Vitex agnus-castus dry extract BNO 1095 (Cyclodynon®) inhibits uterine hyper-contractions and inflammation in experimental models for primary dysmenorrhea

J. Röhrl, O. Werz, A. Ammendola, G. Künstle

Abstract


Background. For many women, the monthly suffering induced by menstrual “cramps” is severe enough to profoundly disrupt their quality of life. In the case of primary dysmenorrhea, a condition related to premenstrual syndrome (PMS), intense uterine contractions are thought to trigger moderate to intense pain despite the absence of an underlying infection or other medically-identifiable disease states. The associated uterine hyper-contractility is reminiscent of labor, and associated pain is likely to be mediated by the release of prostaglandins, leukotrienes and the infiltration of leukocytes that normally accompany the breakdown of the endometrial lining.

Standardized extracts of Vitex agnus-castus berries (VAC extracts of chaste tree, or chaste berries) are clinically effective in treating the symptoms of PMS, yet the mechanisms of how the chemically complex mixture acts are largely unknown.

Methods. Using an in vivo dysmenorrhea model rats were treated with 10 mg/kg estradiol-benzoate i.p. once daily for 12 days and with 2.1, 10.3 or 20.7 mg/kg VAC dry extract p.o. once daily for 7 days prior to induction of convulsions. Uterine contractions where induced with 2 IU/kg oxytocin i.p., followed by monitoring of abdominal convulsions and signs of pain on the last day of the experiment. Moreover, in vitro methods were applied that are described in the methods section.

Results. Here, we show that the VAC herbal dry extract BNO 1095 (commercially available as Cyclodynon®) targets the uterine myometrial tissue and inflammatory signaling molecules of associated migratory/inflammatory cells. Specifically, BNO 1095 dose-dependently inhibited oxytocin-induced uterine contractions in a rat dysmenorrhea model in vivo and drug-induced contractions in isolated human and rat uterine tissue in vitro. Furthermore, BNO 1095 showed a promising anti-inflammatory capacity by potently inhibiting 5-lipoxygenase activity and leukotriene production and by reducing the production of reactive oxygen species and inflammatory cytokines in vitro.

Conclusion. These results provide evidence that BNO 1095 effectively treats menstruation-related complaints including primary dysmenorrhea.


Keywords


cytokines; dysmenorrhea; leukotriene; lipoxygenase; menstrual complaints; premenstrual syndrome; spasmolytic; Vitex agnus-castus; Cyclodynon

References


Dawood, M.Y. “Primary dysmenorrhea: advances in pathogenesis and management.” Obstet Gynecol 108.2 (2006):428–41.

Dickerson, L.M., Mazyck, P.J., Hunter, M.H. “Premenstrual syndrome.” Am Fam Physician 67.8 (2003): 1743–52.

Maybin, J.A., Critchley, H.O., Jabbour, H.N. “Inflammatory pathways in endometrial disorders.” Mol Cell Endocrinol 335.1 (2011): 42–51.

Evans, J., Salamonsen, L.A. “Inflammation, leukocytes and menstruation.” Rev Endocr Metab Disord 13.4 (2012): 277–88.

Finn, C.A. “Implantation, menstruation and inflammation.” Biol Rev Camb Philos Soc 61.4 (1986):313–28.

Salamonsen, L.A., Woolley, D.E. “Menstruation: induction by matrix metalloproteinases and inflammatory cells.” J Reprod Immunol 44.1–2 (1999): 1–27.

Lundstrom, V. “The myometrial response to intra-uterine administration of PGF2alpha and PGE2 in dysmenorrheic women.” Acta Obstet Gynecol Scand 56.3 (1977): 167–72.

Ben-Jonathan, N., Hnasko, R. “Dopamine as a prolactin (PRL) inhibitor.” Endocr Rev 2.6 (2001): 724–63.

Durain, D. “Primary dysmenorrhea: assessment and management update.” J Midwifery Womens Health 49.6 (2004): 520–8.

Sugino, N., Karube-Harada, A., Kashida, S., et al. “Differential regulation of copper-zinc superoxide dismutase and manganese superoxide dismutase by progesterone withdrawal in human endometrial stromal cells.” Mol Hum Reprod 8.1 (2002): 68–74.

Sugino, N., Karube-Harada, A., Taketani, T., et al. “Withdrawal of ovarian steroids stimulates prostaglandin F2alpha production through nuclear factor-kappa B activation via oxygen radicals in human endometrial stromal cells: potential relevance to menstruation.” J Reprod Dev 50.2 (2004): 215–25.

King, A.E., Critchley, H.O. “Oestrogen and progesterone regulation of inflammatory processes in the human endometrium.” J Steroid Biochem Mol Biol 120.2–3 (2010): 116–26.

