Human Reproduction Update Advance Access originally published online on June 16, 2007
Human Reproduction Update 2007 13(5):487-499; doi:10.1093/humupd/dmm015
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Evolution of medical treatment for endometriosis: back to the roots?
1 Division of Gynecological Endocrinology and Reproductive Medicine, University of Vienna, 1090 Vienna, Austria 2 Department of Gynecology and Obstetrics, Emory University School of Medicine, Woodruff Memorial Building, 1639 Pierce Drive, Room 4217, Atlanta, GA 30322, USA 3 UCSF Institute for Health and Aging, San Francisco, CA, USA 4 Health Concerns, Oakland, CA, USA 5 Department of Obstetrics and Gynecology, UCSF, San Francisco, CA, USA
6 Correspondence address. Tel: +1-404-727-9823; Fax: +1-404-727-8609; E-mail: fwieser{at}emory.edu
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Abstract |
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TOP
Abstract
IntroductionExperimental evidence is accumulating to suggest that medicinal botanicals have anti-inflammatory and pain-alleviating properties and hold promise for treatment of endometriosis. Herein, we present a systematic review of clinical and experimental data on the use of medicinal herbs in the treatment of endometriosis. Although there is a general lack of evidence from clinical studies on the potential efficacy of medicinal herbs for the treatment of endometriosis-associated symptoms, our review highlights the anti-inflammatory and pain-alleviating mechanisms of action of herbal remedies. Medicinal herbs and their active components exhibit cytokine-suppressive, COX-2-inhibiting, antioxidant, sedative and pain-alleviating properties. Each of these mechanisms of action would be predicted to have salutary effects in endometriosis. Better understanding of the mechanisms of action, toxicity and herb–herb and herb–drug interactions permits the optimization of design and execution of complementary alternative medicine trials for endometriosis-associated pain. A potential benefit of herbal therapy is the likelihood of synergistic interactions within individual or combinations of plants. In this sense, phytotherapies may be analogous to nutraceuticals or whole food nutrition. We encourage the development of herbal analogues and establishment of special, simplified registration procedures for certain medicinal products, particularly herbal derivates with a long tradition of safe use.
Key words: endometriosis / herbs / botanicals / inflammation / CAM
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Introduction |
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The successful treatment of endometriosis-associated symptoms including dysmenorrhoea, dyspareunia and chronic non-menstrual pain typically requires surgical as well medical intervention (Kennedy et al., 2005
). The use of both general modalities for endometriosis-associated pain has been recently reviewed (Kennedy et al., 2005; Crosignani et al., 2006). The clinical prevalence of endometriosis symptomatology is very high. In a survey of reproductive-aged women in Canada, 60% met the criteria for primary dysmenorrhea (Burnett et al., 2005). In adult women with endometriosis, the prevalence rate of dysmenorrhoea was up to 76% (Kuohung et al., 2002), and in adolescents with endometriosis, it was up to 94% (Reese et al., 1996). This disease constitutes a public health dilemma of major proportion. Although medical therapies are not curative per se, they are nonetheless a mainstay of pain symptom suppression among women with endometriosis.
Initially high-dose diethylstilbestrol and combinations of potent estrogens and progestagens were used to treat endometriosis (Hurxthal and Smith, 1952), but this approach was subsequently replaced by progestagens alone (Kistner, 1958). In 1958, the clinical observation of an apparent resolution of symptoms during pregnancy gave rise to the concept of treating patients with pseudo-pregnancy hormone regimens (Kistner, 1958). Different forms of progestagens and anti-progestagens (including dihydrogesterone, medroxyprogesterone acetate (MPA), gestrinone and mifepristone (RU 486) afforded some improvement in pelvic pain; however, these treatments are ineffective in a subset of women with endometriosis and carry several untoward side effects (Vercellini et al., 1997). In 1973, danazol, a isoxazole derivative of 17-alpha testosterone, was introduced for the treatment of endometriosis-associated pain (Friedlander, 1973). Although danazol is effective, extended use is limited by androgenic and metabolic side effects (Selak et al., 2001). A decade later, in 1982, gonadotrophin releasing hormone agonists (GnRH-a) were first described as an alternative treatment for endometriosis (Lemay and Quesnel, 1982). Although GnRH-a can be used safely with combined estrogen and/or progestagen add-back therapy for up to 2 years, long-term use is constrained by hypoestrogenic side effects (Corson and Bolognese, 1978), especially in adolescents.
