Epimedium

• How It Works

  Scientific evidence to support use of Epimedium is limited. More studies are needed to confirm its safety and efficacy.

  Epimedium is a Chinese herb traditionally used to treat fatigue and sexual problems. Cancer patients may experience symptoms of sexual dysfunction such as painful intercourse, loss of libido, and ability to maintain arousal. These problems can be caused by many factors: stress, emotional distress, hormone changes, as well as various cancer treatments. Initial results suggest that a special blend of Epimedium may help prevent bone loss, but more studies are needed.

  Epimedium may affect hormone levels, and should be avoided in patients with hormone-sensitive cancers or those with heart disease.

• Purported Uses
  • Fatigue
    Epimedium is traditionally used for fatigue but it has not been studied in clinical trials.
  • Osteoporosis
    A small randomized trial shows that Epimedium may help prevent bone loss in women who have had menopause for a long time.
  • Sexual dysfunction
    Epimedium is traditionally used in herbal formulas for sexual dysfunction. More studies are needed to verify such effects.
• Do Not Take If
  • You are sensitive to Epimedium.
  • You have heart disease: Epimedium caused rapid irregular heartbeat and excitability in a patient with heart disease.
  • You are taking drugs that are metabolized by the cytochrome P450 3A4 enzyme, or drugs that are aromatase inhibitors, like anastrozole, exemestane, and letrozole.
• Side Effects
  • Sweating or feeling hot
  • Rapid irregular heartbeat
  • Increase in energy
  • Mood changes
• Scientific Name

  Epimedium sagittatum, Epimedium grandiflorum, Epimedium brevicornum

• Clinical Summary

  Epimedium is an herb used in traditional Chinese medicine to treat fatigue, arthritic pain, nerve pain, and sexual dysfunction. It is thought to alter levels of certain hormones and is marketed as a dietary supplement for libido. Results from in vitro studies suggest that components of Epimedium exhibit antiosteoporotic ⁽¹⁾, neuroprotective ^{(2) (3) (4)} , immunomodulatory ^(5) (6), and anticancer effects ^{(7) (8) (9)}, as well as anti-HIV activity ⁽¹⁰⁾. Epimedium derivatives may produce radiosensitizing effects ⁽¹¹⁾ and reverse multidrug resistance ⁽¹²⁾ in tumor cells.

  In one randomized trial, an herbal regimen containing Epimedium-derived flavonoids was shown to prevent bone loss in postmenopausal women ⁽¹³⁾. The few other clinical trials published tend to combine this herb in a botanical “recipe,” confounding the determination of any specific contributions from Epimedium or its components. Further, the safety of such phytotherapeutic compounds needs to be determined.

  Patients with hormone-sensitive cancers should use Epimedium with caution as it demonstrated estrogenic effects ⁽¹⁴⁾. Cancer patients may experience sexual dysfunction symptoms including painful intercourse, loss of libido, and difficulty in maintaining arousal. These problems are often multifactorial and can be caused by stress, distress, and hormonal changes, as well as treatments involving surgery, radiation, chemotherapy, or hormone therapy. Therefore, patients should consult and be monitored by a physician to properly address individual symptoms of sexual dysfunction.

• Purported Uses
  • Fatigue
  • Osteoporosis
  • Sexual dysfunction
• Mechanism of Action

  Icariin, a major active constituent of Epimedium, promotes estrogen biosynthesis, and enhances aromatase mRNA and protein expression as well as alkaline phosphatase activity in vitro ⁽¹⁾. However, other studies have attributed estrogen-like activity to icariin derivatives icaritin and desmethylicaritin, rather than icariin itself ⁽¹⁴⁾. Icariin can also exhibit a mild phosphodiesterase-5 inhibition effect ⁽¹⁶⁾. It has been implicated in differentiation of stem cells into cardiomyocytes via cell cycle regulation, induction of apoptosis, modulation of reactive oxygen species generation, and the regulation of various signaling pathways ⁽¹⁷⁾. In undifferentiated neuronal cell lines, it exhibited neuroprotective effects through LDH leakage attenuation which reduced GSH depletion, prevented DNA oxidation damage, and inhibited caspase-3 and p53 activation; and inhibited JNK/p38 MAPK pathways ⁽⁴⁾. Icariin was also shown to reduce viability of  human esophageal cancer cells by regulating apoptotic signaling, which is mediated by endoplasmic reticulum stress ⁽²³⁾.

