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Abstract

Endometriosis is a disease that affects approximately 10% of all reproductive-aged women and the prevalence rises to 20–50% in infertile women. There is growing evidence that medicinal Chinese herbs with pain-alleviating and anti-inflammatory properties may be useful in the treatment of endometriosis and infertility, but the mechanisms of action of these herbs have yet to be investigated. In addition, studies of adequate design, sample size and appropriate control are lacking. Therefore, prospective randomized, controlled studies to evaluate the efficacy, mechanism of action and toxicities of Chinese herbs in the treatment endometriosis and infertility are needed.

Keywords

Chinese herbs Chinese medicine endometriosis etiology infertility inflammation

Endometriosis is a common disease defined by the presence and growth of uterine glands and stroma outside the uterine cavity. The etiology of endometriosis is not well understood, but the most widely accepted view is the theory of retrograde menstruation described by Sampson in 1927 [1]. This disease affects approximately 10% of all reproductive-aged women and the prevalence rises to 20–50% in infertile women [2,3]. Endometrial cells are found in the pelvic cavity due to retrograde menstruation in 90% of all women [4], but these usually undergo apoptosis and phagocytosis by macrophages and natural killer (NK) cells and are cleared from the peritoneal cavity [5]. However, in approximately 10% of women, endometrial cells survive, attach and progress, resulting in endometriosis. These cells are under the influence of hormones and proliferate on peritoneal surfaces of the pelvis [6].

Several studies support the theory that this phenomenon is facilitated by an autoimmune mechanism consisting of both autoantibodies and cell-mediated immunity. A host of cells and their products, ranging from cytokines to growth factors (e.g., regulated on activation, normally T-cell expressed and secreted [RANTES], interleukin [IL]-1, IL-6 and vascular endothelial growth factor [VEGF]) all contribute to the proliferation and progression of disease [6]. These inflammatory mechanisms are targets for a variety of anti-inflammatory agents currently used in the treatment of endometriosis. In addition, these theories provide the framework for future therapeutic strategies.

Endometriosis is a progressive disease that is often associated with infertility [7]. The precise cause–effect relationship between endometriosis and infertility is controversial. In cases of severe endometriosis and distorted pelvic anatomy, the mechanism of infertility is more easily explained and the risk of infertility is high [8]. In mild endometriosis with infertility, altered intrafollicular and endometrial cytokine milieu may explain the poor quality oocytes and resulting embryos with a lower capacity to implant in the uterus [9].

Traditionally, both medical and surgical therapies have been offered for alleviation of symptoms associated with endometriosis and the treatment of infertility. The treatment of endometriosis-associated pain has been well studied and all major medical therapies appear to be superior to placebo [10]. However, in the treatment of infertility, medical therapy has not been shown to be of benefit, in contrast to surgical treatment, which improves all stages of infertility [10].

Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and naproxen, are prescribed to alleviate pain associated with endometriosis [11]. Examples of hormonal agents include danazol, medroxyprogesterone acetate (MPA), combined estrogen–progestins, and gonadotropin-releasing hormone (GnRH)-analogs (GnRH-a) [10]. Danazol is a derivative of 17α-testosterone that creates a chronic anovulatory state by inhibiting the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) surge, thereby suppressing endometriosis. Danazol has been shown to be effective in decreasing the severity of endometriosis as well as providing relief of dysmenorrhea [10]. Recent studies using an in vitro mixed lymphocyte culture assay indicate that danazol has immunosuppressive effects similar to those observed with dexamethasone and high-dose progesterone [12]. It has the potential for androgenic side effects, including deepening of voice, alteration in lipoproteins, hirsutism and acne. MPA is a drug that suppresses ovulation and ultimately causes endometrial atrophy. It has also been shown to be quite effective in reducing the severity of endometriosis [13]. The clinical effectiveness of chronic progestin treatment in endometriosis-associated pelvic pain may be attributed to its inhibition of RANTES production and its suppression of inflammatory responses in the pelvis [14]. MPA can cause a wide range of side effects, from nausea to weight gain. In contrast, there is no evidence of the beneficial effect of progesterone in infertility. Combinations of estrogens and progestins are the most commonly prescribed regimen for treating endometriosis, although data describing their efficacy are limited [15]. GnRH-as are medications that downregulate the pituitary gland and lower gonadotropin levels [8]. This results in a hypogonadal state. Similar to MPA, GnRH-a treatment also suppresses nuclear factor (NF)-κB activation and leads to suppression of IL-8 secretion in endometrial cells [16]. Side-effect profiles range from nausea and vomiting to menopausal symptoms such as hot flashes and vaginal dryness.

Surgery via laparotomy or laparoscopy is a common form of therapy used in endometriosis and infertility treatment [17]. It is often performed to remove endometrial implants and adhesions in an effort to restore normal pelvic anatomy. Other goals of surgery can include uterine or ovarian suspension, presacral neurectomy and transection of the uterosacral ligament, all of which may reduce pelvic pain and future adhesion formation.

In this context of treatment of endometriosis and infertility, additional treatment strategies with higher efficacy and fewer side effects are desirable. There is longstanding and growing evidence that medicinal Chinese herbs with anti-inflammatory and pain-alleviating properties may be useful in the treatment of endometriosis and infertility. This is the focus of this review.

