Endometriosis & Infertility& Treatments. A. Musa Zamah, MD, PhD

Transcription

1 Endometriosis & Infertility& Treatments A. Musa Zamah, MD, PhD

2 Full Disclosure of Faculty Financial Interests or Relationships I agree to follow the UIC and ACCME policies and declare that I do not have a financial interest or other relationship with any manufacturers of any commercial products that may be discussed during this presentation.

3 ENDOMETRIOSIS Definition: the presence of viable endometrial tissue (glands and stroma) outside of their normal anatomic location. Know it when you see it (have some pics)

4 CLINICAL BURDEN OF ENDOMETRIOSIS How does endo present? Pain, infertility, or as incidental finding on clinical or ultrasound exam. Presentation is variable and does not correlate well with disease burden

5 PREVALENCE OF ENDO 25-50% of infertile women have endometriosis 30-50% of patients with endometriosis are infertile True Prevalence? 1-7% in women undergoing tubal sterilization 9-50% in women having L/S for infertility 30-80% in women with pelvic pain Infertile women 6-8x more likely to have endo than fertile women Risk Factors Low BMI, smoking, alcohol use, family history, parity Race: AA < Caucasian (OR % CI )

6 FERTILITY BURDEN OF ENDOMETRIOSIS how many patients with endo have fertility problems? Not easy to answer since endo may be asymptomatic What does data suggest? In endo surgery being done for pain, how many women have hx of infert?

7 ENDOMETRIOSIS AND INFERTILITY How might endometriosis cause infertility? Anatomic distortion macroscopic issue. Tubal obstruction, adhesions preventing normal tubal motility even if patency ok. Inflammatory microscopic issue Tubal function, Peritoneal cavity Ovarian Effects macro and micro disease Endometrial Effects -? Intrinsic

8 INFERTILITY AND ENDOMETRIOSIS Clear association of endometriosis and infertility Causal relationship has not been clearly established (outside of anatomic distortion) Monthly Fecundity Untreated endometriosis ranges from 2-7% Normally 15-25%, and with advancing age 50% by late 30s Surgery for Stage III/IV endo may improve fecundity if corrects anatomic distortions Suppressive Medical Therapy does not increase fecundity May Delay more Effective Treatments

9 ANATOMIC DISTORTION Pics or examples and stats on tubal patency in setting of endo? Affect ovum release at ovulation, ovum capture and ovum transport

10 TUBAL MOTILITY Does endometriosis affect tubal function beyond patency? Tubal function by hysterosalpingoscintigraphy in patients with patent tubes and endo 64% had tubal dysmotility compared to 32% of controls (male factor) Dysmotility = less effective gamete and embryo transport. Is endometriosis a risk factor for ectopic?

11 PERITONEAL ENVIRONMENT Increased prostaglandins, cytokines and inflammatory markers in peritoneal fluid (IL-1, IL-6, TNF-alpha) and macrophages Increased peritoneal fluid Hamster model of endometriosis shows presence of ovum capture inhibitor Prevents normal cumulus-fimbriae interaction

12 OOCYTE / EMBRYO QUALITY Alterations in follicular fluid Progesterone and cytokines Abnormalities in oocyte quality and embryo quality in IVF Slower embryo development compared to tubal factor infertility Normal implantation and pregnancy rates when using donor oocytes from women without endometriosis In donor cycles where the donor has known endometriosis, lower implantation rates and embryo quality

13 EUTOPIC ENDOMETRIUM Is the endometrium of endometriosis patients itself normal? Gene array studies Difference in eutopic endometrium in women with endo during follicular phase and implantation window. Lowered integrin adhesion α5β3 integrin Low endometrial levels of ligand for L-selectin (protein that coats the trophopblast) Unclear if these are a cause or effect of endometriosis Extra Progesterone supplementation may reverse some of these alterations

14 MEDICAL TREATMENT FOR ENDOMETRIOSIS AND FERTILITY Medical Treatment relieves pain but does not increase fertility Treatments inhibit ovulation so cannot conceive during therapy Options Progestin only ; progestin-estrogen combo Danazol GnRH agonist and antagonist Aromatase Inhibitors

15 MEDICAL TREATMENT FOR ENDOMETRIOSIS AND FERTILITY What about AFTER medical therapy? Does fecundity improve? Multiple RCTs: GnRH agonists or progestins not effective in improving fertility with minimal-mild endometriosis Danazol not superior to expectant management for mild-mod disease RCT: 71 pts min-mild endo. Treatment with 6 mo GnRHa vs placebo. 1&2 yr cumulative pregnancy rates similar RCT: 37 pts min-mild endo. Pregnancy rates similar at 1 yr for progestin treatment versus expectant management RCT: 31 pts cumulative preg rates 41% progestin, 43% expectant

