Aetiology and medical treatment of endometriosis

PACE REVIEW REVIEW PACE

Aetiology and medical treatment of endometriosis

Jane Moore

Stephen Kennedy

MA MB BS MKCOG

MA MD MRCOG

AETIOLOGY

they are found in most women and therefore represent a physiological phenomenon that often regresses spontam eously.6 Cystic ovarian and deeply infiltrating endometriosis,’ on the other hand. represents a disease state anti probably arises from somatic mutations in genetically predisposed individuals exposed to environmental risk factors. There is growing evidence that factors such as the pollutant dioxinXand genetic susceptibility9play a role in disease aetiology. For example, a strong familial tendency exists,1° and the prevalence of encfometriosis, determined using magnetic resonance imaging. map be as high as 15?/0 in the sisters o f women with severe disease compared with what may he l”/o in the general population.” Factors thought to be protective include current use of the combined oral contrnceptive smoking and exercise.l 3 The existing data suggest that the phenotype arises from the interaction of multiple gene loci with each other and with environmental faclors. The genetic dissection of endornetriosis may therefore revcal a number of disease subtypes of clinical relevance.

The aetiology of endometriosis is uncertain, but it is generally accepted that Sampson’s original theory (retrograde inenstiwition is a permissive factor)l was correct. Tlic formation o f an endoinetriotic lesion is therefore likely to involve the dissemination of viable uterine endornetrium into the peritoneal cavity at the time of menstruation and the attachment of these endometrial cells to the peritoneal surface. An alternative explanation is that endometriosis is the result of i ~ sitid z rnetaplasia. In either model. there is proliferation and differentiation, and subsequent invasion into the underlying tissue. The principal concern about Sarnpson’s theory is the need to explain why endometriosis is not more conimon, given that retrograde menstruation occurs in most women’ and as commonly in wornen with a normal pelvis as in those with endometriosis.3 Research has therefore concentrated on deciding what separate mechanisms are involved in: preventing the clearance o f endometrial cells from the peritoneal cavity allowing the attaclinient of endornetrial cells to the peritoneum.

MECHANISMS In addition t o the uncertainty about the aetiology of endornetriosis. the correlation between the laparoscopic appearance of discasc and the severity of symptoms is obscure. Some women with laparoscopic evidence of endometriosis have no pain symptoms at all,14,15and some authors have found no correlation between pain symptoms and the presence o r severity of disease, as measured by revised American Fertility Society (rAFS) scores.1i,18 However, women with endometriosis are more likely to complain of pain than women who clo not have the c o n ~ l i t i o n ,and ’ ~ ~some ~ ~ studies have been able to correlate the degree of pain with features such as the

For example, there is evidence that decreased natural killer cell activity in the peritoneal cavity leads to decreased clearance of‘ endometrial cells (see Hill4 for review). although this :ilteration in ininiune function may be a consequence o f endometriosis, not a c‘aiise. The traditional models assume that there is progressive continuity between niiniinal and severe endometriosis. I~Iowever,it is increasingly recognised that these are different entities - a concept expressed by- the endometriotic disease theory.’ Stated briefly; superficial peritoneal implants arise because of implantation, hut

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PACE REVIEW e n j a n e M o o r e , S t e p h e n k e n n e d y site” or tlie extentLLof the disease, or the degree of infiltration below the peritoneal surface.23 What might account for these discrepancies? The earlier, more inflammatory form o f superficial disease probably causes rriore pain than tlie ’burnt-out’ black-blue lesions. Pain may be caused by the release of inflammatory rtiediators of pain, such as bradykinins and prostaglandins.’4 Pain from endometriomas and nodular disease. on the other hand, could tlieoretically be caused by traction on tissues or by infiltration or constriction of nerves themselves. Assessments o f disease severity such as the rAFS scores do n o t take these different forms of endometriosis into account and may under-represent the niore painful forms of the disease.”

