medical treatment of

endometriosis

Antti PerheentupaDept of Ob & Gyn

Turku University Hospital

24.9.2015 Helsinki

Sidonnaisuudet•  LT,  dos,  naistentau.en  el,  lisääntymislääke.ede,  andrologian  

eriityispätevyys  

•  Oyl,  lisääntymislääke.eteen  koulu:aja,  Naistenklinikka  VSSHP    

•  Yksityislääkäri,  Pulssi,  Terveystalo,  Konsultoiva  andrologi,  Fer8nova,  Terveystalo  

 •  SGYn  pienryhmän  pj  (reproduk8o  endokrinologia)  

 •  IFFS  hallitus  (Interna8onal  Federa8on  of  Fer8lity  Socie8es)  

 •  NFOG  scien8fic  commiHee  

• ENDOMET ja PROENDO tutkimusprojektien ryhmäjohtaja (TEKES- ja EVO-rahoitus)

•  Luentoja  lääkeyritysten  koulutus8laisuuksissa  (Gedeon  Richter,  MSD,  Merck)  

•  Koulutus8laisuuksien  suunniHelu  (Gedeon  Richter,  MSD,  Merck)  

•  Forendo  Pharma  Ltd.  perustaja  ja  osakas  

endometriosis Should be viewed as a chronic disease that requires a lifelong management plan with the goal of maximizing the use of medical treatment and avoiding repeated surgical procedures

Treatment of pelvic painassociated with endometriosis: acommittee opinionThe Practice Committee of the American Society for Reproductive Medicine

American Society for Reproductive Medicine, Birmingham, Alabama

Pain associated with endometriosis may involve many mechanisms and requires careful evaluation to confirm the diagnosis andexclude other potential causes. Both medical and surgical treatments for pain related to endo-metriosis are effective, and choice of treatment must be individualized. This document replacesthe document by the same name last published in 2008 (Fertil Steril 2008;90:S260–9). (FertilSteril! 2014;101:927–35. "2014 by American Society for Reproductive Medicine.)

Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/asrmpraccom-pelvic-pain-endometriosis/

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E ndometriosis is one of the mostcommon gynecologic disordersand is found in 70%–90% of pa-

tients with pelvic pain symptoms (1, 2).Women with endometriosis have anincreased risk of abdominopelvic pain,dysmenorrhea, and dyspareuniacompared with controls withoutendometriosis (3). The evaluation ofpain from endometriosis and itsresponse to treatment are madedifficult by [1] methodologicdifficulties in measuring pain; [2]incomplete understanding of themechanism by which endometriosiscauses pain; [3] difficulty indetermining the success of medical andsurgical therapies compared withplacebo; [4] the tendency for chronicpain to progressively involvesurrounding organ systems beyond thereproductive tract; and [5] painattributed to endometriosis when othercoexisting conditions may be the truecause of pain. This document addresses

endometriosis and associated pelvicpain and outlines treatment options.

DIFFERENTIAL DIAGNOSISOF PELVIC PAINConditions of the reproductive tract thatcan cause chronic pelvic pain includenot only endometriosis, but also adeno-myosis, pelvic adhesions, pelvic inflam-matory disease, congenital anomalies ofthe reproductive tract, and ovarian ortubal masses. Pelvic pain, however, isnot necessarily due to gynecologiccauses. It can be caused by disorders inthe gastrointestinal, urinary, neurologic,and musculoskeletal systems and alsomay be amanifestation of psychologicalor psychiatric disorders. Common non-gynecologic causes of pelvic pain mayinclude irritable bowel syndrome, inter-stitial cystitis, fibromyalgia, andmuscu-loskeletal disorders such as trigger pointpain and pelvic floor dysfunction (4). Itmay be difficult to distinguish endome-

triosis from these conditions because thesymptomsmay be similar, occurring in acyclic or constant pattern. A thoroughevaluation to exclude other causes ofpelvic pain should be pursued beforeaggressive therapy and also in thosewomen who do not respond to conven-tional therapy for endometriosis.

