Reviewed: van Die MD, Burger HG, Teede HJ, Bone KM. Vitex agnus-castus extracts for female reproductive disorders: a systematic review of clinical trials. Planta Med. November 2012; [epub ahead of print]. doi: 10.1055/s-0032-1327831.

Chaste tree (Vitex agnus-castus, Lamiaceae) berry (VAC) is used for a range of female reproductive conditions, including premenstrual syndrome (PMS) and associated cyclic mastalgia (breast pain), premenstrual dysphoric disorder (PMDD; severe PMS), lactation difficulties, low fertility, and menopause-related complaints. These authors conducted a systematic review to evaluate the evidence of the efficacy and safety of VAC extracts from randomized, controlled trials (RCTs) investigating the effects of various VAC preparations on women’s health.

The authors searched the following electronic databases from earliest publication to 2012: Medline, PubMed, EMBASE, The Cochrane Library, CINAHL, Ovid, Google Scholar, and Web of Science. They searched for RCTs, including crossover trials, of VAC versus placebo or a comparator treatment, with no language restrictions. They extracted details of trial design, duration and setting, condition under investigation, sample size, participants, outcome measures, adverse events, and results. The Jadad scale and the Cochrane risk of bias were used to measure the trials’ methodological quality.

Thirteen trials were identified; twelve trials met the inclusion criteria for this review. Three of the trials continued for two menstrual cycles or months, one continued for six cycles, and eight lasted for three cycles or months; one of them, after a two-month washout, re-administered the same extract treatment on only the last seven days of the luteal phase for another three-month period. Of the 12 RCTs, eight investigated the effects of VAC extracts in women suffering from PMS,^1-8 two examined VAC in PMDD,^9,10 and the other two investigated latent hyperprolactinemia (LHP) with or without mastalgia.^11,12

Six of the PMS studies were placebo-controlled; one compared the effects of VAC with those of pyridoxine (vitamin B6); and another one compared VAC with magnesium. Both RCTs on PMDD compared VAC extracts with fluoxetine (Prozac®, Eli Lilly & Co.). Of the two trials investigating LHP, one was placebo-controlled and the other compared VAC with bromocriptine (a conventional drug used to treat LHP, among other conditions).

Five studies reported sample-size calculation estimates ranging from 55 to 120 subjects per arm. Six studies included data from more than 100 subjects (ranging from 110 to 217).

Eight different outcome measures were used in the RCTs investigating PMS and PMDD. Symptoms were measured by the premenstrual tension syndrome (PMTS) self-rating scale and the premenstrual syndrome diary (PMSD), as well as visual analogue scales and the Hamilton Rating Scale for Depression.

The authors reported that for PMS, VAC extract was superior to placebo in five of the six studies (with a total of 1067 subjects), leading most of the investigators of those studies to conclude that VAC was effective and well-tolerated for the relief of mild-to-moderate PMS symptoms. It also was superior to pyridoxine in one study (105 subjects).8 In the study comparing the use of VAC to magnesium (82 subjects), PMS symptoms were more improved in the VAC group than in the magnesium group for all variables (back pain, menstrual pain, breast fullness, headache, asthenia, irritability, and sleep disturbances).⁷

Regarding PMDD, one study with 38 subjects reported clinical improvement in both the VAC and fluoxetine groups, with 57.9% of subjects responding to VAC, and 68.4% responding to fluoxetine.¹⁰ The authors proposed that “fluoxetine may be more effective for psychological symptoms while VAC may be more effective for physical symptoms.” In the other PMDD study, with 57 subjects, fluoxetine outperformed VAC on all endpoints — depressed mood, work interests, psychic anxiety, and general somatic symptoms; simultaneously, the VAC group significantly improved on all endpoints.