Since 1978, non-hormonal treatment regimens for endometriosis-associated pain, including a variety of non-steroidal anti-inflammatory drugs (NSAIDs), have been promoted (Corson and Bolognese, 1978). Objective evidence on the use of NSAIDs in endometriosis-associated pain is sparse and inconclusive (Allen et al., 2005). Despite the poor quality of evidence, NSAIDs are typically used as first-line drugs in the treatment of endometriosis associated-pain, because they are felt to have fewer limitations (Allen et al., 2005).
Much effort is spent on the development and promotion of new drug treatments with the goal of achieving higher efficacy, fewer side effects and the option of long-term treatment, especially in women with severe endometriosis. These agents include thiazolidinediones (Lebovic et al., 2004), selective progesterone receptor modulators (SPRMs) (Chwalisz et al., 2005), aromatase inhibitors (Amsterdam et al., 2005), cyclooxygenase (COX)-2 selective NSAIDs (Cobellis et al., 2004), recombinant human TNF-alpha binding proteins (Barrier et al., 2004), anti-VEGF therapy (Nap et al., 2005), MMP-inhibitors (Mori et al., 2001) and interferon-alpha-2b (Badawy et al., 2001). Evidence from pre-clinical trials has suggested beneficial effects of these drugs that may be conferred by anti-proliferative, anti-inflammatory or anti-angiogenic mechanisms. However, despite these many therapeutic options, efficient long-term regimens for the treatment of endometriosis-associated symptoms are desperately needed.
In recent years, medicinal herbs and other botanical products have become popular for management of symptoms of several gynaecologic disorders (Eisenberg et al., 1998; Anderson and Johnson, 2005; Comar and Kirby, 2005; Tindle et al., 2005) including endometriosis-associated symptoms (Cox et al., 2003; Fugh-Berman and Kronenberg, 2003). Evidence for the potential efficacy of medicinal herbs in the treatment of endometriosis-associated symptoms has been reported in the literature and is the focus of this review.
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Background |
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Traditional medicine practices refer to health approaches, knowledge and beliefs incorporating natural plant, animal and mineral-based medicines, spiritual therapies, manual techniques and exercises (Chen and Chen, 2004
; Huang, 1998). These can be applied individually or in combination to treat and prevent illnesses or maintain well-being. In industrialized countries, adaptations of traditional medicine are termed complementary and alternative medicine (CAM). CAM is popular in all regions of the developing world and its use is rapidly spreading in industrialized countries. In Europe and North America, over 50% of the population have used CAM at least once (Tindle et al., 2005).
Historically, Chinese culture has relied heavily on herbal treatment of many illnesses. Traditional herbal preparations still account for 30–50% of the total medicinal consumption in China. Written records document the use of Chinese herbal medicine over 3000 years ago. In Chinese medicine, endometriosis is called Neiyi and is considered a ‘Blood stasis syndrome’ resulting in the formation of endometriotic lesions (Flaws, 1989; Maciocia, 1997). Chinese herbal formulae designed for endometriosis therapy are targeted to resolve blood stasis. Despite centuries of use abroad, medicinal herbal treatments for endometriosis-associated symptoms were only introduced in the USA in the mid-1980s. Several medicinal herbs that historically were prescribed for treatment of endometriosis-associated symptoms are still in use today (Chen and Chen, 2004; Huang, 1998) (Table 1). Each of the herbs described is likely composed of several active components with anti-inflammatory, anti-proliferative and pain-alleviating properties (Table 2). Thus, the potential for multiple synergistic interactions is enormous.