MECHANISMS OF PAINFROM ENDOMETRIOSISEndometriosis can appear in differentforms in the female pelvis, includingclear vesicles, red flame lesions, darkpigmented lesions with hemosiderin,and white scarring, each of whichmay contribute to pain by differentmechanisms. Although, in general,there is no established relationship be-tween the extent of disease and symp-toms, the location and type of thedisease can impact pelvic pain (5).Although considered a progressive dis-ease, endometriosis also can remainstatic and even regress without treat-ment (6). The three most commonlysuggested mechanisms for pain pro-duction in endometriosis are [1] pro-duction of substances such as growthfactors and cytokines by activatedmacrophages and other cells asso-ciated with functioning endometriotic

Received and accepted February 7, 2014; published online March 13, 2014.No reprints will be available.Correspondence: Practice Committee, American Society for Reproductive Medicine, 1209

Montgomery Hwy, Birmingham, Alabama 35216 (E-mail: ASRM@asrm.org).

Fertility and Sterility® Vol. 101, No. 4, April 2014 0015-0282/$36.00Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc.http://dx.doi.org/10.1016/j.fertnstert.2014.02.012

VOL. 101 NO. 4 / APRIL 2014 927

ASRM PAGES

medical treatment is not curative– the aim is • symptom alleviation – Quality of Life

• inhibition of disease progression

• delay / stop reoccurrence after surgery

• infertility treatment

• symptoms reappear after discontinuation

traditional treatment- verified dg not required • typical symptoms– start treatment

• dysmenorrea – endometriosis

• sufficient alleviation – follow up

• insufficient response – further invest

• empiric treatment trial is part of the work up

NSAIDs

• should not be overlooked

• decrease prostaglandin production and release – alleviate pain

• adequate regular dosing

• combined with other treatments

• side effect – effect on fertility

• Cochrane (endometriosis vs. dysmenor.)

combined contraception

• atrophy of the endometrium and endometriosis – decreased bleeding and PG release

• inhibit ovulation – inhibit endometriomas

• incidence of endometriosis significantly lower in users of CC – protective effect likely (treat dysmenorrhea)

• combination with NSAID and AIs.

combined contraception

• prospective observational trials demonstrated that continuous that low-dose combined oral contraceptives were more effective than cyclic COC in controlling endometriosis symptoms in patients after surgical treatment if endometriosis Vercellini et al. F&S 2003

oral contraception

progestins •  aim is amenorrhea

•  differences in efficacy and side effect profile (MPA, noretisteroni, lynesteroli, dienogest)

•  efficacy sufficient, problems with side effects: nausea, vertigo, bloating, negaitive effect of glucose and lipid metabolism & bone.

•  nuclear receptor action, perhaps also rapid effect through membrane receptors on MMPs & 17βHSD2

LNG - IUD • high levonorgestrel concentration in

disease tissue, little side effects

• full amenorrhea for many

• efficacy proven in superficial, rectovaginal and recurrent disease as well as in postoperative treatment

Progestiinien teho

GnRH-analogs

•  ovarian estrogen secretion efficiently inhibited

•  agonist flare-effect – E increased (AI, ANT, OC kombi)

•  long term treatment complicated (bone)

•  add back diminish symptoms – in extended treat

•  antagonist lack the flare(pistokset usein)

•  both are used in IVF treatment in infertility

severe endometriosis • the eutopic endometrium is abnormal in endometriosis. • in severe cases the suppression of ovarian estrogen secretion is not sufficient to alleviate the symptoms. • target the estrogen production of the disease tissue. Enzymes of steroidogenesis exist in endometriosis. Aromatase is the final step in production of estradiol. (also HSD17B1)

inhibition of aromatase • do not inhibit aromatase in the ovary –

combination required with combined contraception (or GnRH analog).