MEDICAL TREATMENT Symptomatic endornetriosis is a chronic and debilitating disease and few of the treatment options :ire entirely satisfactory. The principal aims of inanagement should be to relieve symptoms and improve quality of life. An additional aim should be to involve wonien in the decision-making proce Patients often state tliat they are given insufficient information, part.icularly about the likely course of the disease and adverse effects of treatment (J Moore, iinpublished data). The Kational Endometriosis Society is an excellent source of information and support. The choice of treatment will depend upon ktctors such as: the woman’s age and her fertility plans

previous treatments and their effects the nature and severity of the symptoms the location and severity of disease. Thus, it tnay I x better to excise nodular endornetriosis and to treat widespread peritoneal disease medically. For some women, a hysterectoniy and bilateral salpingooophorectomy may be the best solution, as it offers the only realistic chance of ii cure. Wiornen with endometriosisassociated infertility and pain may have t o decide which is the major priority. as there is evidence that hornional therapy alone does not improve fertility.26

Analgesia Some women prefer to avoid hormonal therapy and manage their symptoms effectively with analgesia and non-medicinal methods such as relaxation, gentle exercise and psychological support. Non-steroidal antiinflammatory drugs (NSAIDs) m a y be effective and can sometimes be used in combination with other analgesics such as dihydrocodeine. Ho~vever,the few randomised controlled trials available that have assessed the effectiveness of X A I i l s have involved small numbers of patients.27J8 Some w-omen report effective relief with compleirientary therapies such as traditional Chinese medicine, acupuncture and reflexology.

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Hormonal treatment Endometriotic deposits tend to atrophy in the absence o f ovarian hornional stimulation. However, it is clear that the endometriosis is not eliminated completely, particularly when endoinetriotic cysts are present.2” Symptom recurrence is common following discontinuation of medical treatment. Thus, in a follow-up study) the cumuiative recurrence rates for the fifth year after gonadotropl-iin-releasing hormone (Grim) agonist treatment ended were 37% for minimal disease and 74% for severe disease.3° .dl medical treatments seein to be equally effective during therapy but have a variety of adverse effects. Duration of therapy is limited for some dmg classes nnd this will be a factor to take into consideration in choosing tlie right treatment. The comhined oral contraceptive pill a n d medroxyprogcslerone acetate can be used in the long term, hut the use of other progcstogens, danazol and GnKH agonists is usually restricted to six months. Combined oral contraceptive pill Few studies have assessed the effectiveness of the combined oral contraceptive pill as a treatment f o r endometriosis, despite it being simple, cheap and well studied as a contraceptive. A systematic review”*identified only one relevant raridomised controlled trial, in which a lowdose combined oral contraceptive pill (Lblercilonx, Organon) was shown to be as effective as goserelin for the relief of symptoms.32 The combined oral contraceptive pill has a more favourahle adversc-effect profile than other hormonal treatments arid it is familiar to women. The comhined oral contraceptive pill may l x taken conventionally w-it11monthly bleeds, but it inay be niore effective when taken continuously and there is anecdotal evidence to suggest that it rnay tie also l x more effective when taken in the ‘tricycle‘ regimen (three packets taken continuously followed by a -week’sbreak). The combined oral contraceptive pill may be particularly Iielpful when symptoms are mainly menstrual. Progestogens such as dydrogesterone and medroxyprogesterone acetate, given continuously in moderately high doses, lead to inhibition of ovulation and lowered oestradiol levels. hltho~ightheir precise mode of action is unclear, it is likely chat they have a direct inhibitory effect 011 endonictriotic tissue. The dose should probably be adjusted until amenorrhoea is achieved. The principal adverse effects are weight gain. bloating, moodiness, depression, acne and breast discomfort.33 Spotting o r heavy irregular bleeding may he a problern. particularly initially, but can usually be overcome by increasing the dose. Long-term use of oral progestogens at high doses is theoretically limited by the effect on the blood lipid profile. as high-density lipoprotein levels are lowered and low-density lipoprotein levels raised. The clinical significance of these findings is unclear but long-term lase tnay increase the risk o f cardiovascular disease. There is

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Aetiology and medical treatment of endometriosis

also concern that prolonged amenorrhoea with low oestrogen l t ~ may l ~lead to hone demineralisation.

in a recent study using leuprolide acetate with hormonal add-back therapy, bone density was maintained at the Same level m e r 12 months o f treatrncnt.38

Daiiazol and gestrinone Danazol is a testosterone derivative with a complex mode of action. It acts at both the pituitary and ovarian levels to create :I hypo-oestrogenic slate and also has a direct inhihitory effect upon the endometrium. Dana201 displaces testosterone from sex-hormone-binding globulin, producing androgenic effects. The most imporrant of these is deepening of the voice because this may be irreversible. Danazol niay cause weight gain, acne, greasy hair, hirsutisni, hot flushes. breast atrophy and muscle cramps but increased libido. If pregnancy c)cciirs there rnay be rnasculinisation of a female fetus. A systematic review of danazol (alone o r as adjunctive therapy) versus placebo identified four relevant randoniised controlled trials that showed the drug to be more effective than placebo in relieving symptoms and causing