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Clinical evidence on the efficacy, toxicity and herb–drug interactions of medicinal herbs and herbal combinations used in the treatment of endometriosis |
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We searched Medline (1969 to November 2006), EMBASE (1984 to April 2006) and hand searched several prominent journals published in China. Clinical evidence on the efficacy of herbal combinations in treatment of endometriosis is almost exclusively published in the Chinese scientific literature. As Chinese medicine traditionally uses mixtures of medicinal plants, synergistic as well as interfering effects may occur. The concept of synergistic interaction refers to the possibility that when two (or more) active substances are given concurrently, the substances may interact enhancing the effect of the other and at lower doses. Alternatively, multiple compounds could result in decreased efficacy. These possible interactions between two or more drugs/herbs are classified into pharmacokinetic and pharmacodynamic effects (Harrison and Fauci, 1998
). Examples of medicinal herbal combinations that have been used to treat endometriosis-associated symptoms include: dan'e recipe, Gexia Zhuyu Tang, Keishi-bukuryo-gan (KBG), Neiyi recipe #1, Neiyi recipe #2, Neiyixiao recipe, Shixiao San (Sudden Smile Powder), Shaofu Zhuyu Tang, Shixiao Guijie Tang, Taoren Chenqi Tang, Tongjin San, Tuo Mo Tang, Tao He Cheng Tang, Xuefu Zhuyu Tang, Xiao Yao San, Yi Wei Zhu Yu Fang and Yiweining (YWN) (Shao, 1980; Cai, 1982; Dai, 1982; Cao, 1983; Liu et al., 1983; Lin et al., 1988; Zhuang and Xia, 1990; Jin, 1991; Li, 1991; Wang et al., 1991; Qu, 1992; Yu et al., 1993; Liu, 1994; Hu and Li, 1995; Liu et al., 1998; Wang et al., 1998; Cai et al., 1999; Yang et al., 2006a) (Table 3).
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Unfortunately, the standards of evidence-based principles are sporadically applied in published clinical studies in this area. Published trials of medicinal herbs concerning endometriosis in the Chinese scientific journals of complementary medicine have generally not been conducted according to the guidelines of evidence-based medicine in Western scientific journals. One of the major difficulties in studying the clinical effects of herbal combinations in respect to evidence-based standards is that the composition of herbal formulae is individualized for each patient according to the different syndromes of endometriosis (‘blood stasis syndrome’). Only one randomized controlled trial on the potential effects of medicinal herbs in endometriosis was identified after a thorough search in the English literature (Table 3) (Yang et al., 2006a
). This study demonstrated that YWN (consisting of Chinese angelica, corydalis, curcuma, persica, red peony, safflower, salvia root and tortoise shell) was safe and its efficacy was similar to gestrinone in the prevention of post-operative recurrences of endometriosis. Other trials have been published only as personal communications or as clinical observations in the English literature. At present, a randomized controlled trial is in progress in the USA evaluating the use of traditional Chinese medicine (TCM) at the Women's Health Research Unit of the Oregon Health Sciences University and the Oregon College of Oriental Medicine. The protocol (NCT00034047
[ClinicalTrials.gov]
) is funded by the National Center for CAM (NCCAM). The study tests the hypothesis that TCM (acupuncture and medicinal herbs) will reduce endometriosis-related pelvic pain as effectively as nafarelin therapy without causing the pseudo-menopausal side effects that accompany GnRH-a therapy. Women were randomly assigned to receive either 12 weekly treatments of TCM or 12 weeks of the FDA-approved GnRH-a treatment. This will likely prove to be a landmark study in alternative endometriosis therapy. Despite promising knowledge supporting the potential efficacy of herbal treatments in endometriosis and reports on the efficacy of medicinal herbs in related conditions (e.g. over 80% of pain relief, Table 3), the clinical effects of medicinal herbs on endometriosis remain unclear. Nevertheless, postulated experimental mechanisms of medicinal herbs include demonstrated cytokine suppression, COX-2 inhibition and antioxidant and antinociceptive activities. Treatment of endometriosis-associated symptoms with non-hormonal regimens is a particularly interesting treatment option for adolescent women with endometriosis. Hormonal anti-endometriosis therapies such as GnRH-a, progestins and oral contraceptives bear potential serious side effects, which limit their use in adolescents. As the efficacy of NSAIDs in women with endometriosis remains unclear, non-hormonal treatment of symptoms with medicinal herbs or herbal components may represent an innovative alternative for adolescents with endometriosis. Moreover, since herbal medicines may exert synergistic effects, these combinations may carry potential benefits of higher efficacy while minimizing toxicity.
