- Email: [email protected]
Endometriosis
Current Obstetrics & Gynaecology (2002) 12, 155^160 c 2002 Elsevier Science Ltd doi:10.1054/cuog.2001.0252 available online at http://www.idealibrary.com on
Endometriosis Andrew Prentice Senior Lecturer/Consultant Gynaecologist, University of Cambridge Clinical School, Addenbrooke’s Hospital, Hills Road, Cambridge, UK
KEYWORDS endometriosis; pathophysiology; infertility; medical therapy; surgery
Summary Endometriosis is the presence of endometrium at ectopic sites but is it a disease? The widespread dissemination of endometrium at the time of menstruation is commonif notubiquitous and consequentlyectopicendometriummaybe observed that is not related to the illness the patient experiences. The relationship between ectopic endometrium and symptoms is most unclear in infertility and consequently there remains a doubt over the appropriateness of some therapies. In severe cases, surgery may play a role but at all stages of the disease, there is a place for assisted conception.In the management of pain, medical therapy is e¡ective in a large proportion of cases. Again, surgery is e¡ective for more deeply seated disease but may be complex. Surgeons should only undertake such surgery if they have speci¢c expertise in this area. c 2002 Elsevier Science Ltd
WHAT IS ENDOMETRIOSIS AND IS IT A DISEASE? Endometriosis is the presence of tissue histologically similar to endometrium at sites outside the endometrial cavity. The only exception to this is endometrial tissue within the myometrium, which is known as adenomyosis. In all probability, this tissue is not only histologically similar to endometrium but it is endometrium. Endometriosis is described at most sites in the body and this raises the question of how endometrium is disseminated. That no one mechanism could explain the dissemination of endometrium to all sites resulted in a multitude of theories regarding its pathogenesis. Endometrium is unique as an adult tissue in its ability to regenerate on a monthly basis and it is also unique in that it is the one benign tissue that can be disseminated in all the ways of its malignant counterpart. The most common method of dissemination of endometrium is by retrograde menstruation, resulting in the spillage of viable endometrium into the peritoneal cavity at each menstruation.The viability of shed endometrium and the presence of viable endometrial cells in the endometrial cavity have been established in numerous studies. Retrograde menstruation is an extremely common if not ubiquitous event, the inevitable consequence of the physiological event of menstruation in women with patent Fallopian tubes. Consequently, it must be considered whether the presence of ectopic endometrium in the Correspondence to: AP.Tel.: þ44 (0)1223 336876; Fax: þ44 (0)1223 215327; E-mail: [email protected]
pelvis is physiological or pathological and thus what is the signi¢cance of the visual diagnosis of endometriosis. Put another way, is ectopic endometrium endometriosis? Consideration, however brief, of the nature and the pathogenesis of endometriosis may seem to be somewhat academic. However, an appreciation of what constitutes endometriosis is important. We should be careful as clinicians to appreciate that the visual diagnosis of endometriosis (the disease) may not always correspond with, or indeed be the cause of, the symptoms (the illness) experienced by the patient. Our assumption that whenever we visualize ectopic endometrium it is responsible for the disturbance in the normal physiological function that the patient experiences may in many cases be incorrect. This is perhaps most easily demonstrated by a consideration of the cause of infertility associated with endometriosis. It is obvious that in severe cases of endometriosis the anatomical distortion caused by the disease will interfere with a number of events required in normal conception. These include oocyte release and pick up. However, the importance of small super¢cial implants, perhaps at sites remote from the Fallopian tubes and ovaries remains a matter for debate, despite the recommendation in RCOG guidelines that they should be surgically removed.
THE PRESENTATIONOF ENDOMETRIOSIS Endometriosis presents typically in two ways: with painful symptoms or with the symptom of subfertility. In theory, at least, the diagnosis of endometriosis should be
156
CURRENT OBSTETRICS & GYNAECOLOGY
simple but is compromised by the need to visualize the implants and thus to undertake laparoscopy. Before laparoscopy is undertaken there has to be a consideration of endometriosis in the di¡erential diagnosis. It is suggested that many doctors fail their patients by not considering endometriosis in the di¡erential diagnosis of their complaints. A survey by the National Endometriosis Society in the United Kingdom highlighted some of the problems that in some patients delays diagnosis for up to 8 years from the ¢rst experience of symptoms. Firstly, 46% of women when they ¢rst experience symptoms consider it to be normal and only 19% of women themselves consider that they might have endometriosis. This is further compounded by the fact that 54% of women were told at some point before diagnosis that there was nothing wrong with them. At ¢rst consultation,15% were told that there was nothing wrong and 43% had a non-gynaecological diagnosis. One in nine patients was labelled as experiencing dysmenorrhoea but only one in 12 had the provisional diagnosis of endometriosis. This failure to make or suspect the correct diagnosis is compounded by referral to non-gynaecologists in a third of cases and in a quarter of cases patients had seen two specialists before obtaining a gynaecological opinion. The symptoms of endometriosis are well known (Table 1). The di⁄culties with diagnosis arise because there is no one pattern of symptoms that is common in all patients. With diverse symptom complexes a¡ecting more than one system, commonly the genital tract, the gastrointestinal system and the urinary tract, it is not surprising that diagnosis is di⁄cult on history alone. A high index of suspicion should exist for the diagnosis in any patient who presents with symptoms that display any cyclicity. Particular attention should be paid to enquiring about gastrointestinal symptoms as many gynaecologists fail to adequately explore this area and irritable bowel syndrome is often one of the potential di¡erential diagnoses. A further barrier to diagnosis is the expectation amongst many clinicians that endometriosis is a disease of the late reproductive years but in fact,
Figure 1 Age at ¢rst symptoms of endometriosis.
