The premenstrual syndrome, premenstrual mastodynia, fibrocystic mastopathy and infertility have often common roots: effects of extracts of chasteberry (Vitex agnus castus) as a solution
© The Author(s). 2017
Received: 7 January 2016
Accepted: 24 November 2016
Published: 22 March 2017
The dried fruits of the chaste tree Vitex agnus castus (VAC) were traditionally used by monks as a substitute for pepper and was therefore also called Monk’s pepper. For the last 50 years it is commercially provided for the treatment of premenstrual symptoms, particularly to prevent premenstrual mastodynia (mastalgia). Most studies were performed with the preparation containing an aqueous/ethanolic ectract BNO 1095. A number of placebo controlled studies gave proof that extracts of VAC had beneficial effects on premenstrual breast pain. This breast sensation is induced by latent hyperprolactinemia which is characterized by secretory episodes of prolactin release by the pituitary in response to stress and deep sleep phases. This latent hyperprolactinemia induces also often a corpus luteum insufficiency which is a common reason for infertilty.
It is well accepted that prolactin release can be reduced by dopamine and dopaminergic drugs. The efficacy of VAC extracts to ameliorate prolactin induced premenstrual mastodynia was therefore suggestive that VAC may contain dopaminergic compounds. Indeed, a number of diterpenes were identified that bound to recombinant Dopamine receptors of the 2 subtype (D2 receptors) which are present in pituitary lactotropes and which mediate the inhibitory effects of dopamine and dopaminergic drugs on pituitary prolactin release. Consequently, prolactin release in vitro from dispersed pituitary cells and in vivo in rats and postmenopausal women was inhibited by VAC 1095. Placebo controlled studies proved also the efficacy of VAC extracts to ameliorate premenstrual symptoms. In several placebo-controlled studies a clear relation between reduction of breast pain and reduction of serum prolactin levels could be established. In addition VAC extracts was also highly effective in women suffering from fibrocystic mastopathy. In many of these women serum prolactin levels were also elevated and reduced by VAC extracts.
The results from all trials suggested that VAC extracts ameliorated premenstrual symptoms including mastodynia, premenstrual dysphoric disorder and latent hyperprolactinemia. Cystic mastopathy and sterility due to corpus luteum insufficiencies were also beneficially influenced.
Adverse events with VAC were mild and generally infrequent.
Most common Symptoms of the Premenstrual Syndrome (PMS)
1. Somatic symptoms
2. Psychic Symptoms
failure to concentrate
Premenstrual syndrome (PMS), mastodynia, prolactin and infertility
It is currently generally accepted that high and frequently occurring prolactin episodes stimulate proliferation of mammary gland tissue causing the uncomfortable breast sensations, i.e. mastodynia (mastalgia) . Hence, the latent hyperprolactinemia mimicks effects seen during early pregnancy .
Taken together it appears quite clear that latent hyperprolactinemia is a, if not the major cause of premenstrual mastodynia, mastalgia and infertility due to insufficient function of the corpus luteum. It was therefore very early attempted to cure the painful breast sensations by drugs which inhibit pituitary prolactin release. Under physiologic conditions the biogenic amine dopamine inhibits pituitary prolactin release. This has led to development of synthetic drugs with dopaminergic activity which were all derivatives of ergot alkaloids. It became soon clear that decreased prolactin levels under treatment with the dopamine receptor agonist bromocriptine ameliorated the severity of premenstrual mastodynia, an effect not seen in the placebo treated patients [3, 10]. Also, a study addressing the question whether the synthetic dopamine agonist lisuride ameliorates also other PMS symptoms yielded positive results . But these systemic dopaminergic drugs had all severe side effects such as nausea and orthostatic dysregulation .
Treatment options with Vitex agnus castus (VAC)
As mentioned above synthetic dopaminergic drugs ameliorated premenstrual symptoms including mastodynia. Due to severe side effects of these drugs many women do refuse to use conventional treatment with hormones or psychopharmaceuticals and seek often for plant derived alternatives which become therefore increasingly prevalent in the Western world. In this context, the extracts of Vitex agnus-castus fruit (VAC, chaste tree, chasteberry; family: Verbenaceae) are commonly used for the treatment of premenstrual syndrome which-as elaborated above-is often associated by premenstrual mastodynia, premenstrual dysphoric disorder (PMDD) and corpus luteum insufficiency.
