Practical tips for perioperative

management of endometriosis

Jon I Einarsson, MD PhD MPHDirector of MIGSBrigham and Women’s HospitalAssociate Professor of Ob/GynHarvard Medical School

DisclosuresI have no financial relationships with a commercialentity producing health-care related productsand/or services.

Endometriosis: Ectopic Growth of endometrium (glands & stroma)

Treatments •oral contraceptives•Lupron• aromatase inhibitors•danazol•surgery

•Affects ~10% of women

•Causes debilitating pain, infertility

•Onset often in teens, ~10 years to diagnosis

•Surgery is required for diagnosis

Giudice, NEJM 2010; Potlog-Nahari Fertility & Sterility 2004

Natural History17-29% of lesions resolve spontaneously

24-64% progress

9-59% stable over 12 months

Sutton CJ et al. F&S 1070 1997

Becker +, WERF EPHect Working Groupd Haromonization Project I, Surgical Phenotype Fert & Stert in press (2014)

Filmy adhesions; white, blue/blacksuperficial peritoneal lesions

Superficial ovarian blue/black lesions fibrosis;deep infiltrating lesions utero-sacral ligament

Superficial vesicular/vascular peritoneal lesions

Red/brown superficial peritoneal lesions

Dense adhesions/fibrosis

Lesions are heterogeneous in appearance, location, and invasiveness

~2 cm Bowel lesionRectal lesion, attached to the vagina

Endometriosis can be highly invasive and can be found in downstream lymph nodes

lymph node with endometriotic focus: glandular cystic spaces lined by müllerian serous epithelium and endometriod stroma(Abrão et al, Fert Steril 2006)

Resection of 2 bowel endometriosis lesions + associated other endometriosis, Dr. Mauricio Abrão, Sirio Libanês Hospital 12 July 2011

Clinical presentation Dysmenorrhea – 50-90%

Dyspareunia

Deep pelvic pain

Low abdominal pain and back pain

Cyclic bowel and bladder symptoms

Infertility

Any symptom that intensifies with the menstrual cycle should be considered related to endometriosis

Patient Classification

Enduring mystery why some patients with minimal/mild disease experience debilitating pain and/or infertility while some patients with severe disease are fertile and/or relatively pain free

Diagnosis Ultrasound Ovarian endometriosis 60-98% specificity, 80-90% sensitivity

Bowel endometriosis R/V septum disease

CA-125 Poor sensitivity and specificity for early disease ? Marker for disease progression

Surgical confirmation necessary Visual or histologic if atypical lesion

Pain and endometriosis

Bleeding from implants

Prostaglandin production

Inflammatory cytokines

Uterine/peritoneum neo-innervation

Abnormal dysynergia – contractions

Concurrent conditions – IBS, IC, pelvic muscle syndromes

Endometriosis pain Pain sensitivity increases 40% in premenstrual and

menstrual phase

Estrogen increases pain sensitivity

Genetic neurotransmitter phenotype IBS, TMJ, IC, fibromyalgia, chronic fatigue, levator

spasm

Medical Therapy No benefit for fertility

Used for pain management only Prior to surgical confirmation First line therapies

Post operative adjuvant First or second line therapies

Recurrence First, second or third line therapy

Medical Therapy for Endometriosis First line medical therapies (Fewest side effects) NSAIDS Oral Contraceptives Mirena

Second line therapies Progestins Danazol

Third line therapies (Most side effects) GnRH agonists and antagonist With and without addback therapy

Aromatase Inhibitors

NSAIDSAllen C, Hopewell S, Prentice A, Gregory D. Nonsteroidalanti-inflammatory drugs for pain in women with endometriosis. Cochrane Database of Systematic Reviews 2009

Comparing NSAIDs (naproxen) to placebo, there was no evidence of a positive effect on pain relief (odds ratio (OR) 3.27, 95% CI 0.61 to 17.69) in women with endometriosis. There was also inconclusive evidence to indicate whether women taking NSAIDs (naproxen) were less likely to require additional analgesia (OR 0.12, 95% CI 0.01 to 1.29) or to experience side effects (OR 0.46, 95% CI 0.09 to 2.47) when compared to placebo.

