Endometriosis & Adenomyosis Infertility Treatment Levent M. SENTURK, M.D., Professor in Ob&Gyn Istanbul University Cerrahpasa School of Medicine Dept. of Ob&Gyn, Division of Reproductive Endocrinology, IVF Unit

BRANDI S. MCLEOD, and MATTHEW G. RETZLOFF, 2010

Prevalence of endometriosis according to stage of disease in infertile and fertile women

Deep Endometriosis: Symptoms Pandis GK, 2010

Diagnosis of Endometriosis History (The most important) Symptoms Physical Examination (not much help) Serum Markers (Lacks sensitivity) Ultrasound (of little value except endometrioma) Magnetic Resonance Imaging (MRI) (a good guess!) Other Imaging Modalities immunoscintigraphy and positron emission tomography Transvaginal Hydrolaparoscopy Laparoscopic Visualization of the Pelvis (The gold standard) Biopsy Preferable Over Visual Inspection Novel Diagnostic Test Rule out other Causes of Symptoms (The next most important)

Endometriosis-associated infertility: a decade’s trend study of women from the Estrie Region of Quebec, Canada KRYSTEL PARIS & AZIZ ARIS, 2010 N: 6845 INF ENDO EAI

Effects of endometriosis on human reproduction Dominique de Ziegler, 2010

Pathophysiology of Pain and Infertility Associated with Endometriosis Linda C. Giudice, 2010

Eijkemans et al., 2008

Collins JA, 1995

Cumulative conception rates with untreated endometriosis related to disease grading, compared with normal conception rate Kevin D. Jones, 2002 N Minor Moderate Severe

Fertility in women with minimal endometriosis compared with normal women was assessed by means of a donor insemination program in unstimulated cycles Roberto Matorras 2010 N: 51 N: 24

Success in intrauterine insemination: the role of etiology A total of 1,171 cycles among 532 infertile couples were retrospectively studied and the impact of different prognostic factors on pregnancy rate in five different etiology subgroups was analyzed. Results. The pregnancy rate/cycle was highest (19.2%) among women with anovulatory infertility and lowest (11.9%) in endometriosis based infertility. Katja Ahinko-Hakamaa 2007

Endometriosis COH + IUI Treatment with intra-uterine insemination (IUI) improves fertility in minimal-mild endometriosis: IUI with ovarian stimulation is effective but the role of unstimulated IUI is uncertain (Tummon et al., 1997). Evidence A, Level 1b No RCTs exist for COH+IUI for moderate-severe endometriosis.  COH+IUI should be limited to 3-4 cycles ESHRE Guidelines, Recommedation grade A, evidence level 1b

To develop a clinical tool that predicts pregnancy rates (PRs) in patients with surgically documented endometriosis who attempt non-IVF conception. 2010

Decreased anti-Mullerian hormone and altered ovarian follicular cohort in infertile patients with minimal/mild endometriosis Nadiane Albuquerque Lemos, 2009 E C p:0.004 N:17

Anti mullerian hormone serum levels in women with endometriosis: A case–control study 909 patients undergoing in vitro fertilisation/ intracytoplasmic sperm injection (IVF/ICSI) treatment or consulting our specific endometriosis unit. Mean AMH serum level was significantly lower in the study than in the control group ( ng/ml vs ng/ml, p 0.001). In women with mild endometriosis (rAFS I-II), the mean AMH level was almost equal to the control group ( ng/ml vs ng/ml; p 0.61). A significant difference in mean AMH serum level was found between women with severe endometriosis (rAFS III-IV) and the control group ( ng/ml vs ng/ml; p ). OMAR SHEBL, 2009

A comparison of histopathologic findings of ovarian tissue inadvertently excised with endometrioma and other kinds of benign ovarian cyst in patients undergoing laparoscopy versus laparotomy Saeed Alborzi, 2009 The surgical approach had no statistically significant impact on conservation of ovarian reserves. The nature of the ovarian cyst played a greater role in the quality and quantity of the excised ovarian tissue

Excision of endometriotic cyst wall may cause loss of functional ovarian tissue Umut Dilek, 2006 N:46

The impact of electrocoagulation on ovarian reserve after laparoscopic excision of ovarian cysts: a prospective clinical study of 191 patients 191 patients with benign ovarian cysts undergoing ovarian cystectomy. When comparing the bipolar group and ultrasonic scalpel group (L/S) with the suture (L/T) group, a statistically significant increase of the mean FSH value was found in bilateral-cyst patients at 1-, 3-, 6-, and 12- month follow-up evaluations and in unilateral-cyst patients at the 1- month follow-up evaluation. Statistically significant decreases of basal antral follicle number and mean ovarian diameter were found during the 3-, 6-, 12-month follow-up evaluations as well as statistically significant decreases of peak systolic velocity at all of the follow-up evaluations. Conclusion(s): Bi-polar electrocoagulation after laparoscopic excision of ovarian cysts is associated with a statistically significant reduction in ovarian reserve, which is partly a consequence of the damage to the ovarian vascular system. Chang-Zhong Li, 2009

