{"paper_id":"9099da89-3318-41b8-bbba-121cc7da2823","body_text":"http://dx.doi.org/10.13048/jkm.13004 29\nLiterature Review on Biological Effects of \nGyejibokryeong-hwan against Gynaecological Diseases\nJung-Hoon Kim, Hyeun-Kyoo Shin\nBasic Herbal Medicine Research Group, Korea In stitute of Oriental Medicine, Daejeon, 305-811\nOriginal Article\n⋅Received：2 May 2013 ⋅Revised：20 May 2013 ⋅Accepted：20 May 2013\n⋅Correspondence to：Hyeun-Kyoo Shin\nBasic Herbal Medicine Research Group, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea, \n305-811.\nTel：+82-42-868-9464,  Fax：+82-42-864-2120,  Email：hkshin@kiom.re.kr\nObjectives: To investigate therapeutic mechanisms of Gyejibokryeong-hwan (GJBRH) against gynaecological diseases, \narticles on biological assay were gathered and analyzed.\nMethods: The articles were classified as being from domest ic or international journals, and by their year of \npublication. The mechanisms of the biological e ffects against gynaecological diseases were noted.\nResults: Of the 14 articles analyzed, 13 were published in China and 1 was from Japan. GJBRH showed therapeutic \neffect against uterine and mammary gland diseases. Uterine- related diseases such as endometriosis, hysteromyoma, \nadenomyosis, cancer, and inflammation can be improved by the administration of GJBRH through anti-angiogenesis, \nanti-inflammation, the modulation of immune cell and imm unoglobulin, and the regulation of hormone secretion. \nGJBRH also reduced mammary hyperplasia by regulating hormone and cytokine release.\nConclusions: We speculate that the inhibitory effect against uterine and mammary gland diseases could be related \nto the therapeutic efficacy of GJBRH in improving gynaecological diseases.\nKey Words  : Gyejibokryeong-hwan, gynaecological disease, therapeutic mechanism, uterine, mammary \ngland.\nIntroduction\nGyejibokryeong-hwan (GJBRH) is a traditional \nherbal formula consisting of 5 herbal medicines i.e. \nCinnamomi ramulus, Poria sclerotium, Moutan \ncortex, Paeoniae radix, and Persicae semen. GJBRH \nhas been used to treat symptoms caused by stagnant \nblood which  leads to abnormal mass in lower \nabdomen, amenorrhea, dysmenorrhea, menstrual pain, \ndifficult delivery, retention of placenta, and \nabnormally prolonged discharge of lochia, which \nwere mainly involved in uterine disorders\n1,2). \nThese same symptoms in Korean medicine can be \nexplained as gynaecological diseases of modern \nwestern medicine, especially uterus-related diseases. \nThe uterus is the organ in which offspring are \ncarried and nourished before birth, and menstruation \noccurs. Another name for the uterus is ‘blood \nchamber’ which means the uterus is easily influenced \nby the state of blood flow and its pathogenic \nsymptoms are observed as blood-related disorders in \nmost cases\n2). GJBRH can be applied to stagnant \nblood-induced uterus-related disorders through \npromoting blood flow and dispelling blood stasis. \nClinical studies support that GJBRH can improve \nclinical symptoms of hypermenorrhea, dysmenorrhea \nJ Korean Med. 2013;34(2): 29-40\nhttp://dx.doi.org/10.13048/jkm.13004\npISSN 1010-0695 eISSN 2288-3339\n\nJournal of Korean Medicine 2013;34(2)\nhttp://dx.doi.org/10.13048/jkm.1300430\nElectronic bibliographic databases Search terms\nKorea   Education and Research Information Service http//www.riss4u.net Gyejibokryeonghwan\nGyejibokryonghwan\nGyejibokryunghwan\nKeishi-bukuryo-gan\nGuizhi-fuling capsule\n계지복령환\n桂枝茯苓丸\nKorean   Studies Information Service System http://kiss.kstudy.com\nNational   Discovery for Science Leaders http://www.ndsl.kr\nOriental   Medicine Advanced Searching Integrated System http://oasis.kiom.re.kr\nKorea   Institute of Science and Technology Information http://society.kisti.re.kr/main.html\nKorean   Traditional Knowledge Portal http://www.koreantk.com\nPubMed http://www.ncbi.nlm.nih.gov/pubmed\nGoogle  Scholar http://scholar.google.co.kr\nScienceDirect  http://www.sciencedirect.com/\nNational   Institute of Informatics http://ci.nii.ac.jp\nChina National   Knowledge Infrastructure http://www.cnki.net\n(222)\nand uterine myomas3,4), and decrease the severity of \nmenorrhalgia5).