Toxicity and herb–drug interactions
There is a potential for toxicity and untoward herb–drug interactions using medicinal herbs in the treatment of endometriosis (Table 4). Evidence on toxicity and herb–drug interactions of medicinal herbs used in the treatment of endometriosis is limited (Hoskins, 1984; Moing et al., 1987; Perry et al., 1990; Takasuna et al., 1995; Kuboniwa et al., 1999; Page and Lawrence, 1999; Ishihara et al., 2000; Li et al., 2001; Amato et al., 2002; Chainani-Wu, 2003; Elinav and Chajek-Shaul, 2003; Ikegami et al., 2003; Joshi et al., 2003; Wong and Chan, 2003; Chen and Chen, 2004; Wojcikowski et al., 2004a,b; Zhou et al., 2004; de Boer et al., 2005; Hu et al., 2005; Kelly et al., 2005; Ammon, 2006; Lao et al., 2006; Xie et al., 2006) (Table 4). Toxicity and untoward herb–drug interactions depend on factors associated with drugs (dose, dose regimen and therapeutic range) and as well as the consumer (age, genetic polymorphism, gender and pathological conditions). Toxicity and herb–drug interactions are unlikely to be evaluated because of the lack of current federal regulations in some industrialized countries, including the USA, and the paucity of research funding in this area. Established monitoring of adverse events caused by herb–drug interactions and increased financial support for studies investigating herb–drug interference would provide crucial information regarding public safety.
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Effects of medicinal herbs, their active components and herbal combinations on cytokine expression |
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Suppression of the NF-Kappa B pathway and pro-inflammatory cytokines has been recognized as a major mechanism of conventional drug treatments for endometriosis; progestogens, GnRH-a, danazol and NSAIDs are known to demonstrate cytokine-suppressive activity (Boucher et al., 2000
; Zhao et al., 2002; Wieser et al.,2005c; Yang et al., 2006b). Cytokines and chemokines such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-8, monocyte chemotactic protein (MCP)-1 and regulated on activation, normal T cell expressed and secreted (RANTES) contribute to the pathogenesis of endometriosis by enhancing attachment, angiogenesis and/or proliferation of ectopic endometrial tissues in the pelvis (Bergqvist et al., 2001; Lebovic et al., 2001; Maas et al., 2001).
Curcuma zeodaria is used in many anti-endometriosis formulae (Shao, 1980; Cai, 1982; Lin et al., 1988; Jin, 1991; Qu, 1992; Hu and Li, 1995; Cai et al., 1999; Liu et al., 2006; Yang et al., 2006a). Curcuma zeodaria belongs to the plant family Zingiberaceae, which consists of 
80 different Curcuma species such as Curcuma longa (turmeric). Curcumin is a major active component of Curcuma. There are substantial in vitro and animal data indicating that curcumin has anti-inflammatory activity (Kumar et al., 1998; Siddiqui et al., 2006). Curcumin was shown to suppress the NF-KappaB pathway and NF-KappaB target cytokine genes (Takada et al., 2004) (Tables 1, 2, 5). Cao et al. demostrated anti-inflammatory effects of curcumin in endometrial stromal cells; curcumin inhibited NF-Kappa B induction of a pro-inflammatory and angiogenic cytokine, the macrophage migration inhibitory factor (MIF) in this endometriosis in vitro model (Cao et al., 2005). Recent studies could corroborate that curcumin arbitrates the effects by modulation of several important molecular targets, including NF-KappaB mediated gene expression (e.g. TNF, IL-1, IL-6), other transcription factors (e.g. AP-1, Egr-1, beta-catenin and PPAR-gamma), enzymes (e.g. COX2, iNOS), receptors (e.g. EGFR and HER2) and cell cycle proteins (e.g. cyclin D1 and p21) (Shishodia et al., 2005). Substantial research has shown for other anti-endometriosis herbs (e.g. Chinese angelica) that they modulate cytokine secretion, including TNF-alpha as demonstrated in a variety of model systems (Tseng and Chang, 1992; Lee et al., 1995; Jang et al., 2001; Van Dien et al., 2001; Xu et al., 2002; Tipton et al., 2003; Chen and Chen, 2004; Syrovets et al., 2005; Liu et al., 2006) (Table 5). Moreover, herbal combinations were shown to exert cytokine (e.g. TNF-alpha, IL-6, IL-8) suppressive effects studied in animal models of endometriosis (Yu et al., 2000; Qu et al., 2005). One example is YWN, a traditional anti-endometriosis formula (Table 3, 5), which decreased serum cytokine levels (e.g. TNF-alpha, IL-6 and IL-8) in a rodent model of endometriosis (Qu et al., 2005).