¢rst symptoms usually occur at an earlier age (Figure 1).
MANAGEMENTOF INFERTILITY ASSOCIATED WITH ENDOMETRIOSIS Mechanism of infertility in endometriosis Endometriosis at all stages is associated with a reduction in conception rates. It is obvious that with advanced disease the destruction of the normal anatomy may interfere with normal spatial relationships between the Fallopian tubes and ovaries. Consequently, the disease process may interfere with ovarian motility, oocyte release, oocyte pick up, and tubal motility and patency. With less advanced disease no such obvious relationship exists and many putative mechanisms have been suggested. These fall into three broad groups: disorders of folliculogenesis or endocrine abnormality, in£ammatory or immunological abnormality and increased miscarriage rate. A number of authors have reviewed the literature and have found no convincing evidence of either an abnormality of follicular development or an endocrine abnormality that explains infertility in all cases of endometriosis. Endocrine abnormalities have been reported but there are no convincing data that they are either more common in women with endometriosis than in other infertile women or that they occur consistently in consecutive cycles.
Table 1 Symptoms of endometriosis K
K
Pain Dysmenorrhoea Dyspareunia Pelvic/abdominal pain Particularly mid-cycle and premenstrually Dyschezia Particularly atthe time of menstruation Bleeding Rectal bleeding Haematuria Haemoptysis
Treatment of minimal and mild disease Medical A comprehensive systematic review of medical therapy has clearly indicated that the ovulation suppression associated with medical therapy does not improve fertility rates. However, reviewing the trials included in this review enables us to estimate the expected pregnancy rates with expectant management. Pregnancy rates in the four control groups of the ¢ve comparisons made ranged 23.5^ 47.2%. It would thus appear that expectant
ENDOMETRIOSIS
management provides a realistic chance of the patient achieving a pregnancy. Medical therapy may, however, continue to play a role when patients have the combined problems of infertility and pain. The role of medical therapies in the treatment of painful symptoms is well established. Apart from the lack of bene¢t of medical therapies in treating infertility their traditional use results in 6 months of contraception and further delays pregnancy. As many of these patients will be in the older age group such a delay will further compromise their attempts at conception. Only one group has attempted to provide medical treatment without compromising fertility. They treated patients with either 40 or 60 mg of dydrogesterone in the luteal phase of the cycle. Relief of symptoms was achieved without compromising fertility.
157
be extremely hazardous and should not be undertaken without appropriate training and experience. In some hands, therefore, an open procedure will be more appropriate. What are the potential advantages of a laparoscopic approach? It is generally accepted that a laparoscopic approach has reduced morbidity and is associated with a more rapid return to full activity due to the absence of a large abdominal incision. However, it has to be asked if there are any advantages or disadvantages related to the primary indication and outcome of surgery, namely improvement of fertility and pregnancy. It is appealing to believe that reduced adhesion formation should be bene¢cial to the patient, but should we pay much attention to what is only a surrogate endpoint. The only endpoint that matters is pregnancy rates.
ART and endometriosis Surgical The Endocan study aimed to establish whether the ablation or resection of endometriosis in minimal or mild cases (stage I or II) improved the cumulative probability of pregnancy. The primary outcome was pregnancy progressing beyond 20 weeks’ gestation. This study did demonstrate an improved pregnancy rate in the treated group but pregnancy rates in the control group were extremely low. This study has been further criticized as many of the subjects were subjected to signi¢cant compounding interventions such as assisted conception. An Italian multicentre study, however, has demonstrated no bene¢t from surgical intervention in this group of patients.Thus, despite RCOG recommendations that minimal and mild disease should be treated surgically the literature does not conclusively support such a policy.
The precise relationship between infertility and endometriosis, in the absence of pelvic distortion, is unclear. Many consider the relationship to be purely casual and consider these patients to have unexplained infertility. Whether endometriosis-associated infertility is unexplained or consequent upon pelvic distortion it is appropriate to utilize assisted reproduction techniques (ART) to treat infertility when other treatments or expectant management have been unsuccessful. It has been suggested that endometriosis as a cause of infertility exerts an adverse e¡ect on fertility outcomes. However, a review of the published literature, including French and US national data, suggests that endometriosis does not exert any additional adverse e¡ect on the success rates than any other infertility cause. A doubt still exists on the impact of endometriomata on success, which ART should be employed and the role of medical and surgical treatment before ART.
Surgical treatment of advanced disease It is widely accepted that it is logical to surgically correct the distortion of the pelvic anatomy caused by endometriosis in an attempt to improve fecundity. A number of questions arise regarding the surgical management. These questions include the mode of surgery, laparoscopy or laparotomy, whether medical treatment should be used as an adjunct to surgery either prior to or after surgery and what measures should be taken to prevent adhesion formation. Whatever the answers to these questions are, it is clear that the principles of infertility surgery should be applied, namely good exposure of the operative ¢eld and magni¢cation (easily achieved with the laparoscope), scrupulous haemostasis, minimal tissue handling and attention to the prevention of adhesion formation. In recent years, there has been a move to performing a greater number of procedures laparoscopically. Laparoscopic surgery for advanced endometriosis can
MANAGEMENTOF ENDOMETRIOSISASSOCIATED PAIN Medical treatment is very e¡ective in relieving symptoms of dysmenorrhoea, dyspareunia and pelvic pain associated with endometriosis in the majority of patients. The major advantages it has over surgery are that it avoids the risks associated with a surgical procedure (especially if the patient is overweight or has a morbid condition excluding a surgical procedure), all endometriotic foci are suppressed, the costs are limited, and generally the side e¡ects are usually tolerable. The rationale is that ectopic endometrium responds to ovarian steroids in a similar fashion to intrauterine endometrium. Numerous laboratory and clinical studies have demonstrated oestradiol, progesterone and androgen receptors in endometriosis, but at much lower concentrations. Endometriosis is steroid dependent, with
158
oestrogen playing a central trophic role in its development. Current therapies modulate the hormonal environment by mimicking states where endometriosis is rarely found or where symptoms are naturally alleviated, the menopause, pregnancy, and in men. They act by suppressing the production of ovarian sex steroid hormones that would otherwise normally stimulate the growth of the endometrium, the aim being to prevent proliferation of ectopic endometrium and render it atrophic.