General theories in Chinese medicine

In traditional Chinese medicine, the Yin–Yang theory is the foundation upon which disease processes are understood and treated [18,19]. Yin and Yang are two types of energy that are present in the universe and within the human body. All things in the universe are a balance of these opposite yet complimentary forces. Each body organ has elements of Yin and Yang. It is believed that Qi and blood are the fundamental fluid substances of the body, which sustain the normal physiologic functions of the organs and tissues. Qi is Yang and blood is Yin. The flow of Qi and blood are the foundations of good health. In Chinese medicine, each organ functions in order to uphold Yin and Yang. Specifically, the kidney and liver are the two vital organs responsible for regulating reproductive function [20]. In addition to supervising urinary and reproductive functions, the kidney is responsible for storing the essence of Qi. The liver, on the other hand, stores blood, also known as the essence of reproduction. Together, these organs produce and circulate Qi and blood and thus maintain the Yang and Yin energies within the body.

In traditional Chinese medicine, imbalance of Yin and Yang is thought to cause illness. Any disruption or blockage of the organs and channels is associated with an imbalance of Qi and blood, thus leading to disharmony of Yin and Yang and to diseases such as endometriosis and infertility. Therefore, the goal of treatment in Chinese medicine is to tonify deficiency, open blockages, relieve stagnation and regulate the internal organ balance.

Chinese etiology of endometriosis

Within Chinese medicine, endometriosis is primarily viewed as a blood-stasis syndrome, resulting in the formation of endometriotic lesions [20,21]. The condition of blood stasis is believed to be a phenomenon whereby small vessels are incapable of carrying normal blood flow, thus causing clotting and bleeding, resulting in lower abdominal pain and infertility. There are multiple causes of blood stasis including: liver Qi stagnation, coldness, accumulation of damp heat in the blood and Qi and blood vacuity.

Liver Qi stagnation

Qi stagnation is a syndrome of restricted circulation caused by emotional or physical trauma. Qi stagnation contributes to blood stasis, which leads to pain in the lower abdomen and dysmenorrhea. Stagnation of Qi is thought to be caused by restrained movement or distress, anger and a hectic lifestyle. The most common cause of Qi stagnation is excessive stress, which has been associated with a high rate of endometriosis in women with professional careers [22,23]. Liver Qi stagnation may also lead to Qi deficiency and heat in the spleen (Figure 1).

Figure 1.

Chinese etiology of endometriosis.

Coldness

Coldness is associated with impaired metabolism and circulation. It has been related to the Chinese pattern of kidney Yang deficiency. The condition, known as cold uterus, is a common Chinese diagnosis in cases of endometriosis [16,19]. Cold, causing blood stasis in the uterus or the pelvis, has been attributed to overeating cold, raw and damp foods, or may reflect the patient's decline of Qi. Cold foods include chilled, frozen or cold snacks. Damp foods include dairy products, such as ice cream and chilled milk.

Accumulation of damp heat in the blood

This type of blood stasis pattern is aggravated by oily, spicy, fried and hot foods, and by alcohol.

Qi & blood vacuity

In this condition, women are viewed as having a deficiency of Qi and weak circulation. This in turn leads to blood stagnation. There are three ways of developing this syndrome:

Decreased liver Qi causing blood vacuity and blood stasis

Persistent dampness, worry, exercise and fatigue causing spleen vacuity and dampness leading to blood vacuity and blood stasis

Simple overwork, fatigue and poor nutrition in women who are already predisposed to Qi and blood vacuity

Chinese etiology of infertility

There are seven physically based causes of infertility in women according to several theories in Chinese medicine [20,21].

Jing deficiency

Jing deficiency has been associated with the lack of oocytes or incomplete egg formation. This syndrome is most closely related to a Western diagnosis of diminished ovarian reserve or premature ovarian failure. The technology of in vitro fertilization, with or without ovum donation, is utilized, whereas Chinese medicine cannot be used to treat this form of infertility (Figure 2).

Figure 2.

Chinese etiology of infertility.

Qi & Xue deficiency

Qi and Xue deficiency is associated with a defect in gamete transport through the fallopian tubes. The Qi is responsible for movement and its deficiency prevents oocyte entry into the fallopian tube to undergo fertilization. Another consequence of this deficiency is ectopic (e.g., tubal) pregnancy. Qi and Xue deficiency is also associated with luteal phase deficiency and lower abdominal pain.

Stagnation of Qi & Xue

In this theory, there is stagnation of Qi and Xue due to anatomic causes. Obstructive causes may be due to uterine or ovarian tumors or cysts. Women with severe endometriosis are particularly thought to have stagnation of Qi and Xue.

Heat injury of channels

Within this theory, obstruction of the ovaries, fallopian tubes, uterus or cervix occurs as a consequence of endometriosis, intra-abdominal adhesions or pelvic inflammatory disease (PID). Individuals with these syndromes have chronic pain symptoms also referred to as low-grade heat inflammation. In this instance, herbal medicine may be effective in pain reduction, but it often cannot resolve infertility if there is complete blockage of the tubes.

Kidney & liver Yin deficiency

This syndrome is most commonly observed among women in their mid-thirties and -forties who are experiencing difficulties in trying to conceive. In Western medicine, these women carry diagnoses such as luteal phase deficiency and anovulation associated with irregular menses, mood changes and bloating.

