“ENDOMETRIOSIS”: ALGUNOS CRITERIOS RACIONALES PARA SU MANEJO INTEGRAL” Dr. Neyro

“ENDOMETRIOSIS: SOME RATIONAL CRITERIA FOR ITS INTEGRAL MANAGEMENT” Dr. D. Jose Luis NEYRO Gynecological Endoscopy Unit. HOSPITAL DE CRUCES. 48903 – BARACALDO A)

INTRODUCTION

Endometriosis is a chronic disease, in the classic sense of the term, of uncertain evolution that affects a significant population of women of childbearing age and is defined as the presence of ectopic endometrium in any location; it is an equally uncertain entity of etiopathogeny in which, on many occasions, the intensity of the clinical manifestations is not directly proportional to the findings found during the surgical approach.

The most accepted hypotheses to explain the origin of this pathology are those that defend the ectopic implantation of endometrial tissue through a mechanism of retrograde menstruation, but settling in women with some immune alteration and genetic predisposition, which probably has to do with the expression by some patients of various forms of the c-myc proto-oncogene (the c-myc gene is a cellular homologue of the c-myc viral oncogene and encodes for a nuclear protein that has been positively correlated with cell proliferation and DNA synthesis and inversely correlated with cell differentiation).

A summary of some of the theories involved in the histogenesis of this disease appears in Table 1. Otherwise, without the combination of several factors or histopathogenic mechanisms, it would not be understood that, with retrograde menstrual fluid found in the Douglas pouch of more than 95% of the women investigated, only about 3.5-4% of all will have different stages of the disease. The prevalence of endometriosis is extraordinarily variable depending on the authors and the populations studied. Lesions have been found in 20-50% of infertile women, in 15-80% of patients consulting for chronic pelvic pain, and in approximately 25% of all hysterectomy pieces with double adnexectomy.

When the material studied were patients initially asymptomatic from the gynaecological point of view who were accessing laparoscopy because of their desire for tubal sterilisation, the different authors found figures as disparate as 5 to 64%. All this also speaks of a difficult approach to the standardisation of the results of the different works and authors because often the cataloguing of certain images depends on the experience of the endoscopist, the time taken to carry out the endoscopy itself, the intensity of the search for lesions behind the ovaries or in other locations, the thoroughness of the exploration and not only the appearance of the peritoneum and the lesions themselves.

From an epidemiological point of view, attempts have been made to link, with little success, that is the truth, very different aspects among which age (since oestrogens are necessary in the development of the disease), race (because it seems to be less prevalent among black women and more so among those of eastern origin), and so on, socio-economic conditions (which are very difficult to evaluate in terms of the easy or expensive access to health care that the population studied may have), or even marital status (with wide selection biases if sterile patients are included for the study and, therefore, if not married at least paired).

The aim of this review is to shed some light on the most controversial aspects of the diagnostic and therapeutic approach to this enigmatic disease, without going too deeply into those of its better defined features. A)

DIAGNOSIS

The definitive diagnosis of endometriosis is based on direct visualization of the lesions, usually through laparoscopic inspection, confirmed by histological study. From the histopathological point of view, the presence of at least two of the following findings in the biopsied piece is required for diagnostic confirmation: – Endometrial epithelium. – Endometrial glands. – Endometrial stroma. – Macrophages loaded with hemosiderin.

The clinical manifestations of endometriosis are variable and unpredictable in terms of presentation and evolution. Dysmenorrhoea is the most common symptom, although the presence of chronic pelvic pain, dyspareunia, palpation of painful nodules in utero-sacral ligaments or evidence of adnexal mass may also be indicative.

In any case, a significant number of affected women are asymptomatic. When the anamnesis and examination data are analysed statistically in a systematic way, we have been able to confirm that the only examination data with high predictive value is precisely the nodularity of the utero-sacral ligaments, especially when these are painful.