Types of medical treatment The combined oral contraceptive pill (OCP) The oral contraceptive pill, by its mechanism of inducing pseudo-pregnancy, has been used to treat symptoms of endometriosis since the 1960s. A major advantage it has over other medical treatments is that it can be given inde¢nitely. However, headaches, mastalgia, and bloating are common side e¡ects. In the literature, there is a paucity of data on its e⁄cacy. In their systematic review to evaluate the role of the OCP in the management of pain and endometriosis the Cochrane group identi¢ed only one study that satis¢ed their criteria for inclusion in the review. Here, a cyclic OCP was found to be equally e¡ective as GnRHa in the treatment of non-menstrual pain and dyspareunia, although less e¡ective for dysmenorrhoea as withdrawal bleeding continued in those treated with the OCP in contrast to the group treated with GnRHa in which menstruation was abolished. However, any di¡erence had disappeared at 6 months’ follow-up.The OCP if used continuously would also abolish menstruation and might confer similar e⁄cacy to the GnRHa for dysmenorrhoea; however, this has not been tested formally although it is in common clinical use.
CURRENT OBSTETRICS & GYNAECOLOGY
therapy, although around 20% may have spotting. Side effects include weight gain, acne, bloating, depression and breakthrough bleeding.
Danazol Danazol, a weak androgen derivative of 17a ethinyl testosterone, is e¡ective in the treatment of endometriosis. At doses of 400 ^ 800 mg daily it produces anovulation and amenorrhoea in most women. When compared to placebo, 6 months’ treatment of danazol is signi¢cantly e¡ective in relieving painful symptoms for women with endometriosis. Similarly, when compared to GnRH analogues its e⁄cacy is essentially the same. Its mechanism of action is somewhat complex, caused by its varying metabolites. It interacts with the enzymes of steroidogenesis and is capable of binding to androgen, progesterone and glucocorticoid receptors. It causes suppression of the pituitary gonadotrophins (FSH, LH), subsequent inhibition of ovarian steroidogenesis, and prevention of endometrial proliferation by binding to androgen and progesterone receptors in the endometrium and endometriotic lesions. Its other actions include decreased production of the high-density lipoprotein cholesterol, reduced production of SHBG in the liver, and displacement of testosterone from SHBG increasing the free concentration of circulating testosterone. Atrophy of the endometrium and endometriotic implants occurs because of the resulting low oestrogen and high androgen levels. Danazol was used commonly in the 1980s for the treatment of endometriosis; however, its side e¡ects have resulted in a gradual decrease in the use of the drug and an increase in the use of GnRH analogues.There has been concern that danazol has a tendency to induce insulin resistance, and therefore it may not be the ideal treatment in women with diabetes.
Progestogens Several progestogens are used for the treatment of endometriosis including medroxyprogesterone acetate (MPA), megestrol acetate and dydrogesterone. MPA has been the most studied and used progestogen. At moderately high doses, they induce a pseudo-pregnancy state as well as having an anti-oestrogenic e¡ect. Histology on specimens of endometrium and endometriosis implants reveals atrophic or inactive endometrium with pseudo-decidual reaction consistent with progestational therapy. A meta-analysis of four randomized controlled trials with a total of 89 patients showed progestogens to have similar e⁄cacy in relieving pain as danazol and GnRHa. Similarly, another study demonstrated a signi¢cant improvement in pain when compared to placebo, and equal e⁄cacy (84%) between MPA and danazol. Up to 75% of patients may experience amenorrhoea throughout
Gonadotrophin-releasing hormone analogues (GnRHa) GnRHa are considered by many to be the medical therapy of choice for treating endometriosis. Their continuous action on the GnRH receptor results in the down-regulation and desensitization of the pituitary gonadotroph.This results in the chronic suppression of gonadotrophin secretion, LH and FSH, cessation of ovarian activity and consequently a decrease in circulating oestradiol levels, creating a reversible pseudo-menopausal state. The consequent hypo-oestrogenaemia causes predictable side e¡ects, namely those symptoms experienced by women at menopauseFvasomotor symptoms, dry vagina, and more concerning, for many clinicians, a loss in the bone mineral density (BMD). The reduction in vertebral BMD during a 6 -month course of GnRH analogue is in the order of 3^ 4%, which is equivalent to 6 months breast-feeding or 6 months of
ENDOMETRIOSIS
