Objective: To compare serum Anti MÃ¼llerian Hormone (AMH) levels in infertile women with and without endometriosis, and to determine the mean levels of serum AMH in every stage of endometriosis.
Method: We performed a cross-sectional study. Sixty-eight subjects who have undergone laparoscopy and fulfilled both inclusion and exclusion criteria are recruited consecutively. They are divided into two groups, namely group with endometriosis and without endometriosis. Blood samples are taken from each subject before laparoscopy, where serum AMH levels are then measured. The difference in mean levels of each group are tested with Mann-Whitney test. Result: The mean levels of serum AMH were significantly lower in the endometriosis group than those in the group without endometriosis (2.30 1.8 ng/ml vs 3.75 2.13 ng/ml; p=0.005). Using Kruskal-Wallis test, it was found that there was a statistically significant difference among endometriosis groups based on the severity of endometriosis. There was no significant difference in the mean serum AMH levels between the minimal-mild endometriosis group and without endometriosis group (p=0.34), but the mean levels of serum AMH were significantly lower in the moderate-severe endometriosis compare to the group without endometriosis (p&lt;0.005).
Conclusion: The mean levels of serum AMH in infertile women with endometriosis were significantly lower than those in women without endometriosis. There was no significant difference in the mean serum AMH levels in minimal-mild endometriosis group and those without endometriosis; while in moderate-severe endometriosis group, it was significantly lower than in the group without endometriosis.
Keywords: endometriosis, infertility, serum AM

Harharah, Naivah

Jacoeb, Teuku Z

Natadisastra, Muharam

Indonesian Journal of Obstetrics and Gynecology

Indonesian Journal of Obstetrics and Gynecology (INAJOG)

