Menstrual disorders. Cefak KG. Active ingredient: extract from chaste tree fruits. since 1948

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1 Menstrual disorders Active ingredient: extract from chaste tree fruits Cefak KG since

2 Cefak KG Phone +49 (0) 8 31 / Fax +49 (0) 8 31 / Mail Cefak KG. P.O. Box D Kempten/Germany Cefak KG. Ostbahnhofstr. 15. D Kempten/Germany cefak@cefak.com Internet Rev.: 10/2009

3 List of contents page Chaste tree fruits - effective without hormones in case of menstrual disorders, premenstrual syndrome and mastodynia 4 Endocrine gynaecological functional disorders 4 Menstrual irregularities, premenstrual syndrome (PMS), mastodynia 4 Commonness: high prolactin levels 5 Chaste tree fruits a wise therapeutic approach 5 Botany 6 Pharmacology 6 Ingredients determining efficacy 6 Effects 7 Mechanism of action 7 Toxicology 7 Fields of application 8 Clinical efficacy 8 Rational phytotherapy with Vitex agnus castus 8 Contra-indications 10 Tolerability 10 Interaction 10 Kind and duration of application 10 Cefanorm - advantages at a glance 11 Basic information 11 Monograph 13 Literature 15 3

Chaste tree fruits - effective without hormones in case of menstrual disorders, premenstrual syndrome and mastodynia Today, Chaste tree (monk s pepper, Vitex agnus castus) plays an important role in

4 Chaste tree fruits - effective without hormones in case of menstrual disorders, premenstrual syndrome and mastodynia Today, Chaste tree (monk s pepper, Vitex agnus castus) plays an important role in gynaecology as a therapy with hormone preparations often is not reasonable due to the high potential of side effects and should therefore not be used at all for certain diseases. The fruits of the Chaste tree (Agni casti fructus) are used successfully for the treatment of menstrual disorders, premenstrual syndrome and mastodynia. A therapy with Chaste tree often alleviates the complaints clearly or even eliminates them. In addition to somatic complaints (feelings of swelling and tension in the breasts, headache, edema, abdominal bloating, constipation), also the psychic impairments (irritability, depressive moods, nervousness) are improved demonstrably. In the longterm, this results in a stabilisation of the female hormonal regulative circle. Endocrine gynaecological functional disorders Menstrual irregularities, premenstrual syndrome (PMS), mastodynia Menstrual irregularities can be characterised as absence (secondary amenorrhea) as well as too rarely (oligomenorrhea) or too frequently (polymenorrhea) occurring of menstrual outflows. A hyperprolactinemia can often be verified whereas the level of prolactin correlates with the severity of the cycle disorders. By means of a reduction of the prolactin level, normal cycle functions mostly can be restored. The premenstrual syndrome is a complex of complaints consisting of somatic (headache, painful swelling resp. hyperaesthesia of the breasts, breast tension, edema) and psychic complaints (psychic states of tension, nervousness, restlessness, anxiety, decrease in vitality, lack of concentration, emotional changes, depressions) which start before menstruation and disappear with menstruation. The etiology is largely unexplained. Increased estrogen/progesterone-quotients, hyperprolactinemia and excessive neurotransmitter effects as a result of hormonal change-over at the end of the cycle are discussed among others. 4

5 Mastodynia can mostly be described as painful tension and swelling of the mammary gland, which in general increases in the second half of the cycle and decreases after onset of the period. Secretory anomalies of prolactin have to be considered as releasing factor. mamilla Commonness: high prolactin levels lactiferous gland (mammary gland) Premenstrual syndrome, cycle disorders, infertility. All these complaints and clinical pictures have something in common: They are associated to high prolactin levels. Thus, menstrual and fertility disorders are closely related with an excessive secretion of prolactin from the lactogenic cells of the hypophysis. Hyperprolactinemia is one of the most frequent reasons for a corpus luteum insufficiency. The premenstrual syndrome with its direct symptom of mastodynia is attributed to a latent hypersecretion of prolactin. That means that due to a stimulus, the lactogenic cells of the hypophysis temporarily release unphysiologic amounts of prolactin. Thereby, the mammary gland is stimulated chronically and reacts with typical mastodynia symptoms such as pain and feeling of tension. Chaste tree fruits a wise therapeutic approach A wise therapeutic approach is now to restrict the excessive release of prolactin, possible by influencing the dopaminergic system. The neurotransmitter dopamine acts as natural inhibitor of the release of prolactin from the adenohypophysis. But this approach has not proved its worth as dopamine is instable and is quickly transferred into its inactive form in the organism. Interestingly, preparations from Chaste tree contain dopaminagonists. Investigations have shown that certain ingredients of the extract (probably bi-cyclic diterpenes) bind to the dopamine receptor from type 2 of the lactogenic hypophyseal cells. That way, the release of prolactin can be restricted. A simple but effective mechanism of action! 5

Botany Chaste tree Chaste tree is a shrub up to 4 m high. The leaves are crossed-opposite, long-stemmed and separated finger-shaped with up to 7 lanceolate feathered small leaves.