\nIn vivo experiment is a method that uses an \nanimal model to investigate the efficacy of a \ntreatment or medicine of interest by diverse \nadministration routes including gastrointestinal tract, \nsubcutaneous, intravenous, and intraperitoneal \ninjection. Numerous researches testing Korean \nmedicine have been performed using in vivo \nexperiments to evaluate the therapeutic effect of \nherbal medicines or herbal formulas, although \ncontroversy remains regarding whether experimental \nmethods could properly explain therapeutic \nmechanism of traditional Korean medicine. \nNonetheless, the trials to find the point of connection \nbetween Korean medicine and biological experiments \nwould be beneficial to construct scientific and \nobjective establishment of Korean medicine.\nIn the present study, we searched articles dealing \nwith the biological effects of GJBRH. Articles on \ntreating gynaecological diseases classified by Korean \nstandard classification of diseases (KCD) were \nfurther investigated to figure out the relationship \nbetween the biological and therapeutic effects of \nGJBRH and its mechanisms of action.\nMaterials and Methods\n 1. Search strategy and terms \nWe searched a variety of published papers in \nKorean and foreign electronic bibliographic \ndatabases between 1990 and the present through \nthe Korea Education and Research Information \nService (KERIS), National Discovery for Science \nLeaders (NDSL), Korean Studies Information \nService System (KISS), Korean Traditional \nKnowledge Portal, Oriental Medicine Advanced \nSearching Integrated System (OASIS), PubMed, \nScienceDirect, Google Scholar, China National \nKnowledge Infrastructure (CNKI), and Citation \nInformation from the National Institute of \nInformatics (CiNii) using search terms such as \n“Gyejibokryeonghwan”, “Gyejibokryonghwan”, \n“Gyejibokryunghwan”, “Keishi-bukuryo-gan”, \n“Guizhi-fuling-wan”, “Guizhi-fuling-capsule”, “\n계\n지복령환”, and “ ” (Table 1).\n2. Selection criteria and data extraction\nWe selected 14 full text-papers regarding in \nvivo biological experiments dealing with \ngynaecological diseases referring to KCD index \n(Code No. N60\nN99). Papers were categorized \nby the distribution of their publication year and \ncountry of origin. From the selected papers, data \n\nLiterature Review on Biological Effects of Gyejibokryeong-hwan against Gynaecological Diseases\nhttp://dx.doi.org/10.13048/jkm.13004 31\n(223)\nextraction was conducted as follows: target \ndisease, animal species, induction of symptoms, \nand factors of treatment for parts of the body such \nas serum, organ, or tissue. The outcome measures \nwere further investigated to determine the \nmechanism of the therapeutic effect of GJBRH. \nResults\n1. Distribution of papers by the \npublication year and country\nAs shown in figure 1, most papers dealing with \ngynaecological diseases were published in China \n(92.86%), followed by one paper from Japan. In \nChina, the numbers of published papers sharply \nincreased in the period from 2001 to 2005 and \nshowed slight decrease in the period from 2006 to \n2010. Thereafter, there has been increasing \nfrequency of papers published since 2011 to the \npresent year. The single Japanese paper was \npublished in 1995; no other researches were found \nthroughout the period of publication years \nsearched. \n2. Biological effect of GJBRH on \ngynaecological diseases\nGynaecological diseases were divided by their \nlesions which were uterine & pelvic lesions and \nmammary lesions. Uterine and pelvic diseases \nincluded endometriosis, hysteromyoma, uterine \nadenomyosis, cervical cancer, and pelvic \ninflammation. Mammary lesions included \nmammary hyperplasia.