Cold uterus & Yang deficiency

As noted above, cold uterus is a product of impaired circulation, metabolism and resorption of nutrients. It is commonly seen in women with infertility and mild endometriosis and in diseases such as celiac disease, lactose intolerance, Raynaud's syndrome and hypothyroidism [18,21,22]. There are a number of reasons for this phenomenon, ranging from Yang deficiency to cold invasion. Often, a cold uterus results from the ingestion of cold substances or exposure to cold during the postpartum period.

Extraordinary channel disturbances

Disturbances in extraordinary channels are described as the disruption of the physical connections of the major organ systems. The Chong Mai connects the uterus and the heart and is often called the sea of Qi and Xue. Ren Mai is the channel of fertility and conception and it supports Qi and Xue. Ren Mai is also responsible for nourishing the uterus with fluid through the Yin channels. Together, all of these channels provide fluids to the uterus and create conditions that allow pregnancy to occur. Any disruption can result in infertility.

History of documented use of Chinese herbs

Traditional Chinese medicine is a holistic model of health maintenance based on Chinese herbs, acupuncture and other forms of therapy. The documented use of medicinal Chinese herbs dates back to approximately 100 BC. Records describing herbal treatment of infertility and miscarriage date back to 200 AD, but the first book devoted to obstetrics and gynecology, entitled The Complete Book of Effective Prescriptions for Diseases of Women, was published in 1237 AD. Since then, Chinese herbs have been used for many generations in China and throughout the world [24,25].

Several herbal products are available for the treatment of endometriosis and infertility. Traditionally, Chinese herbalists prescribe combinations of herbal formulae with multiple ingredients. The idea is that each individual herb works synergistically to treat the disease process. The design of the formula varies, but when treating endometriosis and infertility certain ingredients overlap. Herbs may be consumed in a variety of forms including pills, tablets, granules or decoctions (teas). While some formulae are taken once, others are taken regularly at various times and in particular combinations. Usually, Chinese herbs are prescribed by a licensed health professional who determines which formulae and regimens are indicated for a particular set of symptoms.

The practice of traditional Chinese medicine has evolved for thousands of years as practitioners have optimized and updated therapy based on the raw and processed ingredients of plants and their derivatives. Historically, Chinese culture has relied heavily on herbal treatment of many illnesses, with good outcomes.

Herbs commonly used in endometriosis

There is growing evidence that traditional medicinal Chinese herbs have pharmacologic anti-inflammatory effects and pain- and infertility-alleviating properties [24 –26]. Anti-inflammatory actions of Chinese herbs used traditionally for the treatment of endometriosis have been described for Angelica root, Cordyalis rhizome extract, Frankincense, Licorice root, Myrrh resin, Tang gui root and White peony root [25,26]. Table 1 represents a list of commonly cited Chinese herbs used in the treatment of endometriosis, summarizing their pharmacologic properties.

Table 1.

Chinese herbs commonly used in endometriosis.