16 MEDICAL TREATMENT FOR ENDOMETRIOSIS AND FERTILITY RCT: gestrinone 1 yr conception rate 25% with gestrinone vs 24% with placebo. 25% conception rate with patients with no visible 2 nd look Laparoscopy vs. 30% with residual disease. Conception rate 23% in control unexplained infertility group No significant differences, but small study Meta-analysis (7 studies) medical treatment vs placebo OR 0.85 [95% CI 0.95, 1.22] Review ~ 800 patients in 13 studies no evidence that medical treament superior to placebo Hormonal Treatment does NOT improve fertility for women with Stage I/II disease

17 FERTILITY TREATMENT OPTIONS AND OUTCOMES WITH ENDOMETRIOSIS Surgical management prior to treatment Treatment directly (IUI or IVF)

18 FERTILITY: STAGE I/II ENDO AND SURGERY Two RCTs evaluating effectiveness of surgery on fecundity in Stage I/II endometriosis in infertile women. Surgeon discretion for excision or ablation Canadian (Endocan) study Pregnancies within 36 weeks of laparoscopy that progressed to 20 weeks gestation Italian study Pregnancies within 1 yr of laparoscopy that resulted in live birth Powered for 2.7 fold increase in pregnancy for laparoscopy

19 Italian Study Canadian Study Primary Outcome Pregancies in 1 yr causing LB Pregnancies in 36 weeks beyond 20 wk GA Treated Patients 10/51 (20%) 51/172 (29%) Untreated Patients 10/45 (22%) 29/169 (17%) Baseline Untreated Pregnancy Rates Overall Absolute Difference Number Needed to Treat Number of Laparoscopies 22% 17% 8.6% in favor of laparoscopy [95% CI 2.1, 15%] 12 laparoscopies per additional live birth [95% CI 7,49] If 30-50% of women with infertility have endometriosis need ~ 30 surgeries for each additional Live Birth

20 WHAT DO THESE STUDIES TELL US? The presence of minimal-mild disease in patients with infertility does allow for some natural conceptions, with per cycle fecundity rates similar to unexplained infertility. Surgery for Stage I/II endo can increase natural fecundity slightly. NNT = 12 Stage I/II endometriosis cases Most conceptions occur within the first XX months following surgery

21 FERTILITY: STAGE III/IV ENDO AND SURGERY Non-randomized study 216 infertile patients. Cumulative Pregnancy rates over 2 years after laparoscopy (45%) or laparotomy (63%) Laparoscopic cystectomy for endometrioma >4cm improved fertility versus drainage / coagulation Compared to drainage / coagulation cystectomy had less recurrence risk For Stage III/IV endometriosis with no other identifiable factors Surgical treatment with laparoscopy and possible laparotomy can increase fertility Adverse effect of endometrioma is loss of viable ovarian cortex Additional Surgery has not been shown to reproducibly increase fecundity beyond the first surgery. Retrospective study recommend considering ART in these patients

22 FERTILITY: STAGE III/IV ENDO AND SURGERY Retrospective Study IVF (n=23) Repeat Surgery (n=18) Cumulative Pregnancy Rates 70% with 2 IVF cycles 24% in 9 months

23 ROLE OF GNRH AGONIST OR PROGESTIN IN COMBINATION WITH SURGERY FOR FERTILITY? Preoperative therapy reported to pelvic vascularity and size of implants, reducing blood loss and amount of resection needed May make it more difficult to identify and treat lesions at surgery Post-operative therapy Well established studies evaluating post op pain relief showing longer duration of pain relief with post op GnRH agonist. Eradicate residual implants in patients with extensive unresectable disease May treat microscopic disease NO evidence for fertility enhancement in any study, delays use of further fertility treatments

24 ENDOMETRIOSIS & FERTILITY TREATMENTS In patients with presumed endometriosis or documented by ultrasound what are conception rates for IUI? How do these rates compare to other causes of infertility, ie unexplained

25 ENDOMETRIOSIS: SUPEROVULATION AND IUI Complex as studies often designed differently Most studies included women with endometriosis treated prior to IUI or included women with unexplained infertility (some of whom may have had endo) Cross-over RCT: unexplained infertility vs surgically treated Endo Preg rates/cycle higher with 4 cycles of CC-IUI (9.5%) vs timed intercourse (3.3%) RCT: 49 patients with Sage I/II endo and infertility 3 cycles of FSH-IUI vs 6 mo expectant management Preg rate / cycle 15% in FSH-IUI vs 4.5% in untreated group p<0.05 Increased per cycle preg rate with FSH therapy (7%) vs no treatment (3%) in infertile women with Stage I/II endo