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A sophisticated new approach to create novel, low-toxicity anti-inflammatory drugs is to design chemical analogues of naturally occurring medicinal herbal compounds. For example, newly developed synthetic analogues of curcumin (e.g. EF24-tripeptide chloromethyl ketone) have been introduced to treat cancer and chronic inflammatory diseases (Selvam et al., 2005
; Ohori et al., 2006; Sun et al., 2006). This alternative approach to target key cytokines may establish drugs that lack the deleterious side effects of conventional, as well as potential, endometriosis drugs such as anti-TNF biologicals. Anti-TNF protein therapeutics were shown to have potentially severe side effects such as serious infection and to induce drug resistance in treated patients (Kenter and Cohen, 2006; Scott and Kingsley, 2006). Medicinal herbs or designed synthetic analogues of components of herbs with cytokine-modulating effects may provide low-toxicity alternatives to treat endometriosis-associated symptoms (Adams et al., 2004). |
Effects of medicinal herbs, their active components and herbal combinations on the prostanoid pathway |
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The prostanoid pathway is suggested to be one of the key targets involved in the pathogenesis of endometriosis. Locally produced PGE2, a potent stimulator of aromatase, upregulates estrogen production, which in turn stimulates COX-2 to increase PGE2 leading to increased endometrial cell proliferation in endometriosis (Noble et al., 1997
; Attar and Bulun, 2006). COX-2-selective inhibitors were shown to exert anti-proliferative effects (Hasegawa et al., 2005), to decrease implant size in rodent models of endometriosis (Dogan et al., 2004; Matsuzaki et al., 2004) and to diminish endometriosis associated-pain in a clinical setting (Cobellis et al., 2004). Among medicinal anti-endometriosis herbs that inhibit the prostanoid system, dahurian angelica root, cinnamon, licorice root, poria, scutellaria, Curcuma and the formulae KBG, YWN and Neiyi have been best studied (Wang et al., 1991; Mori et al., 1993; Yu et al., 1993; Wang et al., 1998; Giner-Larza et al., 2000; Park et al., 2001; Hong et al., 2002; Huss et al., 2002; Ban et al., 2003; Prieto et al., 2003; Furuhashi et al., 2005; Qu et al., 2006) (Table 6). Cinnamon and poria, both exhibiting COX-2 suppressive activity, are components of the anti-endometriosis herbal formula KBG (consisting of five different herbs cinnamon, poria, red peony, persica and tree peony bark). Treatment with the KBG formula suppressed spontaneous development of adenomyosis in a murine endometriosis model (Mori et al., 1993). The beneficial effects of KBG in the murine endometriosis model may be attributed to the COX-2 inhibiting effect of KBG's constituents poria and cinnamon. YWN, an herbal composition (Chinese angelica, corydalis, curcuma, persica, red peony, safflower, salvia root, tortoise shell) (Table 6), reduced expression of COX-2 mRNA in endometriotic tissues in a rat model (Qu et al., 2006). Furthermore, the anti-endometriosis herbal recipe Neiyi (Table 6) decreased prostaglandins (e.g. PGE2, PgF1-alpha) levels in clinical settings in women with endometriosis (Wang et al., 1991; Wang et al., 1998; Wu et al., 2000).
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The highly regulated enzyme COX-2, which catalyzes prostaglandin production, has become a popular target for the development of new anti-inflammatory drugs. However, some of the COX-2 selective NSAIDs possess gastrointestinal side effects. In addition, recent data suggest that chronic use of COX-2 inhibitors is associated with increased cardiovascular risk (Vonkeman et al., 2006
). As a consequence, some of the COX-2 selective NSAIDS were labelled with black box warning or withdrawn from the market. In the light of recent reports of serious unintended effects and black box warnings of COX-2 selective drugs, plants with direct or indirect suppressive effects on prostanoids (Huss et al., 2002) represent a potential alternative resource of COX-2 selective inhibitors. |
Effects of medicinal herbs, their active components and herbal combinations on oxidative status |
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Reactive oxygen species (ROS) are suggested to play a role in the pathogenesis of endometriosis (Murphy et al., 1998
). Retrograde menstruation allows transport of pro-oxidant factors, such as heme, iron and apoptotic endometrial cells, which are well-known inducers of oxidative stress, into the peritoneal cavity of women with endometriosis (Van Langendonckt et al., 2002). ROS can promote growth of endometrial stromal cells (Foyouzi et al., 2004). Antioxidants, such as vitamin E, showed beneficial effects in an in vitro model of endometrial proliferation (Foyouzi et al., 2004) and anti-inflammatory effects in a rodent model of LPS-induced inflammation leading to increased embryo viability (Mayorga et al., 2004). Drugs with antioxidant properties, such as SPRMs, have been developed as possible treatment choices for endometriosis (Roberts et al., 1996), but conclusive evidence on the benefits of the various modalities is lacking.