Imaging techniques are useful to guide the diagnosis in the presence of an adnexal mass. In this respect, transvaginal ultrasound shows a sensitivity of 83% compared to a specificity of 98% in almost all studies. On the other hand, magnetic resonance imaging (MRI) can detect nodules in the recto-vaginal septum or in utero-sacral ligaments, which are two extraordinarily frequent locations and very difficult to evaluate ultrasonographically; recently there is data that point to the possibility of diagnosing endometriotic lesions in the thickness of broad ligaments, in a retroperitoneal situation, hidden from laparoscopic visualisation with the same MRI method.

As regards the CA 125 serum marker, there has been much discussion about the clinical usefulness of its determination. The measurement of this glycoprotein has limited value as a screening and diagnostic test. Some authors claim that it could be valid for monitoring the effect of treatment in patients with endometriosis (provided of course that we are dealing with an endometriosis disease which has previously expressed the above-mentioned marker), although its use has not been systematically evaluated.

Little or nothing can be said about other protein markers in peripheral blood, as many of them have not even passed the experimental stage and have not yet had any clinical applications. In daily practice, there are basically 3 ways of approaching the diagnosis of this pathology: ¾ Clinical suspicion with/without endometrioma in the examination and ultrasound. ¾ Casual finding in surgery/endoscopy indicated for another reason. ¾ Initially diagnostic laparoscopy, in sterile women.

With regard to this last section, it is not necessary to reiterate that, at least in our opinion, which has already been expressed for a long time, there are no diagnostic laparoscopies, since all are, and must be, diagnostic-operative. So if any organic lesion is found, treatment must be carried out in situ during the endoscopic procedure.

We will discuss these aspects more extensively when we address the section on surgical treatment. At this point we will only make a few references to the different lesions of the disease, which have already been classically divided into typical and atypical, many of which are still controversial and generally underestimated in the scores of the most common classifications of endometriosis.

A brief description of these different lesions can be summarised as follows – Superficial black lesions (on the ovary or peritoneum). 2.- Lesions of atypical, mysterious aspect: – Whitish or white opacifications. – Lesions that look like red flames. – Glandular outgrowths. – Minimal subovarian adhesions with the broad ligament. – Yellow-brown peritoneal patches. – Circular or ovoid peritoneal defects – Petechial peritoneum. – Peritoneal areas of hypervascularization (modified from Non-pigmented endometriosic clinical laparoscopic and pathologic definition). Jansen, RPS and Russell, P. (1986) Am J Obstet Gynecol 155,1154).

Regarding these different appearances it has been mentioned that the latter are precisely the most active, since the typical black ones would denote necrosis and stabilization in time, being those much more difficult to evaluate. The macroscopic appearance of the ectopic endometrium depends mainly on the longevity of the process ( viable endometrial cells can implant and their initial appearance may be just an irregularity or discoloration of the surface of the peritoneum).

One of the most common criticisms made in any publication on the diagnosis of the disease is that the evaluation of atypical lesions depends largely on the experience of the observer and that, moreover, their cataloguing is only standardised and still very incomplete; all this results in an added difficulty when comparing the results of the different authors. Finally, it is important to reiterate that for the definitive diagnosis of a given patient, not only is it necessary to visualize the lesions laparoscopically, but also their biopsy and subsequent histopathological cataloguing. B)

ENDOMETRIOSIS AND PAIN. MEDICAL TREATMENT.

Endometriosis is a pathology for which there is no curative treatment, at least in the long term, and considered to be a cure as the disappearance of the disease without recurrence or subsequent recurrence; however, we have various options for the treatment of the symptoms. The clinical efficacy of the various treatments for endometriosis has been classically evaluated on the basis of two parameters, namely: a) the pregnancy rate achieved after treatment ( obviously only applicable when the patient treated presented a previous problem of sterility which logically biases the results of the studies when pre-selecting the sample) and b) the reduction in the endometriosis score, evaluated according to the American Society for Reproductive Medicine – ASRM ( AFSr, 1985).