26 ENDOMETRIOSIS: SUPEROVULATION AND IUI Multiple studies: Clinical pregnancy rate of SO/IUI shortly after surgical treatment of Stage I/II disease is comparable to women with unexplained infertility. SO/IUI is a viable option for women with surgical diagnosis/ treatment of Stage I/II endometriosis, with success rates similar to unexplained infertility population. Unknown if outcomes are better with surgical treatment than if min/mild endo is undiagnosed or untreated. Preg rate / cycle Minimal endo 21% 70% Mild endo 19% 68% Unexplained infertility 20.5% 66% Cumulative LBR (4 cycles)

27 ART: IVF STIMULATION Baseline U/S (Start of period) hcg Oocyte Retrieval ~ 9-11 days 36 h FSH / LH

28 ART: IVF OVERVIEW

29 ART: IVF AND ENDOMETRIOSIS IVF maximizes per cycle fecundity in women with endometriosis Especially those with anatomic distortion Main concerns for Endometriosis on IVF are effect on gamete quality and ovarian response. Endometrial abnormalities are potentially overcome through supraphysiologic steroid hormones

30 ART: IVF AND ENDOMETRIOSIS SART: IVF-ET outcomes Show graph of SART overall data Across ages delivery rate / retrieval for all diagnoses 33.2% vs 39% for endometriosis.

31 ART: IVF AND ENDOMETRIOSIS Meta-analysis of observational studies Lower IVF pregnancy rates with endometriosis compared to tubal factor infertility (OR 0.56 [95% CI 0.44, 0.70]) Lower pregnancy rates with severe endometriosis vs mild disease (OR 0.60 [95% CI 0.42, 0.87]) Decreased # oocytes, fertilization and implantation rates in patients with endometriosis IVF maximizes per cycle fecundity in women with endometriosis Especially those with anatomic distortion Why the discrepancy in meta-analysis vs SART data? Confounding variables, unadjusted data, SART reporting bias for what is considered endo or how rigorously diagnosed

32 ART: IVF AND ENDOMETRIOSIS Few studies evaluating IVF vs IUI directly or IVF versus expectant management in endometriosis related infertility RCT subgroup of 21 women with endometriosis and infertility: 15 had IVF and 6 expectant None in expectant got pregnant versus 5/15 in the IVF treatment

33 WHEN TO BE CONCERNED ABOUT ENDOMETRIOSIS EFFECT ON IVF If bilateral endometriomas, especially >4cm Unexplained poor ovarian stimulation, embryo quality or abnormal oocyte morphology

34 WHAT CAN WE DO? GNRH AGONIST TREATMENT & IVF Three RCTs of 165 patients total GnRH agonists given 3-6 months prior to IVF in women with documented endometriosis increases pregnancy odds OR 4.28 [95% CI 2-9.1]? Generalizability had very high success of 75% or more in treatment arms Unclear what stage of endo was and whether equally effective in mild or severe disease Mechanism uncertain, may affect ovary, intraperitoneal environment, endometrium, etc. Uncontrolled studies have shown reasonable pregnancy rates for patients with prior failed IVF cycles who are then treated with suppressive hormonal therapy for 1-3 months prior to another IVF cycle

35 EVIDENCE: ENDOMETRIOMAS & IVF Impact is controversial No RCTs comparing expectant management versus laparoscopic excision prior to IVF Case-control study of 189 patients Laparosocpic excision prior to IVF did not increase pregnancy rates Retrospective study 171 patients with endometrioma vs tubal factor Aspiration of endometrioma just before IVF showed no effect on follicular response, # mature oocytes, or clinical pregnancy rate Surgery prior to IVF also did not impair IVF success rates. Current evidence says surgery does not benefit asymptomatic women with endometrioma prior to IVF. Unanswered questions What about for women who have failed IVF and have an endometrioma Does size matter? Bilaterality?

36 ENDOMETRIOMA REMOVAL: BENEFITS? Prevention of ruptured endometrioma Improve follicle access to facilitate safer retrieval Decrease chance of seeding endometrioma during retrieval Detect occult malignancy (assoc of endometriomas and certain ovarian cancers) Potentially improve oocyte environment Prevent follicular fluid contamination by endometrioma fluid Prevent further endometrioma progression Impact is controversial

37 ENDOMETRIOMA REMOVAL: RISKS? Surgical complications Not easy to remove. Pseudocapsule. Can grow into ovary, may require more traumatic technique to remove. Might need to cauterize base. Any evidence for different energies? Decrease ovarian reserve Lack of clear evidence of improved IVF pregnancy rates

38 DOES FERTILITY TREATMENT MAKE ENDOMETRIOSIS SYMPTOMS WORSE? No evidence that SO/IUI or ART treatments cause progression of disease or worsen long term symptoms In theory the higher hormone levels could feed endometriotic implants, but duration short Pregnancy treats endometriosis symptoms Many women with endo say pregnancy was the best time for their disease symptoms!