Commonly used ‘anti-endometriosis' herbs such as Chinese angelica, curcuma and salvia root, turmeric and herbal formulae (e.g. KBG) have potent anti-oxidant effects (Cao et al., 1996; Yoshioka et al., 1998; Quiles et al., 2002; hou et al., 2004; Kang et al., 2004; Moussaieff et al., 2005; Sekiya et al., 2005; Zhou et al., 2005; El-Ashmawy et al., 2006) (Table 7). The ability of KBG and vitamin E to prevent atherosclerosis was compared in diet-induced hypercholesterolemic rabbits (Sekiya et al., 2005). KBG had a stronger anti-oxidant effect than vitamin E shown in this animal model. The superiority of the herbal combination KBG to vitamin E in this animal likely relates to synergistic interactions within the herbal combination.
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In this context, it is noteworthy to mention that although increased serum levels of vitamin E levels were associated with decreased risk for cancer and cardiovascular diseases (Stahelin et al., 1991
), exogenous oral administration of the antioxidant vitamin E did not show benefits in cancer and cardiovascular disease in human intervention studies (Brown et al., 2001; Lichtenstein and Russell, 2005). Data from the HOPE and HOPE-TOO trials showed that vitamin E did not decrease fatal or non-fatal cancer (Lonn et al., 2005). Vitamin E alone also did not reduce myocardial infarction, stroke, CVD death and other cardiovascular morbidities; instead vitamin E increased hospitalization for heart failure (Lonn et al., 2005). In contrast to these findings, diets high in vitamin E showed beneficial influence on the incidence on cardiovascular health and cancer risk (Knoops et al., 2004; Lichtenstein and Russell, 2005). In an elderly population (70–90 years), adherence to a Mediterranean diet and healthful lifestyle is associated with a more than 50% lower rate of all-causes and cause-specific mortality (HALE project) (Knoops et al., 2004). In combination, these studies (HOPE and HALE projects) suggest that either vitamin E has limited or no benefit or that it has benefit only in combination with other food-related substances. In an Italian endometriosis population, higher intake of green vegetables and fresh fruit caused a significant reduction of the risk for endometriosis (Parazini et al., 2004). Interpretation of nutritional studies on the effect of dietary patterns on cancer and cardiovascular disease prevention led to the definition of the ‘whole food' concept (Temple and Galdwin, 2003). Several components in fruits and vegetables with beneficial effects are postulated to prevent disease via their synergistic effects. This 'teamwork' principle is likely to hold for synergistic herbal therapies as well, but research will be needed to delineate optimal combinations. |
Anti-nociceptive of medicinal herbs, their active components and herbal combinations used in the treatment of endometriosis |
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The cellular and neural mechanisms of pelvic pain associated with endometriosis are poorly understood (Gambone et al., 2002
). It has been proposed that direct invasion of pelvic nerves by endometriotic implants or nearby release of inflammatory humoral factors (e.g. prostaglandins, cytokines) stimulate sensory and parasympathetic afferents that carry the perceived painful stimuli (Tulandi et al., 1998). Ectopic endometrial growths themselves develop autonomic and sensory innervations (Berkley et al., 2005).
Drugs most commonly prescribed to treat endometriosis pain symptoms, particularly dysmenorrhea, are NSAIDs, combined oral contraceptives (COC), and other analgesics (e.g. paracetamol). Evidence of the efficacy of COC on dysmenorrhea remains to be determined (Proctor et al., 2001), and there has been reluctance to use the COC at young ages because of possible long-term health risks. The evidence on the efficacy of NSAIDs in the treatment of endometriosis is inconclusive (Allen et al., 2005). Moreover, therapy with NSAIDs can bear side effects. Women using NSAIDs and even over the counter painkillers such as acetaminophen need to be aware of the possibility that these drugs may cause serious unintended effects including increased risk of cardiovascular events, hypertension and gastric ulceration (Dedier et al., 2002; Forman et al., 2005; Johnsen et al., 2005).