• long term treatment COC + AI safer (?) - less side effects

• GnRH ago + AI results in severe hypoestrogenism with side effects and detrimet to the bone

the risk of recurrence after surgery is

• 21.5 % at two years after• 40 – 50 % at 5 years after

Guo Hum Repro Up 2009

• 2nd surgery is risky and rarelyeffective Vercellini et al.2009 Acta

adjuvant therapy

• short course of post oper. hormonal treatment reduces risk of recurrence ?• the idea is ( ? ) that residual (invisible) lesions are treated (=stop regrowth)• risk of de novo lesions remains• 3-6 mos post operat. show no substantial benefit over surgery alone

adjuvant therapy • no benefit on pregnancy rate, pain orrecurrence after one year• no difference with GnRH analogs, progestins or oral contraceptives

Cochrane Syst Rev 2004

• curves illustrating the rate of recurrence are shifted right by the adjuvant therapy

Vercellini et al. BJOG 1999

tertiary prevention

• postoperative hormone treatment may prevent pain and disease recurrence as long as it is used• relief for dysmenorrhea (12 mos) with LNG-IUD & oral contraceptives• continuous OCs lower recurrence• other forms of pain not well reported

tertiary prevention

• important effect on the recurrence of ovarian endometriosis

OR 0.12 (95% CI, 0.05 – 0.29)

cyclic vs. cont. risk of recurrence15 % vs. 8 %

Vercellini et al.2009 Acta

patient education •  patient needs to understand that the treatment

should not be discontinued when symptoms improve !

•  Early effective treatment is beneficial

•  Empirical treatment part of the story – follow-up symptoms?

•  pregnancy and lactation are the only reasons for discontinuing the suitable medication

patient education •  for pregnancy, evaluate all factors affecting

fertility. Plan with the patient how many months without treatment is OK – symptoms

•  Do not hesitate with IVF when EFI is low

•  Breast feeding is beneficial, hormonal treatment may begin after 4 months, with symptoms

•  Significant change in symptoms – contact your doctor !

•  Spontaneous cure from endometriosis is RARE !

•  Better patient info – better compliance !

Endometriosis Fertility Index

FIGURE 1

Endometriosis fertility index surgery form.

Adamson. Endometriosis fertility index. Fertil Steril 2010.

Fertility and Sterility! 1611

Endometriosis Fertility index

FIGURE 1

Endometriosis fertility index surgery form.

Adamson. Endometriosis fertility index. Fertil Steril 2010.

Fertility and Sterility! 1611

KIITOS !

ComContra -endometrioma

• Ovarian lesion have a high risk of recurrence after surgery (30 - 40 %)

•  Postoperative prolonged inhibition of ovulation protects from recurrence : CC 9/102 ja ilman 26/46 (Vercellini et al. -08)

•  Protective effect lost rapidly after discontinuation (Missmer et al. Obst Gyn -04)

•  Protects from ovarian ca (Modugno et al. AJOB -04)

incorrectly raised perplexities about their effectiveness. Ac-cording to a recent meta-analysis, the common relative riskof endometriosis in women who have ever used oral contra-ceptives is 1.19 (95% CI, 0.89–1.60) [45]. A potential con-founding factor is that oral contraceptives are commonlyused to treat dysmenorrhea, a classic symptom of endometri-osis. Affected women commonly report past use of oral con-traceptives, and this has led to underestimation of thetherapeutic potential of these drugs or even to speculationof a detrimental role. In this context, 2 studies have demon-strated that the percentage of women who used estroproges-tins during adolescence because of painful periods ratherthan for contraception is higher in women in whom endome-triosis was later diagnosed [46,47]. Second, designing RCTsto test long-term treatments is difficult [48]. While there isthe need to plan studies lasting several years, it is obviousthat women’s willingness to participate in this kind of trialis low. It is not surprising that few RCTs have demonstratedthe effectiveness of long-term postoperative treatment. Toour knowledge, there are only 4 such trials, 2 using LNG-IUD and 2 using oral contraceptives, and their sample sizeswere limited [33–35,38]. Nonetheless, in our view, theeffectiveness of long-term postoperative hormone therapycannot be disputed. Convincing arguments in this regardare represented by the remarkable magnitude of the detected

benefits, by confirmation of the protective effect in largecohort studies, and by independence of the research groupsinvolved.