Family: Verbenaceae (vervain plants) Synonyms: Origin: Monk s pepper, Mönchspfeffer, Keuschlamm, Abrahamstrauch Mediterranean area, Central Asia, Isle Krim.

6 Botany Chaste tree Chaste tree is a shrub up to 4 m high. The leaves are crossed-opposite, long-stemmed and separated finger-shaped with up to 7 lanceolate feathered small leaves. The mauve, ear-like inflorescences build reddish-black, peppercorn-sized drupes. Time of prosperity: June to September Vitex agnus castus L. Family: Verbenaceae (vervain plants) Synonyms: Origin: Monk s pepper, Mönchspfeffer, Keuschlamm, Abrahamstrauch Mediterranean area, Central Asia, Isle Krim. Preferably also on brooksides and riversides. Medicinal drug: Chaste tree fruits (Agni casti fructus), consisting of the ripe, dried fruits. Pharmacology A positive monograph of the BfArM (Federal Institute for Drugs and Medical Devices), Commission E, exists for the active ingredient Chaste tree fruits. Ingredients determining efficacy iridoid glycosides (aucubin, agnoside) lipophile flavonoids essential oil fatty oil 6

7 Effects inhibition of the prolactin secretion and thus, reduction of increased prolactin levels dopaminergic effect (central nervous component by influence on the catecholamine excretion) balancing on the prolactin level (inhibition of prolactin secretion of the hypophysis in case of too high prolactin level, increase in case of too low level) inhibition of lactation (experiments in animals) Mechanism of action For Vitex agnus castus a prolactin-inhibiting effect as a result of a dopaminergic effect was shown by cell-biological and animal experimental investigations. The effect aims at the hypophyseal portal system. Dopaminergic principle of effect: Selective stimulation of dopamine-2-receptors at the hypophyseal, so-called lactogenic cells. Thereby, the effect of the Chaste tree fruits is dependent on dose and initial situation, i.e. in case of low prolactin level, the secretion is increased, in case of high values, the release is inhibited. The most recent results of the pharmacological profile of an extract from Vitex agnus castus show an outstanding affinity to the dopamine-d3-receptor which is mainly located in the mesolimbic system. On the human estrogen-a-receptor no affinity was observed which is important from the safety point of view. Therefore, there is no direct danger for the proliferation of breast cancer cells. Toxicology Systematic investigations with regard to toxicology do not exist. 7

8 Fields of application Traditional Chaste tree was already used in the antique for women s diseases, especially for fertility disorders. The present common Latin name Agnus castus is derived from the Latin castus (chaste) and the equalisation with agnus (lamb). According to the Greek mythology, the goddess Hera - adored as guardian of the marriage - was born below an Agnus castus shrub. Even nowadays the branches of Vitex agnus castus are considered to be a symbol for chastity. Thus, the German names Keuschlamm and Mönchspfeffer can be explained. Gynaecology For all symptoms of corpus luteum insufficiency and estrogen-progesterone-imbalance. Clinical efficacy Rational phytotherapy with Vitex agnus castus Menstrual irregularities Roeder realised a controlled study against placebo in which the efficacy for elimination of menstrual irregularities is verified clearly. It was also shown that increased prolactin levels, existing before start of the therapy, could be reduced during the treatment (12). The effect can also be understood from the pharmacological point of view as menstrual disorders are frequently related to a corpus luteum insufficiency. Thus, the luteinizing effect of a preparation from Chaste tree fruits has a positive influence on the events. Premenstrual syndrome The premenstrual syndrome is based on a hormonal imbalance whereas finally it is not clarified if a too high estrogen level or a too low gestagen level is responsible. Again, the luteinizing effect is reasonable from the therapeutic point of view in order to restore the disordered balance and to improve the symptoms. 8 By means of an Agnus castus extract it is possible to alleviate the premenstrual complaints of the affected women efficiently, mostly the effect can be noted after 1 to 2 months. In the meantime, these results have been confirmed by open clinical mono resp. multicentre long-term studies (2, 7). The most frequent and most