Since ancient times, herbal medicine has been used to relieve pain and discomfort from wounds and burns. Evidence confirms pain alleviating mechanisms of several medicinal herbs used for endometriosis (e.g. cnidium fruit, corydalis, curcuma, dahurian angelica, frankincense, myrrh and white peony root) and herbal formulae (e.g. Neiyi) (Tuttle et al., 1989; Liu et al., 1990; Yu et al., 1993; Yu et al., 1995; Dolara et al., 1996; Wang et al., 1998; Wei et al., 1999; Zhang et al., 2000; Tsai et al., 2001; Navarro Dde et al., 2002; Kimmatkar et al., 2003; Tatsumi et al., 2004; Yuan et al., 2004; Zhou et al., 2005) (Table 8).
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Corydalis is one of the most commonly used herbs in pain related syndromes (Chen and Chen, 2004
), and is also used in many Chinese formulae designed for the treatment of endometriosis-associated pain (Dai, 1982; Cao, 1983; Lin et al., 1988; Jin, 1991; Qu, 1992; Wieser et al.,2005a,b; Yang et al., 2006a) (Table 3). Tetrahydropalmatine (THP) is thought to be the main active pharmacological component of cordyalis (Brown et al., 2001); THP has been shown to exhibit anti-inflammatory, sedative, analgesic, hypnotic and muscle relaxant properties shown in vitro and rodent models (Wei et al., 1999; Chen and Chen, 2004).
Anti-nociceptive CAM treatments are gaining increased popularity for treatment of dysmenorrhoea in industrialized countries (Fugh-Berman and Kronenberg, 2003). Therapies shown to be potentially effective in the treatment of dysmenorrhoea include vitamin E (Butler and McKnight, 1955), vitamin B1 (Gokhale, 1996; Wilson and Murphy, 2001) and 
-3 fatty acids (fish oil) (Deutch, 1995). One randomized controlled trial was conducted to evaluate the efficacy of an herbal combination consisting of corydalis, Chinese angelica and white peony root on the efficacy of dysmenorrhoea (Kennedy et al., 2006); however, the sample size of this trial was too small. Herbal therapy may serve as a potential alternative especially for young adults with endometriosis-associated pain syndromes.
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Discussion |
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A significant increase in lifetime use of herbs and other natural products was noted from 12.1% to 18.6% between 1998 and 2002 in the USA (Tindle et al., 2005
). On 16 May 2002, the WHO released its first global strategy on traditional medicines and announced that it will be greatly extending its activities in non-allopathic therapies. Several important drugs are derived from natural products: aspirin (1889; from willow bark), penicillin (1940s; from fungus), artemisinin (1980; from quinghaosu), mevacor (1987; from fungus), taxol (1993; from the pacific yew tree) and byetta (2005; from Gila monster saliva). It is hoped that medicinal herbs or combinations of medicinal herbs and drugs will promote health and well being, while minimizing toxicities and side effects.
Alternative pain therapies have gained popularity particularly among women with endometriosis. It is predicted that CAM will be used in combination with allopathic medicine or will completely replace standard pharmacological options for some women with endometriosis as shown in an Australian population (Cox et al., 2003). Despite the lack of rigorous evidence, many recipients of herbal therapy view these natural products to be safer and more effective alternatives to Western medicine. Other CAM users believe them to be more compatible with their beliefs even if they are less efficacious than conventional therapy (Astin et al., 2000). In view of the need for alternatives in pain management, CAM therapies such as medicinal herbs and other botanicals with anti-inflammatory and pain-alleviating properties may be useful particularly in the treatment of endometriosis-associated symptoms. Herbal medicine has been prescribed safely by professionals in the USA for many years; however, there are only few formal studies on safety and efficacy of combining herbal combinations with prescription drugs.