Oral contraceptives for pain associated with endometriosisLucy-Jane Davis1, Stephen S Kennedy2, Jane Moore3, Andrew Prentice4

Cochrane Database of Systematic Reviews, 2009

Moghissi (Clin Obstet Gynecol;p620, 1999)

Non-randomized, Continuous OCP with 20 or 35ug dose of EE for 6-9 mos

Pain relief in 75%-100% of patients

Continuous OCPs

Vercellini F&S p560 2003 50 women with dysmenorrhea who failed cyclic

OCP use VAS 75 at baseline; 31 at two year follow up 26% very satisfied 54% satisfied 10% dissatisfied

Side effects 14% Wt gain 4%, bloating 4%, headache 2%, labido 2%

Continuous OCP

Herada T F&S 2008 p 1583 Blinded RCT 100 patients Cont OCP (35 ug monophasic) vs placebo 4

months VAS - Pain Reduction in both Greater reduction in dysmenorrhea and

endometrioma size in the COC group (p< 0.001) Non menstrual pain reduced only in the COC

group

Summary for Continuous Oral Contraceptives (COC)

Insufficient level one evidence to show superiority of COC over cyclic OCP for chronic pain and dyspareunia.

Effective for dysmenorrhea.

All COC formulas effective

Most affordable long term therapy until pregnancy

Chronic therapy associated with break through bleeding. Treat with periodic pill free intervals

Progestins

Mechanism of action Decidual reaction and atrophy of lesions Reduce E2 receptors Inhibit stroma cell proliferation Expression of MMPs Inhibit angiogenisis Endometriosis with reduced progsterone sensitivity –

Progesterone receptor resistance

Common ProgestinsProgestin Dose Duration Pain reductionProvera (oral MPA)

30 mg/d 6 months 80% pain improve

Aygestin(NorethindroneAcetate)

5-10 mg/d 6 months 80% improve

Depot MPA 150mg q12-14 wks

Equal to lupronand danazol

Mirena LNG IUS 20ug/d 5 years Improved painscore

Etonogestrel sub q implant

68mg over 3 yrs 36 mos 4/5 with pain relief

Bedalwy and Liu. SRM vol 8 p10 2010

Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Database of Systematic Reviews 2000, Issue 2. Telimaa et al 1987

Authors' conclusions. The limited available data suggests that both continuous progestagens and anti-progestagens are effective therapies in the treatment of painful symptoms associated with endometriosis. Progestagens given in the luteal phase are not effective. Clinical efficacy similar to continous oral contraceptives

Side Effects of Progestins

Breakthrough bleeding – 40%

Weight gain – 20%

Bloating and edema – 15%

Breast tenderness – 12%

Mood changes – 10%

Headache – 10%

Nausea – 10%

Vercelleni P F&S 1997 Vol 68 p393

Danazol 17-ethinyl testosterone derivative Inhibits gonadotropin secretion Local estrogen production Atrophy of implants Immune modulation

400 mg – 800 mg daily for 6 months

Recent reports of lower dose and pain reduction with Danazol IUD, vaginal tablets and rings. (Razzi et al F&S 2007 p 789, Cobellis et al)

Danazol vs GnRHa

Henzl NEJM 1998

o 213 patients RCTo More AE with Danazol (wt gain, edema, myalgia) drop out 18% vs Nafarelin (decrease labido, vaginal dryness, hot flashes and irritation) drop out 5%o Danazol increased LDH and reduced HDL

Side Effects of DanazolAcne, oily skin, facial hair, deepening of voice, hot flashes, atrophic vaginitis, wt gain, muscle mass, breast atrophy, fluid retention etc.

Gonadotropin-releasing hormone analogues for pain associated with endometriosis Julie Brown1, Alice Pan , Roger HartEditorial group:

Cochrane Menstrual Disorders and

SubfertilityGroup 2010. 41 RCT trials – 4935 patients

GnRHas appear to be more effective at relieving pain associated with endometriosis than no treatment/placebo. There was no evidence of a difference in pain relief between GnRHas and danazol although more adverse events reported in the GnRHa groups. There was no evidence of a difference in pain relief between GnRHas and progestins and no studies compared GnRHaswith analgesics.

GnRH agonistsMeta-analysis Guidice L NEJM

Deplete the pituitary of gonadotropins Hypoestrogenic state, endometrial atrophy, amenorrhea

15 RCTs 1821 women 60%-100% improve dysmenorrhea and pain Similar to danazol, progestins, COC

Route of administration irrelevant

13% bone loss in 6 months (mostly reversible)

Estrogen threshold hypothesis 30-35 pg/ml Maintain bone density and give pain relief Addback 5 mg Norethindrone acetate, +/- 1 mg Estradiol Maintains bone mineral density up to 12 mos (more effective with

E2)