Research ArticleOvarian Reserve In Infertile Women with and without EndometriosisMeasured with Anti Müllerian HormoneCadangan Ovarium pada Perempuan Infertil dengan dan tanpaEndometriosis Diukur dengan Anti Müllerian HormoneNaivah Harharah, Muharam Natadisastra, Teuku Z JacoebDepartment of Obstetrics and GynecologyFaculty of Medicine University of Indonesia/Dr. Cipto Mangunkusumo HospitalJakartaINTRODUCTIONEndometriosis is implantation of endometrium-liketissue (stroma and glands) outside of the uterinecavity, inducing chronic inflammation. The processcan affect all organs, but primarily encountered inpelvic organs, including the ovaries.1-4 Most com-monly, the complaints of endometriosis patientsare pain and infertility.5,6AbstractObjective: To compare serum Anti Müllerian Hormone (AMH) le-vels in infertile women with and without endometriosis, and to de-termine the mean levels of serum AMH in every stage of endo-metriosis.Method: We performed a cross-sectional study. Sixty-eight subjectswho have undergone laparoscopy and fulfilled both inclusion andexclusion criteria are recruited consecutively. They are divided intotwo groups, namely group with endometriosis and without en-dometriosis. Blood samples are taken from each subject before la-paroscopy, where serum AMH levels are then measured. The differ-ence in mean levels of each group are tested with Mann-Whitneytest.Result: The mean levels of serum AMH were significantly lower inthe endometriosis group than those in the group without endo-metriosis (2.30 1.8 ng/ml vs 3.75 2.13 ng/ml; p=0.005). UsingKruskal-Wallis test, it was found that there was a statistically signifi-cant difference among endometriosis groups based on the severityof endometriosis. There was no significant difference in the mean se-rum AMH levels between the minimal-mild endometriosis groupand without endometriosis group (p=0.34), but the mean levels ofserum AMH were significantly lower in the moderate-severe en-dometriosis compare to the group without endometriosis (p<0.005).Conclusion: The mean levels of serum AMH in infertile women withendometriosis were significantly lower than those in women with-out endometriosis. There was no significant difference in the meanserum AMH levels in minimal-mild endometriosis group and thosewithout endometriosis; while in moderate-severe endometriosisgroup, it was significantly lower than in the group without endo-metriosis.[Indones J Obstet Gynecol 2014; 4: 188-192]Keywords: endometriosis, infertility, serum AMHAbstrakTujuan: Membandingkan rerata kadar AMH serum pada perempuaninfertil dengan dan tanpa endometriosis, serta untuk mengetahuirerata kadar AMH serum pada tiap derajat endometriosis.Metode: Kami melakukan penelitian potong lintang (cross sectional).Enam puluh delapan subjek yang menjalani laparoskopi dan me-menuhi kriteria inklusi dan eksklusi direkrut secara konsekutif dandibagi menjadi dua kelompok yang sama besar, yakni kelompok en-dometriosis dan tanpa endometriosis. Sampel darah dari masing-masing subjek diambil sebelum dilakukan laparoskopi, kemudian di-ukur kadar AMH serum. Perbedaan rerata masing-masing kelompokdiuji dengan uji Mann-Whitney.Hasil: Rerata kadar AMH serum pada kelompok endometriosis secarasignifikan lebih rendah dibandingkan dengan kelompok tanpa en-dometriosis (2,30 1,8 ng/ml vs 3,75 2,13 ng/ml; p=0,005). Menggu-nakan uji Kruskal-Wallis, ditemukan perbedaan yang bermakna se-cara statistik pada subjek kelompok endometriosis berdasarkan dera-jat endometriosis (p=0,005). Tidak ditemukan perbedaan kadar AMHserum yang bermakna pada kelompok endometriosis minimal-ringandengan kelompok tanpa endometriosis (p=0,34), sedangkan padakelompok endometriosis sedang-berat rerata kadar AMH serum se-cara signifikan lebih rendah dibanding kelompok tanpa endometriosis(p<0,005).Kesimpulan: Rerata kadar AMH serum pada perempuan infertil de-ngan endometriosis lebih rendah dibandingkan dengan yang tanpaendometriosis, dan secara statistik terdapat perbedaan bermakna. Ti-dak ditemukan perbedaan kadar AMH serum yang bermakna padakelompok wanita infertil dengan endometriosis derajat minimal-ringan dibandingkan dengan kelompok wanita infertil tanpa endo-metriosis, tetapi ditemukan perbedaan kadar AMH serum yang ber-makna antara kelompok wanita infertil dengan endometriosis derajatsedang-berat dan kelompok wanita infertil tanpa endometriosis.