Common name	Pharmaceutical name	Official name	Chinese name	Main constituents	Pharmacology	Chinese mechanism of action	Other uses in Chinese medicine	Ref.
Pubescent Angelica root	Radix angelicae dahuricae	Angelica dahurica var. formosana	Bai Zhi	Coumarin and furocoumarin	Activates lipolytic hormones Inhibits COX-2 expression and prostaglandin E synthase Antagonizes TNF-α	Analgesic and anti-inflammatory	Colds Headaches Toothache Dysmenorrhea Menorrhagia Rheumatalgia Mastitis	[24, 29]
Angelica root	Radix angelica sinensis	Angelica sinensis	Dang Gui	Ferulic acid and ligustilide	Inhibits/relaxes uterus Dilates coronary vessels Inhibits platelet aggregation Potentiates phagocytosis of macrophages Enhances IL-2	Improves blood circulation nourishes the blood Improves Qi circulation Antispasmolytic	Menorrhagia Dysmenorrhea Lowers blood cholesterol Systemic lupus erythrematosus Nephritis Aortitis Anemia Eczematous dermatitis Rheumatalgia	[25, 30]
Cinnamon	(1) Ramulus Cinnamomi (2) Cortex cinnamomi	Cinnamomum cassia Presl	(1) Gui zhi (2) Rou Gui	Cinnamaldehyde, cinnamic acid and coumarin	Bactericidal Fungicidal Sedative Peripheral vasodilation Inhibits gastric secretion	Improves blood circulation Warms the body	Influenza Rheumatalgia Bronchitis Colds Fevers Oral inflammation Dyspepsia Diarrhea	[24, 31]
Corydalis rhizome extract	Rhizoma corydalis	Corydalis turtschannovii Bess. F. yanhusuo	Yan Hu Suo	Ditetrahydropalmatine	Blocks postsynaptic dopaminergic receptors	Analgesic Promotes blood circulation Promotes Qi	Arthritis Hypertension Diarrhea Tumors Fever Irregular menses Induction of abortion	[28, 24, 25]
Frankincense resin	Resina Olbani, Boswellia	Boswelia serrata	Ru Xiang	Triterpene acids/boswellic acids	Inhibits lipoxygenase Inhibits DNA/RNA/protein synthesis in leukemia HL-60 cells	Muscle relaxant Alleviates pain Decreases bleeding Improves blood circulation	Arthritis Asthma Diarrhea Syphilis Tumors Rheumatoid arthritis Ulcerative colitis	[37 –40]
Licorice root	Radix glycyrrhizae	Glycyrrhiza uralensis Fisch. G. inflata Bat	Gan Cao	Triterpene Saponin Glycyrrhizin Sapogenin Glycyrrhetic acid Flavenoids	Inhibits gastric secretion Mineralocorticoid-like effects Antiallergic activity Anti-inflammatory Stimulates B lymphocytes Induces cytochrome P40 enzyme activities and anti-inflammatory activity by inhibiting prostaglandin production via inhibition of phospholipase A2	Replenishes Qi	Analgesic treatment for GI and pulmonary disorders Asthma Laryngitis Bronchitis Tonic Expectorant Mucolytic Hepatitis	[34 –36]
Myrrh resin	Resina myrrhae		Mo Yao	Volatile oils Resin Steroids Terpenoids Gum	Anti-inflammatory Antipyretic Antibacterial Antiseptic Antifungal Astringent	Alleviates pain Breaks up static blood Aids in tissue repair	Aphthous ulcers Gingivitis Pharyngitis Wounds Abrasions Pulmonary congestion Hemorr-hoids Antimicrobial activity in HIV/AIDS	[41]
Persica	Semen persicae	Prunus persica	Tao Ren	Emulsin, allantoinase, lipids, essential oils, vitamin B1	Dissolves clots Anti-inflammatory properties	Breaks static blood Alleviates pain	Menstrual pain Amenorrhea Pospartum pain Constipation Angiitis Schistosomal cirrhosis Sedative Antitussive Diuretic	[47]
Salivia root	Radix salviae multiorrhizae	Salvia multiorrhiza	Den Shen	Diterpene pigments with phenanthrene quinone structure	Increases arteriolar diameter and microcirculation rate Dilates coronary arteries	Improves blood circulation Anti-inflammatory Antibacterial	Dysmenorrhea Menorrhagia Insomnia Blood circulation diseases Angina pectoris	[24, 32, 33]
Sparganium	Rhizoma sparganii	Sparganium stoloniferum	San Leng	Essential oils and starch	Inhibits aggregation of platelet Prolongs thrombin time Induces IL-8	Breaks static blood Reduces masses Activates Qi circulation	Ectopic pregnancies Hepatic carcinomas Malignant tumors GI pain	[24]
Typha angustifolia	Pollen typhae	Typha angustifolia	Pu Huang	Isorhamnetin, pentacosane, arachidonic acid, palmitic acid	Increases platelets and reduces bleeding time Immune-enhancing effect with large doses	Works simultaneously to move the blood and reduce menstrual bleeding	Hemoptysis Hematemesis Epistaxis Coronary artery disease Hypercholesterolemia Exzema Colitis	[24]
White peony root	Radix paeoniae albae	Paeonia lactiflora	Bai Shao	Paeoniflorin	Reduces production of NO & TNF Inhibits histamine release Inhibits platelet coagulation Inhibits plasmin and plasminogen Peripheral vasodilator Inhibits smooth muscle of uterus	Nourishes blood and preserves Yin	Sedative Depressant Rheumatalgia Allergies	[25]
Zedoaria	Rhizoma curcumae	Curcuma aromatica	E Zhu	Curcumi, D-camphene, starch, lipids, essential oils	Anti-inflammatory properties Inhibits lipopolysaccharide-induced prostaglandin E2 production Antagonizes TNF-α activity	Alleviates menstrual pain due to Qi and blood stagnation Breaks static blood	Coronary artery disease GI bleeding Preventricular contractions	[24, 44 –46]

COX: Cyclooxygenase; GI: Gastrointestinal; HL: Human leukocyte; IL: Interleukin; NO: Nitrous oxide; TNF: Tumor necrosis factor.

Corydalis rhizome extract is a herb used in many Chinese formulae for the treatment of endometriosis. Tetrahydropalamatine is the main active pharmacologic component of Cordyalis rhizome extract and has been shown to block postsynaptic dopaminergic receptors [24,27]. Chinese herbalists use Corydalis rhizome to promote Qi, by enhancing blood circulation and overcoming the blood-stasis syndrome. In one study, it was shown to be effective in adjuvant-induced inflammation and hyperalgesia in rats [28]. Corydalis rhizome extract has also been shown to have sedative, analgesic, hypnotic and muscle relaxant properties, which are consistent with its dopamine receptor antagonism.

Three different species of Angelica root are used in Chinese medicine. They are bai zhi, dang gui, and du huo. Two of these are used in herbal combinations to treat endomteriosis. Bai zhi, or Angelica dahurica, is a root that contains various coumarin and furocoumarin derivatives. One of its mechanisms of action is to block cycloxygenase (COX)-2 activity and prostaglandin synthesis [29]. It also known to antagonize tumor necrosis factor (TNF)-α expression, inhibit antilipolytic hormones and activate lipolytic enzymes. It is commonly used as an analgesic and antipyretic in Chinese medicine and can alleviate chronic pain and dysmenorrhea associated with endometriosis.

Dang gui, or Angelica sinensis, has also been used in endometriosis formulae to help improve Qi circulation. It has been shown to enhance IL-2 production and inhibit formation of thromboxane-A2 [25]. Animal studies have reported that A. sinensis can increase proliferation of splenic lymphocytes and upregulate interferon (IFN)-γ expression [30].