Aromatase InhibitorsSystematic review of the effects of aromataseinhibitors on pain associated with endometriosis.Nawathe A, Patwardhan S, Yates D, Harrison GR, Khan :BJOG. 2008 Jul;115(8):1069. Endometriotic lesions contain aromatase and can make their

own estrogen

8 studies, 137 women

Letrozol effective when used in combination with OCP, Progestins and GnRHa vs these agents alone

Used most frequently with refractory pain from recto-vaginal endometriosis

Post surgical management

Surgery is effective, but endomay come back

RCT by Vercellini et al on surgical excision in 180 patients with stage I-IV endo 29% recurrence in dysmenorrhea in 1

year 36% recurrence in dsymenorrhea in 3

years

Retrospective cohort study in 57 women ≤21 y/o 32 (56%) had a recurrence in a 5 year

follow up 11 women had repeat laparoscopy

with endo seen in all these patients

Prospective observational cohort study by P. Yeung et al in 20 teenagers reported 47% rate of repeat surgery, but no endo was identified Pain is multifactorial in these patients

2

Surgical Treatment of Endometriosis: A 7‐Year Follow‐up on the Requirement for Further Surgery.Shakiba, Khashayar; Bena, James; McGill, Kimberly; Minger, Jill; Falcone, Tommaso

Obstetrics & Gynecology. 111(6):1285‐1292, June 2008.DOI: 10.1097/AOG.0b013e3181758ec6

Fig. 1.  Reoperation‐free survival estimates are shown for groups defined by surgery type and ovary preservation.Shakiba. Surgical Treatment of Endometriosis. Obstet Gynecol 2008.

Type of surgery affects recurrence risk 240 patients

Removal of ovaries in the 30-40 year age group did not affect risk of recurrence

Reoperation risk by ageSurgery type # 2 years post-op 5 years post-op 7 years post-op

Age 19-29Laparoscopy 36 36.1% 66.7% 72.2%

Age 30-39Laparoscopy 50 12% 42% 56.2%

With Hyst 22 0% 4.8% 10.5%

Hyst + ovaries

21 9.5% 14.3% 14.3%

Age ≥40Laparoscopy 21 14.3% 23.8% 23.8%

With Hyst 21 4.8% 19.6% 35.7%

Hyst + ovaries

28 0% 4% 4%

Options for medical therapy following surgery for EndometriosisOral ContraceptivesCyclic vs. continuous

Progestins

Progesterone antagonists

Danazol

GnRH agonists and antagonistsWith and without add-back therapy

Aromatase Inhibitors

SERMs

Oral Contraceptives Most affordable long term therapy until pregnancy

Not all patients are good candidates >35 years old Smokers Hypertension

Largest RCT among 311 women who underwent laparoscopic excision for symptomatic endometrioma; divided into 3 groups; no therapy, cyclic and continuous OCPs for 2 years

Significant reduction in recurrence rate and VAS scores for dysmenorrhea in continuous users vs. cyclic and non-users at 6 months

No difference in recurrence rate and VAS for dyspareunia and chronic pelvic pain among the groups

Significantly more increase in dysmenorrhea, dyspareunia and chronic pelvic pain at 6-24 months among non-users

Seracchioli et al. Fertil Steril. 2010;94(2):464-71

Alternative delivery methods

In a cohort study of 207 patients with recurrent endometriosis related pain after surgical treatment, women received either a vaginal ring or a transdermal system for 12 months

Women using the vaginal ring were significantly more satisfied and showed better compliance with treatment

Both systems reduced pain, but the vaginal ring was more effective in treating dysmenorrhea and rectovaginal lesions

A total of 36% of vaginal ring users and 61% of patch users withdrew from treatment due to side effects

Vercellini et al. Fertil Steril. 2010;93(7):2150-61

LNG-IUDVercellini 2003 F&S 80:305 (now 3 small RCTs)• Randomized IUD (20) vs no therapy (20) post excision

surgery for dysmenorrhea and dyspareunia (dysp)• 12 month evaluation

• Compliance was 68-82% and most removals were due to persistent pain, irregular bleeding and weight gain

• Another study found 60% reduction in endo lesions after Mirena insertion

Pre-op dyspareunia (VAS) Post-op dyspareunia (VAS)

Mirena 79 (52) 22 (16)*

Non Mirena 77 (55) 41 (34)*

Progestins or surgery? A prospective non-randomized cohort study in

patients with persistent or recurrent severe deep dyspareunia after first line therapy

Patients were offered a choice between 2.5 mg/day of norethindrone acetate (n=103) vs. repeat surgery (n=51) and followed for 12 months