menopause.This concern has therefore limited the use of GnRH analogue therapy to 6 months’ duration. For symptom relief numerous randomized prospective clinical trials have directly compared the e⁄cacy of the GnRH analogues versus danazol in the treatment of endometriosis. Essentially, all the studies demonstrated that GnRH was as e¡ective. A large Cochrane metaanalysis of 26 RCTs con¢rmed GnRH analogue to be e¡ective in relieving pain. When compared to danazol, gestrinone (another androgenic compound) and the oral contraceptive pill had a similar e⁄cacy after 6 months’ of therapy. Not surprisingly, the main di¡erence between the varying treatments relates to their respective side e¡ect pro¢les. Both danazol and gestrinone were found to have more side e¡ects that are androgenic while GnRHa produced the hypo-oestrogenic symptoms seen in the menopause. The addition of hormone replacement therapy as ‘addback’ to a course of GnRHa is a strategy that would help ameliorate the menopausal symptoms, but is low enough in dose to retain the symptomatic relief of pain, protect the vertebral bones from demineralization and osteoporosis, and provide longer duration of use. A number of di¡erent addback regimes are utilized; combined oestrogen and progestogen, progestogen only, or tibolone. Several clinical trials have demonstrated that HRT addback does not reduce the e⁄cacy of GnRHa treatment, or exacerbate the disease. Furthermore, addbacktreated patients su¡ered signi¢cantly fewer hot £ushes. Five RCT studies examining GnRHa alone versus GnRHa with addback found no di¡erence in e¡ectiveness with pain scores and AFS scores; however, the addback group had signi¢cantly less menopausal-type side e¡ects such as hot £ushes.There appears to be no di¡erence on symptoms or AFS scores or side e¡ects with mode of GnRH analogue administration. A multi-centred randomized double-blinded trial using a12-month course of GnRH alone or with addback found that those women receiving GnRHa alone experienced a loss of bone mineral density of 3.2% at 6 months and 6.3% at12 months in the lumber spine, and complained of hot £ushes which were dramatically suppressed in the addback groups, while women receiving addback for 12 months had (o1%) negligible BMD loss. Women receiving higher dose-conjugated equine oestrogens (1.25 mg) are more likely to have breakthrough bleeding. The e¡ect of long-term GnRHa use (2 years) on BMD was recently reported in the literature in a limited study. They found that the reduction of BMD that occurred had not fully recovered even up to 6 years after treatment and surprisingly, the use of HRT addback did not make any signi¢cant improvement to the recovery. The ¢ndings of this study need to be con¢rmed by other studies as they are at variance with the studies of short-term therapy with addback.
159
Figure 2 Severe endometriosis with the involvement of both sigmoid colon and rectum.This patient had disease that was visible in the posterior vaginal fornix and involved the rectovaginal septum.
Surgical treatment Medical therapy is not e¡ective in every case. In such cases, surgery may be of value although surgery may also be used as an alternative to medical therapy. Surgical treatment appears most e¡ective, the more severe the disease. It is the excision of deep deposits of endometriosis that appears to give the greatest improvement in symptoms. Such surgery, however, may be technically dif¢cult and may involve other organs such as the bowel and the ureters (Figure 2). Complex surgery on patients with severe endometriosis should only be undertaken by individuals with expertise in this area.
CONCLUSION Endometriosis is a complex condition, which presents clinically in many di¡erent ways.The diagnosis can be dif¢cult and consequently may be missed. This may lead to dissatisfaction among patients over the care they receive.Treatment should be directed to the illness the patient experiences with careful consideration of the mechanism by which the disease creates the illness. It is this interaction between illness and disease that makes endometriosis such a di⁄cult and fascinating condition to manage.
PRACTICE POINTS K
K
The signi¢cance of the visual diagnosis of endometriosis should always be carefully considered The diagnosis of endometriosis is often missed or not considered
160
K
K
K
CURRENT OBSTETRICS & GYNAECOLOGY
Surgery has a role in the management of infertility associated with moderate and severe endometriosis Medical therapy is e¡ective in most patients but will not treat deep implants. Surgical therapy can be complex and involve other tissues
FURTHER READING Adamson GD, Pasta DJ. Surgical treatment of endometriosis-associated infertility: meta-analysis compared with survival analysis. Am J Obstet Gynecol 1994; 171: 1488 ^1505. Hughes E, Fedorkow D, Collins J,Vandekerckhove P.Ovulation suppression vs placebo in the treatment of endometriosis (Cochrane review). In: Cochrane Library, Issue 4. Oxford: Update Software, 2001.
Marcoux S, Maheux R, Be¤rube¤ S and the Canadian Collaborative Group on Endometriosis. Laparoscopic surgery in infertile women with minimal and mild endometriosis. N Engl J Med1997; 97: 212^222. Moore J, Kennedy S, Prentice A. Modern combined oral contraceptives for the treatment of painful symptoms associated with endometriosis (Cochrane review). In: The Cochrane Library, Issue 4. Oxford: Update Software, 2001. Prentice A. Advances in the management of endometriosis related infertility. In: Bonnar J (ed). Recent Advances in Obstetrics and Gynaecology,Vol. 21. London: Churchill Livingstone, 2001; 101^109. Prentice A, Deary AJ, Bland E. Progestagens and Anti-progestagens for pain associated with endometriosis (Cochrane review). In: The Cochrane Library, Issue 4. Oxford: Update Software, 2001. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis (Cochrane review). In: The Cochrane Library, Issue 4. Oxford: Update Software, 2001. Selak V, Farquhar C, Prentice A, Singia A. Danazol versus placebo for the treatment of endometriosis (Cochrane review). In: The Cochrane Library, Issue 4. Oxford: Update Software, 2001. Vercillini P, De Giorgi O, Pesole A. Endometriosis: drugs and adjuvant therapy. In: Templeton A, Cooke I, O’Brien PMS (eds). Evidencebased FertilityTreatment. London: RCOG Press,1999; 225^245.