Although clinical studies on herbs in the literature show promising effects, conclusive clinical evidence of the efficacy of medicinal herbs in the treatment of endometriosis-associated pain is lacking. The effects of Chinese herbal medicine for treating endometriosis remain unclear for several reasons. First, most herbs currently used in human populations have been available for the last 2000 years and no efficient regulation mechanisms control their use (Wolsko et al., 2005). Since 1994, phytomedicinal products (medicines derived from plants) are legally classified in the USA as dietary supplements. Included in this category are vitamins, minerals, herbs or other botanicals, amino acids and other dietary substances derived from animals or plants. The US Food and Drug Administration lacks quality standards (De Smet, 2005) and does not require levels of therapeutic evidence in the form of randomized clinical trials before such products are marketed to consumers. Some European countries, such as Germany and France, were among the first to introduce simplified registration procedures for herbal products. In order to harmonize different registration procedures, the European parliament has installed specific regulatory mechanisms covering medicinal herbal products (De Smet, 2005). Directive 2004/24/EC requires a special, but simplified registration procedure for certain medicinal products (De Smet, 2005). In addition, European legislation introduced a list of recognized herbs and mandates adverse-event reporting. Secondly, specific mechanisms of action of herbs are underreported and have not been tested using appropriate study designs including in vitro and animal models (Cao et al., 2005; Qu et al., 2005; Wieser et al.,2005b). Finally, single herbs (e.g. Curcuma) and herbal combinations are composed of a number of bioactive compounds, complicating the investigation of their mechanisms of actions. Benefits of the inherent synergism within single herbs and herbal combinations are enhanced efficacy and reduced toxicity. Of course, liabilities are also possible as some interacting substances might compete with each other or increase toxicity. The potential for both positive and negative interactions necessitates careful study and validations of existing and new permutations.
Investigations of the efficacy, toxicity and herb–herb and drug–herb interactions should include testing in in vitro and rodent (e.g. rat) models and subhuman primate models (e.g. baboon) of endometriosis (Ryan et al., 1994; D'Hooghe, 1997; Awwad et al., 1999; Fazleabas et al., 2002). Moreover, investigators should be encouraged to provide information on the purity, quality and composition of the herbs tested in experimental trials. Standardization would enhance interpretation of CAM data and thus the applicability of the findings. After acquiring mechanistic and safety data, we propose that randomized clinical trials be planned and implemented using human subjects with endometriosis. Adolescents with endometriosis are the most likely to benefit from disease prevention, preservation of fertility and pain relief with innovative herbal treatments. The use of standard 'single drug' hormonal endometriosis regimens (e.g. GnRH-a, danazol and progestagens) is most likely to have untoward side effects and long-term morbidities in this important patient population.
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Conclusion |
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Over the next 20 years, major shifts are likely to occur in the use of herbal compounds, vitamins, minerals, supplements, nutraceuticals or whole food nutrition. We should anticipate a wave of new natural medicines based on scientifically substantiated health claims. In the near future, we predict that more US adults will use medicinal herbs and herbal products to treat their diseases as we change our perspective from treating disease to promoting better health. Formal clinical trials testing the mechanisms of action, efficacy and toxicities of CAM therapies are needed. The establishment of the NCCAM Institute of the NIH was an important step towards the validation of popular and effective traditional treatments (Stokstad, 2000
). Despite the limited growth in the NIH, the Fiscal Year (FY) 2006 President's budget for the NCCAM increased to $122 692 000. NCCAM has sponsored several clinical trials on the efficacy of medicinal herbs in the treatment of irritable bowel syndrome, menopausal symptoms, hepatitis C, AIDS and cancer. Controlled clinical studies will be needed to clarify the clinical efficacy of natural medicinal herbs or synthetic herbal analogues in the treatment of endometriosis-associated pain and investigate herb–herb and drug–herb interactions and other toxicities. A potential benefit of herbal therapy is the likelihood of synergistic interactions within individual (e.g. Curcuma) or combinations of plants and the constraint of untoward side effects. Experimental and epidemiological data (e.g. HOPE and HALE trials) infer that health promotion involves addressing many important determinants rather than adjusting the level of a single substance. We, therefore, believe that it is critical to establish streamlined registration procedures for natural medicinal products, particularly herbal ones that have a long tradition of safe use.
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Acknowledgements |
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Supported by Erwin Schroedinger Auslandsstipendium (J2288-B13) and Emory University Research Committe (2007068).
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