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 Premenstrual Syndrome (PMS) also called premenstrual disorders (PMDs) affect up to 70% of women and between 10–20% of them have a severe form, the Premenstrual Dysphoric disorder (PMDD). The definition, diagnosis and management have always been challenging. These conditions affect reproductive aged women and can have a substantial impact on quality of life, with resultant impairment of education/work. The definition of PMSD is somehow weak but there is consensus that symptoms of the core menstrual disorders occur pemenstrually, may occur already during the luteal phase but exacerbate premenstrually and ease during the menstrual period. The symptoms may be primarily psychic or somatic with a wide overlap. The most common symptoms of PMS are listed in Table 1.

One of the most common and frightening symptoms for women is premenstrual breast pain - premenstrual mastodynia - which occurs in more than 20% of the female population. When this discomfort is extreme it is classified as mastalgia (severe mastodynia) [1‐3]. There is evidence that in women suffering from premenstrual mastodynia or mastalgia a latent hyperprolactinemia is one of the major reasons for the development of the complaints [3, 4]. Patients suffering from premenstrual mastodynia have under resting conditions often normal serum prolactin levels, under stress situations however, pituitary prolactin release seems to be augmented. The spontaneous release of prolactin occurs in pulses and in the luteal phase these pulses occur synchronously with LH pulses [5]. In women with a latent hyperprolactinemia these prolactin pulses are higher than in women with normal prolactin release (Fig. 1). Hence, highest prolactin pulses in women suffering from PMS are observed in the late luteal and the premenstrual phase (Fig. 1) and also stress and deep sleep induced prolactin release is exaggerated during the luteal phase. This was studied in some more detail and results are shown in Fig. 2. These results stem from a study comprising women with PMdy and women without breast discomfort. They were investigated during the late luteal phase. Prolactin levels in women suffering of premenstrual mastodyniay were in a pathologic range i.e. > 500 μU. Such effects were not observed in the women who did not suffer from premenstrual breast pain. Interesting, in comparison to women without breast complaints the women with premenstrual mastodynia had significantly lower serum progesterone values and these low levels were in the pathologic range indicating a corpus luteum insufficiency (Fig. 2) which is a common reason for infertility. These findings confirm and extend earlier results demonstrating increased prolactin and low progesterone levels in women suffering from premenstrual mastodynia [3, 6, 7].

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) [8]. Hence, the latent hyperprolactinemia mimicks effects seen during early pregnancy [9].

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 [11]. But these systemic dopaminergic drugs had all severe side effects such as nausea and orthostatic dysregulation [12].

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.

A number of plants produce substances which bind to one or both estrogen receptors (ERα and ERβ). Most adverse effects of estrogens in the mammary gland and uterus are exerted via the ERα. The uterotrophic assay in ovariectomized rats is the OECD recommended test system for ERα activity [13]. Administration of the VAC extract BNO 1095 over a period of 3 months even at high doses neither stimulated uterine weights nor were estrogen stimulated genes affected (Fig. 3a, b and c, unpublished data). In earlier studies we demonstarted the presence of apigenin in VAC BNO 1095 which binds to ERß [14]. In another study [15] linoleic acid was isolated from a VAC extract which stimulated some ERα specific events in ERα expressing cells and recently some substances have been isolated with affinities to both ER subtypes [16].

Particularly the beneficial effects of VAC extract on mastalgia were suggestive that extracts of the dried fruit may contain dopaminergic compounds which inhibit pituitary prolactin release. Consequently it was indeed shown that VAC extracts may fulfill these prolactin inhibiting conditions [17‐19]. Dopaminergic activity via binding to dopamine-2 (DA-2) receptors [17] was proven by several experimental approaches:

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 [21].

Most publications specified several different VAC preparations with VAC BNO 1095 present in Mastodynon® and Agnucaston®. The PMS studies as well as studies on mastodynia/mastalgia, latent hyperprolactinemia and fibrocystiv mastopathy are specified in Table 2. The most commonly prescribed dose was 40 mg/day dried fruit which is equivalent to 4.0 mg extract.

According to our literature survey 21 studies were published in which effects of VAC extracts on PMS were investigated (Table 2 a-c). In all but one study beneficial effects on all symptoms listed in Table 1 were reported.

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 [22] 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 [24].

How can the effects of VAC on luteal function be explained? Continuously high prolactin levels inhibit the hypothalamic pulse generator [25]. This results in infertility because normal gonadotropin release is inhibited. In latent hyperprolactinemic patients the hypothalamic GnRH pulse generator appears to function normally because LH pulses of normal height are present (Fig. 1). Hence we face the possibility that the exaggerated height of prolactin pulses during the luteal phase (Fig. 1) have a direct inhibitory effect on luteal progesterone secretion. It appears therefore safe to conclude that VAC preparations contain dopaminergic substances which normalize the exaggerated height of prolactin pulse which allows normal luteal progesterone secretion, thereby preventing luteal insufficiency and promoting fertility. This suggestion is graphically outlined in Fig. 8.

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. [8]. 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 [8] 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 [29]. 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 [30]. 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 [31].

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 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 [35]. 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 [32]. There is also evidence that patients with high mammographic density have elevated prolactin levels [36] 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 [37]. There is also some recently described evidence that such mutated prolactin receptors may be constitutively active [38]. Under these conditions a number of paracrine acting factors are locally secreted which stimulate further proliferation of surrounding cells [39]. 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 [39] 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 [40]. 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 [41]. 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 [40].

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 [3].

Women with a latent or manifest hypothyroidism suffer often from mastodynia [41‐43] and are often hyperprolactinemic [44], 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.

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.