Endometriosis Andrew Prentice Senior Lecturer/Consultant Gynaecologist, University of Cambridge Clinical School, Addenbrooke’s Hospital, Hills Road, Cambridge, UK
KEYWORDS endometriosis; pathophysiology; infertility; medical therapy; surgery
Summary Endometriosis is the presence of endometrium at ectopic sites but is it a disease? The widespread dissemination of endometrium at the time of menstruation is commonif notubiquitous and consequentlyectopicendometriummaybe observed that is not related to the illness the patient experiences. The relationship between ectopic endometrium and symptoms is most unclear in infertility and consequently there remains a doubt over the appropriateness of some therapies. In severe cases, surgery may play a role but at all stages of the disease, there is a place for assisted conception.In the management of pain, medical therapy is e¡ective in a large proportion of cases. Again, surgery is e¡ective for more deeply seated disease but may be complex. Surgeons should only undertake such surgery if they have speci¢c expertise in this area. c 2002 Elsevier Science Ltd
WHAT IS ENDOMETRIOSIS AND IS IT A DISEASE? Endometriosis is the presence of tissue histologically similar to endometrium at sites outside the endometrial cavity. The only exception to this is endometrial tissue within the myometrium, which is known as adenomyosis. In all probability, this tissue is not only histologically similar to endometrium but it is endometrium. Endometriosis is described at most sites in the body and this raises the question of how endometrium is disseminated. That no one mechanism could explain the dissemination of endometrium to all sites resulted in a multitude of theories regarding its pathogenesis. Endometrium is unique as an adult tissue in its ability to regenerate on a monthly basis and it is also unique in that it is the one benign tissue that can be disseminated in all the ways of its malignant counterpart. The most common method of dissemination of endometrium is by retrograde menstruation, resulting in the spillage of viable endometrium into the peritoneal cavity at each menstruation.The viability of shed endometrium and the presence of viable endometrial cells in the endometrial cavity have been established in numerous studies. Retrograde menstruation is an extremely common if not ubiquitous event, the inevitable consequence of the physiological event of menstruation in women with patent Fallopian tubes. Consequently, it must be considered whether the presence of ectopic endometrium in the Correspondence to: AP.Tel.: þ44 (0)1223 336876; Fax: þ44 (0)1223 215327; E-mail: [email protected]
pelvis is physiological or pathological and thus what is the signi¢cance of the visual diagnosis of endometriosis. Put another way, is ectopic endometrium endometriosis? Consideration, however brief, of the nature and the pathogenesis of endometriosis may seem to be somewhat academic. However, an appreciation of what constitutes endometriosis is important. We should be careful as clinicians to appreciate that the visual diagnosis of endometriosis (the disease) may not always correspond with, or indeed be the cause of, the symptoms (the illness) experienced by the patient. Our assumption that whenever we visualize ectopic endometrium it is responsible for the disturbance in the normal physiological function that the patient experiences may in many cases be incorrect. This is perhaps most easily demonstrated by a consideration of the cause of infertility associated with endometriosis. It is obvious that in severe cases of endometriosis the anatomical distortion caused by the disease will interfere with a number of events required in normal conception. These include oocyte release and pick up. However, the importance of small super¢cial implants, perhaps at sites remote from the Fallopian tubes and ovaries remains a matter for debate, despite the recommendation in RCOG guidelines that they should be surgically removed.
THE PRESENTATIONOF ENDOMETRIOSIS Endometriosis presents typically in two ways: with painful symptoms or with the symptom of subfertility. In theory, at least, the diagnosis of endometriosis should be
156
CURRENT OBSTETRICS & GYNAECOLOGY
simple but is compromised by the need to visualize the implants and thus to undertake laparoscopy. Before laparoscopy is undertaken there has to be a consideration of endometriosis in the di¡erential diagnosis. It is suggested that many doctors fail their patients by not considering endometriosis in the di¡erential diagnosis of their complaints. A survey by the National Endometriosis Society in the United Kingdom highlighted some of the problems that in some patients delays diagnosis for up to 8 years from the ¢rst experience of symptoms. Firstly, 46% of women when they ¢rst experience symptoms consider it to be normal and only 19% of women themselves consider that they might have endometriosis. This is further compounded by the fact that 54% of women were told at some point before diagnosis that there was nothing wrong with them. At ¢rst consultation,15% were told that there was nothing wrong and 43% had a non-gynaecological diagnosis. One in nine patients was labelled as experiencing dysmenorrhoea but only one in 12 had the provisional diagnosis of endometriosis. This failure to make or suspect the correct diagnosis is compounded by referral to non-gynaecologists in a third of cases and in a quarter of cases patients had seen two specialists before obtaining a gynaecological opinion. The symptoms of endometriosis are well known (Table 1). The di⁄culties with diagnosis arise because there is no one pattern of symptoms that is common in all patients. With diverse symptom complexes a¡ecting more than one system, commonly the genital tract, the gastrointestinal system and the urinary tract, it is not surprising that diagnosis is di⁄cult on history alone. A high index of suspicion should exist for the diagnosis in any patient who presents with symptoms that display any cyclicity. Particular attention should be paid to enquiring about gastrointestinal symptoms as many gynaecologists fail to adequately explore this area and irritable bowel syndrome is often one of the potential di¡erential diagnoses. A further barrier to diagnosis is the expectation amongst many clinicians that endometriosis is a disease of the late reproductive years but in fact,
Figure 1 Age at ¢rst symptoms of endometriosis.
