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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