\n1) Biological effects on the diseases of uterine \n& pelvic lesions\nAs shown in Table 2, most of the reported \npapers have dealt with biological effects of \nGJBRH on endometriosis. Rats, especially \nSprague-Dawley rats, were used as an animal \nmodel and endometriosis symptoms were induced \nby the endometrial autografts in the abdomen. \nAfter the oral and intragastric administration of \nGJBRH, histological changes were observed in the \nendometriotic area such as reduced endometrial \nvolume and gland or a decrease in microvessel \ndensity\n6,8,10,11). Additionally, the levels of vascular \nendothelial growth factor (VEGF), MCP-1 \n\nJournal of Korean Medicine 2013;34(2)\nhttp://dx.doi.org/10.13048/jkm.1300432\nTarget   disease Animal Induction Outcome   (cytokines or molecules)\nOrgan   & tissue Blood   & fluid\nEndometriosis SD rats 6-10)\nWistar rats11)\nAutograft of \nendometrium in\nabdomen\n6-11)\nEctopic endometrium \nVEGF ↓6)\nMCP-1 &   ICAM-1 ↓8,10)\nMMP-2 &   MMP-9 ↓11)\nSpleen\nCD4+Tcell↑9,10)\nCytotoxic NK cell activity ↑\n9,10)\nPeripheral fluid   & blood\nMacrophage ↓6)\nIL-8 ↓6)\nTNF-α ↓6)\nIgG,   IgM, IgA ↓7)\nCD3+,CD4+↑7)\nCD8+↓7)\nSerum & plasma\n6-keto-PGF1α↑11)\nβ-EP   ↑11)\nTXB2↓11)\nHysteromyoma Wistar rats 12)\nKunming mice13)\nEstradiol12)\nEstradiol \nbenzoate\n13)\n- Serum & blood\nestradiol   ↓12,13)\nprogesterone   ↓12,13)\nUterine \nadenomyosis\nSHN mice\n14) Ectopic pituitary \nisografting14)\nUterine \nTS activity ↓14)\n-\nCervical cancer BALB/c nu \nmice15)\nHeLa cell15) Tumor \nMMP-2, MMP-9 expression \n↓15)\nangiogenesis ↓15)\n-\nPelvic \ninflammation\nWistar rats16) Bacteria & \nmechanical \ndamage\n16)\nUterine tissue\nTNF-α & TNF-β1expression\n↓16)\nVEGF   expression ↓16)\n-\n VEGF, vascular endothelial growth factor; MCP-1, monocyte chemoattractant protein-1; ICAM-1, inter-cellular adhesion molecule-1; MMP, \nmatrix metalloproteinases; IL, interleukin; TNF, tumor necrosis factor; Ig, immunoglobulin; TS, thymidylate synthetase; 6-keto-PGF1α, \n6-ketone-prostaglandin F1α;EP,β-endorphin;TXB2,thromboxaneb2.\n(224)\n(monocyte chemoattractant protein-1), ICAM-1 \n(inter-cellular adhesion molecule-1), and matrix \nmetalloproteinases (MMP) were reduced in the \nendometrium while there were increases of CD4+ \nT cell and NK cell activity in the spleen from \ntreatment with GJBRH\n6,8-11). In the peripheral fluid \nand blood, GJBRH reduced the production of \nmacrophages, interleukin-8 (IL-8), tumor necrosis \nfactor-\nα (TNF-α), and immunoglobulin A, G, and \nM. GJBRH also inhibited the production of CD8+ \ncells while stimulated those of CD3+ and CD4+. \nSerum expressions of 6-keto-prostaglandin F1\nα \n(PGF1α) and β-endorphin (EP) were enhanced \nwhile that of thromboxane B2 (TXB2) was \ninhibited by the administration of GJBRH. \nGJBRH showed therapeutic effect against \nhysteromyoma induced by estradiol and its \nderivative. Excessive uterine weight and smooth \nmuscle proliferation were reduced by the \nadministration of GJBRH. It also decreased the \nlevels of estradiol and progesterone in serum and \nplatelet aggregation, and viscosity of blood \nwhereas enhanced blood coagulation time, kaolin \npartial thromboplastin time, and prothrombin \ntime\n12,13). Thymidylate synthetase (TS) activity in \nrats with adenomyosis induced by pituitary \nisografting was inhibited by the treatment of \nGJBRH, which showed decreased adenomyosis \ndevelopment\n14). GJBRH suppressed the growth of \ncervical cancer and angiogenesis, and the \nexpressions of MMP-2 and MMP-9 were also \ninhibited\n15). Pelvic inflammation was improved by \nGJBRH through the inhibition of TNF and VEGF \nexpression in uterine tissues\n16).\n\nLiterature Review on Biological Effects of Gyejibokryeong-hwan against Gynaecological Diseases\nhttp://dx.doi.org/10.13048/jkm.13004 33\nTarget disease Animal Induction Outcome\nOrgan & tissue Blood & fluid\nMammary hyperplasia  SD rats 17-19) Estradiol & progesterone17-19) Mammary gland\nER   ↓17-19)\nPR   ↓17-19)\nBlood &   plasma & \nserum\nEstradiol   \n↓17-19)   \nProgesterone   ↑17-19)\nIL-2   ↑18,19)\nTNF-α ↓18,19)\n ER, estrogen-receptor; PR, progesterone- receptor; IL, interleukin; TNF, tumor necrosis factor.