From these points of view, all the drugs used are equally effective or, to be more precise, there is no treatment that is more effective than any other when the studies analysed were carried out prospectively. They act by inducing atrophy of the endometrium by two distinct mechanisms: altering the effect of estrogen on endometrial tissue or reducing blood estradiol levels.

The choice between oral contraceptives, gestagens, danazol or GnRH agonists (the antagonists have not yet demonstrated, according to their short follow-up period, an effectiveness that can be superimposed on the others), will depend on other variables such as: possible side effects, comfort of use, price of the product, etc. Thus, for example, if the use of danazol has as a disadvantage its androgenic effect and secondarily its protein anabolic effect (acne, alopecia, weight gain,…), the GnRH analogues present the disadvantage of the hypoestrogenism they produce (hot flushes, decrease in bone density, vaginal dryness,…).

However, it is possible to associate hormone therapy (“add-back therapy”) with aGnRH treatment, such as various gestagens, combined estroprogens or even tibolone to alleviate the hypoestrogenic clinic, without losing effectiveness against the disease, which allows a longer therapy. In this analysis, some authors have pointed out the preference for the use of Danazol over aGnRH precisely because it induces less clinical hypoestronism or none at all and because it is the only treatment of the disease that, at the same time, is immunomodulator of the patient’s immune response ( circumstance increasingly pointed out as highly protagonist of the physiopathology of the disease).

Thus, aGnRH would be reserved for those circumstances of anatomical alteration that require the use of assisted reproduction techniques (ART) after endoscopic or laparotomic surgery and would be used for only two cycles in a pre IVF “long braking” regime. Non-steroidal anti-inflammatory drugs, ideally those that are not gastro-erosive, can also be effective in reducing the pain associated with endometriosis.

When faced with treatment of a woman with well-founded clinical suspicion of endometriosis, without gestational desire and without evidence of pelvic masses, treatment with gestagens or anovulatories may be resorted to to relieve the pain. If these are not effective, some authors advocate the use of GnRHa for 3 months, before considering an initial diagnostic laparoscopy; this possibility is far from being the one chosen by us in our environment, in view of the important secondary factors that would not justify “blind” treatment, nor with the intention of “ex-juvantibus” diagnosis.

Regarding the choice of the type of oral contraceptives, there are no prospective studies that support the convenience of a continuous pattern of use versus the usual cyclical pattern. If there is an indication for surgical treatment, the possibility of preoperative hormonal therapy should not be considered since, with this, the only thing we do is postpone the benefit of surgery.

Although the use of aGnRH before surgery can decrease the volume of the endometrioma by up to 25%, it does not reduce the surgical time or the rate of recurrence. It should be remembered that the pain associated with endometriosis depends more on the lesions that deeply infiltrate the peritoneum than on the endometrioma. There is no scientific evidence to support the efficacy of pre-surgical hormone therapy.

However, some authors, mainly from Belgian groups, have advocated the use of aGnRH for three cycles (depot administration), after a first laparoscopy for diagnosis and drainage of the endometriomas, and then endoscopic surgery to destroy the capsule of the endometrioma by CO2 laser vaporisation, which was reserved for the first surgical act. In general, almost all the authors agree that dissection of endometriomas becomes extraordinarily difficult when the cleavage planes disappear due to atrophy caused by hypostronism

Also, although several authors advocate the use of hormone therapy after surgery in order to decrease the risk of disease recurrence, post-surgical medical treatment is of uncertain value, with contradictory results drawn from different studies. However, its use does appear to prolong the recurrence-free interval.

Pharmacological treatment is not effective in the resolution of endometriomas. Be that as it may, and in general, the approach and long-term management of the patient with symptomatic endometriosis or affected fertility should be continuous over time, as we still do not have any really effective parameters that allow us to predict the course of the disease in the future. If at a particular moment in the patient’s history her disease has been so important as to develop endometriomas that put the ovary at risk, or caused painful symptoms, sometimes really disabling, or altered her fertility in any way and by any mechanism, while we do not have a parameter that allows us to predict relapses and/or recurrences with sufficient reliability our attitude must be aggressive with the underlying disease.