  Icaritin, a prenylflavonoid derivative, induced sustained activation of extracellular signal-regulated kinase (ERK) pathway and apoptosis in both breast ⁽⁹⁾ and endometrial cancer cells ⁽¹⁸⁾. It also induced G2/M phase cell-cycle arrest and downregulated G2/M regulatory protein expression ⁽⁹⁾. Its radiosensitizing effects suggest ERK1/2 and AKT pathway suppression, enhanced apoptosis, and induced G2/M blockage ⁽¹¹⁾. Also, icaritin may reverse doxorubicin resistance in human hepatoma cells by increasing intracellular drug accumulation, and by decreasing MDR1 and P-glycoprotein expression ⁽¹²⁾. In another study, addition of an epimedium extract to gefitinib was shown effective against drug resistance caused by T790M mutation in non-samll cell lung cancer cells ⁽²⁴⁾.

• Contraindications
  • Hypersensitivity to Epimedium ⁽¹⁹⁾
  • Cardiovascular disease ⁽²⁰⁾
• Adverse Reactions

  Sweating or feeling hot in high doses; however, toxicity and safety evaluations are lacking ⁽²¹⁾

  Case reports

  Vasculitic rash, pain, and burning sensation: Induced by either ginkgo and/or horny goat weed herbal remedies that a 77-year-old male colorectal cancer survivor reported taking to improve memory and libido. Patient was hospitalized for 3 days. Medical history included curative resection 8 years prior, hypertension managed with lisinopril for 4 years, and no other medication or health complaints. A working diagnosis of vasculitic rash secondary to adverse reactions to either herbal preparation was made due to cessation of symptoms upon discontinuation of these products and after 3 weeks’ follow-up ⁽¹⁹⁾.

  Tachyarrhythmia and hypomania: A 66-year-old man with congestive heart failure was hospitalized following symptoms of shortness of breath, chest pain, and new-onset symptomatic arrhythmia. He reported taking Epimedium daily for 2 weeks to increase sexual pleasure. His symptoms were brought under control by administering olanzapine along with lorazepam ⁽²⁰⁾.

• Herb-Drug Interactions
  • Cytochrome P450 substrates: Prolonged use of Epimedium can induce CYP3A4 through the activation of pregnane X receptor ⁽²²⁾ .
  • Aromatase Inhibitors: Icariin enhances the action of aromatase ⁽¹⁾. This may reduce the effect of aromatase inhibitors, like anastrozole, exemestane, and letrozole.
• References

  1. Yang L, Lu D, Guo J, et al. Icariin from Epimedium brevicornum Maxim promotes the biosynthesis of estrogen by aromatase (CYP19). J Ethnopharmacol. Feb 13 2013;145(3):715-721.

  2. Wang Z, Zhang X, Wang H, et al. Neuroprotective effects of icaritin against beta amyloid-induced neurotoxicity in primary cultured rat neuronal cells via estrogen-dependent pathway. Neuroscience. Mar 30 2007;145(3):911-922.

  3. Liu B, Zhang H, Xu C, et al. Neuroprotective effects of icariin on corticosterone-induced apoptosis in primary cultured rat hippocampal neurons. Brain Res. Feb 23 2011;1375:59-67.

  4. Li WW, Gao XM, Wang XM, et al. Icariin inhibits hydrogen peroxide-induced toxicity through inhibition of phosphorylation of JNK/p38 MAPK and p53 activity. Mutat Res. Mar 15 2011;708(1-2):1-10.

  5. Kim JH, Mun YJ, Im SJ, et al. Effects of the aqueous extract of Epimedii Herba on the induction of oral tolerance in mice. Biol Pharm Bull. Aug 2002;25(8):1000-1005.