\n(225)\n2) Biological effects on the disease of \nmammary gland\nTable 3 shows that GJBRH inhibited mammary \nhyperplasia of rats which was induced by the \nstimulation of estradiol and progesterone through \nreducing duct epithelia, acinus and nipple height, \nand suppressing papilledema, lobular proliferation \nand hyperemia\n17-19). It also decreased hematocrit \nand viscosity in blood, and the levels of estradiol \nand TNF- α while enhance the secretions of \nprogesterone and interleukin-2 (IL-2) in serum and \nplasma17-19).\nDiscussion\nIn the present study, we gathered articles \nregarding biological effects of GJBRH against \ngynaecological diseases and investigated the \noutcomes to show whether the therapeutic effects \nof the herbal formula could be related to \nexperimental results. \nEndometriosis is characterized by endometrial-li\nke tissue outside the uterus in adjacent organs or \nbody parts such as pelvic peritoneum, ovaries, and \nabdomen\n20). Endometrium was surgically auto-graf\nted in the abdomen, which is conducted by transpl\nanting an autologous fragment of endometrial tissu\ne onto the inner surface of the abdominal wall as \ndepicted in the literature\n21). The development of e\nndometriosis is known to relate to the recruitment \nof blood vessels to the endometriotic lesions whic\nh induce angiogenesis 22). Vascular endothelial gro\nwth factor (VEGF), an important mediator of angi\nogenesis, is expressed at high levels in the periton\neal fluid and endometrial tissues\n22-24). Matrix metal\nloproteinases-2 and -9 (MMP-2 and -9), a family \nof zinc-dependent endopeptidases, can degrade the \ncollagen IV and play a key in the pathogenesis of \nendometriosis by degrading extracellular cellular \nmatrix (ECM) and promoting the release of key fa\nctors\n25). The serum level of MMP-2 is elevated in \ninfertile women with advanced stages of endometr\niosis and the expressions of MMP-2 and 9 are als\no increased in the patients of ectopic endometrium\n23,26). In addition, it is reported that MMPs is highl\ny correlated with tumor aggressiveness of various \nhuman cancers 27). The oral administration of GJB\nRH can reduce the expressions of VEGF and MM\nPs by preventing the angiogenesis and the degrada\ntion of ECM.\nEndometriosis is associated with an immune-in-\nflammatory process that occurs in the peritoneal \ncavity of patients\n28). GJBRH can inhibit mono-\ncytes migrated from the peripheral blood to the \nperitoneal cavity by monocyte chemotactic pro-\ntein-1 (MCP)-1 which makes monocytes transform \ninto macrophages and bring about peritoneal in-\nflammation characterizing endometriosis\n29). The in-\ncreased accumulation of activated macrophages \nand their products found in patients with endome-\ntriosis are reported to influence the development \nof endometriotic tissues, and it is also known that \n\nJournal of Korean Medicine 2013;34(2)\nhttp://dx.doi.org/10.13048/jkm.1300434\n(226)\nthe cytokines such as IL-6 and TNF- α, released \nby activated macrophages, can promote aromatase \nactivity in endometriotic stromal cells and increase \nthe production of estrogen charging the growth of \nendometriotic lesions\n30).\nIntercellular adhesion molecule-1 (ICAM-1) \nfound in the human endometrium is known to be \nrelated to the defective functions of natural killer \n(NK) cells and mediate interactions between \nendometrial cells and lymphocytes during the \ninitial and sustained formation of \nendometriosis\n31-33). NK cells recruited to eutopic \nendometrium in the onset of menstruation \nparticipate in endometrial remodelling and repair \nby clearing the endometrial products following \nmenstrual shedding, so decreased NK cell activity \nand the resulting impaired clearance of \nendometrium can contribute the development of \nendometriosis\n34-36). Interleukin-8 (IL-8), a \npro-inflammatory chemokine, initiates many \ndifferent signalling pathways and results in \nangiogenesis, mitogenesis and