AUTHOR DETAILS Jane Moore MA hi^ BS ~IKCOC;,Registrar, Royal Berkshire I Iospital, Keading, UK

Stephen Kennedy MA LID MRCOG, Clinical Readep in Obstetrics and ( ; y i i a e c o l r ) ~ ~ l r zCon.subant, ~ ) ~ a ~ Nu f field Department of Obstetrics and Gynaecologp, University o f Oxford, John Kadcliffe Hospital, Oxford OX3 W U , UK (corresponding author) References

1 %impsonJA. I'critoncal endometriosis. clue to nienstnral dissemination of endometrial tissue into the peritoneal cavity. A m J 0h.wr (;y~zeco/

1927;14:422-69 2 Liu TIT, Hitchcock A. Endomctriosis. its associacion a i r h r-ctrograde menstruation, dysnieriorrhoea and tuba1 pstlidogy. Br J O&e/ C;Yrmcol 1986;93:859-62 3 Uartosik U, Jacobs SL. Kelly LJ. Endometrial tissue in peritoneal fluid. Fcwil Stmil 1923686:46:79&300 t Hill JA. Immunology and cntlometriosis. Fact. artifact. or epiphenomenon? Obslt.( G:)necol C h i Xorh Am 1937:24:291-306 5 Koninckx PR. Barlow DH. Kennedy SH. Implantation versus infiltration: thc Sampson vcrsu the cndometriotic disrase theor).. Gq'tz"~.oLOCxtcJt fnwsl 1999:47(suppl 1):Sy. discussion 9-1i) 6 Wardle PG. Hull MG. Is endonietiiosis a disease? Ba

tiisease

Danazol has the Same effects on blood lipids as progestogens. Long-term use rnay therefore liave cardiovascular risks: it has also been associated with the development of hepatomas. The androgenic effects of danazol protect against bone density loss despite the low oestrogen levels. Gestrinone has androgenic and progestogenic effects and leads t o reduced oestrogen levels. Its mode of action is unclear hut it acts centrally and peripherally. It has a similar adverse-effect profile to danazol but its long halflife means that medication is only taken twice weekly.

C~zuecol 1993:767.5-85

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GnRH agonists

GnRH agonists cause pituitary downregulation and a hypogonadotrophic hypogonadism (a reversible menopausal state, with predictable adverse effects such as hot flushes, vaginal dryness, headaches, loss of libido and mood changes). hgoiiists initially cause release of luteinising hormone and follicle-stimulating hormone (the so-called flare effect), which explains the brief exacerbation of symptoms that some women experience when commencing therapy. A systematic review of GnKH agonists versus other medical therapy or placebo identified 26 relevant randomised controlled trials, which showed agonists to be as effective as other active comparators (principally danazol) in relieving symptoms and causing disease regression.35 Therapy should be limited to six months hccause up to 6% of bone mineral density may be lost during this time, although there is evidence showing that the loss is restored completely two years after cessation of therapy..56 'Add-back' therapy (tibolone or a progestogen plus or minus an oestrogen) can be used with no loss of efficacy37to relieve menopausal effects, prevent bone loss and allow therapy to continue heyoid six months. How long this regimen may safely be continued is unclear, hutl Zbe Obstetrician & Gvnuecologist " i