9 important symptoms such as headache, breast tension, peripheral edema, psychic states of tension, nervousness, restlessness, anxiety, aggressions, decrease in vitality, lack of concentration, emotional changes and depressions showed a clear improvement. Double-blind study: The treatment of PMS with monk s pepper is effective A placebo-controlled, randomised double-blind study investigated the influence of monk s pepper for PMS. 87 women received one tablet Agnus castus daily and 91 women received placebo over a period of 3 menstrual cycles. 90 % of all women finished the study. From the statistical point of view, Agnus castus proved to be significantly more effective than placebo in the treatment of premenstrual complaints. The symptoms improved in 52 % of the women in the verum group. In the investigated variables irritability, mood swings, aggressiveness, headache, breast tensions and other premenstrual syndromes, a significant reduction to placebo could be shown (13). Mastodynia In general, mastodynia can not be described as an independent clinical picture but rather as a symptom within the scope of the premenstrual syndrome. Likewise, a positive influence can be noted. The active ingredients of the extract have an impact on the release of the neurotransmitter dopamine and thus, normalise the release of prolactin in the hypophysis. That way, the inconvenient feeling of tension and swelling in the breast before menstruation is reduced. These results could be confirmed in a double-blind, randomised comparative clinical trial with female patients suffering from cyclically recurrent mastodynia (5). Two double-blind studies according to GCP-guidelines Two further randomised, placebo-controlled double-blind studies were carried out in female patients with painful mastodynia over 3 cycles according to the GCP-guidelines (Good Clinical Practise). For the evaluation of the efficacy, the intensity of the breast pains had to be marked on a visual pain scale. At the end of the study, the difference between verum and placebo was significant. Verum did not have any influence on progesterone, FSH (follicle-stimulating hormone) and LH (luteinizing hormone). The 17β-estradiol-values dropped more strongly under verum than under placebo. After verum, the basal prolactin values were significantly below the placebo values (8). Fertility disorders In a randomised double-blind study, 37 women suffering from fertility disoders because of latent hyperprolactinemia were treated over 3 months. In the group of women treated with verum, the release of prolactin after stimulation decreased significantly. The duration of the menstrual cycles remained the same in both groups. Whereas the duration of the luteal phases remained constant in the placebo group, 9

10 it increased clearly from 5.5 to 10.5 days under therapy with Agnus castus. Mid-luteally suppressed progesterone- and 17β-estradiol levels increased under the extract. After the end of the treatment, only 2 of 9 women complained about premenstrual disorders, 2 women of the verum group became pregnant (11). As shown by further investigations, it is worth to use Chaste tree in case of an unfulfilled desire for children. Preparations from Chaste tree fruits normalise the functions of corpus luteum. Therefore, the extract can help in cases where the infertility is attributed to disorders in the production of corpus luteum. Contra-indications Preparations from Chaste tree fruits should not be taken in when suffering from hypersensitivity to Chaste tree. So far it is not known if Agnus castus could influence tumours of the hypophysis or the mammary gland. Therefore, patients suffering from hypophyseal tumours and mamma carcinoma should be excluded from the therapy. Based on the mechanism of action, a use in pregnancy seems not to be reasonable and should not be taken into consideration with regard to the indication either. Experiments in animals show an impairment of milk production. Tolerability Rarely there can be itching, urticarial skin changes. In case of allergic reactions, the intake of the medicament has to be stopped. Interaction Due to the postulated dopaminergic effect, an alternating weakening of the effect is possible in case of administration of dopamine-receptor-antagonists. Kind and duration of application Preparations from Chaste tree fruits should always be taken in at the same time of day and at least over 3 menstrual cycles. 1 capsule daily resp drops once daily. This corresponds to the effective daily dose stipulated in the monograph. Risks from an intake on a long-term basis are not apparent. 10

Cefanorm - advantages at a glance normalises cycle disorders in a natural and gentle way stimulates corpus luteum reduces prolactin level does not contain any hormones Basic information Fields of