Even if we believe that long-term hormone therapy aftersurgery to treat endometriosis should be systematically rec-ommended, 2 main points remain to be clarified. First, thereis the need for more experimental evidence. In particular,even if available evidence supports the benefits in preventingthe recurrence of dysmenorrhea and endometrioma forma-tion, data on other symptoms such as dyspareunia and otherforms of the disease such as peritoneal lesions and adhesionsare insufficient. Further evidence is thus required to supportthe effectiveness of estroprogestins in this regard. Moreover,the protective effect of estroprogestins can be attributed toprevention of establishment of the disease itself. This viewis no doubt valid for endometriomas but warrants confirma-tion for dysmenorrhea. Estroprogestins are highly effectivefor treatment of menstrual pain, and we cannot excludethat the observed benefits of postoperative administrationare due to a priori treatment of pain rather than to preventionof recurrent episodes.

Second, clear data are lacking insofar as the most suitableestroprogestin to be used [30,40,49,50]. It may be speculatedthat regimens that create a steady state such as continuousoral contraceptives or continuous progestins may be more

Table 1

Studies of long-term hormone therapy after surgery to treat endometriosis

Study and source

Study

design Hormone therapy

No. of women

(treated/control)

Follow-up,

mo

Primary result:

rate of recurrence, %a p value

Outcome: Recurrence of pelvic pain

Dysmenorrhea

Vercellini et al [33], 2003 RCT LNG-IUD/EM 20/20 12 10/45 .01

Seracchioli et al [34], 2010 RCT Cyclic OC/continuous OC/EM 92/95/87 24 31/4/40 ,.01

Tanmahasamut et al [35], 2012 RCT LNG-IUD/EM 28/26 12 7/39 .01

Dyspareunia

Vercellini et al [33], 2003 RCT LNG-IUD/EM 9/8 12 Median VAS score reduction 31/15 NS

Seracchioli et al [34], 2010 RCT Cyclic OC/continuous OC/EM 92/95/87 24 27/29/35 NS

Tanmahasamut et al [35], 2012 RCT LNG-IUD/EM 12/7 12 Median VAS score reduction 15/19 NS

Nonmenstrual pain

Vercellini et al [33], 2003 RCT LNG-IUD/EM 5/7 12 Median VAS score reduction 17/20 NS

Seracchioli et al [34], 2010 RCT Cyclic OC/continuous OC/EM 92/95/87 24 29/27/40 NS

Tanmahasamut et al [35], 2012 RCT LNG-IUD/EM 17/19 12 Median VAS score

reduction 48/22

.04

Outcome: Anatomical relapse

Endometrioma

Vercellini et al [36], 2008 Cohort Cyclic OC/EM 102/46 28 9/56 ,.001

Takamura et al [37], 2009 Cohort Cyclic OC/EM 34/39 24 3/44 .001

Seracchioli et al [38], 2010 RCT Cyclic OC/continuous OC/EM 75/73/69 24 15/8/29 .003

Lee et al [39], 2010 Cohort Cyclic OC/EMb 175/187 35 7/29 .001

Cuccinella et al [40], 2013 Cohort Cyclic OC/EM 126/38 24 8/39 .001

EM5 expectant management; LNG-IUD5 levonorgestrel-releasing intrauterine device; NS5 not significant; OC5 oral contraception; RCT5 randomized controlled trial;VAS 5 visual analog scale.a If outcome is not given as rate of recurrence, this is stated.b Both groups received an initial short course of gonadotropin-releasing hormone analogues.

Somigliana et al. Medical Therapy After Surgery to Treat Endometriosis 331