39 PREGNANCY OUTCOMES IN ENDOMETRIOSIS Swedish cohort ~ 9,000 women diagnosed with endometriosis delivering infants from national birth registry Unclear if associations are related to the endometriosis, the resulting subfertility, or any treatments. Compared to women without endometriosis Odds Ratio (95% CI) Pre-term birth w/ ART 1.24 ( ) Pre-term birth w/o ART 1.37 ( ) Pre-Eclampsia 1.13 ( ) Antepartum bleeding / placental complications 1.76 ( ) C-section 1.47 ( ) SGA / Stillbirth No association

40 OVARIAN RESERVE AFTER ENDO SURGERY What do we know about this?

41 CLINICAL DECISIONS: INFERTILE PATIENT WITH ENDOMETRIOSIS Can be Difficult Most clinical decision points have not been assessed in RCTs Observational data are often conflicting

42 CLINICAL DECISIONS: INFERTILE PATIENT WITH STAGE I/II ENDOMETRIOSIS Decide whether to perform laparoscopy before offering fertility treatments Consider age, duration of infertility, ability to undergo IVF, pelvic pain symptoms Most clinical decision points have not been assessed in RCTs Observational data are often conflicting Low utility in laparoscopy in asymptomatic women with infertility If laparoscopy is done Ablate / excise visible lesions For younger patients can consider expectant management for 6-12 months SO/IUI (CC or FSH) has success rates similar to unexplained infertility

43 CLINICAL DECISIONS: INFERTILE PATIENT WITH ENDOMETRIOSIS ADVANCING AGE Age > 35 : normal decline in fecundity and increase miscarriage rate There may be additive effect of endometriosis on the baseline issues with increased age Recommend either SO/IUI or IVF IVF may have decreased success rates compared to other infertility causes (but SART data does not show this)

44 CLINICAL DECISIONS: INFERTILE PATIENT WITH STAGE III/IV ENDOMETRIOSIS Anatomic distortion may well be an issue Options are laparoscopy, laparotomy, or IVF Studies show increase in pregnancy rates with surgery over no surgery when evaluating natural fertility. If the initial surgery is unsuccessful for fertility, most effective treatment is IVF (70% preg rate in 2 cycles) vs repeat surgery (24% preg rate in 9 months) Not clear that surgery prior to IVF is better than going directly to IVF.

45 CLINICAL DECISIONS: INFERTILE PATIENT WITH ASYMPTOMATIC ENDOMETRIOMA Insufficient evidence to recommend removal prior to IVF for intent of increasing pregnancy rates If large (>4cm) Consider removal histologically confirm diagnosis Improve ability to access follicles in retrieval and decrease ivf risks Potentially improve oocyte environment Removal may compromise ovarian function and ovarian reserve (even put older patients into perimenopausal state) Consider removal regardless of size if unexplained failed IVF cycles, poor egg or embryo quality.

46 IVF IMPLANTATION AND ENDOMETRIOSIS What do we know about this? Even though eutopic endometrium molecularly has diff signal, IR similar when controlling for embryo quality or for ex using donor eggs with current uterine prep regimens. Could be that the supplemental hormones correct endometrial defect.

47 WHAT DID WE LEARN? Burden of endometriosis on fertility Endometriosis can affect fertility in a variety of ways (ovaries egg quality, tube patency and function, uterus abn molecular markers) Surgery is very reasonable option for younger women with mild-mod disease resulting in natural conception rates of ~ half of age expected within 1 yr of surgery.

48 WHAT DID WE LEARN? Not everyone needs IVF, but SO-IUI and IVF are effective techniques for helping endometriosis patients conceive. Failed IVF or Poor embryo quality patients may benefit from disease reducing surgery or Lupron pre-treatment

49 BEFORE REFERRAL Ovarian Reserve Testing (AMH, D3 FSH/E2) Tubal Patency (HSG, chromotubation) Male Factor (Semen analysis)

50 CLINICAL MANAGEMENT PLAN For significant QOL symptoms I tend to recommend consideration of surgery prior to any fertility treatment If clinically suspect endo and HSG shows abnormality such as limited flow, tubal distortion / blockage then also recommend surgical pre-treatment if patient wants to try naturally or IUI. Laparoscopy for unexplained infertility in setting of asymptomatic patient is not recommended by ASRM In setting of endometrioma(s) I tend to recommend moving directly to fertility treatments, fine to start with IUI then progress to IVF. In setting of multiple failed IVF cycles or unexpectedly poor embryo quality, recommend either depot Lupron tx or Laparoscopy even if no significant symptoms. For any endometrioma surgery counsel patient about potential effect on ovarian reserve (balance effects on quality and quantity)

51 ACKNOWLEDGEMENTS UIC Department of Obstetrics & Gynecology ASRM Practitioner Resources ACOG Practitioner Resources

52 REFERENCES

53 QUESTIONS