Abu, J.I., Konje, J.C. “Leukotrienes in gynaecology: the hypothetical value of antileukotriene

therapy in dysmenorrhoea and endometriosis.” Hum Reprod Update 6.2 (2000): 200–5.

Nigam, S., Benedetto, C., Zonca, M., et al. “Increased concentrations of eicosanoids and plateletactivating factor in menstrual blood from women with primary dysmenorrhea.” Eicosanoids 4.3 (1991): 137–41.

Carraher, R., Hahn, D.W., Ritchie, D.M., McGuire, J.L. “Involvement of lipoxygenase products in myometrial contractions.” Prostaglandins 26.1 (1983): 23–32.

Institut für Demoskopie Allensbach. Naturheilmittel 2010. Ergebnisse einer bevölkerungsrepresentativen Befragung. Available from: [http://www.ifd-allensbach.de/uploads/tx_studies/7528_Naturheilmittel_2010.pdf], last accessed Oct 2 2017.

European Medicines Agency, Committee on Herbal Medicinal Products. Community herbal monograph on Vitex agnus castus L., fructus (2010). EMA/HMPC/144006/2009, Google Scholar.

Berger, D., Schaffner, W., Schrader, E., et al. “Efficacy of Vitex agnus castus L. extract Ze 440 in patients with pre-menstrual syndrome (PMS).” Arch Gynecol Obstet 264.3 (2000): 150–3.

Carmichael, A.R. “Can Vitex Agnus Castus be Used for the Treatment of Mastalgia? What is the Current Evidence?” Evid Based Complement Alternat Med 5.3 (2008): 247–50.

Schellenberg, R. “Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study.” BMJ 322.7279 (2001): 134–7.

Halaska, M., Beles, P., Gorkow, C., Sieder, C. “Treatment of cyclical mastalgia with a solution containing a Vitex agnus castus extract: results of a placebo-controlled double-blind study.” Breast 8.4 (1999): 175–81.

Afifi, F.U., Khalil, E., Abdalla, S. “Effect of isoorientin isolated from Arum palaestinum on uterine smooth muscle of rats and guinea pigs.” J Ethnopharmacol 65.2 (1999): 173–7.

Borghi, S.M., Carvalho, T.T., Staurengo-Ferrari, L., et al. “Vitexin inhibits inflammatory pain in mice by targeting TRPV1, oxidative stress, and cytokines.” J Nat Prod 76.6 (2013): 1141–9.

European Medicines Agency, Committee on Herbal Medicinal Products. Assessment report on Vitex agnus-castus L., fructus (2010). EMA/HMPC/144003/2009, Google Scholar.

Hajdu, Z., Hohmann, J., Forgo, P., et al. “Diterpenoids and flavonoids from the fruits of Vitex agnuscastus and antioxidant activity of the fruit extracts and their constituents.” Phytother Res 21.4 (2007): 391–4.

Hogner, C., Sturm, S., Seger, C., Stuppner, H. “Development and validation of a rapid ultra-high performance liquid chromatography diode array detector method for Vitex agnus-castus.” J Chromatogr B Analyt Technol Biomed Life Sci 927 (2013): 181–90.

Jarry, H., Leonhardt, S., Gorkow, C., Wuttke, W. “In vitro prolactin but not LH and FSH release is inhibited by compounds in extracts of Agnus castus: direct evidence for a dopaminergic principle by the dopamine receptor assay.” Exp Clin Endocrinol 102.6 (1994): 448–54.

Meier, B., Berger, D., Hoberg, E., et al. “Pharmacological activities of Vitex agnus-castus extracts in vitro.” Phytomedicine 7.5 (2000): 373–81.

Sliutz, G., Speiser, P., Schultz, A.M., et al. “Agnus castus extracts inhibit prolactin secretion of rat pituitary cells.” Horm Metab Res 25.5 (1993): 253–5.

Wuttke, W., Jarry, H., Christoffel, V., et al. “Chaste tree (Vitex agnus-castus) – pharmacology and clinical indications.” Phytomedicine 10.4 (2003): 348–57.

Winterhoff, H. “Die Hemmung der Laktation bei Ratten als indirekter Beweis für die Senkung von Prolaktin durch Agnus castus.” Zeitschrift für Phytotherapie (Sonderdruck) 12.6 (1991): 175–9.

Sotocinal, S.G., Sorge, R.E., Zaloum, A., et al. “The Rat Grimace Scale: a partially automated method for quantifying pain in the laboratory rat via facial expressions.” Mol Pain 7.55 (2011).

Goldstein, L.B., Davis, J.N. “Beam-walking in rats: studies towards developing an animal model of functional recovery after brain injury.” J Neurosci Methods 31.2 (1990): 101–7.

Flierl, M.A., Stahel, P.F., Beauchamp, K.M., et al. “Mouse closed head injury model induced by a weight-drop device.” Nat Protoc 4.9 (2009): 1328–37.