White peony root is another common herb used in the treatment of endometriosis. It has immunomodulating effects and exerts negative effects on IL-2 production by macrophages and B-lymphocyte proliferation. White peony has been shown to reduce the production of nitric oxide (NO) and TNF-α by peritoneal macrophages [25].

Cinnamon is used in traditional Chinese medicine to help improve circulation in endometriosis patients. It is thought to accomplish this by vasodilating peripheral blood vessels and inhibiting platelet aggregation. Cinnamon is also used to treat abdominal pain, peptic ulcer disease, diarrhea, colds and hypertension, as well as a variety of female reproductive disorders [31].

Salvia root is commonly known as red sage in traditional Chinese medicine. In endometriosis treatment, Salvia root is thought to quicken the movement of the blood, invigorating Qi circulation. It increases the activity of superoxide dismutase in platelets, reducing oxygen-free radicals and platelet aggregation [32]. Recently, as described in a study by Wong and colleagues, Salvia root was shown to elevate peripheral blood mononuclear cell gene expression of IL-2 receptors when used in combination with another Chinese herb, demonstrating a potential effect on cell-mediated immunity [33].

Licorice is one of the most frequently used traditional drugs for enhancing the overall immune response. It is thought to replenish Qi, dissipate heat and reduce pain. It has several pharmacologic properties, including the conversion of cortisol to cortisone, which exerts an anti-inflammatory effect [34]. In addition, licorice promotes proliferation and production of IL-2 by murine thymocytes [35]. Licorice root was also found to inhibit phospholipase A2 and prostaglandin production in human uterine myometrium in vitro [36].

Frankincense contains boswellic acids that are known to have anti-inflammatory and analgesic properties, which make them useful in the treatment of endometriosis. Frankincense is used to reverse Qi stagnation and promote circulation. In animal and in in vitro studies, boswellic acids have been shown to inhibit lipoxygenase, an enzyme responsible for leukotriene synthesis [37]. Other studies in mice and rats corroborate its anti-inflammatory effects [38]. Interestingly, randomized, controlled trials have been conducted on boswellic acids where they were shown to be effective in the treatment of ulcerative colitis and asthma [39,40].

Myrrh has been used in endometriosis to break up static blood and alleviate pain. Other common uses include the treatment of wounds, hemorrhoids, ulcers and infections. It has some anti-inflammatory and antinociceptive properties, shown using the acetic acid-induced writhing and hot-plate tests in mice [41].

Black cohosh is commonly used in the treatment of menstrual disorders, including dysmenorrhea and premenstrual syndrome, although it is not a traditional Chinese herb. Most research has focused on its estrogenic activity. In rats, black cohosh was found to suppress FSH and LH release, presumably through negative feedback [42]. Other uses include the treatment of arthritis, osteoporosis, diarrhea, kidney disorders and menopausal symptoms, although data are inconclusive [43].

Zedoaria and Sparganium are two Chinese herbs commonly used together in endometriosis formulae. In Chinese medicine, these herbs are used to treat blood stasis, promote circulation and break up clotted blood. Both agents have powerful analgesic and anti-inflammatory properties. Zedoaria's main chemical constituents are sesquiterpenoids. Laboratory studies have revealed that these compounds inhibit lipopolysaccharide (LPS)-induced prostaglandin E₂ production in cultured mouse macrophages [44]. In other studies, Zedoaria was found to antagonize TNF-α activity [45]. Sparganium has inhibitory effects on IL-8 induction in rats and is used in Chinese medicine to treat splenomegaly, liver cirrhosis, ectopic pregnancy and cancer [46].

Persica, or Prunus persica, is a herb extract obtained from the inner pit of the peach fruit. In endometriosis treatment, Chinese herbalists use persica paired with other herbs including rhubarb and carthamus. Sakamoto and colleagues conducted animal studies in which a herbal formula containing persica had LH-antagonist activity and weak antiestrogenic activity [47]. However, the use of this herb has been cautioned against due to the risk of cyanide poisoning caused by its cyanogenic glycoside constituents. Typha angustifolia is a Chinese herb used to reduce clotting and menstrual bleeding. It is also a powerful analgesic for severe dysmenorrhea associated with endometriosis [24].

Herbs commonly used in infertility

Often, the treatment of endometriosis overlaps with the treatment of infertility and other menstrual disorders (Table 2). Therefore, many Chinese herbs and formulae are interchangeable. However, remedies for infertility depend on the preference of the herbalist who designs the formula. Most of the materials are derived from common roots, barks, leaves, flowers and fruits. However, some of the formulae contain animal materials, including deer antler and seahorse (the authors discourage the use of products derived from endangered species).

Table 2.

Chinese herbs commonly used in infertility.