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Cornillie rJ.Oosterlynck D, Law-evns JM, Koninckx PK. lkeply itlfiltniting pelvic endoiiietriosis: histology and clinical significance. Fertil S t e d 1990;53:978-83 Koninckx PR. Braet P, Kennedy SH, Barlow- DH. Dioxin pollution and endometriosis in Kclgiuni. Htun Reprod 1994:9: 1001-2 Kennedy S. Is there a genetic basis t o endometriosis? Semiti Kc$r-od Edocrinol 1997;15:309-18 Kennedy SH, PPardon HJ, Harlow TIH. Familial endonietriosis. JA.s.skr RQ+odGellet 1995;12:324 Kennedy SH, Hidfield F%l, Westbrook C. Weeks DE. Barlow DH. Golding S. M K I scans in the relatives of women xvith endometriosis to determine familial risk. LLwicel 19%3:352:lt4G-1 Ticsscy MI', Villard M:ickintosh L, Painter R. Epidemiology of endonietriosis in wunien atrending Fdrnily planning clinics. KbiJ 1993;306:182J1 Cramer l)W, Wilson E: Stillman RJ, Bcrger MJ? Belisle S, Schiff I. ef al The relation of endonietriosis tw menstrual characteristics, stnoking, and exercise.JA.WA 1986;255:IOi-li B.1. d asch .. J. Crcus M, Pabregues F, Cdrrnona F, Ordi J , Martinez KS, el c d Visilde and non-visible endoiiietriosis at laparoscopy in fertile and infertile women and in patients nit11 chronic pelvic pain: :I prospective study. I l i ~ n Reprod i 1996:11:387-91 Raknyi T, Hoshiai H, Yajima A. Is pelvic endomctriosis alv~iys associated with chronic pain? A retrospective study of 618 cases diagnosed by laparoscopy. h i -/ Obsk/ Gq'lzecol1993:169:719-22 Howard FM. The role of laparoscopy in chronic pelvic pain: promise and pitfalls. Oixtet G;>wecol.'hin)1993:48:357-87 Matonas R, Rodriguez F. Pijoan JI, Soto E. Perez C. Ramon 0, c't a/. Are there any clinical signs and symptoms that are related t o endometriosis in irlfertile women? AnzJ Obstet C;lnec-ol 1996,174:62&3 Revised Ainerican Fertility Society Classification of Endometriosis: 1985. Fertil Steril 1985:43:351-2 Mahmood TA, 'Templeton AA, Thomson L, Fraser C. Menstrual symptoms in w x ~ i e ~ with i pel\ ic endornetnosis. Br J Ohstct Gjmaecol 199I ;98:55M3 S!out i\L, S t e e p JF, Uo&on WC, Hughes CL. Relationship of laparoscopic findings to self-report of pelvic pain. 4n2.J Ohtet Gyzecol 1991:164:7+9 Vercdlini P, Trespidi L, De GO, Cortesi I. Pmzzini E Crosigmini PG

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Fndometriosia and pelbic p i n : relation t o disease stage and 1oc:tlization. Fwt.,?ilS t d 1996;65.29~t304 Perper MM, Nezhar F, Goltlsiein H. Nezhat (31, Nezlrat C. Dysnienorrhca is related to the nurnlxr 01 implants in endometriosis patients. Perti1 Strril 1995;63:500-3 Konincli.; I'R. Oosterlynck D. D'Hooghe T, Meulemm C. Ileeply infiltrating endornctriosis is a diarase \\hereas mil Ix. considered a nori-disease. 14t271 ;\-YAiud Sci \'emon WRV, Be:trd JS. Ctrivcs K. Wilson endometriotic iinpbrits by niorphologic appt.rirance and c a p c i t y t o synthesize prostaglantlin F. Fwi'zl .Yfwi/ 1986;46:8016 Revised ..\meric:in Society for Kt.pr(JdL1Cth.e bkclicine Classification of Endonietriosis: 1996. FcMl Stwil 1997;67S17-2 1 Hughes E, Fcdorkow 11, Collins J, kmdt.herckhin-e P. 0)-ulation suppression vx. placebo in the trtwnient o f endometri C l i h m g : lssric- 1. Oxford: 1;pdate Review). T ~ JCochvmzc Emppila A. Puobdkka .J. l'likorkala 0.Prostighndin biosynthesis inhibilors and endometrio . Prustu,slnndi?ls1979:18:65541 Kauppila 4. Ronnberg 1.. proxcii sodium in dysmentarliea secondOhsirl eai-y AJ. Goldlxck-%btxI S, f.'arqulnr C. Sniitli SK. Gonadotrophiri~releasinghornitme analogues for pain azsociated 1% ith entloinctriosis (Cochranc Review). The Cochmiii? Lil?iui?: Issue 1 Oxford: I;pdate S o h a r e ; 1999 holetti .mI. Sen2 GG. Cagnacci -4. Vacca AM,Gunriero S, Soll;~E. ihility of hone loss induced b y gon:idotropinreleasing liornione analog treatment. Fertii Sleiil1096 flowt.ll R; Eclmoiicls DK,Dowsett hl. Crook D. Lees Goi~~dotropiti-rclrasingh o r m o n c :malo#ie (goserelin) plus hormone replacenient therapy for the treatment of endometrio. controllctl trial Fw-fil Stwil 199564 Hornstein h l l l , Surrey l b , Weislxrg GW. Casino L4.leu pro lid^ acetate depot and horint)iial add-lxick in enclonietrio Lti pron A dd-Rack Study C, or ip . Oi7~slf.t((1 ,izec.col1(Y)8:9 1 : 16-24

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