¢rst symptoms usually occur at an earlier age (Figure 1).
MANAGEMENTOF INFERTILITY ASSOCIATED WITH ENDOMETRIOSIS Mechanism of infertility in endometriosis Endometriosis at all stages is associated with a reduction in conception rates. It is obvious that with advanced disease the destruction of the normal anatomy may interfere with normal spatial relationships between the Fallopian tubes and ovaries. Consequently, the disease process may interfere with ovarian motility, oocyte release, oocyte pick up, and tubal motility and patency. With less advanced disease no such obvious relationship exists and many putative mechanisms have been suggested. These fall into three broad groups: disorders of folliculogenesis or endocrine abnormality, in£ammatory or immunological abnormality and increased miscarriage rate. A number of authors have reviewed the literature and have found no convincing evidence of either an abnormality of follicular development or an endocrine abnormality that explains infertility in all cases of endometriosis. Endocrine abnormalities have been reported but there are no convincing data that they are either more common in women with endometriosis than in other infertile women or that they occur consistently in consecutive cycles.
Table 1 Symptoms of endometriosis K
K
Pain Dysmenorrhoea Dyspareunia Pelvic/abdominal pain Particularly mid-cycle and premenstrually Dyschezia Particularly atthe time of menstruation Bleeding Rectal bleeding Haematuria Haemoptysis
Treatment of minimal and mild disease Medical A comprehensive systematic review of medical therapy has clearly indicated that the ovulation suppression associated with medical therapy does not improve fertility rates. However, reviewing the trials included in this review enables us to estimate the expected pregnancy rates with expectant management. Pregnancy rates in the four control groups of the ¢ve comparisons made ranged 23.5^ 47.2%. It would thus appear that expectant
ENDOMETRIOSIS
management provides a realistic chance of the patient achieving a pregnancy. Medical therapy may, however, continue to play a role when patients have the combined problems of infertility and pain. The role of medical therapies in the treatment of painful symptoms is well established. Apart from the lack of bene¢t of medical therapies in treating infertility their traditional use results in 6 months of contraception and further delays pregnancy. As many of these patients will be in the older age group such a delay will further compromise their attempts at conception. Only one group has attempted to provide medical treatment without compromising fertility. They treated patients with either 40 or 60 mg of dydrogesterone in the luteal phase of the cycle. Relief of symptoms was achieved without compromising fertility.
157
be extremely hazardous and should not be undertaken without appropriate training and experience. In some hands, therefore, an open procedure will be more appropriate. What are the potential advantages of a laparoscopic approach? It is generally accepted that a laparoscopic approach has reduced morbidity and is associated with a more rapid return to full activity due to the absence of a large abdominal incision. However, it has to be asked if there are any advantages or disadvantages related to the primary indication and outcome of surgery, namely improvement of fertility and pregnancy. It is appealing to believe that reduced adhesion formation should be bene¢cial to the patient, but should we pay much attention to what is only a surrogate endpoint. The only endpoint that matters is pregnancy rates.
ART and endometriosis Surgical The Endocan study aimed to establish whether the ablation or resection of endometriosis in minimal or mild cases (stage I or II) improved the cumulative probability of pregnancy. The primary outcome was pregnancy progressing beyond 20 weeks’ gestation. This study did demonstrate an improved pregnancy rate in the treated group but pregnancy rates in the control group were extremely low. This study has been further criticized as many of the subjects were subjected to signi¢cant compounding interventions such as assisted conception. An Italian multicentre study, however, has demonstrated no bene¢t from surgical intervention in this group of patients.Thus, despite RCOG recommendations that minimal and mild disease should be treated surgically the literature does not conclusively support such a policy.
The precise relationship between infertility and endometriosis, in the absence of pelvic distortion, is unclear. Many consider the relationship to be purely casual and consider these patients to have unexplained infertility. Whether endometriosis-associated infertility is unexplained or consequent upon pelvic distortion it is appropriate to utilize assisted reproduction techniques (ART) to treat infertility when other treatments or expectant management have been unsuccessful. It has been suggested that endometriosis as a cause of infertility exerts an adverse e¡ect on fertility outcomes. However, a review of the published literature, including French and US national data, suggests that endometriosis does not exert any additional adverse e¡ect on the success rates than any other infertility cause. A doubt still exists on the impact of endometriomata on success, which ART should be employed and the role of medical and surgical treatment before ART.
Surgical treatment of advanced disease It is widely accepted that it is logical to surgically correct the distortion of the pelvic anatomy caused by endometriosis in an attempt to improve fecundity. A number of questions arise regarding the surgical management. These questions include the mode of surgery, laparoscopy or laparotomy, whether medical treatment should be used as an adjunct to surgery either prior to or after surgery and what measures should be taken to prevent adhesion formation. Whatever the answers to these questions are, it is clear that the principles of infertility surgery should be applied, namely good exposure of the operative ¢eld and magni¢cation (easily achieved with the laparoscope), scrupulous haemostasis, minimal tissue handling and attention to the prevention of adhesion formation. In recent years, there has been a move to performing a greater number of procedures laparoscopically. Laparoscopic surgery for advanced endometriosis can
MANAGEMENTOF ENDOMETRIOSISASSOCIATED PAIN Medical treatment is very e¡ective in relieving symptoms of dysmenorrhoea, dyspareunia and pelvic pain associated with endometriosis in the majority of patients. The major advantages it has over surgery are that it avoids the risks associated with a surgical procedure (especially if the patient is overweight or has a morbid condition excluding a surgical procedure), all endometriotic foci are suppressed, the costs are limited, and generally the side e¡ects are usually tolerable. The rationale is that ectopic endometrium responds to ovarian steroids in a similar fashion to intrauterine endometrium. Numerous laboratory and clinical studies have demonstrated oestradiol, progesterone and androgen receptors in endometriosis, but at much lower concentrations. Endometriosis is steroid dependent, with
158
oestrogen playing a central trophic role in its development. Current therapies modulate the hormonal environment by mimicking states where endometriosis is rarely found or where symptoms are naturally alleviated, the menopause, pregnancy, and in men. They act by suppressing the production of ovarian sex steroid hormones that would otherwise normally stimulate the growth of the endometrium, the aim being to prevent proliferation of ectopic endometrium and render it atrophic.
