We measured serum anti-Müllerian hormone levels before and after surgery in women undergoing unilateral and monolocular cystectomy for benign ovarian diseases. Comparing to control benign cysts, we found a significant decline in serum anti-Müllerian hormone levels with consequent depletion of follicles in tissue specimens after surgery for women with ovarian endometrioma

Fujishita Akira

Hiraki Koichi

Inoue Tsuneo

Khan Khaleque Newaz

Kitajima Michio

Masuzaki Hideaki

Nagasaki University's Academic Output SITE: NAOSITE

F&S 10295 decline and resubmit 1 Running title Pre- and post-operative serum AMH levels F&S 10295 decline and resubmit  2 Correspondence Title: Changes in serum anti-Müllerian hormone levels may predict damage to residual normal ovarian tissue after laparoscopic surgery for women with ovarian endometrioma  Authors: Michio Kitajima1*, MD, PhD; Khaleque Newaz Khan1, MD, PhD; Koichi Hiraki1, MD; Tsuneo Inoue1, MD; PhD, Akira Fujishita2, MD, PhD; Hideaki Masuzaki1, MD, PhD  Institutional affiliation: 1Department of Obstetrics and Gynecology  Nagasaki University School of Medicine  Graduate School of Biomedical Sciences 2Department of Obstetrics and Gynecology  Nagasaki Saiseikai Hospital  Conflict of interest: There is no conflict of interest related to this study Financial support: none  Address of corresponding author* Department of Obstetrics and Gynecology,  Nagasaki University School of Medicine Graduate School of Advanced Medical Sciences 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan TEL: +91-95-819-7363 Fax: +91-95-819-7365 e-mail: m-kita@nagasaki-u.ac.jp F&S 10295 decline and resubmit  3 Capsule Post-operative changes in serum AMH levels correlate with surgical damage to normal ovarian tissue after cystectomy for women with ovarian endometrioma. Measuring serum AMH levels may be clinically useful to identify the efficacy of surgical procedure in terms of fertility preservation. F&S 10295 decline and resubmit  4 Abstract  We measured serum AMH levels before and after surgery in women undergoing unilateral and monolocular cystectomy for benign ovarian diseases. Comparing to control benign cysts, we found a significant decline in serum AMH levels with consequent depletion of follicles in tissue specimens after surgery for women with ovarian endometrioma.  Key words: Ovarian endometrioma; cystectomy; ovarian damage; serum AMH F&S 10295 decline and resubmit  5 Therapeutic approach for women with ovarian endometrioma may vary according to the age of women, size of the cyst, symptoms, and desire for future conception. Laparoscopic cystectomy for endometrioma is common and seems to be feasible in terms of post-operative fecundability and recurrence rate comparing to that of fenestration and coagulation of cyst wall (1, 2). However, the safety of this technique with respect to residual ovarian damage has been questioned. On the other hand, there had been conflicting reports on ovarian response to ovulation induction in infertile women with previous surgical excision of endometrioma (3, 4). Even skilled hands show excellent results, cystectomy for endometrioma may cause unavoidable risk of surgical injury to residual normal ovarian tissue. This may cause loss of ovarian follicles in women had operated on for endometrioma (5, 6). According to a recent report, absence of follicular growth was observed in 13% of operated ovaries although this event never occurred in the contralateral gonad (7). Therefore, an objective clinical parameter(s) is needed to evaluate damaging efficacy of surgical procedure in terms of preserving one’s fertility potential. Anti-Müllerian hormone (AMH) is a dimeric glycoprotein, belongs to the F&S 10295 decline and resubmit  6 transforming growth factor-β family and is produced solely by the granulosa cells of the recruited follicles until they become sensitive to follicle-stimulating hormone (8, 9). Serum level of AMH declines with age, is menstrual cycle independent, and is unaffected by gonadotrophin or GnRH agonist administration (10). Therefore, it may represent the most reliable serum marker to indicate the number of growing follicles and reflect ovarian follicular reserve.  Hence, it is worthy to elucidate the changes in serum AMH levels after ovarian surgical procedure to evaluate its efficacy (11). One recent report found an insignificant association between post-surgical serum AMH levels and size of endometrioma (12) and another study demonstrated variable time-dependent changes in serum AMH levels after ovarian surgery (13). However, information regarding association between post-cystectomy serum AMH levels and presence of normal ovarian tissue containing follicles within cyst wall is lacking. Here, we report changes in serum AMH levels and their possible relationship with depletion of follicles in tissue specimens removed during cystectomy in women with ovarian endometrioma.  