Practical tips for perioperative management of endometriosis

Practical tips for perioperative management of endometriosis Jon I Einarsson, MD PhD MPH Director of MIGS Brigham and Women’s Hospital Associate Profe...
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Practical tips for perioperative management of endometriosis Jon I Einarsson, MD PhD MPH Director of MIGS Brigham and Women’s Hospital Associate Professor of Ob/Gyn Harvard Medical School

Disclosures I have no financial relationships with a commercial entity producing health-care related products and/or services.

Endometriosis: Ectopic Growth of endometrium (glands & stroma) •Affects ~10% of women •Causes debilitating pain, infertility •Onset often in teens, ~10 years to diagnosis •Surgery is required for diagnosis

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

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

Natural History 17-29% of lesions resolve spontaneously 24-64% progress 9-59% stable over 12 months

Sutton CJ et al. F&S 1070 1997

Lesions are heterogeneous in appearance, location, and invasiveness Red/brown superficial peritoneal lesions

Filmy adhesions; white, blue/black superficial peritoneal lesions

Superficial vesicular/vascular peritoneal lesions

Dense adhesions/fibrosis Superficial ovarian blue/black lesions fibrosis; lesionsHaromonization utero-sacral Project I, Surgical Phenotype Fert & Stert in Becker +, WERF deep EPHectinfiltrating Working Groupd ligament press (2014)

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

~2 cm Bowel lesion

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

to the vagina

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

NSAIDS

Allen C, Hopewell S, Prentice A, Gregory D. Nonsteroidal anti-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 endometriosis

Lucy-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 Progestins Provera (oral 30 mg/d 6 months

Pain reduction

Aygestin (Norethindrone Acetate)

5-10 mg/d

80% improve

Depot MPA

150mg q12-14 wks

Mirena LNG IUS

20ug/d

Progestin

Dose

Duration

MPA)

Etonogestrel sub 68mg over 3 yrs q implant

6 months

80% pain improve

Equal to lupron and danazol 5 years

Improved pain score

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 o 213 patients RCT o 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

Henzl NEJM 1998

Side Effects of Danazol Acne, 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 GnRHas with analgesics.

GnRH agonists Meta-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 Inhibitors

Systematic review of the effects of aromatase inhibitors 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 endo may 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

Type of surgery affects recurrence risk  240 patients  Removal of ovaries in the 30-40 year age group did not affect risk of recurrence

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.

2

Reoperation risk by age Surgery type

#

2 years post-op

5 years post-op 7 years post-op

Age 19-29 Laparoscopy 36

36.1%

66.7%

72.2%

Age 30-39 Laparoscopy 50

12%

42%

56.2%

With Hyst

22

0%

4.8%

10.5%

Hyst + ovaries

21

9.5%

14.3%

14.3%

Age ≥40 Laparoscopy 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 Endometriosis  Oral Contraceptives  Cyclic vs. continuous

 Progestins  Progesterone antagonists  Danazol  GnRH agonists and antagonists  With 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-IUD Vercellini 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 Pre-op dyspareunia (VAS)

Post-op dyspareunia (VAS)

Mirena

79 (52)

22 (16)*

Non Mirena

77 (55)

41 (34)*

• 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

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-30 Vercellini et al. Hum Reprod 2012;27(12):3450-9

Progesterone Antagonists  Mifepristone (RU-486)  Reduces ER and PR  Inhibits endometrial stromal cell proliferation  50 mg per day for 6 months – reduces implants and improves symptoms  Side effects  Vasomotor symptoms  Anti 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 production  Atrophy 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 Dienogest group 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, Progestins and GnRHa vs these agents alone  Used most frequently with refractory pain from rectovaginal endometriosis  One RCT found less pain with letrozole plus norethindrone vs. 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 Recommendations Post-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 rectovaginal endometriosis 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. vs 30%)  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

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