Vitex agnus-castus dry extract BNO 1095 (Agnucaston ® ) inhibits uterine hyper-contractions and inflammation in experimental models for primary dysmenorrhea
Primary dysmenorrhea refers to menstrual cramping in the absence of pelvic pathology [1] and is closely linked to a large group of related menstrual conditions that are collectively termed premenstrual syndrome (PMS) [2]. Primary dysmenorrhea represents a common gynecological complaint especially in young women, with a prevalence estimated to be as high as 40–50 % in women from this age group [1]. The intensity of pain associated with uterine cramps in affected women may range from moderate to severe, and cramps are frequently accompanied by back pain, nausea, vomiting and diarrhea. In some cases, the suffering in affected women prevents them from working, going to school, or normal daily activities.
Physiologically, the pain is most intense in the days just prior to menstrual flow, and has been proposed to arise from at least three temporally-related biological processes. First, the spasmodic uterine contractions in affected women are often more intense, more frequent, and of longer duration compared to non-dysmenorrheic women, and in some cases are described as “labor-like” [1]. Second, these uterine contractions may constrict the oxygenated blood supply by vasoconstriction within the endometrium, leading to enhanced cell death, ischemia [3] and the production of reactive oxygen species (ROS). Finally, even in the absence of an infection, there is a concomitant “immune-like” influx of inflammatory/migratory cells including mast cells, eosinophils, neutrophils, and macrophages immediately prior to menses that likely assists in the breakdown of endometrial tissue through the release of proteases and pro-inflammatory prostaglandins (PGs), leukotrienes, cytokines, and chemokines [3–6]. While these three processes plausibly act in concert to intensify the pain experienced during menstrual cramping, molecular details of how this process occurs are complex and poorly understood [1].
Amongst various pro-inflammatory mediators, PGF2? and PGE2 are known to play a central role in modulating uterine contraction and vasoconstriction in non-pregnant and pregnant females, respectively. Intrauterine administration of PGF2? (but not PGE2) during the secretory phase of the menstrual cycle has been shown to increase uterine contractility, and implicates this PG as a key player in primary dysmenorrhea and pain [3, 7]. There are also highly complex interactions between hormones and mediators, basal body temperature, sleep patterns, and the central nervous system which are not completely understood [8, 9].
In one possible molecular scheme for primary dysmenorrhea, the withdrawal of estrogen and progesterone leads to pro-inflammatory and pro-contractile cascades, as well as a reduction in superoxide dismutase (SOD) enzyme levels [10] that normally keep ROS levels low and protect cells against ROS-induced damage [4]. The menstrual cycle-dependent increase in ROS production activates transcription factor NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells), resulting in increased prostaglandin (especially PGF2?), chemokine and pro-inflammatory cytokine production [4, 11]. Finally, PGF2?-induced uterine contraction and vasoconstriction leads to hypoxia and pain in the respective myometrial tissue. This, together with the expression of pro-inflammatory mediators, used for (and by) the recruitment and activation of leukocytes results in inflammation, tissue breakdown and ultimately a characteristic menstrual bleeding [4, 6, 12], after which the pain tends to subside.
Nonsteroidal anti-inflammatory drugs (NSAIDs, such as naproxen sodium or ibuprofen) are widely used to treat PMS and primary dysmenorrhea by reducing PG production via the inhibition of cyclooxygenases (COX-1 and COX-2). However, most prescription-free NSAIDs can be associated with gastrointestinal side effects such as nausea and gastric ulceration as well as renal dysfunction [2]. Also 10–30 % of dysmenorrheic women are not responsive to COX inhibitors [13], suggesting the role of other mediators in this condition. For example, an elevation of leukotrienes observed in women with primary dysmenorrhea has been suggested to contribute to uterine hypercontraction in humans [14] and as shown in a guinea pig experimental model [15]. However, no medicinal products acting on the 5-lipoxygenase pathway have been approved for treatment of PMS so far.
From the women’s perspective, effective alternatives, particularly herbal medicines with fewer side effects are preferred [16] to treat PMS-related symptoms. Fruits of Vitex agnus-castus tree, also known as chasteberry, have traditionally been used [17] to treat minor symptoms related to the monthly pain, swelling, and mood disorders that are collectively termed PMS [2]. Standardized herbal extracts from Vitex agnus-castus fruits (VAC dry extracts) are recognized and sold in Europe as “well-established use” herbal medicinal products that are effective for relief of PMS with fewer side effects than NSAIDs. The efficacy and safety of VAC dry extracts in treating PMS symptoms such as irregular menstruation and breast pain (mastodynia) have been confirmed by several controlled clinical studies [18–21].
The mechanism of action of VAC herbal extracts in treating menstrual symptoms has not been completely elucidated, perhaps due to the large number of potentially active extract constituents, including iridoids, flavonoids, and diterpenes [22–26]. For example, a large body of evidence suggests that VAC extracts acts in the brain at dopamine D2 receptors of the hypothalamus/pituitary gland axis to inhibit the systemic release of prolactin from the pituitary gland resulting in the relief of PMS symptoms [27–31]. However, the potential for localized anti-contractive and anti-inflammatory actions of VAC extracts in primary dysmenorrhea has not been investigated up to now.
Therefore, in the present studies, we investigated the ability of the standardized VAC extract BNO 1095 (commercially-available as Agnucaston®) to modulate a number of potential mechanisms responsible for dysmenorrhea using in vivo, in vitro, and enzymatic assays, with a special emphasis on uterine contraction, pain, and the production and release of the pro-inflammatory molecules PGs, leukotrienes, cytokines and ROS.