[Maj Obstet Ginekol Indones 2014; 4: 188-192]Kata kunci: amh serum, endometriosis, infertilitasCorrespondence: Naivah Harharah. Department of Obstetrics and Gynecology/Dr. Cipto Mangunkusumo Hospital, JakartaTelephone: 081338737374 Email: dr.naivah@gmail.comIndones J188  Harharah et al Obstet GynecolThe hypothesis that endometriosis causes infer-tility or decreased fertility remains a controversy.It has been shown that the prognosis of assistedreproductive technique in endometriosis patientsis worse than that in patients with tubal occlu-sion.7-9 One of the mechanisms causing infertilityin endometriosis is the change in folliculogenesisresulting in ovulatory dysfunction and poor oocytequality.8 To evaluate the ovarian follicular status,classically, early follicular phase serum FSH, in-hibin-B, and E2 levels have to be measured. How-ever, the utility of those measurements and theirclinical value is still limited.10,11 A new way toevaluate the ovarian follicular status is by measur-ing Anti Müllerian Hormone (AMH).Anti Müllerian Hormone (AMH) is produced bysmall, early anthral follicles and is more stronglyassociated with the number of small anthral folli-cles compared to FSH, E2, and even inhibin-B levels.In vivo and in vitro studies showed that AMH hasan inhibitory effect on primordial follicular recruit-ment and decreases the sensitivity of follicles forthe FSH-dependent selection for dominance. Be-side its functional role in the ovary, serum AMHlevel serves as an excellent candidate marker ofovarian reserve.11-13Hendarto found that infertile women with endo-metriosis have an increase in TNF-  and hyaluro-nan levels with a decrease in GDF-9 level, causingdisturbance in folliculogenesis and low oocyte qua-lity.14 In another study, Kusuma found that meanlevel of serum AMH in postpartum women with en-dometriosis is lower than the control group (non-endometriosis women).15 The mean level of serumAMH in baby girls born from mother with endo-metriosis was clinically lower than that in the con-trol group (baby girls with non-endometriosis mo-ther). This study showed that there was a correla-tion between endometriosis and the low level ofAMH, and the decrease of AMH level begins in thepostnatal period.The aims of this study are to compare the levelsof serum AMH in infertile women with and with-out endometriosis, and also to determine the meanserum AMH levels in different stages of endome-triosis.METHODSDesignA cross-sectional study was conducted at the Infer-tility Clinic and Yasmin Clinic at Dr. Cipto Mangun-kusumo Hospital and Sam Marie Wijaya InvasiveClinic, Jakarta, from January 2011 until June 2013.Patients were consecutively recruited and dividedinto two groups: group I (study group) consistingof infertile patients with endometriosis as provenby laparoscopy (n=38) and group II (control group)consisting of infertile patients without endometrio-sis (n=30). All patients underwent routine explora-tion and laparoscopy for the investigation of infer-tility and as a part of this study. Endometriosis sta-ging was performed according to the classificationof the American Society for Reproductive Medicine1996.All patients younger than 35 years old who wereinfertile and agreed to be included in the study wererecruited. The following exclusion criteria were ap-plied: body mass index (BMI) >30 kg/m2; history ofovarian surgery, including ovarian drilling and/oruterine artery ligation, history of cancer or havingtherapy that can affect ovarian function, history ofsevere pelvic infection (frozen pelvis) and patientswith previous hormonal therapy for endometriosis.Venous blood samples were collected (3 ml) fromeach patient before laparoscopic surgery, to measurethe serum AMH levels. AMH levels were measuredusing a commercial enzyme-linked immunosorbentassay (ELISA) kit according to the manufacturer’s in-struction.All data were collected in a computerized data-base. Statistical analysis was performed using SPSS20.0 for Windows. Data were presented as mean, me-dian (minimal-maximal range), and standard devia-tion. Independent t-test and ANOVA were used if thesample was normally distributed. Otherwise, Mann-Whitney and Kruskal-Walls tests will be used.We calculated that a sample size of more than 22subjects in each group would allow us to show a dif-ference in AMH level between subject and control of0.76 ng/ml9 with type I error of 0.05 and type II errorof 0.2. A p-value <0.05 was considered as statisticallysignificant.Vol 2, No 4October 2014 Ovarian reserve in infertile women  189RESULTSIn the endometriosis group, there were 6 patients(15.8%) with stage 1 endometriosis (minimal en-dometriosis), 13 patients (34.2%) with stage 2 en-dometriosis (mild endometriosis), 11 patients(28.9%) with stage 3 endometriosis (moderate en-dometriosis), and 8 patients (21.1%) with stage 4endometriosis (severe endometriosis). In the con-trol group there were 21 patients (70%) with tubalocclusion or hydrosalphinx, 6 patients (20%) withsubserosal myoma, and 3 patients (10%) with en-dometrial polyp.The baseline characteristics of both groups werecomparable. The median age in the study groupwas 33 (range = 23-35) years and 32.5 (range =25-35) years for the control group (p>0.05). In ad-dition, BMI (22.4 2.06kg/m2 for the study groupand 23.1 2.04kg/m2 for the controls) were alsosimilar between groups.As shown in Table 1, the mean serum