During the period between 2007 and 2009, we prospectively recruited F&S 10295 decline and resubmit  7 thirty-two women aged <40 years, had unilateral laparoscopic cystectomy for endometriotic cyst  (study group, endometrioma, n=19) and other benign ovarian cysts (control group, n=13; mature cystic taratoma, n=8; serous or mucinous cystadenoma, n=5) for pelvic pain, infertility and persistent ovarian cystic mass. These cysts were all >4cm in size, monolocular and diagnosed pre-operatively by trans-vaginal ultrasonography/MRI and subsequently confirmed by histology. Women had previous surgery with ovarian involvement were excluded. Ten women with endometrioma had GnRHa therapy for 3-5 month before surgery. Approval for the study was obtained by the local Institutional Review Board. All patients gave informed consent for this study.  Blood samples were collected from all women at one month before surgery and within three month after the surgery (mean 2.2 ± 1.0 month) and sera were stored at -80℃ until assayed. Pre- and post-operative serum AMH concentrations were measured by an enzyme immunoassay kit according to the manufacture’s instructions (EIA AMH/MIS; Immunotech, Beckman Coulter, Marseille, France). All assays were performed in duplicate and mean values were used for data analysis. The intra- and inter-assay coefficients of variation for AMH assay were below 10% with a detection limit of F&S 10295 decline and resubmit  8 0.14ng/mL. The percentage (%) change between pre- and post-operative serum AMH values was calculated as follows:  % AMH change = (pre-operative AMH value minus post-operative AMH value) / pre-operative AMH value X 100 After careful adhesiolysis and determination of tentative cleavage plane, stripping of the endometrioma cyst wall was performed by gentle counter traction by grasping forceps. Operated ovaries were left in place without suturing. For non-endometriotic ovarian cysts, extracorporeal manual stripping with double-balloon suction catheter (S.A.N.D. balloon catheter, Hakko, Nagano, Japan) or intra-corporeal stripping was performed according to the size and mobility of the cyst. Surface of the ovary was then sutured with absorbable surgical strings. Laparoscopic surgery was performed by two authors (K.H./A.F.). Presence of follicles and normal ovarian tissue in enucleated cyst wall were examined by studying the routine hematoxyline-eosin stained histological preparations. We evaluated the presence of healthy ovarian tissue (nested primordial and primary follicles within densely packed ovarian stroma) in enucleated cyst wall by examining two F&S 10295 decline and resubmit  9 5µm sections derived from each of endometriotic and non-endometriotic cyst wall. Histological analysis was performed by one investigator (M.K.) without knowledge of pre- and postoperative AMH results in a blind fashion.  Data were analyzed by student’s t-test for continuous variables and by Mann- Whitney U-test when there was skewed distribution. Multivariate analysis of variance (ANOVA) was performed with some possible confounding variables, such as tumor type, cyst wall with healthy ovarian tissue, age of the patient, size of the cyst, pre-operative AMH levels, and difference in operator. A value of P<0.05 was considered to be significant. Although women with endometrioma were significantly older than women with non-endometriotic control cyst [29.8 ± 5.4 (mean ± SD) vs. 25.9 ± 5.6 years old, P=0.046], we did not find any significant difference in pre-operative AMH levels between these two groups [4.27 ± 3.00 (mean ± SD) vs. 3.98 ± 2.16 ng/mL]. The mean diameter of the cyst was comparable between two groups [6.7 ± 1.9cm (mean ± SD) vs. 6.8 ± 2.1cm].  Percentage changes in serum AMH level were significantly larger in women F&S 10295 decline and resubmit  10 with endometrioma than in control women [-24.6 ± 29.3% (mean ± SD) vs. 3.3 ± 34.5%, P=0.02]. Presence of normal ovarian tissue was confirmed in 13 women (nine in endometiroma and four in control). In women with endometrioma, % change in AMH levels was significantly larger in women with cyst that contains normal ovarian tissue comparing to that of women without healthy ovarian tissue [-42.0 ± 32.9% (mean ± SD) vs. –8.9 ± 13.4%, P=0.01, Figure 1]. On the other hand, we did not find any significant difference in AMH levels between control women having cyst walls with and without normal ovarian tissue (Figure 1).  