Common name	Pharmaceutical name	Official name	Chinese name	Main constituents	Pharmacology	Chinese mechanism of action	Other uses in Chinese medicine	Ref.
Angelica root	Radix angelicae sinensis	Angelica sinensis	Dang Gui	Ferulic acid, ligustilide	Inhibits/relaxes uterus Inhibits platelet aggregation Potentiates phagocytosis of macrophages Enhances IL-2 Inhibits thromboxane-A2	Improves blood circulation Nourishes the blood Improves Qi circulation	Menorrhagia Dysmenorrhea Systemic lupus erythrematosus Nephritis Anemia Rheumatalgia	[25, 30]
Astragalus membranaceus	Radix astragali	Astragalus membranaceus	Huang Qi	Acetylastragal oside, cyclo-astragenol	Dilates peripheral blood vessels Increases cAMP Increases IgM in mice	Tonifies Qi and increases Yang	Common colds Rhinitis Peptic ulcer disease Hepatitis Leukopenia Psoriasis	[24, 25]
Bupleuri	Radix bupleuri	Bupleurum chinese	Chai Hu	Triterpenoids, essential oils, coumarin, flavone	Reduces inflammation Stimulates humoral and cellular immunity in mice	Relieves liver Qi stagnation	Hepatitis Hyperlipidemia Cirrhosis	[24, 25]
Cinnamon twig	(1) Ramulus Cinnamomi (2) Cortex Cinnamomi	Cinnamomum cassia	(1) Gui zhi (2) Rou Gui	Cinnamaldehyde, cinnamic acid, coumarin	Peripheral vasodilation Inhibits gastric secretion	Tonifies kidney Yang Encourages production of Qi and blood	Impotence Decreased libido Bronchitis Colds Diarrhea	[24]
Cistanche	Herba cistanches	Cistanche salsa	Rou Cong Rong	β-sitosterol, succinic acid, caffeic acid	Increases phagocytosis in macrophages Stimulates the endocrine system	Tonifies kidney Yang and blood Often used in impotence, infertility and spermatorrhea	ImpotenceD ecreased libido Constipation Joint pain	[24, 25]
Cnidium fruit	Fructus cnidii	Cnidium monnieri	She Chuang Zi	L-pinene, L-camphene, bornyl acetate	Increases weight of uterus, ovaries and testicles in mice Inhibits trichomonas vaginalis	Warms the kidney and strengthens Yang Often used to treat impotence and infertility in men and women	Dermatitis Exzema Pruritis Hemorr-hoids	[24, 25]
Cornus officinalis	Fructus corni	Cornus officinalis	Shan Zhu Yu	Cornin, ursolic acid, verbenalin	Reduces inflammation	Tonifies liver and kidney	Menorrhagia Urinary incontinence Polyuria	[24]
Cuscuta	Semen cuscutae	Cuscuta chinensis	Tu Si Zi	Cholesterol, campesterol, β-sitosterol	Hematoprotective effect in mice	Tonifies kidney Yin and Yang Treats deficiencies such as impotence, vaginal discharge, uterine bleeding and spermatorrhea	Urinary incontinence Restless fetus Enuresis Diarrhea	[24]
Dipsacus	Radix dipsaci	Dipsacus asper	Xu Duan	β-sitosterol, hederagenin, ursol-aldehyde, ursolic acid	Beneficial in mice with vitamin E deficiency	Tonifies liver and kidney Calms the fetus and stops uterine bleeding due to liver and kidney deficiencies	Polyuria Spermatorr-hea Breast abscesses	[24]
Donkey-hide gelatin	Colla corii asini	Equus asinus	E Jiao	Collagen, amino acids	Increases red blood cell count and hemaglobin Increases plasma calcium	Tonifies blood and stops bleeding Used in bleeding in pregnancy and common gynecologic bleeding problems	Tuberculosis Chronic ulcers Unstable pregnancies and restless fetuses Leukopenia Anemia	[24]
Dried human placenta	Placenta homini	Homo sapiens	Zi He Che	Proteins, amino acids, hormones	Increases immunity and IgM in mice	Nourishes blood in Qi and blood deficiencies	Asthma Lung cancer Chronic tracheitis Insufficient lactation	[24]
Epimedium saggittatum	Herba epidimii	Epimedium sagittatum	Ying Yang Huo	Icariine	Increases sperm production Increases sexual desire and activity	Tonifies Qi Strengthens Yang Increases libido	Anti-inflammatory drug Coronary artery disease Neutropenia Bronchitis	[24, 25]
Eucommia ulmoidis	Cortex eucommiae	Eucommia ulmoides	Du Zhong	Pinoresinol, proteins, eucommioside, alkaloids	Blocks stimulation and contraction of the uterus	Tonifies liver and kidney Yang Calms the fetus to prevent miscarriages	Hypertension Sciatica Anti-inflammatory drug	[24, 25]
Gecko	Gecko	Gekko gecko	Ge Jie	Carnoside, carnitine, guanine, albumin	Increases weight of testicles in male mice Prolongs estrus periods in female mice Increases WBCs and phagocytosis in macrophages	Tonifies kidney Yang and augments the blood	Impotence Decreased libido Bronchitis Colds Diarrhea	[24, 25]
Gentiana	Radix gentianae	Gentiana scabra bunge	Long Dan Cao	Gentiopicrin, gentiopicroside, sweroside	Shows hepato-protective effects in mice	Clears heat and dries dampness	Hepatitis Encephalitis Sedative	[24, 25]
Litchi seed	Semen litchi	Litchi chinensis	Li Zhi He	3-acetoin 2,3-butanediol, copaene	Lowers blood glucose levels in mice	Regulates liver Qi	Epigastric pain Hernial disorders Pain in testicles	[24, 25]
Polygonatum rhizome	Rhizoma polygonati	Polygonatum kingianum	Huang Jing	Azetidine-2-carboxylic acid, aspartic acid, homoserine	Increases heart rate Decreases blood pressure Reduces plasma glucose levels in rabbits	Tonifies kidney	Hypotension Tuberculosis Hypercholesterolemia	[24, 25]
Poria scleroticum	Poriae albae	Poria cocos	Fu Ling	Pachymose, pachyman, tumulosic acid	Antineoplastic activity in mice Diuretic	Promotes urination and resolves dampness Strengthens the spleen	Schizo-phrenia Edema	[24, 25]
Testudinis-“tortoise shell”	Plastrum testudinis	Chinemys reevesii	Gui Ban	Collagen, protein, lipids, amino acids	Useful in treating liver cirrhosis and sarcoma	Tonifies kidney Stops bleeding	Burns Sarcoma Cirrhosis	[24, 25]
Tortoise shell	Carapax trionycis	Trionyx sinensis	Bie Jia	Gelatin, collagin. colloid, keratin, vitamin D, iodine	Inhibits proliferation of connective tissue and dissolves masses	Softens hardness and dissipates nodules Treats amenorrhea caused by Yin and blood deficiencies failing to nourish the ren/conception	Headaches Costal chondritis Malaria Goiters Intestinal abscesses	[24]
White peony root	Radix paeoniae albae	Paeonia lactiflora	Bai Shao	Paeoniflorin	Reduces production of NO & TNF Inhibits histamine release Inhibits platelet coagulation, plasmin and plasminogen Peripheral vasodilator Inhibits smooth muscle of uterus	Nourishes blood and preserves Yin	Dysmenorrhea Amenorrhea Sedative Depressant Rheumatalgia Allergies	[25]