AMH lev-els were lower in the endometriosis group than inthe control group and it was found to be statisti-cally significant (2.30 1.8 ng/ml vs 3.75 2.13 ng/ml; p = 0.005).Using Kruskal-Wallis test, it was found that therewas a statistically significant difference of serumAMH levels among endometriosis subgroups basedon the stages of endometriosis.We divided the endometriosis group into mini-mal-mild endometriosis and moderate-severe en-dometriosis and compared the serum AMH levelswith the control group. There was no significantdifference in the mean serum AMH level betweenthe group with minimal-mild endometriosis andthe control group (3.12   1.97 ng/ml vs 3.75   2.13ng/ml, p=0.34). Meanwhile, the mean serum AMHlevel was significantly lower in the moderate-se-vere endometriosis compared to the control group(1.48   1.30 ng/ml vs 3.75   2.13 ng/ml, p<0.005).DISCUSSIONIn this study, we found that patients with en-dometriosis have lower serum AMH level thanthose in the control group, and AMH level de-creases in relation to the severity of endometriosis.Our finding was concordant with results from astudy by Streulli et all.16 They found that the dif-ference in serum AMH levels between women inendometriosis and controls did not reach signifi-cance (3.6 3.1 ng/ml vs 4.1 3.4 ng/ml, p=0.06).The AMH level was only found to be significantlylower in patients aged >40 years old or patientswith history of surgery for endometriosis cyst(either laparotomy or laparoscopy).Table 1. Serum AMH Levels in Infertility Groups (ng/ml)Serum AMH levelsInfertility Groupsp*With Endometriosis (n = 38) Without Endometriosis (n = 30)Mean   SD 2.30   1.8 3.75   2.13 0.005Median (range) 2.35 (0.16-7.20) 3.0 (0.71-8.30)* Mann-Whitney testTable 2. Serum AMH Levels in Endometriosis Group, based on Stages of     Endometriosis (ng/ml).Stage of Endometriosis n Mean   SD Median (range) p*AMH Minimal 6 4.13   2.05 3.3 (230-9.25) 0.005Mild 13 2.65   1.82 2.6 (0.41-7.0)Moderate 11 1.97   1.30 2.3 (0.2-4.18)Severe 8 0.82   1.04 0.2 (0.16-2.8)*Kruskal-Wallis test.Post-hoc test with ANOVA-LSD: minimal vs moderate endometriosis p=0.007; minimal vssevere endometriosis p<0.001; moderate vs severe endometriosis p=0.048Indones J190  Harharah et al Obstet GynecolIn women, serum AMH significantly declineswith increasing age. After reaching 37 years old,the number of oocytes is reduced with decreasedfertility potential, even when menstrual cycles arestill regular. This condition will continue until me-nopause, when the remaining follicles were appro-ximated to be only 1000 follicles.17-19In this study we discovered that the mean serumAMH levels is decreasing in relation with the se-verity of endometriosis. After we did post-hocanalysis and divided them into 3 groups (the mildendometriosis is considered to be the level bet-ween minimal and moderate endometriosis), wefound that there are significantly different AMHlevels between minimal and moderate endome-triosis, minimal and severe endometriosis, and alsobetween moderate and severe endometriosis. Thisresult is similar to the study conducted by Youssefand Anwar.20 They concluded that AMH levelscould be used as a sensitive marker to predict stageof endometriosis in infertile women.We divided the endometriosis group into mini-mal-mild endometriosis and moderate-severe en-dometriosis and compared the serum AMH levelswith the group without endometriosis. There wasno difference in the mean serum AMH levels bet-ween groups with minimal-mild endometriosis andwithout endometriosis, but the mean serum AMHlevel was lower in the group with moderate-severeendometriosis compared to the group without en-dometriosis and it was statistically significant. Thisfinding shows that not all of infertile women withendometriosis become poor responder. Moreover,it should be considered that in infertile womenwith minimal-mild endometriosis it is not neces-sary to provide any intervention since the serumAMH level is not significantly different from thelevels in infertile women without endometriosis.This result is contradictory with the study con-ducted by Lemos et al9, where they found that theserum AMH levels in infertile women with mini-mal-mild endometriosis were significantly lowerthan serum AMH levels in infertile women withtubal factor. They also found that the number ofbasal anthral follicles in both groups were compa-rable. The rationale for this result was the fact thatpatients with minimal/mild endometriosis had amore heterogeneous follicular cohort, with a meanfollicular diameter larger than that of patients withtubal obstruction.Moreover Shebl et al16 found that the serumAMH levels in minimal-mild endometriosis did notshow any difference from serum AMH levels in in-fertile women without endometriosis (3.28 1.93ng/ml vs 3.44 2.06 ng/ml, p=0.61). In moderate-severe endometriosis, however, the serum AMHlevels was