Therefore, once the treatment has been completed (surgical, if required), we must keep the ovaries “at rest” in the safest way possible for the patient while maintaining the most effective treatment possible against the disease. D)

ENDOMETRIOSIS AND PAIN. SURGICAL TREATMENT. The goal of surgery is to destroy the endometriotic lesions and release adhesions to relieve symptoms. The use of resorbable cellulose derivatives (Interceed® ) prevents the formation of adhesions. Surgical treatment is of choice if endometriomas or associated infertility is present, as opposed to medical or expectant management. The laparoscopic approach is preferable to laparotomy as it allows faster recovery, produces fewer adhesions and a lower rate of complications in expert hands.

The data given in table 2 are interesting in relation to the therapeutic approach to the disease. Endometriotic lesions can be treated by excision, laser vaporisation (with different energy sources) or electrocoagulation. As far as recurrence rates after laparoscopic surgery are concerned, no technique used in the destruction of the lesions has proved more advantageous. In severe forms of the disease, with persistent pain, in women who have undergone previous medical or surgical treatment, abdominal hysterectomy with double adnexectomy should be considered as definitive therapy. This aggressive treatment leads to improvement or resolution of pain in 90% of patients.

The preservation of the ovaries in radical surgery for extensive and/or unreliable endometriosis exposes the patient to a risk of recurrence that is 6 times higher and increases the chances of additional surgery by 8 times, which makes this practice inadvisable.

When a woman wants hormone replacement therapy (HRT) after removal of the uterus and adnexa, it can be prescribed immediately after surgery, as there is no advantage in delaying it any longer (delaying the start of HRT was thought to reduce the risk of recurrence of symptoms, although there is no evidence to support this). Some authors, on the basis of the estrogen dependence of these lesions, have advocated the addition of gestagens to estrogen therapy in order to prevent the recurrence/reactivation of endometriosis sites as far as possible. There are no evidence-based results to support this recommendation.

Denervation procedures (presacral neurectomy and destruction of the uterine nerve) are not recommended because of their unproven efficacy and the risks of complications they entail. As a corollary to this section of surgical treatment we could conclude with a small group of items that should preside over the philosophy, the rationale in the classic version, of the treatment of endometriosis; faced with a lesion of this type it is necessary to be: – as aggressive as possible with the lesion (until its total destruction), – as conservative as possible with the organ on which it rests (to preserve as much healthy ovarian tissue as possible) and – as respectful as possible with the patient (in case this is not the last surgical procedure she will undergo).

Despite all this, these maxims of surgical treatment of endometriosis do not allow us to drool over exactly how the disease will evolve after our action; in fact, recurrence rates vary between 20-50% within 5 years of surgery. C)

ENDOMETRIOSIS AND INFERTILITY.

In general, we could say that medical treatment does not solve infertility in women with endometriosis, even when there is no other apparent cause of sterility. The expectant attitude that in other conditions could have some predicament and a role in certain circumstances does not seem to be appropriate, once we have diagnosed a disease that could very well explain the situation of lack of offspring. Although, in general, surgical treatment is more decisive than hormonal treatment or an expectant attitude in terms of improving pregnancy rates, it is necessary to differentiate between the various degrees of injury: ¾ In moderate and severe endometriosis, surgery improves the rate of gestation (and that must meet the philosophical principles that we encouraged in the previous section). ¾

Regarding minimal or mild endometriosis and surgical treatment: There are no differences between treated and untreated women. There is no difference between patients with endometriosis I-II and those without endometriosis.

An appropriate attitude in these patients would be to institute postoperative treatment with gonadotropin analogues to induce ovarian rest followed by the application of assisted reproduction techniques; these are the “long braking” protocols mentioned above.