cAMP: Cyclic adenosine-5-phosphate; Ig: Immunoglobulin; IL: Interleukin; NO: Nitric oxide; TNF: Tumor necrosis factor; WBC: White blood cell.

Several formulae contain herbs that are thought to regulate hormone balances and help restore hormonal harmony. They include bupleurum, peony, gentian, Angelica sinensis and litchi seed [24,25]. Some herbs, including cinnamon and peoria, are used to improve circulation in the pelvic organs to enhance fertility [20]. Xia and colleagues conducted a study which showed that a certain Chinese herbal formula increased blood circulation in the uterus and ovary and promoted growth and development of the follicle compared with clomiphene citrate [48]. Another study by Liu and colleagues investigated the treatment of 46 endometriosis patients with Chinese herbs designed to treat blood stasis and resolve lumps. In this study, approximately 60% of the infertility patients became pregnant after treatment [49]. Similar outcomes after conservative surgery for endometriosis are reported [10,50].

Limited clinical evidence on Chinese herbs in endometriosis & infertility

In China and throughout the world, endometriosis was first widely detected in the 1980s when laparoscopy became popular. Chinese researchers reported on the disease at that time, with a rush of clinical trials on endometriosis starting in the 1980s. English translations of Chinese herbal treatment strategies first appeared in the mid 1980s. Since then, Chinese herbal therapy for endometriosis and infertility has been become popular in the USA. Few researchers in the USA have investigated the use of Chinese herbs in the treatment of endometriosis and infertility. Most of the studies that have been conducted are anecdotal and statistically insufficient. Many Chinese herbalists who treat endometriosis and infertility rely on individual patient outcomes to guide their treatment, rather than evidence-based medicine standards. To date, there are no randomized, controlled trials evaluating the efficacy of Chinese herbs on endometriosis or infertility published in the English-speaking scientific literature. However, there are a number of animal and human pharmacokinetic studies investigating the dynamics and mechanisms of action of individual ingredients of many Chinese herbal complexes [25,26].

Although herbal remedies have increased in popularity in the USA, limited data exist since these are categorized by the US Food and Drug Administration (FDA) as traditional food supplements rather than drugs. As such, there has been no formal testing of either the safety or efficacy of many of the individual herbs or formulas. Despite the lack of evidence, many adults in the USA are using some form of complementary, alternative medicine. Surveys on complementary, alternative medicine performed in the USA in the last 15 years have reported that the most commonly used complementary alternative modality was herbal therapy (18.6%), representing over 38 million adults in the USA [51,52]. In addition, complementary therapies were considered valid by an Australian population of women with endometriosis [53]. For some women in this Australian population, alternative therapies had replaced allopathic medicine, completely managing their disease and quality of life [53]. In addition, a study carried out by the Center for Disease Control and Prevention (CDC) based on 31,044 interviews of adults aged 18 years and over reported that adults who used complementary alternative medicine were likely to do so because they believed that complementary alternative medicine combined with conventional medical treatments would improve their symptoms (54.9%) [54].

Therefore, formal clinical trials testing themechanisms of action, efficacy and toxicities of Chinese herbal therapies are needed. The establishment of a new National Institutes of Health (NIH) institute for complementary and alternative medicine is an important step toward the validation of popular and effective traditional treatments of endometriosis and infertility.