Pharmacology of VAC
RadioreceptorassaysThe D2 receptor is nowadays available as recombinant protein. When incubated with radioactively labeled dopamine a large fraction of this labeled amine binds to the receptor and this bound radioactive dopamine can be dose dependently displaced by non labeled dopamine (Fig. 4). When the VAC extract BNO 1095 was added instead of the non labeled dopamine this resulted also in a dose dependent displacement of the labeled dopamine (Fig. 4) indicating binding to the recombinant dopamine receptor and thereby displacing the radioactively labeled dopamine from the receptor.
In vitro studiesRat pituitary cells, kept under culture conditions secrete large amounts of prolactin and this can be effectively inhibited by dopamine and dose dependently by the VAC extract BNO 1095 which is used commercially for the production of Mastodynon and Agnucaston (Fig. 5). The receptor specificity of the extract was proven by the fact that haloperidol, a specific dopamine receptor antagonist prevented the inhibitory effects of dopamine as well as of the VAC extract (Fig. 5).
- 3.In vivo studies
In ratsIt was already mentioned above that stress is a potent stimulus for pituitary prolactin release in women. Also rats react to stress with massive release of prolactin (Fig. 6). When rats were pretreated with the VAC extract BNO 1095 prior to application of an ether stress this prevented prolactin release significantly (Fig. 6).
In womenAlso women suffering from premenstrual mastodynia have supraphysiologic high prolactin pulses resulting premenstrually in supraphysiologic mean prolactin levels (Fig. 1 and 2). Such high prolactin levels can be normalized by the treatment with the BNO 1095 containing extract in Mastodynon and Agnucaston (Fig. 7) . In this and in another trial  the effects of a VAC BNO 1095 containing preparation on premenstrual mastodynia were significantly better than those of placebo (Fig. 7).
In attempts to identify the dopaminergic substances 2 different VAC extracts (one of them was BNO 1095) were shown to contain a number of diterpenes with dopaminergic activities [18, 19]. In addition to these prolactin inhibiting substances VAC extracts were shown to contain flavonoids which bound to μ- and δ-opioid receptors and it was suggested that such compound may also ease premenstrual symptoms .
Effects of VAC preparations in placebo controlled clinical studies on PMS, PMDD, and premenstrual mastodynia
Ref. (only placebo controlled)
Patient Characteristics and Age
Treatment, Dose, and Duration
Finding and Comments
Effects in short No = Ø Signif. pos = + Signif. neg = −
Milewicz et al., 1993 
Randomized, placebo controlled trial
11 VAC extract. 11placebo treated women with PMS and latent hyperprolactinemia, mean age 30 y
20 mg of an extract of VAC dried fruits (Strotan) for 3 months
PMS. Basal and TRHstimulated prolactin, lutael phase progesterone
Reduction of PMS in 9 verum but only in 2 placebo treated women
Turner et al., 1993 
Randomized, double blind placebocontrolled trial
600 verum, 217 soy based placebo. age 18–46 y
3×600 mg/day of a not defined VAC extract, 3 months
Moos Menstrual Distress Questionnaire
No significant effects on all but one item placebo effects better than verum, note however, the extremely high dose
Lauritzen et al., 1997 
Randomized, double blind. comparatorsudy
46 VAC. 57 pyridoxine treated women with PMS, 18–45 y
3.5–4.2 mg dried VAC extract (Agnolyt) vs pyridoxine, 3 cycles
PMS was measured by VAS premenstrual Tension Scale
Significant “excellent” reduction of PMS superior to pyridoxine
Schellenberg et al., 2001 
Randomized, double-blind, placebocontrolled
170 women with PMS Mean age 36 y
86 VAC, 84 placebo treated women with PMS, 3 cycles
20 mg of a VAC extract Ze 440,
Significant reduction of all symptoms in comparison to placebo (except bloating)
Wuttke et al. 1997 
Randomized, double-blind, placebocontrolled
104 patients with premenstrual mastodynia determined by VAS
66 patients treated with 40 mg dried fruit VAC, 38 placebo, 3 cycles
Visual analogue score of mastodynia
Significantly better improvement of mastodynia under both VAC peparations
Halaska et al. 1999 
Randomized, double-blind, placebo controlled
97 patients with premenstrual mastodynia determined by VAS