  6. Kim JH, Mun YJ, Im SJ, et al. Effects of the aqueous extract of epimedii herba on the antibody responses in mice. Int Immunopharmacol. May 2001;1(5):935-944.

  7. Mao H, Zhang L, Wang Y, et al. [Experimental studies of icariin on anticancer mechanism]. Zhong Yao Cai. Sep 2000;23(9):554-556.

  8. Mao H, Zhang L, Wang Y, et al. [Influence of icariin on cell membrane of highly metastatic human lung tumor cell line]. Zhong Yao Cai. Jan 1999;22(1):35-36.

  9. Guo Y, Zhang X, Meng J, et al. An anticancer agent icaritin induces sustained activation of the extracellular signal-regulated kinase (ERK) pathway and inhibits growth of breast cancer cells. Eur J Pharmacol. May 11 2011;658(2-3):114-122.

  10. In vitro screening of traditional medicines for anti-HIV activity: memorandum from a WHO meeting. Bull World Health Organ. 1989;67(6):613-618.

  11. Hong J, Zhang Z, Lv W, et al. Icaritin synergistically enhances the radiosensitivity of 4T1 breast cancer cells. PLoS One. 2013;8(8):e71347.

  12. Sun L, Chen W, Qu L, et al. Icaritin reverses multidrug resistance of HepG2/ADR human hepatoma cells via downregulation of MDR1 and Pglycoprotein expression. Mol Med Rep. Dec 2013;8(6):1883-1887.

  13. Zhang G, Qin L, Shi Y. Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a 24-month randomized, double-blind and placebo-controlled trial. J Bone Miner Res. Jul 2007;22(7):1072-1079.

  14. Ye HY, Lou YJ. Estrogenic effects of two derivatives of icariin on human breast cancer MCF-7 cells. Phytomedicine. Nov 2005;12(10):735-741.

  15. Wang GJ, Tsai TH, Lin LC. Prenylflavonol, acylated flavonol glycosides and related compounds from Epimedium sagittatum. Phytochemistry. Oct 2007;68(19):2455-2464.

  16. Dell’Agli M, Galli GV, Dal Cero E, et al. Potent inhibition of human phosphodiesterase-5 by icariin derivatives. J Nat Prod. Sep 2008;71(9):1513-1517.

  17. Sun X, Sun X, Jin X, et al. Icariin induces mouse embryonic stem cell differentiation into beating functional cardiomyocytes. Mol Cell Biochem. Mar 2011;349(1-2):117-123.

  18. Tong JS, Zhang QH, Huang X, et al. Icaritin causes sustained ERK1/2 activation and induces apoptosis in human endometrial cancer cells. PLoS One. 2011;6(3):e16781.

  19. Metz D, Weston P, Barker D. Case report of vasculitic rash induced by Ginkgo biloba and/or Horny Goat Weed. BMJ Case Rep. 2009;2009.

  20. Partin JF, Pushkin YR. Tachyarrhythmia and hypomania with horny goat weed. Psychosomatics. Nov-Dec 2004;45(6):536-537.

  21. Ma H, He X, Yang Y, et al. The genus Epimedium: an ethnopharmacological and phytochemical review. J Ethnopharmacol. Apr 12 2011;134(3):519-541.

  22. Yu C, Chai X, Yu L, et al. Identification of novel pregnane X receptor activators from traditional Chinese medicines. J Ethnopharmacol. Jun 14 2011;136(1):137-143.

  23. Fan C, Yang Y, Liu Y, et al. Icariin displays anticancer activity against human esophageal cancer cells via regulating endoplasmic reticulum stress-mediated apoptotic signaling. Sci Rep. 2016 Feb 19;6:21145.

  24. Song J, Zhong R, Huang H, et al. Combined treatment with Epimedium koreanum Nakai extract and gefitinib overcomes drug resistance caused by T790M mutation in non-small cell lung cancer cells. Nutr Cancer. 2014;66(4):682-9.