The choice between IAC-IU (intrauterine insemination with the partner’s sperm), in vitro fertilization or oocyte donation will depend on the quality of the sperm, the tubal permeability, the functional capacity of the residual ovary and all the other conditions that make it possible to decide in the face of a sterility problem which ART is the most appropriate at each moment and for each patient .

Among the reasons that try to explain the greater difficulty of women with endometriosis to achieve pregnancies is that of a lower quality of eggs. This fact has been proven repeatedly and prospectively in oocyte donation programs, which are the best biological laboratories that could be designed. It has been seen that when gametes are obtained from women without endometriosis, the rate of implantation of the resulting embryos is the same in recipients with and without this pathology, while when the donor has endometriosis, the rate of implantation in recipients not affected is lower.

Therefore, it has been proven that the results of “ovodon” programs in endometriotic patients without ovarian function are as good as in other indications, or in other words, endometriosis does not seem to affect the patient’s implantation conditions: women with endometriosis implant as well as those without endometriosis, as long as the oocytes do not come from ovaries affected by the disease D)

THE FUTURE IN ENDOMETRIOSIS THERAPY.

As in any other pathology, the ideal is the optimal aetiological treatment, for which it is necessary to improve the aetiopathogenic knowledge available to us. This will enable us to achieve the desired curative treatment. So far, there is no news in the literature to suggest that we are close to such a circumstance.

As for immunotherapy, there are two possible approaches. On the one hand, immunosuppressive treatment is an option, based on the role that the immune disorder seems to play in the genesis of this pathology. Likewise, the development of antibodies that recognize only the ectopic endometrium and focus the immune response against this tissue could be effective.

Recently, the use of GnRH antagonists for ART has been commercialized, although preliminary studies show similar efficacy to the analogues in the management of endometriosis, providing a faster initial response by avoiding the “flare-up” effect of the agonists.

In the coming years we will probably see once again that endometriosis is the most widely published gynecological item, and all this without yet being able to offer our patients therapeutics based on the aetiology and not just on the mechanism that triggers the damage, as has been the case up to now.

Let’s turn the page and stop considering endometriosis to be just a hormonal disease, a mistake that has been perpetuated until not so long ago. Perhaps the selective identification of other proto-oncogenes and their subsequent manipulation will provide us with the key to success; the future must be promising. Table 1.: Some theories involved in the histopathogenesis of endometriosis 1.- Development “in situ”: * From the germinal epithelium of the ovary * From trapped embryonic cells: – from the Wolf’s ducts. – From the Müller ducts. * Cellular metaplasia. * Induction theory ( omnipotent blastema ). * From the secondary Müllerian system. 2.- Endometrial implantation. 3.- Combination of mechanisms between endometrial implantation and “in situ” development. ( modified from “Retrograde menstruation”. Kruitwagen, RFPM. In The current Status of Endometriosis; research and management. By Brosens I and Donnez J. The Proceedings of the 3rd Congress on Endometriosis, Brussels, June 1992. The Parthenon Publishing Group. New York, 1993). Table 2.: Opinion of seven world experts who spoke at the 3rd World Congress on Endometriosis, held in Brussels in June 1992, on the surgical approach to the different locations of endometriosis. Location B C D E Q R S Adhesions + + + + + + + Deep infiltration of the recto-vaginal septum + + + + + + + Endometriotic cyst + + + + + + Ç + Intestinal endometriosis + + + Peritoneal endometriosis + + + $ * Endometriotic invasion of the utero-sacral ligaments + + + + + B, Buttram, C, Canis; D, Dones; E, Evers; Q, Querleu; R, Rolland; S, Schweppe. Ç: in cases of sterility. * : if the cyst has at least 5 cm. $ : if the condition is persistent or recurrent after medical treatment ( modified from ” Endometriosis: rationale for suegery”. Dones J; Nisolle M; CasanasRoux F; Clerckx F. In The current Status of Endometriosis; research and management. By Brosens I and Donnez J. The Proceedings of the 3rd ld Congress on Endometriosis, Brussels, June 1992. The Parthenon Publishing Group. New York, 1993).