significantly lower (2.38 1.83 ng/ml vs3.58 2.46 ng/ml, p<0.0001). Further, Campos etal21 found that follicular-fluid AMH concentrationin infertile women with minimal-mild endometrio-sis was similar to the concentration in infertile wo-men without endometriosis (1.8 0.3 ng/ml vs1.5 0.1 ng/ml, mean difference=0.33 ng/ml, 95%CI -0.21 to 0.88). AMH in the follicular fluid playsan important role in oocyte development and fer-tilization. High levels of follicular fluid AMH had apositive correlation with successful oocyte fertili-zation; this result showed that follicular fluid AMHplays a role in oocyte development and fertilizationstimulated by exogenous FSH.When serum AMH is compared to follicularAMH, some authors have demonstrated a positivecorrelation between them, indicating that periphe-ral AMH concentrations are modulated not only bythe number of follicles, but also by the individualability of the follicle itself to produce AMH.22 Thismechanism is not applicable to endometriosis pa-tients, considering that these patients represent aheterogeneous follicular cohort as has alreadybeen shown.12In conclusion, the mean serum AMH levels in in-fertile women with endometriosis were significan-tly lower than that in the group without endome-triosis. There was no difference between the meanlevels of serum AMH in minimal-mild endometrio-sis group and the levels in women without endo-metriosis, while in the moderate-severe endome-triosis group, serum AMH level was significantlylower than the group without endometriosis.REFERENCES1. D’Hooghe TM, Hill JA. Endometriosis. In: Berek JS. (ed.)Berek and Novak’s Gynecology. Philadelphia: LippincottWilliams and Wilkins; 2007: 1137-85.2. Speroff L, Glass RH, Kase NG. Endometriosis. In: ClinicalGynecologic Endocrinology and Infertility. 7th ed. Philadel-phia: Lippincott Williams and Wilkins; 2005: 1103-34.3. Gazvani R, Templeton A. New considerations for the patho-genesis of endometriosis. Int J Gynecol Obstet 2002; 76:117-26.4. Jacoeb TZ, Hadisaputra W. (eds). Penanganan Endometrio-sis. Panduan Klinis dan Algoritme. Jakarta: CV. Sagung Seto;2009.Vol 2, No 4October 2014 Ovarian reserve in infertile women  1915. American Society for Reproductive Medicine. Endometrio-sis and infertility. Fertil Steril 2006; 86 (5 Suppl 1): 156-60.6. Baziad A. Endometriosis. Endokrinologi Ginekologi. Jakarta:Media Aesculapius FKUI; 2008.7. Lebovic DI, Mueller MD, Taylor RN. Immunobiology of en-dometriosis. Fertil Steril 2001; 75(1): 1-10.8. Cahill DJ. What is the optimal medical management of in-fertility and minor endometriosis? Analysis and future pros-pects. Hum Reprod 2002; 17(5): 1135-40.9. Lemos NA, Arbo E, Scalco R, et al. Decreased anti-Müllerianhormone and altered ovarian follicular cohort in infertilepatiens with mild/minimal endomeriosis. Fertil Steril 2008;89(5): 1064-8.10. Van Rooij IAJ, Broekmans FJM, Velde ERT, et al. Serum anti-Müllerian hormone levels: a novel measure of ovarian re-serve. Hum Reprod 2002; 17(12): 3065-71.11. Ebner T, Sommergruber M, Moser M, et al. Basal level ofanti-Müllerian hormone is associated with oocyte quality instimulated cycles. Hum Reprod 2006; 21(8): 2022-6.12. Gruijters MJG, Visser JA, Durlinger ALL, et al. Anti-Müllerianhormone and its role in ovarian function. Mol Cel Endocri-nol 2003; 211: 85-90.13. Mahmood TA, Templeton A. Folliculogenesis and ovulationin infertile women with mild endometriosis. Hum Reprod1991; 6(2): 227-31.14. Hendarto H. Profil Kadar TNF , GDF-9 dan Hyaluronanpada Gangguan Folikulogenesis sebagai Gambaran Penu-runan Kualitas Oosit Pasien Endometriosis yang Infertil.Surabaya: Universitas Airlangga; 2007.15. Kusuma N. Perbandingan Kadar Anti-Müllerian Hormone(AMH) darah tali pusat bayi baru lahir perempuan antarabayi dari ibu dengan endometriosis dan ibu tanpa endo-metriosis. Tesis Subspesialisasi FER. Universitas Indonesia;2011.16. Shebl O ET, Sommergruber M, Sir A, et al. Anti-Müllerian hor-mone serum levels in women with endometriosis: a case-con-trol study. Gynecol Endocrinol 2009; 25 (11): 713-6.17. Sattar AAT. Ovarian Reserve. ASJOG. 2005; 2: 338-43.18. Visser JA, Themmen APN. Anti-Müllerian hormone and fol-liculogenesis. Mol Cel Endocrinol 2005; 234: 81-6.19. Coccia ME, Rizello F. Ovarian Reserve. Ann N Ac Sci. 2008;1127: 27-30.20. Anwar D, Yousef M. Anti-Müllerian hormone as a markerfor severity of endometriosis: A pilot study. EBWHJ 2011;1(2): 61-3.21. Campos DV, C Andreoli, AC Martins, et al. Follicular-fluidanti-Müllerian hormone concentration is similar in patientswith endometriosis compared with non-endometriotic pa-tients. Reprod Bio Med Online 2010; 21: 470-3.22. Fanchin R, Schonauer LM, Righini C, et al. Serum anti-Müllerian hormone is more strongly related to ovarian fol-licular status than serum inhibin B, estradiol, FSH, and LHon day 3. Hum Reprod 2003; 18(2): 323-7.Indones J192  Harharah et al Obstet Gynecol