Pts in surgery group had rapid improvement in pain with gradual recurrence of pain

Pts in norethindrone group had a more gradual improvement in pain

At 12 months, norethindrone outperformed surgery in Frequency of intercourse per month (5.3 vs. 4.6 p=0.02) Satisfaction (59% vs. 43% p=0.015)

No difference in FSFI or EHP-30Vercellini et al. Hum Reprod 2012;27(12):3450-9

Progesterone AntagonistsMifepristone (RU-486) Reduces ER and PR Inhibits endometrial stromal cell proliferation 50 mg per day for 6 months – reduces implants and

improves symptoms Side effectsVasomotor symptomsAnti glucocorticoid

Asoprisnil - SPRM Reduces pain without hypoestrogenic side effects Induces vasoconstriction, inhibits angiogenesis,

reduces PG production

Danazol 17-ethinyl testosterone derivative Inhibits gonadotropin secretion Local estrogen productionAtrophy of implants Immune modulation

One RCT compared 600 mg danazol vs. placebo in 77 women with moderate to severe endometriosis for 3 months after laparoscopic conservative surgery

No significant difference in pain relief 6 months after finishing treatment

Yap et al. The Cochrane Library: Issue 4, 2009

Gonadotropin-releasing hormone analogues

7 randomized trials

Mixed results

5 trials with no positive effect vs. placebo

2 trials with significantly lower risk of recurrence after surgery with the use of GnRH agonists

13% bone loss in 6 months (mostly reversible)

Estrogen threshold hypothesis 30-35 pg/ml Maintain bone density and give pain relief Add-back 5 mg Norethindrone acetate, +/- 1 mg Estradiol Maintains bone mineral density up to 12 mos (more effective with

E2) Prolonged therapies (>12 months) with add-back have been reported Bone density monitored every 6-12 months

GnRHa vs. progestin One RCT compared 1 mg Dienogest daily vs. 3.75

mg Triptorelin

142 patients were enrolled, but due to protocol violations 59 were included in the Dienogestgroup and 61 in the Triporelin group

No difference in efficacy between the groups

Dienogest is only available as a combination OCP (with estradiol) in the US (Natazia)

This is a phasic pill containing 0 to 3 mg of Dienogest

Aromatase Inhibitors

Endometriotic lesions contain aromatase and can make their own estrogen

Letrozole and anastrozole have been shown to be effective when used in combination with OCP, Progestinsand GnRHa vs these agents alone

Used most frequently with refractory pain from recto-vaginal endometriosis

One RCT found less pain with letrozole plus norethindronevs. norethindrone alone

Another RCT compared 6 months of goserelin plus anastrozole vs. goserelin only after endometriosis surgery = significantly longer time to symptom recurrence in combo regimen (>24 months vs. 17 months)

Aromatase inhibitors

Another RCT in 106 women after cauterization of endo between 2.5 mg of Letrozole vs. Danazol 600mg vs placebo for 6 months

Pain was significantly lower in letrozole and danazol vs. placebo

Yet another RCT in 144 women after excision of endo between letrozole (2.5mg), triptorelin(3.75mg) or placebo Post-surgical treatment was 2 months in all groups Rate of recurrence was similar in all groups at one

year – approx 5-6%

Selective estrogen receptor modulators (SERMs) One double blind prospective study in 93 women

with endometriosis related pain after surgery treatment

Randomized to raloxifene vs placebo for 6 months

Study was halted early due to significantly earlier pain and need for a second surgery in the raloxifene group

SERMs may act like estrogen in the modulation of lesions and chronic pelvic pain

Summary and RecommendationsPost-surgical management

First line therapy Continuous OCPs Norethindrone Acetate Mirena IUD

Second line therapy GnRHa with add-back Norethindrone Combined E+P

Depo-provera

Third line therapy Aromatase inhibitors Danazol Progesterone antagonists

Women with rectovaginalendometriosis are more attractive! Case control study among 300 nulliparous women

Attractiveness was assessed by 4 independent female and male observers

Attractive or very attractive 31/100 in rectovaginal endometriosis group (cases) 8/100 in peritoneal and ovarian endometriosis group 9/100 in subjects without endometriosis

A higher proportion of cases had intercourse before age 18; 53 vs. 39. vs30%)

Cases also had a leaner silhouette and larger breasts

No difference in eye or hair color between the groups

Women with higher estrogen levels have been found to have more feminine, attractive and healthy looking faces than those with lower levels

Vercellini P et al. Fertil Steril 2013;99(1):212-8

Thank you for your attention