48 patients with dried VAC fruit, 49 with placebo, 3 cycles
Visual analogue score of mastodynia
Significantly better reduction of mastodynia under VAC
He at al., 2009 
Randomized, double-blind, placebocontrolled trial
101 women verum vs 101 placebo for 3 cycles
40 mg dried fruit powder (equivalent to 4 mg dried extract vs placebo
Moderate to severe forms of PMS assessed by DSM IV and PMTS score greater than 18
Significantly greater improvement under VAC (80%) than under placebo (50%)
Ma et al., 2010 
Randomized, double blind, placebo controlled trial
31 women with verum vs 33 women under placebo, 3 cycles
40 mg dried fruit powder vs placebo given during luteal phase
PMSD score greater 16 points
Significantly greater improvement under VAC (85%) vs placebo (56%)
Kilicdag et al., 2004 
Randomized, double blind comparator controlled trial
40 women with mastodynia and 40 women with latent hyperprolactinemia
2×40 mg dried fruit vs 2×2.5 bromocriptine daily for 3 months
Breast discomfort by VAS
Both treatments were similarly effective Fewer side effects under VAC
Gumenyuk (2010) 
Randomized oprn 3 months
31 with PMS 19 of them PMDy
40 mg VAC(Mastodynon)
PMS, mastodynia, prolactin
Significant reduction of all parameters
Pakgohar et al., 2009 
Randomized, double-blind, placebocontrolled,
39 women with verum, 50 with placebo
4.3–4.8 mg dried VAC extract vs placebo
PMS diagnosed by general practitioner
Improvement significantly better under VAC (61%) vs placebo (29%)
Ciotta et al., 2011 
Randomized, double blind, comparator controlled
31 women under verum vs 26 under fluoxetine, 2 months
20 mg dried fruit powder vs 20–40 mg fluoxetine
DSM IV criteria for severe PMS
Both treatments improved symptoms significantly with better outcome for fluoxetine
Zamani et al., 2012 
Randomized, double-blind, placebocontrolled trial
62 verum vs 66 women under placebo for 6 days prior to expected menstrual bleeding for 6 cycles
40 drops of an undefined VAC extract vs placebo
Selection by DSM IV criteria i
Significantly better effects for all items under VAC in comparison to placebo
Schellenberg et al. 2012 
Randomized, double-blind, placebo controlled,
4 groups of women (3 verum. Vs placebo) with PMS, 18–45 y
8, 20 and 30 mg drie VAC fruit vs plavebo40 mg VAC dried fruit (Mastodynon) vs placebo
Premensrual mastodynia i
Dose dependent significant reduction of mastodynia
Malykhina 2006 
Randomized single-blind, comparator controlled
120 women with mastalgia and latent hyper-prolactinemia divided in 3 groups
2.5 mg bromocriptine, 0.25 mg Dostinex, 40 mg dried fruit VAC (Agnucaston) all given for 3 months
Mastalgia and latent hyperprolactinemia
Breast pain absent within 2 weeks in all 3 groups. Normalization of prolactin at the end of the study in all 3 groups
Suturina and Popova, 2010 
Randomized, single-blind, comparator controlled
2 goups of women (24 in each group) after intensive gynecologic check up
40 mg of dried VAC fruit (Cyclodynon) vs 2.5 mg bromocripitine, twice daily for 3 months
Questionnaire and serum prolactin
Significant reduction of mastalgia in both groups, Cyclodynon improved symptoms in all bromocriptine only in 16 patients,
Tuganbekov and Oralbay 2012 
Non randomized, prospective study, 2 monnths
30 women with fibrocystic mastopathy with mastodynia
40 mg VAC dried fruit (Mastodynon)
Changes in fibrocystic appearance, serum prolactin, TSH and estradiol
Significant (90%) reduction of fibrocystic appearance, mastodynia and prolactin
Ledina and Prelipskaya 2011 
Randomized. 2 months
50 women with mastalgia
1 group (n = 30) with VAC, the other with an COC (n = ` 20)
Visual analogue scale
Significant effects of both treatments VAC > than COC
v Kubista et al. 1986
Randomized, double-blind trial vs placebo and a progestin
38 verum vs 28 progestin vs 55 placebo
VAC 1095 (Mastodynon) vs a progestin vs placebo
Mastodynia, often in combination with fibrocystic mastopathy
Reduction under progestin 89%, under VAC 74% and under placebo 37%
Fourteen of 21 PMS studies were placebo-controlled while 7 studies compared the effects of VAC with the serotonin reuptake inhibiting antidepressant fluoxetine, or with other plant derived non-estrogenic extracts or with pyridoxine (vitamin B6) and magnesium, respectively.