11 Cefanorm - advantages at a glance normalises cycle disorders in a natural and gentle way stimulates corpus luteum reduces prolactin level does not contain any hormones Basic information Fields of application: irregularities of the menstrual cycle, sensations of tension and swelling in the breasts (mastodynia), monthly recurring complaints before the onset of the menstruation (premenstrual symptoms). In the leaflet the following is pointed out to the patient: in case of feelings of tension and swelling in the breasts as well as disorders in menstruation, a physician should be consulted since there may be underlying diseases for which a medical examination may be essential. Composition: Active ingredient: Hard capsules: 1 hard capsule contains: dry extract from chaste tree fruits (7-13 : 1) 4 mg. Extraction solvent: ethanol 60% (m/m). Drops: 100 g (= 109 ml) contain: (1 ml corresponds to 40 drops) tincture from chaste tree fruits (1:5) 20 g. Extraction solvent: ethanol 70% v/v. Excipients: Hard capsules: glucose syrup, lactose monohydrate, talc, maize starch, magnesium stearate, colloidal anhydrous silica, gelatin, sodium laurilsulfate (dodecylsulfate), purified water, dyestuff E171. Drops: ethanol 96%, purified water. Contra-indications: Cefanorm must not be used in case of - hypersensitivity to chaste tree fruits (monk s pepper) or to one of the excipients of the pharmaceutical - hypophyseal tumour - mammary carcinoma. Application during pregnancy and lactation: due to not sufficient investigations and because of the alcohol content of the drops, Cefanorm 11

12 must not be taken in during pregnancy and lactation. After administration of chaste tree fruits (monk s pepper) an impairment of milk production was observed in animal experiments. Additionally for drops: do not apply in case of alcohol disease. Due to the alcohol content, Cefanorm drops should only be taken in by liver patients, epileptics, brain patients or braindamaged patients after consultation of a physician. Interactions with other substances: interactions are not known. There are references - based on experiments in animals - to a dopaminergic effect of the drug; thus an alternating weakening of the effect could be possible in case of administration of dopamine-receptor-antagonists. Warning: Hard capsules: patients suffering from the rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption, should not take Cefanorm. Drops: Cefanorm drops contain 55 vol.-% alcohol. Dosage: Hard capsules: intake of 1 hard capsule daily (corresponding to 40 mg drug). Drops: unless otherwise prescribed, adults take in drops in the morning before eating and drinking. Kind and duration of application: Hard capsules: Cefanorm hard capsules should preferably always be taken in at the same time of day. Drops: Cefanorm drops are taken in diluted with some liquid (e.g. water). The preparation should be taken in over 3 menstrual cycles at least. Undesirable effects: Hard capsules: occasionally headache, itching, abdominal complaints such as nausea, stomach ache or pains in the lower abdomen as well as systemic hypersensitivity reactions with exanthema, urticaria, facial swelling, dyspnea and swallowing complaints. Drops: after intake of pharmaceuticals containing chaste tree fruits, headache, itching, abdominal complaints such as nausea, stomach ache or pains in the lower abdomen are described. Cases of systemic hypersensitivity reactions with exanthema, urticaria, Quinke edema, dyspnea and swallowing complaints are described as well. In the leaflet, the patient is instructed to stop the intake and immediately consult a physician in case of signs of hypersensitivity reactions. In the leaflet, the following is pointed out to the patient: in case of occurrence of above mentioned undesirable effects, stop the intake of the preparation and consult a physician. If you notice undesirable effects, not mentioned in this leaflet, inform your physician or pharmacist. Commercial forms: Hard capsules: 30 pcs., 60 pcs., 100 pcs. Drops: 100 ml 12

13 Monograph Chaste Tree fruit, Agni casti fructus Official Monograph of the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) (German Federal Institute for Drugs and Medical Devices) Commission E (Phytotherapy), BAnz.-No. 226 dated December 02, 1992 Name of Drug Agni castus fructus; chaste tree fruit, vitex fruit. Composition of Drug Chaste tree fruit composed of the ripe, dried fruits of Vitex agnus castus L. [Fam. Verbenaceae], as well as their preparations in effective dosage. Pharmacological Properties, Pharmacokinetics, Toxicology There is evidence that aqueous-alcoholic extracts of chaste tree fruit inhibit secretion of prolactin in vitro. In human pharmacology there are no data about the lowering of prolactin levels. There is no knowledge regarding pharmacokinetics. Systematic studies about toxicology are unknown. Clinical data 1. Uses Irregularities of the menstrual cycle. Premenstrual complaints. Mastodynia. Note: In case of feeling of tension and swelling of the breasts and at disturbances of menstruation, a physician should be consulted for diagnosis. 2. Contraindications None known. 3. Undesirable Effects Occasional occurrence of itching, urticarial exanthemas. 4. Special Cautions for Use None known. 5. Use During Pregnancy and Lactation No application during pregnancy. In animal experiments an influence on the nursing performance was observed. 6. Interactions with Other Drugs Interactions are unknown. In animal experiments there is evidence of a dopaminergic effect of the drug; therefore, a reciprocal weakening of the effect can occur in case of ingestion of dopamine-receptor antagonists. 13