Analysis of risk factors for the removal of normal ovarian tissue during laparoscopic cystectomy for ovarian endometriosis A total of 121 patients who had histologically confirmed ovarian endometriosis and 56 control patients who had other histologically confirmed benign cysts were included Normal ovarian tissue adjacent to the cyst wall was detected in 71 patients (58.7%) with endometriosis, whereas normal ovarian tissue was removed from only three patients (5.4%) with other benign cysts. A significant factor that was independently associated with the removal of normal ovarian tissue with ovarian endometriosis was pre-operative medical treatment Sachiko Matsuzak,2009

IVF-ICSI outcome in women operated for bilateral endometriomas 68 cases (bilat. cystectomy) controls the number of follicles (p=0.006), oocytes retrieved (p=0.024) and embryos obtained (p=0.024) were significantly lower. The clinical pregnancy rate per started cycle in cases and controls was 7% and 19% (p=0.037) CONCLUSIONS: IVF outcome is significantly impaired in women operated on for bilateral ovarian endometriomas. Edgardo Somigliana1, 2008

NS

P¨ aivi H¨arkki, 2010

Effects of (unilateral) ovarian endometrioma on the number of oocytes retrieved for IVF 81 women with unilateral endometrioma who underwent their first IVF cycle Conclusion(s): The presence of ovarian endometrioma in a controlled ovarian hyperstimulation cycle for IVF treatment is not associated with a reduced number of oocytes retrieved from the affected ovary Benny Almog, 2010

(41%) Spontaneous Pregnancy After 1  surgery 236/577 (41%) (23%) Spontaneous Pregnancy After 2  surgery 28/124 (23%)

Sp. Pregnancy following L/T(27%) Sp. Pregnancy following L/T 12 – 47% (27%) Sp. Pregnancy following L/S(25%) Sp. Pregnancy following L/S22 – 42% (25%)

P. Vercellini, 2009 Results of studies comparing IVF-ET with second-line surgery in infertile women with recurrent moderate to severe endometriosis

30 June 2007 Laparoscopic ovarian cystectomy is recommended if an ovarian endometrioma ≥4 cm in diameter, is present to confirm the diagnosis histologically; reduce the risk of infection; improve access to follicles and possibly improve ovarian response. The woman should be counselled regarding the risks of reduced ovarian function after surgery and the loss of the ovary. The decision should be reconsidered if she has had previous ovarian surgery. GPP Endometrioma and IVF

Endometriosis-associated infertility: surgery and IVF, a comprehensive therapeutic approach Pedro N Barri, patients, , observational study

Does Controlled Ovarian Hyperstimulation in Women with a History of Endometriosis Influence Recurrence Rate? Retrospective cohort study of 592 patients submitted to laparoscopy for endometriosis, 177 with infertility-related endometriosis who underwent a periodic ultrasound follow- up after laparoscopy were selected. Women who started ART after laparoscopy (n=90) were compared with the control group, who did not undergo ART (n=87). Recurrence of endometriosis was defined as the presence of endometriotic lesions observed through TV-US. During a long-term TV-US follow-up (1–15 years), 40 (22.6%) recurrences were observed. Patients submitted to ART showed a cumulative recurrence rate similar to that of the control group (28.6% and 37.9% respectively, p=0.471) Maria Elisabetta Coccia, 2010 (28.6% vs. 37.9%, p=0.471)

SART-2005

SART-2006

SART-2007

Endometriosis-GnRHa Pain After operation for the prevention Before IVF Empirical

Pathophysiology of Pain and Infertility Associated with Endometriosis Linda C. Giudice, 2010

Three randomised controlled trials (with 165 women) were included

GnRH agonist vs no agonist before IVF (Clinical pregnancy rate per woman) Sallam et al, Cochrane Database Syst Rev 25;(1):CD004635, 2006 Live birth rate OR 9.19, (95% CI 1.08 to 78.22) Clinical pregnancy rateOR 4.28, (95% CI 2.00 to 9.15) CONCLUSIONS: The administration of GnRH agonists for a period of three to six months prior to IVF or ICSI in women with endometriosis increases the odds of clinical pregnancy by fourfold. Data regarding adverse effects of this therapy on the mother or fetus are not available at present. N=165

Use of oral contraceptives in women with endometriosis before assisted reproduction treatment improves outcomes In women with endometriosis, including those with endometriomas, 6 to 8 weeks of continuous use of oral contraception (OC) before assisted reproduction treatment (ART) maintains ART outcomes comparable with the outcomes of age-matched controls without endometriosis. In contrast, ART outcomes are markedly compromised in endometriosis patients who are not pretreated with OC. Ovarian responsiveness to stimulation was not altered by 6 to 8 weeks’ use of pre-ART OC, including in poor responders with endometriomas Our data indicate that 6 to 8 weeks of continuous OC use before ART not only improves outcomes in endometriosis but possibly is as effective as 3 months of GnRH-agonist treatment before ART Dominique de Ziegler, 2010