Of the LHP studies, one trial reported VAC to be superior to placebo in treating luteal phase defects due to LHP, as evidenced by its role in reducing thyrotropin-releasing hormone-stimulated prolactin secretion, normalizing a shortened luteal phase, and increasing mid-luteal progesterone and 17β-estradiol levels. In another study, VAC was comparable to bromocriptine in reducing serum prolactin levels and ameliorating cyclic mastalgia.¹¹

Because of the “range of conditions under investigation, outcome measures, and expression of results,” the authors could perform a meta-analysis on only two of the PMS studies. Combining the results of the multicenter study reporting total PMS symptoms on the PMSD and PMTS scales³ (including 217 subjects) with the outcome reported on the Penn Daily Symptom Report4 (with 116 subjects), VAC showed a greater benefit than placebo.

Adverse events associated with VAC were mild, generally infrequent, and less severe than those reported with fluoxetine or bromocriptine.

The methodological quality of the included studies varied, but was generally moderate to high. Even with the methodological limitations, the RCTs to date appear to support the efficacy and tolerability of VAC extracts in the treatment of PMS, PMDD, and LHP. “However, lack of transparency in the reporting of some studies limits assessment of trial design and, in some cases, results. Future research into Vitex extracts for these conditions would benefit from use of tightly defined patient populations and common endpoints,” concluded the authors.

Agnucaston^® (Bionorica; Neumarkt, Germany), Ze 440 (Zeller AG; Romanshorn, Switzerland), Agnolyt^® (Madaus GmbH; Cologne, Germany), and Monoselect Agnus^® (PharmExtracta; Pontenure, Italy) were among the commercial products used in the trials in which products were specified.

—Shari Henson

References

1. Zamani M, Neghab N, Torabian S. Therapeutic effect of Vitex agnus castus in patients with premenstrual syndrome. Acta Med Iran. 2012;50(2):101-106.
2. Ma L, Lin S, Chen R, Wang X. Treatment of moderate to severe premenstrual syndrome with Vitex agnus castus (BNO 1095) in Chinese women. Gynecol Endocrinol. 2010;26(8):612-616.
3. He Z, Chen R, Zhou Y, et al. Treatment for premenstrual syndrome with Vitex agnus castus: a prospective, randomized, multi-center placebo controlled study in China. Maturitas. 2009;63(1):99-103.
4. Pakgohar M, Moradi M, Jamshidi AH, Mehran A. Assessment of Vitex agnus-castus L. extract effect on treatment of premenstrual syndrome. Journal of Medicinal Plants. 2009;8(32):98-107,185.
5. Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study. BMJ. 2001;322(7279):134-137.
6. Turner S, Mills SY. A double-blind clinical trial on a herbal remedy for premenstrual syndrome: a case study. Complement Ther Med. 1993;1(2):73-77.
7. Di Pierro F, Prazzoli R, Candidi C, Attolico M. Premenstrual syndrome: controlled clinical trial with a fast acting form of a highly standardized extract of Vitex agnus castus. Giorn It Ost Ginecol. 2009;31:153-157.
8. Lauritzen C, Reuter HD, Repges R, Böhnert KJ, Schmidt U. Treatment of premenstrual tension syndrome with Vitex agnus castus controlled, double-blind study versus pyridoxine. Phytomedicine. 1997;4(3):183-189.
9. Ciotta L, Pagano I, Stracquadanio M, Di Leo S, Andò A, Formuso C. Psychic aspects of the premenstrual dysphoric disorders. New therapeutic strategies: our experience with Vitex agnus castus. [Article in Italian]. Minerva Ginecol. 2011;63(3):237-245.
10. Atmaca M, Kumru S, Tezcan E. Fluoxetine versus Vitex agnus castus extract in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol. 2003;18(3):191-195.
11. Kilicdag EB, Tarim E, Bagis T, et al. Fructus agni casti and bromocriptine for treatment of hyperprolactinemia and mastalgia. Int J Gynaecol Obstet. 2004;85(3):292-293.
12. Milewicz A, Gejdel E, Sworen H, et al. Vitex agnus castus extract in the treatment of luteal phase defects due to latent hyperprolactinemia. Results of a randomized placebo-controlled double-blind study. [Article in German]. Arzneimittelforschung. 1993;43(7):752-756.