Types of medical treatment The combined oral contraceptive pill (OCP) The oral contraceptive pill, by its mechanism of inducing pseudo-pregnancy, has been used to treat symptoms of endometriosis since the 1960s. A major advantage it has over other medical treatments is that it can be given inde¢nitely. However, headaches, mastalgia, and bloating are common side e¡ects. In the literature, there is a paucity of data on its e⁄cacy. In their systematic review to evaluate the role of the OCP in the management of pain and endometriosis the Cochrane group identi¢ed only one study that satis¢ed their criteria for inclusion in the review. Here, a cyclic OCP was found to be equally e¡ective as GnRHa in the treatment of non-menstrual pain and dyspareunia, although less e¡ective for dysmenorrhoea as withdrawal bleeding continued in those treated with the OCP in contrast to the group treated with GnRHa in which menstruation was abolished. However, any di¡erence had disappeared at 6 months’ follow-up.The OCP if used continuously would also abolish menstruation and might confer similar e⁄cacy to the GnRHa for dysmenorrhoea; however, this has not been tested formally although it is in common clinical use.
CURRENT OBSTETRICS & GYNAECOLOGY
therapy, although around 20% may have spotting. Side effects include weight gain, acne, bloating, depression and breakthrough bleeding.
Danazol Danazol, a weak androgen derivative of 17a ethinyl testosterone, is e¡ective in the treatment of endometriosis. At doses of 400 ^ 800 mg daily it produces anovulation and amenorrhoea in most women. When compared to placebo, 6 months’ treatment of danazol is signi¢cantly e¡ective in relieving painful symptoms for women with endometriosis. Similarly, when compared to GnRH analogues its e⁄cacy is essentially the same. Its mechanism of action is somewhat complex, caused by its varying metabolites. It interacts with the enzymes of steroidogenesis and is capable of binding to androgen, progesterone and glucocorticoid receptors. It causes suppression of the pituitary gonadotrophins (FSH, LH), subsequent inhibition of ovarian steroidogenesis, and prevention of endometrial proliferation by binding to androgen and progesterone receptors in the endometrium and endometriotic lesions. Its other actions include decreased production of the high-density lipoprotein cholesterol, reduced production of SHBG in the liver, and displacement of testosterone from SHBG increasing the free concentration of circulating testosterone. Atrophy of the endometrium and endometriotic implants occurs because of the resulting low oestrogen and high androgen levels. Danazol was used commonly in the 1980s for the treatment of endometriosis; however, its side e¡ects have resulted in a gradual decrease in the use of the drug and an increase in the use of GnRH analogues.There has been concern that danazol has a tendency to induce insulin resistance, and therefore it may not be the ideal treatment in women with diabetes.
Progestogens Several progestogens are used for the treatment of endometriosis including medroxyprogesterone acetate (MPA), megestrol acetate and dydrogesterone. MPA has been the most studied and used progestogen. At moderately high doses, they induce a pseudo-pregnancy state as well as having an anti-oestrogenic e¡ect. Histology on specimens of endometrium and endometriosis implants reveals atrophic or inactive endometrium with pseudo-decidual reaction consistent with progestational therapy. A meta-analysis of four randomized controlled trials with a total of 89 patients showed progestogens to have similar e⁄cacy in relieving pain as danazol and GnRHa. Similarly, another study demonstrated a signi¢cant improvement in pain when compared to placebo, and equal e⁄cacy (84%) between MPA and danazol. Up to 75% of patients may experience amenorrhoea throughout
Gonadotrophin-releasing hormone analogues (GnRHa) GnRHa are considered by many to be the medical therapy of choice for treating endometriosis. Their continuous action on the GnRH receptor results in the down-regulation and desensitization of the pituitary gonadotroph.This results in the chronic suppression of gonadotrophin secretion, LH and FSH, cessation of ovarian activity and consequently a decrease in circulating oestradiol levels, creating a reversible pseudo-menopausal state. The consequent hypo-oestrogenaemia causes predictable side e¡ects, namely those symptoms experienced by women at menopauseFvasomotor symptoms, dry vagina, and more concerning, for many clinicians, a loss in the bone mineral density (BMD). The reduction in vertebral BMD during a 6 -month course of GnRH analogue is in the order of 3^ 4%, which is equivalent to 6 months breast-feeding or 6 months of
ENDOMETRIOSIS