motogenesis by \nbinding to the chemokine receptors CXCR1 and \nCXCR2, which is observed at higher concentration \nin patients with endometrioma\n37,38). TNF- α, a \nprimary effector of inflammatory responses, \nproceeds one of the major mechanisms of \nendometriosis by increasing expression of \ncytokines such as MCP-1 and IL-8 and its \nproduction is increased in endometriotic epithelial \ncells\n39). TNF- α also stimulates the expression of \nmatrix metalloproteinases (MMPs) in endometrial \ntissue\n40). Transforming growth factor- β1 (TGF- β\n1), a molecular mediators of pathological tissue \nfibrosis, can stimulate the fibroblasts to produce \ncollagen, fibronectin, and integrins, and also \ninhibit the production of collagenase and \nheparinase to degrade the extracellular matrix in \nvarious cell types, including platelets, \nmacrophages, ovarian cells, uterine tube cells, and \nuterine endometrial cells\n41). Inflammatory \nresponses characterized in endometriosis can be \nameliorated by decreasing macrophage \naccumulation, the expressions of MCP-1, ICAM-1, \nIL-8, TNF-\nα and TGF-β1, and activating NK cells \nby the administration of GJBRH. \nGJBRH also improves the immune responses \nthrough regulating immunoglobulin (Ig) secretion \nand T lymphocyte activation. Among the three \nmajor classes (IgG, IgA, and IgM), IgG and IgA \nwhich are detected in sera, cervical, and vaginal \nsecretions in patients with endometriosis are \nconsidered as candidates for the autoantigens \nresponsible for the immune response\n42). IgM is \nalso immunodominant in the sera of endometrial \npatient and the serum levels of IgG, IgA as well \nas IgM are increased in endometriosis\n43,44). \nImpaired Th immune response has been reported \nas a main factor causing the development and \nprogression of endometriosis\n45). T-cells in CD4+ \n(helpers) suppress the proliferation and function of \nT cells in CD8+ suppressor (cytotoxic) \nphenotype\n46). The decreased level and ratio of \nCD3, CD4/CD8 observed in peripheral blood of \npatients with endometriosis represented the \nautocrine and regulatory function of T cells in \nendometriotic tissues\n47). \n6-ketone-prostaglandin F1 α (6-keto-PGF1α) has \nbeen used as a substitute of prostacyclin which is \na major metabolite of arachidonic acid (AA) \nproduced by vascular endothelial cells, and its \nlevel is decreased in rats with endometriosis\n48-50). \nβ-Endorphin, a pain-reducer released following \nexposure to a painful stimuli, is found at low \nlevel in the endometriosis patients with moderate \nor severe pain 51,52). Thromboxane b2 (TXB2) is a \nhydrolyzed metabolite of TXA2, which is an \noxidation product derived from AA in \ncyclooxygenase (COX) and thromboxane synthase \ndependent reactions\n53). The production of serum \nTXB2 is a specific and most common index for \nevaluation of COX-1 activity in humans and \n\nLiterature Review on Biological Effects of Gyejibokryeong-hwan against Gynaecological Diseases\nhttp://dx.doi.org/10.13048/jkm.13004 35\n(227)\nothers, and the plasma level of TXB2 is increased \nin rats with endometriosis 50,53). GJBRH can \nimprove the expressions of 6-keto-PGF1 α and EP \nwhile reduce that of TXB2, which leads to \nregulating the inflammatory and immune response.\nAdenomyosis is described as a diffuse invasion \nof endometrial elements into the uterine \nmyometrium without apparent border between the \nnormal uterine tissue and the lesion\n54). SHN mice \nare known to develop uterine adenomyosis \nspontaneously and the development is can be \neasily induced by ectopic pituitary isografts (EPI) \nwhich are found in a high incidence of uterine \nadenomyosis\n55,56). Thymidylate synthase (TS) are \nrecognized as an indicator of cell proliferation and \npromotes DNA precursor synthesis, especially de \nnovo pyrimidine synthesis 57,58). Hysteromyoma, a \nbenign tumor growing from the muscle or \nconnective uterine tissue, causes heavy and \nprolonged menstrual bleeding, painful \nmenstruation, pain