Conclusion & future perspective

Traditional Chinese medicine has been used for thousands of years and is still used today by millions of Asians, Americans and other populations. Many recipients of Chinese herbal therapy consider these natural products to always be safe and beneficial alternatives to Western medicine. However, many of the side effects and toxicities of Chinese herbs have not been analyzed or tested. Although the trend in Western medicine is moving towards a more integrated method of treating disease, most Chinese herbs are not regulated by Western standards. Most of the research is derived from poorly controlled studies. In addition, a number of herbs are studied in formulae and not individually, thus creating difficulty in identifying the efficacy of each individual herb. Strategies for further evaluation of these therapies include testing the herbs in in vitro models of endometriosis [55,56] and infertility. The authors demonstrated in an in vitro model using endometriotic stromal cells, that a Chinese herbal remedy exerts an anti-inflammatory effect by downregulation of cytokine production [55] and an antiproliferative effect [56]. Furthermore, relevant animal models should be used to investigate the effect of herbal treatments, including rodent [57,58] and baboon models of endometriosis [59]. In the rat, surgically transplanted endometrial tissue provides an animal model to study the effects of experimental drugs on ectopic endometrial tissue [58]. The advantage of rodents, including rat and rabbit models, is the low cost compared with the monkey model. In addition, the baboon model for endometriosis would be an excellent opportunity to test Chinese herbs in the prevention or treatment of endometriosis, endometriosis-associated disease and subfertility [59]. The baboon model offers many advantages over the rodent model. Since baboons menstruate, they develop spontaneous endometriosis and their reproductive endocrinology is comparable to that in women [59]. On the basis of the safety data acquired from rodent and monkey models, the authors recommend that randomized, clinical trials be designed and executed in human subjects with endometriosis and subfertility.

In the future, it is predicted that more adults in the USA will be using Chinese herbs to treat their symptoms as the perspective on treating disease changes. Therefore, we must continue to test these herbs individually in clinical trials, in order to better serve patients and enhance the body of Chinese literature and anecdotal evidence that currently exists.

Executive summary

Background

Endometriosis is a disease that affects approximately 10% of all reproductive-aged women and the prevalence rises to 20–50#x0025; in infertile women. Endometriosis is defined by the presence and growth of uterine glands and stroma outside the uterine cavity. A host of cells and their products, ranging from cytokines to growth factors, all contribute to the progression of endometriosis and associated infertility.

Nonsteroidal, hormonal and surgical therapies have been traditionally offered in the treatment of endometriosis and infertility. Additional treatment strategies with higher efficacy and fewer side effects are desirable. There is longstanding and growing evidence that medicinal Chinese herbs with anti-inflammatory and pain-alleviating properties may be useful in the treatment of endometriosis and infertility.

Chinese etiology of endometriosis & infertility

In Chinese medicine, endometriosis is primarily viewed as a blood (Xue) stasis syndrome resulting in the formation of endometriotic lesions caused by: liver Qi Stagnation, coldness, accumulation of damp heat in the blood (Xue) and Qi and blood vacuity.

There are seven physically-based types of infertility in Chinese medicine, including: Jing deficiency, Qi and Xue deficiency, heat injury of channels, stagnation of Qi and Xue, kidney and liver Yin deficiency, cold uterus and Yang deficiency and extraordinary channel disturbances.

History of documented use of Chinese herbs

Traditional Chinese medicine is a holistic model of health maintenance based on Chinese herbs, acupuncture and other forms of therapy.

Several Chinese herbs have been used for centuries in treating Chinese diagnostic patterns associated with endometriosis and infertility.

Herbs commonly used in endometriosis

There is growing evidence that medicinal Chinese herbs with anti-inflammatory and pain-alleviating properties may be utilized in the treatment of endometriosis-associated symptoms.

Examples include Angelica root, Cinnamon twig, Corydalis rhizome extract, Frankincense, Myrrh, Salvia root, Licorice root, Persica, Sparganium, White peony root and Zedoaria.

Herbs commonly used in infertility

Often, treatment of endometriosis overlaps with the treatment of infertility and other menstrual disorders; therefore, many of the Chinese herbs and formulae are interchangeable.

Examples are Angelica root, Astragalus membranaceus, Bupleuri, Cistanchi, Cnidium fruit, Cornus officinalis, Cuscuta, Depsacus, Dried human placenta, Donkey-hide gelatin, Epimedium saggittatum, Eucommia ulmoidis, Gecko, Gentiana, Litchi seed, Polygonatum rhizome, Poria, Tortoise shell and White peony root.

Limited clinical evidence on Chinese herbs in the treatment of endometriosis & infertility

36% of adults in the USA use some form of complementary, alternative medicine.

Women with endometriosis commonly describe complementary therapies as vital in the management of their disease.

Although herbal remedies have increased in popularity in the USA, limited data exist because they are categorized by the US Food and Drug Administration as traditional food supplements rather than drugs. There are no controlled trials on the use of Chinese herbs in the treatment of endometriosis and infertility.

Future of Chinese & Western medicine

It is mandatory that Chinese herbs be tested rigorously in preclinical models and randomized clinical trials in order to better serve patients and to enhance the body of Chinese literature and anecdotal evidence that currently exists.

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A Western Primer of Chinese Herbal Therapy in Endometriosis and Infertility

Abstract

Keywords

General theories in Chinese medicine

Chinese etiology of endometriosis

Liver Qi stagnation

Coldness

Accumulation of damp heat in the blood

Qi & blood vacuity

Chinese etiology of infertility

Jing deficiency

Qi & Xue deficiency

Stagnation of Qi & Xue

Heat injury of channels

Kidney & liver Yin deficiency

Cold uterus & Yang deficiency

Extraordinary channel disturbances

History of documented use of Chinese herbs

Herbs commonly used in endometriosis

Herbs commonly used in infertility

Limited clinical evidence on Chinese herbs in endometriosis & infertility

Conclusion & future perspective

References