Mastodynia and fertility
As outlined above stress- and sleep related increased prolactin levels appear to inhibit corpus luteum function and to reduce the secretion of progesterone in the luteal phase of the menstrual cycle  and this has led to clinical studies in latent hyperprolactinemic women with premenstrual mastodynia (Fig. 2). Improved fertility was later confirmed in a trial involving 44 infertile patients due to luteal phase defects, treatment with 40 mg of a dried Vitex agnus castus (VAC BNO 1095) preparation increased both, serum progesterone and estradiol [23, 24]. Following this treatment ovulatory cycles were present in 93% and fertility rate was restored in 71.4% of the patients. These results are comparable to those shown in Figs. 1 and 2 and indicate that VAC extracts may indeed be helpful in cases of infertility. The same group demonstrated a significant reduction of serum prolactin levels under a VAC preparation in patients suffering from polycystic ovarian disease .
Another additional positive effect of the dopaminergic effects in VAC may be the demonstration that dopamine receptors of the 1, 2, 4 and 5 subtype are expressed in follicular granulosa and in luteal cells which opens the possibility that the dopaminergic compounds in VAC promote follicular development and luteal function [26–28].
The issue of a relation between premenstrual symptoms, particularly of premenstrual mastodynia and the effectiveness of VAC preparations was recently reviewed by van Die et al. . This review lacks, however, a number of European, particularly East European studies. A wider review of placebo controlled studies utilizing VAC extract are shown in Table 2a-c. In all, but one of a total of 21 well conducted, placebo- or comparator controlled clinical trials such effects were well documented.
Results of studies not included in the recent review by van Die  are briefly discussed in the following: Women who start contraception with combined oral contraceptives (COC) frequently experience mastodynia which may last several months. Of particular interest is therefore the large study involving patients who suffer from mastodynia under COC . In this study BNO 1095 (Mastodynon) proved highly effective to reduce the COC induced painful sensations.
In a solid comparator controlled trial the effects of a treatment with 40 mg of a dried VAC fruit preparation for 3 months on premenstrual mastalgia, other PMS symptoms an on latent hyperprolactinemia in 2×24 patients were compared with effects of 2×2.5 mg bromocriptine . Although bromocriptine was more effective to reduce serum prolactin levels into the normal range, the VAC preparation reduced mastalgia and PMS symptoms more efficiently than the synthetic dopamine agonist. While a small number of VAC treated women reported mild side effects (8.3% experienced headache and 5.8% nausea), such effects occurred more frequently in the bromocriptine treated women (21% headache, 15.8% nausea and 12.3% constipation).
In a large study, comprising 129 women, the effects of 40 mg dried VAC fruit on latent hyperprolactinemia in patients suffering from mastodynia were compared to those of a treatment with bromocriptine or Dostinex. The latent hyperprolactinemia was successfully treated, i.e. prolactin levels were normalized in all 3 treatment groups which caused cessation of the painful breast sensations. Interestingly mammary duct thickness was reduced by the 2 synthetic but not by the VAC preparation.
In another trial severity of PMS and of premenstrual mastodynia was evaluated in 31 subjects with latent hyperprolactinemia prior to and after treatment with 40 mg of a VAC dried fruit preparation, which resulted in a significant reduction of both parameters .
In summary for the efficacy of VAC preparations and premenstrual PMS and mastodynia: Almost all placebo controlled studies published hitherto agree that extracts of the fruit of this plant have beneficial effects on PMS, particularly on premenstrual mastodynia (Table 2).
Fibrocystic mastopathy (FCM)
Fibrocystic mastopathy is the most common mammary pathology and affects 60–80% of women in the reproductive age [32–34]. Many women are frightened that the development of fibrous nodes and/or cysts indicates malignity and there is evidence that the incidence of mammary cancers is indeed higher in women with fibrocystic mastopathy . These fibrocystic phenomena increase mammographic breast density which represents a risk for the development of mammary carcinomas (for review s.36). The etiology of FCM is not totally clear: Estrogens and progestins in combination with latent hyperprolactinemia are the most commonly accused hormones which cause proliferation of mammary gland epithelia and connective tissue and which results in enlargement of ducts into cysts and proliferated connective tissue cause the nods . There is also evidence that patients with high mammographic density have elevated prolactin levels  On the other hand many patients with FCM have normal prolactin levels. A possible explanation for this phenomenon is a mutation of prolactin receptors which results in their hypersensitivity . There is also some recently described evidence that such mutated prolactin receptors may be constitutively active . Under these conditions a number of paracrine acting factors are locally secreted which stimulate further proliferation of surrounding cells . These abnormalities seem often to be accompanied increased local by production of proinflammatory cytokines and/or higher susceptibility of cytokine receptors due to gene polymorphisms  causing local, often painful inflammatory processes and consequently high local oxidative stress. In each case, it appears from early studies that dopaminergic drugs are able to reduce both subjectively felt pain and objectively measured fibrocystic structures. The most detailed and recent information of effects of VAC preparations on FCM with or without latent hyperprolactinemia or mastodynia stem from East European studies. A brief overview of these studies is given in Table 2 and further detailed in the following text.