14 7. Dosage Unless otherwise prescribed: Daily dosage: aqueous-alcoholic extracts corresponding to mg of the drug. 8. Mode of Administration Aqueous-alcoholic extracts (50 70 percent v/v) from the crushed fruits taken as liquid or dry extract. 9. Overdosage None known. 10. Special warnings None known. 11. Effects on Operators of Vehicles and Machines None known. 14

15 Literature 1 Chaste Tree fruit, Agni casti fructus: Official Monograph of the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) (German Federal Institute for Drugs and Medical Devices) Commission E (Phytotherapy), BAnz.-No. 226 dated December 02, Berger D, Schaffner W, Schrader E, Meier B, Brattstrom A, (2000): Efficacy of Vitex agnus castus L. extract Ze 440 in patients with premenstrual syndrome (PMS). Arch Gynecol Obstet. Nov; 264 (3): ESCOP-Monographs, (2003): Herbal Medicinal Products, G. Thieme Verlag, Stuttgart 4 Hänsel, et al. (Hrgs.), (1994): Vitex. Auszug aus Hagers Handbuch der pharmazeutischen Praxis, Band 6, Drogen P - Z.: Springer-Verlag, Halaska M, Beles P, Gorkow C, Sieder C, (1999): Treatment of cyclical mastalgia with a solution containing a Vitex agnus castus extract: results of a placebo-controlled double-blind study. Breast. 8 (4): Houghton P, (1994): 4. Agnus Castus. The Pharmaceutical Journal (Vol. 253), Loch EG, Selle H, Boblitz N, (2000): Treatment of premenstrual syndrome with a phytopharmaceutical formulation containing Vitex agnus castus. J Womens Health Gend Based Med. 9 (3): Loew D, Habs M, Klimm HD, Trunzler G, (1999): Phyto-Pharmaka Report. Rationale Therapie mit pflanzlichen Arzneimitteln. Steinkopff, Darmstadt 9 Meier B, Berger D, Hoberg E, Sticher O, Schaffner, (2000): Pharmacological activities of Vitex agnuscastus extracts in vitro. Phytomedicine 7 (5): Meier B, Hoberg E, (1999): Agni-casti fructus. Neue Erkenntnisse zur Qualität und Wirksamkeit. Zeitschrift für Phytotherapie 20: Milewicz A, Gejdel E, Sworen H, Sienkiewicz K, Jedrzejak J, Teucher T, Schmitz H, (1993): [Vitex agnus castus extract in the treatment of luteal phase defects due to latent hyperprolactinemia. Results of a randomized placebo-controlled double-blind study] Arzneimittelforschung 43 (7): Roeder D, (1994): Therapie von Zyklusstörungen Vitex agnus-castus. Zeitschrift für Phytotherapie 15, Schellenberg R, et al., (2001): Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomized, placebo controlled study. BMJ 322: Schilcher H, Kammerer S, (2003): Leitfaden Phytotherapie. 2. Auflage Urban & Fischer 15 Weiß RF, (1991): Vitex agnus castus. Auszug aus dem Lehrbuch der Phytotherapie. Hippokrates Verlag Stuttgart, 7. Auflage, Wenigmann M, (1999): Phytotherapie. Arzneipflanzen Wirkstoffe Anwendung. Urban & Fischer 17 Wuttke W, Gorkow C, Jarry H; (1995): Dopaminergic compounds in Vitex Agnus Castus. In: Phytopharmaka in Forschung und klinischer Anwendung von Loew D, Rietbrock N (Hrsg.), Steinkopff, Darmstadt, Wuttke W, Jarry H, Christoffel V, Spengler B, Seidlova-Wuttke D, (2003): Chaste tree (Vitex agnuscastus)-pharmacology and clinical indications. Phytomedicine May; 10 (4): Van Wyk BE, Wink C, u. Wink M, (2004): Handbuch der Arzneipflanzen, Wiss. Verlagsges.mbH, Stuttgart 15

16 Rev.: 10/2009 since 1948 P.O. Box D Kempten/Germany Cefak KG

Chasteberry Snapshot Monograph

herbs Chasteberry Snapshot Monograph Chasteberry (Vitex agnuscastus) Most Frequent Reported Uses: - Helps balance pituitary function. - Helps balance sex hormonal levels for men and women. - Reported progesterone