Fischer, L., Szellas, D., Radmark, O., et al. “Phosphorylation and stimulus-dependent inhibition of cellular 5-lipoxygenase activity by nonredox-type inhibitors.” FASEB J 17.8 (2003): 949–51.

Werz, O., Burkert, E., Samuelsson, B., et al. “Activation of 5-lipoxygenase by cell stress is calcium independent in human polymorphonuclear leukocytes.” Blood 99.3 (2002): 1044–52.

Bartsch, O., Bartlick, B., Ivell, R. “Phosphodiesterase 4 inhibition synergizes with relaxin signaling to promote decidualization of human endometrial stromal cells.” J Clin Endocrinol Metab 89.1 (2004): 324–34.

Franova, S., Janicek, F., Visnovsky, J., et al. “Uterorelaxant effect of PDE4-selective inhibitor alone and in simultaneous administration with beta2-mimetic on oxytocininduced contractions in pregnant myometrium.” J Obstet Gynaecol Res 35.1 (2009): 20–5.

Mehats, C., Tanguy, G., Dallot, E., et al. “Is up-regulation of phosphodiesterase 4 activity by PGE2 involved in the desensitization of beta-mimetics in late pregnancy human myometrium?” J Clin Endocrinol Metab 86.11 (2001): 5358–65.

Oger, S., Mehats, C., Barnette, M.S., et al. “Anti-inflammatory and utero-relaxant effects in human myometrium of new generation phosphodiesterase 4 inhibitors.” Biol Reprod 70.2 (2004): 458–64.

Bieglmayer, C., Hofer, G., Kainz, C., et al. “Concentrations of various arachidonic acid metabolites in menstrual fluid are associated with menstrual pain and are influenced by hormonal contraceptives.” Gynecol Endocrinol 9.4 (1995): 307–12.

Clark, K., Myatt, L. “Prostaglandins and the Reproductive Cycle.” Glob libr women’s med (2008). DOI: 10.3843/GLOWM.10314

Kelly, R.W., Illingworth, P., Baldie, G., et al. “Progesterone control of interleukin-8 production in endometrium and chorio-decidual cells underlines the role of the neutrophil in menstruation and parturition.” Hum Reprod9.2 (1994): 253–8.

Akerlund, M. “Vasopressin and oxytocin in normal reproduction and in the pathophysiology of preterm labour and primary dysmenorrhoea. Development of receptor antagonists for therapeutic use in these conditions.” Rocz Akad Med Bialymst 49 (2004): 18–21.

Chan, W.Y. “Relationship between the uterotonic action of oxytocin and prostaglandins: oxytocin action and release of PG-activity in isolated nonpregnant and pregnant rat uteri.” Biol Reprod 17.4 (1977): 541–8.

Calis, K., Erogul, M., Popat, V., et al. “Dysmenorrhea.” Medscape (2015). Available from: [http://emedicine.medscape.com/article/253812-overview], last accessed Oct 2 2017.

Stöppler, M., Shiel, W. “Menstrual Cramps (Dysmenorrhea).” MedicineNetcom (2015). Available from: [http://www.medicinenet.com/menstrual_cramps/article.htm], last accessed Oct 2 2017.

Ignacak, A., Kasztelnik, M., Sliwa, T., et al. “Prolactin – not only lactotrophin. A “new” view of the “old” hormone.” J Physiol Pharmacol 63.5 (2012): 435–43.

Bigazzi, M., Nardi, E. “Prolactin and relaxin: antagonism on the spontaneous motility of the uterus.” J Clin Endocrinol Metab 53.3 (1981): 665–7.

Lessing, J.B., Brenner, S.H., Weiss, G. “Effect of prolactin and relaxin on in vitro rat uterine contractions and prolactin interaction with relaxin.” Obstet Gynecol 64.1 (1984): 97–100.

Critchley, H.O., Jones, R.L., Lea, R.G., et al. “Role of inflammatory mediators in human endometrium during progesterone with drawal and early pregnancy.” J Clin Endocrinol Metab 84.1 (1999): 240–8.

Saglam, H., Pabuccuoglu, A., Kivcak, B. “Antioxidant activity of Vitex agnus castus L. extracts.” Phytother Res 21.11 (2007).

Sarikurkcu, C., Arisoy, K., Tepe, B., et al. “Studies on the antioxidant activity of essential oil and different solvent extracts of Vitex agnus castus L. fruits from Turkey.” Food Chem Toxicol 47.10 (2009): 2479–83.

Choudhary, M.I., Azizuddin, C., Jalil, S., et al. “Antiinflammatory and lipoxygenase inhibitory compounds from Vitex agnus-castus.” Phytother Res 23.9 (2009): 1336–9.


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DOI: https://doi.org/10.18370/2309-4117.2017.37.78-88

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