menopause.This concern has therefore limited the use of GnRH analogue therapy to 6 months’ duration. For symptom relief numerous randomized prospective clinical trials have directly compared the e⁄cacy of the GnRH analogues versus danazol in the treatment of endometriosis. Essentially, all the studies demonstrated that GnRH was as e¡ective. A large Cochrane metaanalysis of 26 RCTs con¢rmed GnRH analogue to be e¡ective in relieving pain. When compared to danazol, gestrinone (another androgenic compound) and the oral contraceptive pill had a similar e⁄cacy after 6 months’ of therapy. Not surprisingly, the main di¡erence between the varying treatments relates to their respective side e¡ect pro¢les. Both danazol and gestrinone were found to have more side e¡ects that are androgenic while GnRHa produced the hypo-oestrogenic symptoms seen in the menopause. The addition of hormone replacement therapy as ‘addback’ to a course of GnRHa is a strategy that would help ameliorate the menopausal symptoms, but is low enough in dose to retain the symptomatic relief of pain, protect the vertebral bones from demineralization and osteoporosis, and provide longer duration of use. A number of di¡erent addback regimes are utilized; combined oestrogen and progestogen, progestogen only, or tibolone. Several clinical trials have demonstrated that HRT addback does not reduce the e⁄cacy of GnRHa treatment, or exacerbate the disease. Furthermore, addbacktreated patients su¡ered signi¢cantly fewer hot £ushes. Five RCT studies examining GnRHa alone versus GnRHa with addback found no di¡erence in e¡ectiveness with pain scores and AFS scores; however, the addback group had signi¢cantly less menopausal-type side e¡ects such as hot £ushes.There appears to be no di¡erence on symptoms or AFS scores or side e¡ects with mode of GnRH analogue administration. A multi-centred randomized double-blinded trial using a12-month course of GnRH alone or with addback found that those women receiving GnRHa alone experienced a loss of bone mineral density of 3.2% at 6 months and 6.3% at12 months in the lumber spine, and complained of hot £ushes which were dramatically suppressed in the addback groups, while women receiving addback for 12 months had (o1%) negligible BMD loss. Women receiving higher dose-conjugated equine oestrogens (1.25 mg) are more likely to have breakthrough bleeding. The e¡ect of long-term GnRHa use (2 years) on BMD was recently reported in the literature in a limited study. They found that the reduction of BMD that occurred had not fully recovered even up to 6 years after treatment and surprisingly, the use of HRT addback did not make any signi¢cant improvement to the recovery. The ¢ndings of this study need to be con¢rmed by other studies as they are at variance with the studies of short-term therapy with addback.
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Figure 2 Severe endometriosis with the involvement of both sigmoid colon and rectum.This patient had disease that was visible in the posterior vaginal fornix and involved the rectovaginal septum.
Surgical treatment Medical therapy is not e¡ective in every case. In such cases, surgery may be of value although surgery may also be used as an alternative to medical therapy. Surgical treatment appears most e¡ective, the more severe the disease. It is the excision of deep deposits of endometriosis that appears to give the greatest improvement in symptoms. Such surgery, however, may be technically dif¢cult and may involve other organs such as the bowel and the ureters (Figure 2). Complex surgery on patients with severe endometriosis should only be undertaken by individuals with expertise in this area.
CONCLUSION Endometriosis is a complex condition, which presents clinically in many di¡erent ways.The diagnosis can be dif¢cult and consequently may be missed. This may lead to dissatisfaction among patients over the care they receive.Treatment should be directed to the illness the patient experiences with careful consideration of the mechanism by which the disease creates the illness. It is this interaction between illness and disease that makes endometriosis such a di⁄cult and fascinating condition to manage.
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The signi¢cance of the visual diagnosis of endometriosis should always be carefully considered The diagnosis of endometriosis is often missed or not considered
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Surgery has a role in the management of infertility associated with moderate and severe endometriosis Medical therapy is e¡ective in most patients but will not treat deep implants. Surgical therapy can be complex and involve other tissues
FURTHER READING Adamson GD, Pasta DJ. Surgical treatment of endometriosis-associated infertility: meta-analysis compared with survival analysis. Am J Obstet Gynecol 1994; 171: 1488 ^1505. Hughes E, Fedorkow D, Collins J,Vandekerckhove P.Ovulation suppression vs placebo in the treatment of endometriosis (Cochrane review). In: Cochrane Library, Issue 4. Oxford: Update Software, 2001.
Marcoux S, Maheux R, Be¤rube¤ S and the Canadian Collaborative Group on Endometriosis. Laparoscopic surgery in infertile women with minimal and mild endometriosis. N Engl J Med1997; 97: 212^222. Moore J, Kennedy S, Prentice A. Modern combined oral contraceptives for the treatment of painful symptoms associated with endometriosis (Cochrane review). In: The Cochrane Library, Issue 4. Oxford: Update Software, 2001. Prentice A. Advances in the management of endometriosis related infertility. In: Bonnar J (ed). Recent Advances in Obstetrics and Gynaecology,Vol. 21. London: Churchill Livingstone, 2001; 101^109. Prentice A, Deary AJ, Bland E. Progestagens and Anti-progestagens for pain associated with endometriosis (Cochrane review). In: The Cochrane Library, Issue 4. Oxford: Update Software, 2001. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis (Cochrane review). In: The Cochrane Library, Issue 4. Oxford: Update Software, 2001. Selak V, Farquhar C, Prentice A, Singia A. Danazol versus placebo for the treatment of endometriosis (Cochrane review). In: The Cochrane Library, Issue 4. Oxford: Update Software, 2001. Vercillini P, De Giorgi O, Pesole A. Endometriosis: drugs and adjuvant therapy. In: Templeton A, Cooke I, O’Brien PMS (eds). Evidencebased FertilityTreatment. London: RCOG Press,1999; 225^245.