Two studies addressed alternatives to the disturbed estradiol/progesterone relation as causative factor for FCM. In one trial 90 women with FCM had significantly higher serum prolactin levels in comparison to 20 women without mammary gland symptoms . In this study differences in E2 metabolites in women with primarily glandular or cystic or fibrotic components were found. Similarly, in another study 60 patients with FCM were either treated with Mastodynon or received a placebo preparation . In 30 of the patients the VAC preparation BNO 1095 normalized the 16-α-hydroxy metabolites and increased the 2-α-hydroxyderivatives of E2. Such effects were not seen in the placebo group and. The authors claim that this disturbance of E2 metabolism is the major reason for the development of FCM.
In aother study 120 women with latent hyperprolactinemia and mastalgia-some with nipple discharge, some without-were either treated with 2.5 mg bromocriptine or 0.24 mg Dostinex or with 40 mg of a dried VAC fruit preparation used to produce the VAC extract BNO 1095. Pain was improved and serum prolactin levels reduced in all groups. Severe side effects such as nausea and orthostatic dysregulation occurred only in the bromocriptine group. The size of mammary gland ducts, as measured by ultrasound sonography became thinner in the bomocriptine and the Dostinex group but not in the VAC group. Authors conclude that AC BNO 1055 should be the treatment of first choice in patients with mastodynia whereas Dostinex should be given in more severe forms of FCM. Elevated serum prolactin levels were also published for a group of women suffering from FCM in combination with premenstrual mastodynia .
It is also of interest that blockade of prolactin release by bromocriptine prevented stimulation of lobulo-alveolar tissue in women with FCM. This observation confirms and extends earlier reports which demonstrated also a higher prolactin release in women with fibrocystic mastopathy in response to a TRH stimulus .
Women with a latent or manifest hypothyroidism suffer often from mastodynia [41–43] and are often hyperprolactinemic , a phenomenon which is easily explainable: In an attempt to stimulate the thyroid function the hypothalamus releases high amounts of thyroid hormone releasing hormone (TRH) which is also stimulatory to prolactin release.
Relation to breast cancer
A mammary cancer promoting effects of prolactin was already suggested more than 50 years ago but it was for a long time almost a dogma that this effect occurs only in rodents. Indeed in rats high prolactin levels stimulate mammary cancers. It is however, now well established that in women local production of prolactin occurs in the mammary gland and prolactin receptor mRNA and its protein has also been demonstrated in mammary gland tissue and is overexpressed in malignant breast epithelia. Both, prolactin mRNA and the protein appear to be overexpressed and to exert paracrine effects which may be causally linked to development end growth of mammary cancers. In addition high circulating prolactin levels are present in most mammary cancer patients and are indicators for progression of the tumor. Such high prolactin levels in 2250 mammary cancer patients were recently confirmed.
Taken together it appears now well established that prolactin is indeed involved in generation and promotion of breast cancer. This makes it highly likely that such cancers may be prevented and their progression slowed down by dopamine agonists. Particularly VAC extracts with their low side effects seem favorable for the prevention of breast cancer by reducing mastodynia and fibrocystic mastopathy.
Despite small sample and often poorly defined patient populations sizes in most studies, randomised, controlled trials support the efficacy and tolerability of Vitex agnus-castus extracts in the treatment of premenstrual syndrome, premenstrual dysphoric disorder, premenstrual mastodynia and mastalgia accompanied by latent hyperprolactinaemia and of fibrocystic mastopathy. Future investigations with Vitex agnus castus extracts would benefit from use of tightly defined patient populations and common endpoints.
Both authors read and approved the final manuscript.
Both authors are advisors of the Bionorica SE, Neumarkt, Germany.
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