Deep Endometriosis: Symptoms Pandis GK, 2010

Deep endometriosis: Excisional surgery Pregnancy rates Vercellini et al., Hum Reprod (2009)

Fertility and clinical outcome after bowel resection in infertile women with endometriosis 62 infertile women who underwent laparoscopic excision of endometriosis with segmental bowel resection performed for severe intestinal symptoms. Among women younger than 30 years trying to conceive spontaneously, the cumulative pregnancy rate was 58% and the cumulative pregnancy rate was 45% in those aged 30–34 years. Anna Stepniewska, 2010

Results of first in vitro fertilization cycle in women with colorectal endometriosis compared with those with tubal or male factor infertility Emmanuelle Mathieu d’Argent, 2010

Deep endometrisois: Complications Vercellini et al., Hum Reprod (2009)

Endometrioma ve oosit toplanması Hacim artması Enfeksiyon, abse Akut abdomen Toksik etki Malignite

Endometrioma and oocyte retrieval–induced pelvic abscess: a clinical concern or an exceptional complication The authors evaluated the risk of developing a pelvic abscess in a series of 214 in vitro fertilization cycles that were performed in women with endometriomas. This complication was never recorded, indicating that its risk is very low (0.0; 95% confidence interval, 0.0– 1.7%). Literature nine cases were described. Prophylactic antibiotics have been administered in at least eight cases. The endometrioma was punctured at the time of oocyte retrieval in at least six cases. Laura Benaglia, 2008

Preterm birth, ovarian endometriomata, and assisted reproduction technologies Shavi Fernando, 2009

Adenomyosis A benign disorder, characterized with the presence of glandular and stromal endometrial tissue in myometrium

Adenomyosis Myometrial location Diffuse Focal Adenomyotic cyst Adenomyoma

≈ %20 of women. (J Minim Invasive Gynecol 2009; 16:622–625) More frequently seen in women with endometriosis. More frequently seen in women with low BMI. (Hum Reprod 2010; 25:1325–1334) Adenomyosis Epidemiology

Dysmenorrhea (66% vs 42%) Chronic pelvic pain (53% vs 21+) Fertil Steril 2010;94:1223–8 MenorrhagiaMenorrhagia InfertilityInfertility Adenomyosis Symptoms

Globular uterus Asymmetric thickening of anterior and/or posterior uterus wall Difficulty in distunguishing the endometrial- myometrial junction Focal or diffuse heterogenous myometrial echogenity Myometrial cyst Increased vascularity Adenomyosis Diagnosis - US

3D TV-US: Normal Uterus Minimum JZ Maximum JZ Total myometrial thickness

3D TV-US: Adenomyosis

T2 T1 Adenomyosis Diagnosis - MRI

Adenomyoma Diagnosis - MRI

Retrospective study in 74 infertile patients with surgically proven endometriosis The diagnosis of adenomyosis was based on transvaginal ultrasound criteria All patients were pretreated with long-term (  3 months) GnRH-agonist prior to IVF/ICSI. Endometriosis rASRM stages III-IV + adenomyosis

mean dosage of FSH used was 208IU the mean number of oocytes retrieved was 8.73 the mean number of embryos obtained was 3.86 the mean number of embryos transferred was 1.6 a mean fertilization rate of 43.6% a mean implantation rate of 26.3% a mean miscarriage rate of 24.3% and a clinical pregnancy rate (  12 gw) of 31.7%

No significant differences were found for any of the IVF/ICSI outcomes between women with and without adenomyosis. CONCLUSIONS: Adenomyosis had no adverse effects on IVF/ICSI outcomes in infertile women with proven endometriosis who were pretreated with long-term GnRH-agonist.

Algorithm for management of infertility associated with endometriosis Dominique de Ziegler, 2010

Endometriosis - Infertility Q&A Does stage I-II endometriosis cause infertility ? Yes Is COH + IUI effective in EA infertility? Yes in I-II / Data is not sufficient for III-IV Does endometriosis decrease ovarian reserve? Yes Does deep endometriosis cause infertility? Yes, probably Does endometriosis cause pregnancy loss? No

Does endometriosis decrease IVF success? No (???for St IV  ovarian reserve) Endometrioma and infertility? Not related Surgery for endometrioma before IVF? Not effective (May decrease ovarian reserve) Does IVF treatment increase endometriosis recurrence rate? No Role of surgery after an unsuccessful IVF cycle Not effective except few cases Endometriosis - Infertility Q&A

GnRHa use before IVF in endometriosis? May be helpful, more studies are needed Management of recurrent endometrioma (IVF vs surgery)? IVF Which protocol? No difference Adenomyosis – ART? Had no adverse effect on IVF/ICSI outcomes Endometriosis - Infertility Q&A