Ovarian Reserve In Infertile Women with and without Endometriosis Measured with Anti MÃ¼llerian Hormone: Cadangan Ovarium pada Perempuan Infertil dengan dan tanpa Endometriosis Diukur dengan Anti MÃ¼llerian Hormone

Objective: To compare serum Anti Müllerian Hormone (AMH) levels in infertile women with and without endometriosis, and to determine the mean levels of serum AMH in every stage of endometriosis.



Method: We performed a cross-sectional study. Sixty-eight subjects who have undergone laparoscopy and fulfilled both inclusion and exclusion criteria are recruited consecutively. They are divided into two groups, namely group with endometriosis and without endometriosis. Blood samples are taken from each subject before laparoscopy, where serum AMH levels are then measured. The difference in mean levels of each group are tested with Mann-Whitney test. Result: The mean levels of serum AMH were significantly lower in the endometriosis group than those in the group without endometriosis (2.30 1.8 ng/ml vs 3.75 2.13 ng/ml; p=0.005). Using Kruskal-Wallis test, it was found that there was a statistically significant difference among endometriosis groups based on the severity of endometriosis. There was no significant difference in the mean serum AMH levels between the minimal-mild endometriosis group and without endometriosis group (p=0.34), but the mean levels of serum AMH were significantly lower in the moderate-severe endometriosis compare to the group without endometriosis (p<0.005).



Conclusion: The mean levels of serum AMH in infertile women with endometriosis were significantly lower than those in women without endometriosis. There was no significant difference in the mean serum AMH levels in minimal-mild endometriosis group and those without endometriosis; while in moderate-severe endometriosis group, it was significantly lower than in the group without endometriosis.



Keywords: endometriosis, infertility, serum AM

Naivah Harharah

Muharam Natadisastra

Teuku Z Jacoeb

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Ovarian Reserve In Infertile Women with and without Endometriosis Measured with Anti Müllerian Hormone

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Ovarian Reserve In Infertile Women with and without Endometriosis Measured with Anti MÃ¼llerian Hormone: Cadangan Ovarium pada Perempuan Infertil dengan dan tanpa Endometriosis Diukur dengan Anti MÃ¼llerian Hormone

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