After analyzing several confounding variables, ANOVA revealed that the type of the cyst and the presence of healthy ovarian tissue were significantly associated with the post-operative decline in serum AMH levels (Table 1). However, when we analyzed the model with these two variables together, the statistical significance for the type of the cyst was lost (Table 1).  We report here for the first time that comparing to control benign cysts, a significant decline in serum AMH levels occurred within three months with consequent depletion of follicles in tissue specimens removed during excision surgery for women F&S 10295 decline and resubmit  11 with ovarian endometrioma. Each woman had first ovarian surgery and had single cyst excision. Although over the years, various tests and markers of ovarian reserve have been reported, the clinical value of testing for basal FSH and inhibin-B is limited (14, 15). Again, ultrasonogrphic markers such as antral follicle count and ovarian volume can be used as indicators of ovarian reserve. However, it is difficult to assess the exact number of antral follicles and ovarian volume of the cystic ovary before cystectomy (16). Therefore, we believe that as the most reliable and easily measurable test, post-operative serum AMH levels could be clinical useful to assess the status of ovarian reserve after excision surgery for endometrioma and also for the selection of patients who wish to preserve future fertility.        We measured post-operative serum AMH levels at variable time within three months after surgery. Issues regarding recovery of these values within this time frame need to be addressed. Recently, Chang, et al. (13) reported time-course follow-up of serum AMH levels after ovarian cystectomy. They found largest decline in serum AMH levels one week after surgery and variable recovery during follow-up periods. Indeed, complete recovery of serum AMH levels was not observed at three month after surgery F&S 10295 decline and resubmit  12 especially in women with endometrioma (12). Women with endometrioma may need longer duration for recovery in serum AMH levels, because surgical injury itself and inflammatory reaction could be more detrimental to the surrounding ovarian cortex in these women. Prolonged follow-up studies with larger subjects are needed to strengthen our findings of post-operative AMH levels and examine its pattern of recovery.   Age is a major determinant of serum AMH levels (8, 10). Age may affect the duration of recovery from surgery-related decline in serum AMH levels. Even a significant difference in the age of women between study and control groups was observed, we did not find any significant difference in pre- or post-operative AMH levels in these two groups of women. Moreover, multivariate analysis indicated that loss of normal ovarian tissue and the type of the cyst were more significant confounding factors related to change in AMH levels after surgery. Finally, Our current findings may indicate the importance of measuring pre- and post-operative serum AMH levels as a marker of ovarian reserve to evaluate the efficacy of surgical procedure in terms of fertility preservation. F&S 10295 decline and resubmit  13 Acknowledgements We thank to Miss Kazumi Hayashida and Miss Kyoko Ishida, Department of Obstetrics and Gynecology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, for their excellent technical assistance.  F&S 10295 decline and resubmit  14 References 1. Canis M, Mage G, Pouly JL, Wattiez A, Manhes H, Bruhat MA. Laparoscopic diagnosis of adnexal cystic masses: a 12-year experience with long-term follow-up. Obstet Gynecol. 1994;83:707-12. 2. Alborzi S, Momtahan M, Parsanezhad ME, Dehbashi S, Zolghadri J, Alborzi S. A prospective randomized study comparing laparoscopic ovarian cystectomy versus fenestration and coagulation in patients with endometriomas. Fertil Steril 2004;82:1633-7. 3. Ho HY, Lee RK, Hwu YM, Lin MH, Su JT, Tsai YC. Poor response to ovaries with endometrioma previously treated with cystectomy to controlled ovarian hyperstimulation. J Assist Reprod Genet 2002;19:507-11. 4. Loh FH, Tan AT, Kumar J, Ng SC. Ovarian response after laparoscopic ovarian cystectomy for endometriotic cysts in 132 monitored cycles. Fertil Steril 1999;72:316-21. 