{"paper_id":"e9cab342-a3fa-41f9-8b88-645c77adf56f","body_text":"Hanafi et al. : The Effect of Curcumin to the Anti Mullerian Hormone Serum Concentration   \n  \n  \n  96 \nThe Effect Of Curcumin to the Anti Mullerian Hormone Serum Concentration  in \nEndometriotic Rat Model  \n   \nNova Hanafi, Ashon Sa’adi,Widjiati  \nDepartment of Obstetrics and Gynecology,   \nFaculty of Medicine, Airlangga University,   \nDr. Soetomo Hospital, Surabaya  \n  \n  \nABSTRAK  \n  \nTerapi medis endometriosis hanya dapat digunakan dalam waktu yang terbatas karena timbul efek samping. Salah satu metode \npengobatan yang dikembangkan untuk terapi medis tersebut adalah dengan menggunakan bahan-bahan herbal, antara lain kurkumin. \nTujuan dari penelitian ini adalah untuk mempelajari konsentrasi AMH dalam serum dari model tikus endometriotik dengan \nsuplementasi kurkumin. Penelitian eksperimental dilakukan pada laboratorium embriologi Fakultas Kedokteran Hewan Universitas \nAirlangga, Surabaya, Juli-Oktober 2011. Ini adalah tes laboratorium menggunakan 38 tikus betina (Rattus novergicus) yang tak sesuai \nkriteria inklusi. Untuk membuat model tikus endometriotik, masing-masing tikus disuntik dengan: A cyclosporin dan ethynil estradiol \nintramuskuler, jaringan endometrium manusia jinak intraperitoneal ovarium tumor. Model tikus endometriotik secara acak dibagi  \nmenjadi dua kelompok. Kelompok intervensi diberi kurkumin 24 mg (240 mg/kg) sekali sehari sampai empat belas hari. Tikus -tikus \ndikorbankan dan konsentrasi AMH dari serum diukur dengan alat tes ELISA kit dari Cusabio Biotech, Wuhan, Cina. Ada perbedaan \nyang signifikan pada konsentrasi serum AMH antara kurkumin kelompok (44.9 ± 20.1) kelompok plasebo (29.8 ± 11.9) (p <0.05). \nSebagai kesimpulan, konsentrasi serum AMH lebih tinggi dalam model tikus endometriotik dengan suplementasi kurkumin. (MOG \n2011:19;96-101)  \n  \nKata kunci: kurkumin, endometriosis, hormon anti-Mullerian  \n  \n  \nABSTRACT  \n  \nMedical therapy of endometriosis can only be used within a limited time because of arising side effects. One method of medica l \ntreatment that was developed for this purpose is using her bal ingredients, the curcumin. The objective of this study was to study the \nAMH concentration in serum of endometriotic rat model with curcumin supplementation. This experimental study was performed at  \nembryology laboratory Faculty of Veterinary Medicine o f Airlangga University, Surabaya, July – October 2011. This was an \nexperimental laboratory tests using 38 female rats (Rattus novergicus) with the inclusion criteria. To make endometriotic rat  model, \neach rat was injected with: both cyclosporin A and ethyn il estradiol intramuscularly, human endometrial tissue of benign ovarian \ntumors intraperitoneally. The endometriotic rat model were randomly divided into two groups. The intervention group was comsuming \ncurcumin 24 mg (240 mg/kg) once daily until fourteen days. The rats were sacrificed and the AMH concentration from serum were \nmeasured by ELISA kit assay from Cusabio Biotech, Wuhan, China. There was a significant difference in serum concentration of AMH \nbetween curcumin group (44.9 ± 20.1) an placebo group (29.8 ± 11.9) (p < 0.05). In conclusion, the concentration of serum AMH is \nhigher in endometriotic rat models with curcumin supplementation. (MOG 2011:19;96-101)  \n  \nKeywords: curcumin, endometriosis, anti mullerian hormone   \n  \nCorrespondence: Nova Hanafi, Department of Obstetrics and Gynecology, Faculty of Medicine, Airlangga University,   \nDr. Soetomo Hospital, Suraba, novahanafi75@yahoo.co.id   \n  \n  \nINTRODUCTION  \n  \nEndometriosis is a disease that remains a problem for \nwomen of reproductive age. The prevalence in the general \npopulation of reproductive-age women between 3-10%.15 \nGenerally they are visiting a doctor with chief complaints \nof chronic pelvic pain, dysmenor rhoe, dyspareuni, and \ninfertility. Data on dr.Soetomo Hospital Surabaya \nshowed the incidence of endometriosis during \nlaparoscopic procedure in patient with infertility, namely \nin 1987 and 1991 of 23.8%, in 1992 to 1993 increased to \n37.2%, and the last in 2002 reached 50%.  \nThere are several factors that cause high rates of infertility \nin patients with endometriosis, mechanical factors that \ncause adhesions of the reproductive organs and disrupt \noocyte retrieval by fimbria during ovulation, another \nfactors ar e defects of the immunological response and \noocyte quality degradation due to interference \nfolliculogenesis process. This decline in oocyte quality \n\nMajalah Obstetri & Ginekologi Vol. 19 No. 3 September - Desember 2011 : 96-101  \n  97 \nwill lead to low rates of pregnancy in women with \nendometriosis to less than 35% and the high incidence of \nabortion up to 27%.  \n  \nDefective immunological response characterized by an \nincrease in the inflammatory process induced by the \nactivity of macrophages in the peritoneal fluid, \nmacrophages will secrete excessive number of cytokines \nincluding TNF -α. TNF -α will diffuse into the follicle, \nthen through binding to its receptor (TNF -R1) on the \nmembrane of granulosa cells, TNF -α activates the cell \ndeath signals and induce the occurrence of the caspase \ncascade and stimulate the process of apoptosis in \ngranulosa cells. TNF-α also increases the production of \nROS via the JNK-1 and will increase the oxidative stress \nthat stimulates the process of granulosa cell apoptosis. 1 \nThese pathological process of apoptosis will cause \ninterference with the function of granulosa cell s. Has \nbeen demonstrated in previous studies that the \nfolliculogenesis process obtained cooperation between \ngranulosa cells and oocyte cells. 3 Both of these cells \ncommunicate with each other through paracrine pathways \nto produce good quality oocytes for fe rtilization, so that \nif an interruption occurs in granulosa cell function may \nresult in decreased quality of oocytes and increased rates \nof infertility in patients with endometriosis.  \n  \nCommonly therapies used in endometriosis is by surgery \nor medically with hormonal medication or combination \nof both. The basic principle of therapy is to suppress \nsymptoms and prevent progression to reduce \nendometriosis implants. Cure rate of surgical ther apy \nabout 80%, but surgery is too invasive and the number of \nrecurency about 10% -20% and still require additional \ntherapy. Some hormonal therapies currently used are to \ninhibit the growth of endometriosis implants by pressing \nthe steroid hormone released b y the ovaries and cause \nhipoestrogenik circumstances. Medical therapy of \nendometriosis can only be used within a limited time \nbecause of side effects arising hipoestrogen, so people \nexpected on the new problem of infertility. The high \nrecurrence rate reached 45% after completion of medical \ntherapy is still an issue today.  \n  \nIn line with the above conditions, the scientists tried to \nfind new therapies with different molecular targets, has a \nhigh effectiveness and fewer side effects. One method of \nmedical treatment that was developed for this purpose is \nusing herbal ingredients that is curcumin. Curcumin is the \nactive ingredient extracted from  \nCurcuma longa, called turmeric in English and in \nIndonesian called kunir. Curcumin is known to suppress \nmutagenesis and used as a chemopreventive agent for \nvarious cancers such as colon, breast, prostate, \nesophagus, lung, and inhibiting atherosclerosis, inhibits \nthe growth of viruses and bacteria. Curcumin also has \nanti-inflammatory effects through suppression of \nactivation of nuclear factor -κB (NF -κB), anti -\nproliferative effects through suppression of cyclin D1 and \nantiapoptotic gene product, induces release of \ncytochrome C and has the effect of anti -angiogenesis. 12 \nand also known to have antioxidant effects.13  \n  \nIn p revious research has demonstrated that curcumin \ninhibited the growth of endometriosis cells via \nsuppression of expression of VEGF (vascular endothelial \ngrowth factor) and a study by Johari 8 has shown that \ncurcumin can increase the number and maturation of ova \nin mice endometriosis model performed ovarian \nstimulation through suppression of inflammatory \nprocesses curcumin can suppress angiogenesis factor \nVEGF and widespread endo -metriosis implants in mice \nmodel of endometriosis is comparable with progestin \n(MPA).  \n  \nOne marker that can be used to determine the function of \ngranulosa cells was AMH (anti -Mullerian hormone) or \nMIS (müllerian inhibiting substance) which is a dimer \nglikoproterin included in the transforming growth factor-\nbeta (TGF-ß) superfamily. AM H in women is produced \nby the granulosa cells of pre -antral follicles and antral \nwho played a role in folliculogenesis. 16 AMH is secreted \nby the ovaries into the circulation so it can be measured \nin serum.   \n  \nThe levels of serum AMH in patients with endometriosis \nhas found decrease and proportional to the degree, the \nmore severe the levels of AMH are also on the downside \nas well as on the levels of AMH in follicular fluid.3 AMH \nhas advantages in describing the function of granulosa \ncells because it is not influenced by the menstrual cycle \nand use of contraceptive drugs, so it can be measured at \neach phase.   \n  \nAMH is a fairly good marker as a prognostic value in \npredicting number of mature oocytes obtained in an \nassisted reproductive technologies (ART) afte r \ngonadotropin stimulation. AMH even has a better \nprognostic value than other markers such as FSH, inhibin \nB, and estradiol. AMH serum level is important for \npredicting response to ovarian endometriosis in women \nwho followed the ART program. Expected if ob tained \nAMH levels are high then the success rate of ART \nprogram is also expected to rise.  \n  \nThe following research proposes that granulosa cell \napoptosis that occurs due to an increase in inflammatory \nfactors in endometriosis will cause a decrease in AMH \n\nHanafi et al. : The Effect of Curcumin to the Anti Mullerian Hormone Serum Concentration   \n  \n  \n  98 \nlevels. Expected with the administration of curcumin can \ninhibit inflammatory processes and apoptosis so as to \nsuppress granulosa cell dysfunction characterized by high \nlevels of AMH. With high levels of AMH are also \nexpected to increase fertility.   \n  \n  \n  \nMATERIALS AND METHODS  \n  \nAnimals used in this researcg were 38 mature female rats \n(Rattus novergicus), weighing 100-150 g. Animals were \nkept in cages in a well environment and has adaptated for \n1 week. The fresh humans endometrial tissues was \nobtained from women undergoing elective hysterectomy \nfor benign gynecological disease. The endometrial tissues \nthen washed twice with phosphatebuffered saline (PBS) \nthen suspended as coarse fragments in PBS with 200 \nIU/ml of penicillin and 200 µg/ml of streptomycin. \nEndometrial tissues then injected intraperitoneally using \n16G neddle in rats. After injection of cyclosporin A and \ninjection of estradiol on day 1 and day 5, the sampels then \ndivided into two groups. Began the day -14 group A \nreceived curcumin per sonde during 14 days, while group \nB received placebo for 14 days per sonde. The rats then \nsacrificied at day 28 using high concentration of ether in \na closed chamber.  \n  \nThe AMH concentration from serum were measured by \nELISA kit assay for rat from Cusabio Biotech, Wuhan, \nChina. Absorbance was measured at wavelength 450 nm \nby using a multiplate reader. The AMH result was \ncalculated using the standard curve with a base valu e of \nthe manufacturer's standard assay kit (Cusabio Biotech), \nand data are presented as ng/ml. Statistical analysis was \nperform using SPSS program (version 19.0.1). Before \nstatistical analysis, the data conducted \nKolgomorovSmirnov normality test. If the normality test \nresults are normally distributed, then proceed with \nparametric statistical tests of comparison of the mean of \ntwo groups using independent two -sample t test.This \nstudy uses a significance level of 0.05.   \n  \n   \nRESULTS AND DISCUSSION  \n  \nThe wei ght variable are analyze using the test for \nnormality of distribution by Kolmogorov -Smirnov test. \nThe curcumin group obtained p  =  0.416 (before \ntreatment) and p  =  0.712 (after treatment). Similarly, in \nthe placebo group, p  =  0.787 obtained (before treatment) \nand p  =  0.711 (after treatment). Since p > 0.05 then the \ntwo groups of normally distributed. Because the \ndistribution is normal, then performed independent two -\nsample t test, and the obtained p> 0.05 in both groups so \nthat it can be concluded th at there was no significant \ndifferences. Similarly, the change in weight between the \ntwo groups, obtained p > 0.05, so no significant \ndifferences found in both groups and both groups are said \nto be homogeneous. Because the body weight of rats is \nhomogeneous then the BB variables were not included in \nsubsequent analysis.  \n  \nVariable levels of serum AMH Normality was tested \nusing Kolmogorov -Smirnov one sample, where the \nobtained p  =  0.061 (p > 0.05), mean normal distribution. \nBecause normally distributed, s tatistical tests used is \nparametric test using independent two-sample t test. Two-\nsample t test results obtained p  =  0.008 (p  =  0.05) which \nmeans the average obtained significant differences \nbetween groups of AMH serum levels of curcumin and \nplacebo groups.  \n  \nEndometriosis model made in rat does not fully represent \nthe state of endometriosis in humans. But the \nendometrial-like lession resulting from the manufacture \nof this model is most similar to endometriosis cells in \nhumans in terms of morphology and histopatology, so the \nstate is considered to adequately represent the \nexperimental model.  \n  \nMaking a rat model of endometriosis performed by \nlowering the immune response function artificially, ie \nsuppress lymphocyte proliferation and differentiation \nusing cyclosporine A (an immunosuppressant). \nFurthermore, extracts of human endometrial cells injected \ninto the abdominal cavity of mice. Inflammat-ory process \nis expected to occur due to the inclusion of foreign objects \ninto the abdominal cavity of mice.  \n  \nThis process will take about 3 -6 days, then continued \nproliferation phase that aims to form granulation tissue. \nIntramusculus estrogen injection is used to enable the \nproliferation and growth of endometrial tissue in the \nabdominal cavity. Granulation tissu e formation lasted \nuntil day 14, the process can continue until day 28. On \nday 14, treatment of curcumin and placebo on the rat \nmodel endometrosis begins. We did not conduct the \nconfirmation incidence of endometriosis in macroscopic \nor histopathology speci mens, therefore the success rate \nrefers to the incidence of endometriosis is based on  \nprevious studies conducted by Kuswojo and Sa'adi.9   \n  \nIn this study we have found that although a statistically \nsignificant difference in mean AMH levels in both \ngroups, but we see that the results in each group is not \nuniform. In the curcumin group, we still get a sample with \nlow levels of serum AMH, as well as in the placebo group, \n\nMajalah Obstetri & Ginekologi Vol. 19 No. 3 September - Desember 2011 : 96-101  \n  99 \nwe still get the serum AMH levels are quite high. This \npossibility can be explained by previous studies by \nGrummer et al. 6 that it is influenced by the ability of rat \nmodel of recovery by itself. It is said that the ability of \nrecovery varies between individuals and does not exceed \nthe figure of 30%. This needs to be considered in \nanalyzing the results of research, remember when we \nwould do certain drug trials, because of differences in the \nnumber of lesions in both groups of experimental animals \ncan be caused by differences in recovery at the beginning \nof the experiment compared the effects of the drugs \ntested. In this study, we divided rats randomly into 2 \ngroups: group by treatment with curcumin \nsupplementation and one group with  placebo \nsupplementation treatment (NaCl fluid).   \n  \nIt is therefore worth nothing that the study sample \ncharacteristics affect the results of the study, namely age \nand body weight of rats. We used female rats of the same \nage that is 3 months. At this age,  rat are considered \nsexually mature so it is considered the same hormonal \nstatus. We did not do a vaginal smear to see the estrous \ncycles of rat when began the treatment or when taking a \nblood sample because it has been demonstrated by Aoki \net al. 2 that th e growth of endometrial cells that \ntransplanted into SCID mice is not affected by the estrous \ncycle of mice, thereby allowing endometrial tissue \ntransplants done at all estrous cycle of rats. AMH levels \nin human are not influenced by the menstrual cycle an d \nuse of contraceptive drugs, so it can be measured at each \nphase of the menstrual cycle, therefore the measurement \nof serum AMH levels in rats in our research is also \nconsidered to be unaffected.  \n  \nBody weight of rats on our research about 100-150 grams. \nWe measured body weight of rats at random. Body weight \nof rats we are testing with one sample Kolmogorov \nSmirnof, it obtained a normal distribution. After that we \ndid a statistical analysis by independent two-sample t test \nand not found significant differ ences in body weight \nmeasurements before and after treatment as well as on \nchanges in body weight in both groups (p> 0.05) so that \nthe variable weight is homogeneous. In comparison there \nare few human studies that connecting between body \nmass index (BMI) and endometriosis. BMI in 366 women \nwith endometriosis was lower than 268 women who \nunderwent laparoscopy because of other minor \ngynecological problems. There is relationship between \nthe degree of endometriosis with a BMI of women with \nendometriosis. In wom en with severe endometriosis \ndegrees obtained a lower BMI compared with mild or \nmoderate degree. We analogy there are similarities \nbetween the calculation of body weight of rats with BMI \nmeasurements in humans, so as a result we consider \nhomogeneous then i t is likely that the degree of \nendometriosis are positive in both groups was similar. \nMeanwhile, the study by Freeman et al. 5 found that in \nwomen who are obese have a lower AMH levels than \nnon-obese, because the weight of rats homogeneous, we \nconsider the differences in levels of serum AMH in our \nresearch not affected by body weight of rats.  \n  \nUntil now the method of treatment for endometriosis in \nhumans is still not give encouraging results. One problem \nis the fear of side effects arising from such treatment, for \nexample due to the effects of GnRH agonists \nhipoestrogenik or hiperandrogen effects on danazol \nadministration. Thought that it tries to be developed is an \nattempt to discover new drugs that do not inhibit the \nhypothalamic-pituitary-ovarian, so peo ple are not faced \nwith infertility problems. One alternative that could be \nused is the use of curcumin herbal medium.  \n  \nA mixture of several drugs including curcumin has the \nsame safety and efficacy compared gestrinone in the \nprevention of recurrence in patients with endometriosis \npost-surgery. One mechanism is believed to be the effect \nof curcumin here is the suppression o f proinflammatory \ncytokines, inhibition of COX-2 and antioxidant effects.17   \n  \nSeveral studies have proven the cause of increased \napoptosis in endometriosis is stimulated by increased pro-\ninflammatory cytokines, including the widely studied is \nTNF-α. Found an increase in TNF-α in both the fluid and \nfollicular fluid peritoneum. Research by Hendarto 7 have \nelevated levels of TNF -α in the fluid peritoneum \nendometriosis women and the increase is in accordance \nwith the degree of endometriosis. The higher the rank the \nlevels of TNF -α is increasing. While the study by \nFalconer et al. 4 found levels of TNF-α in follicular fluid \nof endometriosis women taller than women infertile due \nto tubal factor.  \n  \nMolecular mechanisms that could explain the \ninvolvement of TNF-α in the process of apoptosis is due \nto activation of one transcription factor NF-Κß is. Studies \nin vitro showed activation of NF -Κß in endometriosis \nstromal cells via the classical pathway of NF-Κß induced \nby IL -1. TNF -α or lipopolysaccharide. 11 NF-Κß \ntranscription factor known to play a role in the \npathogenesis of endometriosis, which stimulate the \nprocess of adhesion, invasion, angiogenesis, \ninflammation, proliferation, and inhibits cell apoptosis \nendometriosis. The role of classical pathway activation of \nNF-Κß is a natural immune response that stimulates \ninflammation and maintain endometriosis lesions. 11 \n\nHanafi et al. : The Effect of Curcumin to the Anti Mullerian Hormone Serum Concentration   \n  \n  \n  100 \nActivation of transcription factor NF-Κß is also associated \nwith increased ROS (Reactive Oxygen Species). There is \nan increase in ROS in the stromal and epithelial cells from \nendometriomas and endometrium of endometriosis \nwomen. ROS are the main ingredients of superoxide (O2-\n) is converted to H2O2 by the enzyme SOD (super oxide \ndismutase), can further form hydroxyl Radicals (OH) ions \ndue to the influence of H2O2 Fenton or Haber -Weiss \nreactions of O2. Hydroxyl Radicals have a short half-life \nand is much more reactive than superoxide. Schreck et al. \n(1991) proved H2O2 activates transcription factor NF -\nΚB. H2O2 causes the release of NF-ΚB binding to IκB.  \n  \nIn several studies have demonstrated a decrease in both \nserum AMH levels in follicular fluid and endometriosis \nwomen. The study by Lemos et al. 10  obtain serum levels \nof AMH in women endometriosis was lower than that of \ncontrol women with infertility due to tubal factor (1.26 ± \n0.7 vs. 2.02 ± 0.72 with p  =  0.004). Research by Shebl14 \nalso show decreased levels of serum AMH in women \nendometriosis compared to controls (husband factors) \nand increases with the degree of endometriosis, in women \nwith mild endometri osis obtained mean AMH levels do \nnot differ from controls (3.28 ± 1.93 vs 3, 44 ± 2.06, p  =  \n0.61) in women with severe degrees obtained mean AMH \nlevels are significantly different (2.38 ± 1.83 vs. 3.58 ± \n2.46, p <0.0001).   \n  \nWhile the study by Falconer et al. 4 find evidence of \ndecreased levels of AMH in follicular fluid of \nendometriosis women. The mechanism of decrease in \nAMH levels has not been fully explained, this is likely to \nbe influenced elevated levels of TNF-α in follicular fluid \nof endometriosis  women, which ultimately induces an \nincrease in the apoptotic process in granulosa cells. AMH \nlevels decrease is probably caused by a reduced number \nof granulosa cells in cumulative result of an increase in \nthe apoptotic process. However, this requires fur ther \nresearch to prove it.  \n  \nIn our study, mean AMH levels in the rat model of \nendometriosis curcumin group higher than the placebo \ngroup (44.9 ± 20.1 vs. 29.8 ± 11.9). Based on two samples \nindependent t test found significant differences between \nthe two groups (p  =  0.008). Difference in results is likely \ndue to the success of curcumin in inhibiting the apoptotic \nprocess that occurs, as for the mechanism could be \nthrough multiple pathways including inhibition of \nactivation of the transcription factor NF -Κß by a variety \nof consequence s, suppression of inflammatory activity \nthrough the suppression of TNF -α directly or through \nantioxidant effect.   \n  \nCurcumin can inhibit the activation of the transcription \nfactor NF-Κß to the target before the phosphorylation Ißa \nemphasis. Curcumin was s hown to reduce negative \nimpacts resulting from endometriosis patients with \nimmune defects by anti TNF-α, anti-NF-Κß, antioxidant, \nanti-JNK and anti-caspase activation pathway. Curcumin \ncan suppress NF -ΚB pathway and NF -ΚB target genes \ncytokines.  \n  \nCurcumin also has strong antioxidant capabilities. TNF α \nalone induces the formation of oxidative stress via JNK -\n1 pathway that ultimately can induce apoptosis process. 1 \nCurcumin has anti -oxidant effect and this has been \ndemonstrated in several studies. Curcumin i nhibits \nformation of hydroxyl Radicals (OH) from Fenton \nreaction or Haber -Weiss by increasing the activity of \nantioxidants such as SOD, GPX, GSH, and GST. \nSimilarly, the chain termination or chain addition of \nhydrogen on the phenolic structure of materials  can \ncatalyze hydrogen peroxide (H2O2) into H2O and O2. \nCurcumin is an antioxidant by breaking the chain of \nexogenous oxidants that inhibit lipid peroxidation.  \n  \nWith inhibition of apoptosis that occurs will cause the \nnumber of granulosa cells that survived became higher so \nthat proteins and hormones are secreted also higher. With \nmore number of granulosa cells that survived the process \nof abnormal apoptosis, it is hoped will improve fertility \nin patients with endometriosis. This has been \ndemonstrated in t he study by Johari 8, which found \npositive effects of supplementation of curcumin in mice \nmodel of endometriosis with the acquisition of \nfertilization success rates higher than placebo in terms of \nthe number of ova and the ability of oocytes to complete \nthe meiosis process. In the group given supplements of \ncurcumin obtained a mean number of ova 15.42 ± 3.17 \ncompared with the placebo group the mean number of ova \n8.21 ± 2.82 (p  =  0.0001).   \n  \nThese results may explain our study in which oocytes \nalleged role in the regulation of AMH by granulosa cells. \nThe expression of AMH by granulosa cells is reduced \nwhen performed oositektomi and increased again when \noocytes were cultured granulosa cells back together. The \nresearch studied the effect of curcumin on levels of AMH \nuntil now has not been reported. Our research has shown \nthat the obtained serum AMH levels are higher in the \ngroup receiving curcumin supplementation, but further \nresearch needs to better understand the mechanisms \nunderlying these findings.  \n  \n  \n\nMajalah Obstetri & Ginekologi Vol. 19 No. 3 September - Desember 2011 : 96-101  \n  101 \nCONCLUSION  \n  \nSerum AMH levels in rat model of endometriosis who \nreceived curcumin supplementation is higher than  \nplacebo  \n  \n  \nREFERENCES  \n  \n1. Antosiewicz J, Ziolkowski W, Kaczor JJ, \nAntosiewicz AH. Tumor necrosis factor -a induced \nreactive oxygen species formation is mediated by \nJNK1-dependent ferritin degradation and elevation of \nlabile iron pool. Free Radic Biol Med. 2007; 43: 265-\n270.   \n2. Aoki D , Katsuki Y, Shimizu A, Kakinuma C. \nSucessfull heterotransplantation of human \nendometrium in SCID mice. Obstet. 1994.  \n3. Elvin JA, Clark AT, Wang P, Wolfman NM, Matzuk \nMM. Paracrine actions of GDF -9 in the mammalian \novary. 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