matthews KA, Strandberg TE, Kajantie E.

26 Am J Epidemiol. 2009;170(9):1137–46. Maternal licorice consumption and detrimental cognitive and psychiatric outcomes in children. Räikkönen K, Pesonen AK, Heinonen K, Lahti J, Komsi N, Eriksson JG, Seckl JR, Järvenpää AL, Strandberg TE.

27 Birth Defects Res B Dev Reprod Toxicol. 2011;92(6):553–9. Licorice extract increases cyclophosphamide teratogenicity by upregulating the expression of cytochrome P-450 2B mRNA. Park D, Yang YH, Choi EK, Yang G, Bae DK, Lee SH, Kim TK, Kyung J, Kim D, Choi KC, Kim YB.

28 Eur J Endocrinol. 2003;149(3):163–8. Tissue-specific Cushing’s syndrome, 11beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action. Stewart PM.

29 Ned Tijdschr Geneeskd. 2007;151(12):692–4. From gene to disease; ‘apparent mineralocorticoid excess’ syndrome, a syndrome with an apparent excess of mineral corticoids. Levtchenko EN, Deinum J, Knoers NV, Hermus AR, Monnens LA, Lenders JW.

30 Ann Med. 2010;42(6):465–74. Licorice-induced hypertension and common variants of genes regulating renal sodium reabsorption. Miettinen HE, Piippo K, Hannila-Handelberg T, Paukku K, Hiltunen TP, Gautschi I, Schild L, Kontula K.

31 Nihon Ronen Igakkai Zasshi. 2007;44(4):513–6. A 87-year-old woman with mineralocorticoid excess due to 11 beta-HSD2 deficiency. Inada M.

32 Semin Vasc Med. 2004;4(2):121–8. Cortisol, 11beta-hydroxysteroid dehydrogenases, and hypertension. van Uum SH, Lenders JW, Hermus AR.

33 Biochim Biophys Acta. 2010;1802(12):1178–87. 10. The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Ferrari P.

34 J Nutr. 2003;133(11):3369–77. A licorice ethanolic extract with peroxisome proliferator-activated receptor-gamma ligand-binding activity affects diabetes in KK-Ay mice, abdominal obesity in diet-induced obese C57BL mice and hypertension in spontaneously hypertensive rats. Mae T, Kishida H, Nishiyama T, Tsukagawa M, Konishi E, Kuroda M, Mimaki Y, Sashida Y, Takahashi K, Kawada T, Nakagawa K, Kitahara M.

35 Am J Med Sci. 2009;338(6):500–4. Bartter’s syndrome in pregnancy: review of potassium homeostasis in gestation. Luqman A, Kazmi A, Wall BM.

36 Regul Toxicol Pharmacol. 2006;46(3):167–92. Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. Isbrucker RA, Burdock GA.

37 Horm Res. 1999;52(5):253–5. Liquorice, growth retardation and Addison’s disease. Doeker BM, Andler W.

38 J Endocrinol Invest. 2007;30(4):341–5. Hypokalemic periodic paralysis in a patient with acquired growth hormone deficiency. Lanzi R, Previtali SC, Sansone V, Scavini M, Fortunato M, Gatti E, Meola G, Bosi E, Losa M.

39 Zhonghua Yi Xue Za Zhi. 1973;11:693–4. Successful treatment of postpartum hypopituitarism with decoction of Radix glycyrrhizae and Radix ginseng: report of a case. Lei CC, Tang CC.