below the stomach, and \nincreased demand of urination associated with \npressure on the bladder and constipation, and is \nknown to be related with the growth of uterine \nmyomas and activity of estrogens\n59). The rat \nhysteromyoma model can be established by the \ninjection of estradiol benzoate and progesterone\n60). \nThe amount of estradiol and progesterone secreted \nby the cells and endometrium of hysteromyoma \nwas significantly larger than those of normal \ncontrol groups\n61,62). GJBRH inhibits the \ndevelopment of pathogenic invasion of \nendometrium and benign uterine tumor growth by \ndecreasing TS activity and hormones such as \nestradiol and progesterone.\nMammary hyperplasia is characterized by an \nenlargement of multiple mammary glands and in-\ncreases breast cancer risk when hyperplasia is ag-\ngravated\n63). Estrogens, especially 17 β-estradiol \n(estradiol), and progesterone have critical func-\ntions in mammary gland development and \ncarcinogenesis. The estrogen/estrogen receptor \n(ER)-α signaling pathway stimulates proliferation \nof mammary epithelium, and estrogens can have \nepithelial cells and stromal cells secrete growth \nfactors and pituitary prolactin that induce mito-\ngenesis in the epithelium\n64,65). Progesterone re-\nceptor (PR) is expressed by the great number of \nepithelial cells within the estradiol-induced atyp-\nical hyperplastic foci and the mammary carcino-\nmas\n66). Tumor necrosis factor- α (TNF- α) involved \nin the pathogenesis of inflammatory, autoimmune \nand malignant diseases can be also produced in \nthe mammary glands changed by tumor infiltrating \nlymphocytes or by cells of tumor stroma, and pro-\nmote angiogenesis by stimulating endothelial cell \nproliferation and modulating expression of pro-an-\ngiogenetic factors\n67,68). Interleukin 2 (IL-2), a lym-\nphocytotrophic cytokine, is involved in the growth \nand differentiation of T and B cells and improves \nNK cells to enhance the cytolytic 69). The serum \nlevel of IL-2 is decreased in rats with mammary \ngland hyperplasia 70). Mammary hyperplasia which \ncan worsen to breast tumors is suppressed by the \nadministration of GJBRH through regulating hor-\nmone levels (estradiol and progesterone) and cyto-\nkines (IL-2, TNF-\nα).\nConclusions\n We researched articles regarding the curative \neffect against gynaecological diseases of GJBRH to \nevaluate the relationship between the biological \neffect and therapeutic efficacy as defined in Korean \nmedicine. Most papers were published in China, \nfollowed by Japan, and studies of GJBRH have \nbeen reported constantly up to the present. GJBRH \ninhibited uterine-related diseases including \nendometriosis, hysteromyoma, adenomyosis, cancer, \nand inflammation by suppressing the \nanti-angiogenesis and anti-inflammation, modulating \n\nJournal of Korean Medicine 2013;34(2)\nhttp://dx.doi.org/10.13048/jkm.1300436\n(228)\nthe immune cells and immunoglobulin, and \nregulating hormone secretion. GJBRH also \ndecreased = hyperplasia of the mammary gland \nthrough the down-regulation of hormones and \ncytokine release. These biological effects against \ngynaecological diseases could be associated with the \ntherapeutic efficacy of GJBRH as defined by \nKorean medicine, namely curing uterine and \nmammary gland-related disorders.\nAcknowledgment\n This study was supported by a grant from the \nKorea Institute of Oriental Medicine (K13030).\nReferences\n1. Professor association of herbal formula of Korea \nmedicine. Herbal formula. Seoul:Youngrimsa. \n2003:409.\n 2. Western Pacific region of the World Health \nOrganization. WHO international standard \nterminologies on traditional medicine in the \nwestern pacific region. World Health \nOrganization. 2007:186. \n 3. Sakamoto S, Yoshino H, Shirahata Y, Shimodair\no K, Okamoto R. Pharmacotherapeutic effects of \nKuei-chih-fu-ling-wan (Keishi-bukuryo-gan) on \nhuman uterine myomas. Am J Chin Med. 1992;2\n0:313.\n 4. Cho JH. 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