5. Muzii L, Bellati F, Bianchi A, Palaia I, Manci N, Zullo MA, et al. Laparoscopic stripping of endometriomas: a randomized trial on different surgical techniques. Part F&S 10295 decline and resubmit  15 II: pathological results. Hum Reprod 2005;20:1987-92. 6. Dilek U, Pata O, Tataroglu C, Aban M, Dilek S. Excision of endometriotic cyst wall may cause loss of functional ovarian tissue. Fertil Steril 2006;85:758-60. 7. Benaglia L, Somigliana E, Vighi V, Ragni G, Vercellini P, Fedele L. Rate of severe ovarian damage following surgery for endometriomas. Hum Reprod 2010;25(3):678-82. 8. van Rooij IA, Broekmand FJ, te Velde ER, Fauser BC, Bancsi LF, de Jong FH, et al. Serum anti-Mullerian hormone levels: a novel measurement of ovarian reserve. Hum Reprod 2002;17:3065-71. 9. Visser JA and Themmen AP. Anti-Mullerian hormone and folliculogenesis. Mol Cell Endocrinol 2005;234:81-86. 10. Seifer DB, MacLaughlin DT. Mullerian Inhibiting Substance is an ovarian growth factor of emerging clinical significance. Fertil Steril 2007;88:539–46.  11. Tsolakidis D, Pados G, Vavilis D, Athanatos D, Tsalikis T, Giannakou A, Tarlatzis BC. The impact on ovarian reserve after laparoscopic ovarian cystectomy versus three-stage management in patients with endometriomas: a prospective randomized F&S 10295 decline and resubmit  16 study. Fertil Steril 2010;94:71-7. 12. Ercan CM, Sakinci M, Duru NK, Alanbay I, Karasahin KE, Baser I. Anti-müllerian hormone levels after laparoscopic endometrioma stripping surgery. Gynecol Endocrinol 2010;26(6):468-72. 13. Chang HJ, Han SH, Lee JR, Jee BC, Lee BI, Suh, CS, Kim SH. Impact of laparoscopic cystectomy on ovarian reserve: serial changes of anti-Müllerian hormone levels. Fertil Steril 2010;94:343-9.   14. Brockmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006;12:685-718. 15. Bancsi LF, Brockmans FJ, Mol BW, Habbena JD, te Velde ER. Performance of basal follicle-stimulating hormone in the prediction of poor ovarian response and failure to become pregnant after in vitro fertilization: a meta-analysis. Fertil Steril 2003;79:1091-100.  16. Maheswari A, Fowler P, Bhattacharya S. Assessment of ovarian reserve-should we perform tests of ovarian reserve routinely? Hum Reprod 2006;21:2729-35.    F&S 10295 decline and resubmit 17 Figure Legend:  Figure 1. Shows % changes in serum AMH levels after post-operative cystectomy according to the type of the cyst and presence or absence of normal ovarian tissue within cyst wall. Woman had unilateral cystectomy for endometrioma showed significant decline in post-operative serum AMH levels than in control women with benign cyst (*P=0.02, Student’s t-test). In women with endometrioma, % change in serum AMH levels was significantly higher in women with cyst wall containing normal ovarian tissue comparing to that of women containing similar cysts without normal ovarian tissue (**P=0.01, Mann-Whitney U-test). No significant difference between pre- and post-operative serum AMH levels was observed in control women having these two types of cysts. Boxes represent the distance (interquartile range) between the first (25%) and third (75%) quartiles, and horizontal lines in the boxes represent median values. F&S 10295 decline and resubmit  18 Table 1. Multivariate analysis of variance (ANOVA) utilizing possible confounders to relative change in post-operative serum AMH levels             *The values when “the presence of healthy ovarian tissue” were omitted from the model.  Confounding variables F value P value F value* P value* Diameters of the cyst (cm)   0.0005 0.98 0.03 0.86 Difference in primary operator 0.41 0.53 1.46 0.24 Age (years) 1.55 0.23 0.43 0.52 Preoperative serum AMH value (ng/mL) 1.88 0.18 3.01 0.09 The type of cyst  2.20 0.15 4.55 0.04 Presence of healthy ovarian tissue 4.91 0.04 • • 

Changes in serum anti-Müllerian hormone levels may predict damage to residual normal ovarian tissue after laparoscopic surgery for women with ovarian endometrioma.

Kitajima, Michio

Khan, Khaleque Newaz

Hiraki, Koichi

Inoue, Tsuneo

Fujishita, Akira

Masuzaki, Hideaki

Nagasaki university's Academic Output SITE

Institutional Repositories DataBase (IRDB)

https://nagasaki-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=13553&item_no=1&attribute_id=18&file_no=1

Changes in serum anti-Müllerian hormone levels may predict damage to residual normal ovarian tissue after laparoscopic surgery for women with ovarian endometrioma.

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Nagasaki University's Academic Output SITE: NAOSITE

Nagasaki university's Academic Output SITE

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