Managing endometriosis
a complex mission
Given that the origin and mechanism of onset of endometriosis lesions remain unknown to this day, and that endometriosis lesions are highly heterogeneous in terms of their appearance, composition and behavior, we don't have a medical treatment capable of specifically destroying endometriosis cells while preserving the body's normal cells.
Principles of drug treatment
The only principle of medical treatment today is to block menstruation, with drugs that mimic either pregnancy or menopause (the two physiological periods of absence of menstruation in the life of an adult woman).
In the vast majority of cases, this strategy blocks the development of endometriosis lesions and reduces painful symptoms, but does not eliminate them. On the other hand, because it blocks ovulation, medical treatment is also contraceptive and should be discontinued in women who wish to become pregnant.
To be effective, medical treatment requires amenorrhea (menstruation must be completely absent) and has 2 main objectives:
- Improve painful symptoms by reducing inflammation and providing analgesic benefits (non-steroidal anti-inflammatory drugs, various levels of analgesics);
- Stop the progression of lesions by blocking ovarian activity (continuous hormone therapies such as estrogen-progestin pills, ovulation-blocking microprogestin pills, synthetic macroprogestin, GhRH agonists).
Given that endometriosis can be active from adolescence through to the menopause, it makes sense that hormone treatment could be justified for 35-40 years of a woman's life. For this reason, estrogen-progestogen, macroprogestogen and microprogestogen pills are the first choice for medium- to long-term medical treatment. Despite their efficacy, GnRH analogues are reserved for short courses of treatment, lasting just a few months, in accordance with their marketing authorization, which limits their administration to 6 consecutive months, and in association with addback estrogen therapy to reduce undesirable effects.
The ideal hormone treatment
In this ideal world, as the exclusive treatment for endometriosis, hormone therapy could :
- Suppress menstrual periods for the duration of the medication
- Stop the progression of the disease (the size and number of endometriosis lesions no longer increase during amenorrhea)
- Prevent recurrence after complete surgery (recurrence prophylaxis effect)
- Eliminate all painful symptoms and digestive and urinary disorders for the duration of treatment
- Do not produce undesirable effects
While some women are fortunate enough to meet all these criteria and benefit from years of effective and appropriate treatment, the reality on the ground is usually very different.
The vast majority of cells express hormone receptors, nevertheless the activity of hormones (their effects on leș cellular functions) on different tissues is variable due to the different type of receptors (ERA or ERB for estrogen, PRA or PRB for progesterone) which result in different effects, their level of expression, or the presence of modulators of intracellular signal transmission or epigenetic factors which modify the response to hormones. As a result, hormones circulating in the blood can bind to these receptors and modify the activity of different cells, and this is true not only of natural hormones produced by women themselves, but also of hormones administered to treat endometriosis.
For this reason, the administration of a hormonal treatment generally results in the appearance of certain changes, more or less marked, more or less bothersome, called " side effects "These will influence the decision to continue or stop treatment.
Undesirable effects
The list of undesirable effects is very long, and grows longer as events are reported, even if in some cases the relationship with the drug taken is not certain. In other cases, certain adverse effects are suspected, but the studies needed to specify the order of magnitude of the risk are not yet available. This was the case for meningiomas until a few years ago...
Some side effects are serious and life-threatening, and frighten both users and prescribers, such as thromboembolic accidents due to hypercoagulability of the blood, especially in the presence of other risk factors or behaviors such as smoking. Other undesirable effects are more frequent, and far more distressing for patients and their families than for prescribers, such as weight gain, mood disorders and blood loss during treatment (metrorrhagia). Given the endless list of adverse effects associated with hormonal treatments, it is virtually impossible to mention and discuss them exhaustively during a routine gynecological consultation, so information prior to initiating treatment mainly concerns the effects encountered most often, or those that seem most likely to occur in a given patient.
Other rare undesirable effects may occur over the long term, making it difficult to identify the product involved and estimate the precise risk, especially as women may have changed their contraception or hormone treatment several times in the meantime. This is the case with certain hormone-dependent tumors, where the use of certain hormonal treatments can increase or lower the risk level. This is the case with meningiomas, whose incidence rate is multiplied several times by the use of certain progestins, at high doses and for longer periods. Conversely, the incidence rate of ovarian cancer appears to be reduced by the use of estrogen-progestin oral contraceptives, which block ovulation.
In the case of a young woman consulting us with painful endometriosis, the decision to treat her exclusively with hormonal therapy logically implies prescribing it for over 20 years, practically until the menopause. Short-term treatments make little sense, except when they are administered to complement another therapy, such as surgery or medically assisted reproduction. A doctor who initiates treatment in 2023 in a 25-year-old woman has little visibility of the full list of adverse drug reactions that will be known in 2050, when the woman may stop treatment as a result of the onset of menopause. Over the next 25 years, both doctor and patient will have to juggle between the fear of a resumption of pain and disease progression if treatment is stopped, and the fear of an as yet unknown or poorly documented side effect due to prolonged use of the drug that was supposed to treat her.
Would I have had another choice?
This is the legitimate question women ask themselves when a serious adverse event occurs due to the hormone treatment taken to treat endometriosis: "Could I have made a different choice? "The answer, of course, is yes, but it's not certain that, at the time of choice, alternative courses of action would have seemed more attractive.
Surgery
Surgery is an alternative to medical treatment. Its aim is to remove the visible endometriosis lesions as completely as possible, while preserving as much as possible of the organs affected by the disease. Ideally, at the end of the operation, surgery means that the patient no longer has any visible endometriosis lesions, at least for the time being, unlike medical treatment, which merely blocks the evolution of the lesions without making them disappear.
Broadly speaking, surgery is recommended:
- Patients who continue to experience troublesome symptoms despite medical treatment;
- patients with contraindications, poor tolerance or refusal of medical treatment;
- patients with organ damage that may irreversibly compromise organ function, even in the absence of specific pain (sub-occlusive lesions of the bowel, lesions responsible for ureteral stenosis with risk of kidney atrophy, deep nerve damage with bladder denervation or motor or sensory disorders, etc.);
- for infertile patients, in order to improve their chances of natural conception, and in the absence of criteria that make in vitro fertilization compulsory (bilateral tubal obstruction, major sperm abnormalities, etc.).
Patients' and doctors' views on endometriosis surgery are extremely varied and not always accurate. This is due to the extraordinary variety of forms of endometriosis, from the simplest to the most complex, requiring very different surgical interventions, some of which are accessible to all surgeons and others should be reserved for a handful of experts. It is accepted that 5-10% of women could be affected by endometriosis, but in the vast majority of cases they present with minor or moderate forms and stages, whose surgery would not require extraordinary expertise and could be performed in local facilities. Surgeries on minor or moderate forms are rarely followed by post-operative complications, and their evolution is generally favorable.
Conversely, in severe forms of the disease, with involvement of organs such as the rectum, colon, bladder, ureters, diaphragm and pelvic nerves, surgical treatment can be laborious. What's more, the outcome of surgery, in terms of the quality of excision or complications, depends directly on the surgeon's experience and know-how, the technical resources available in the facility, and the availability of other surgeons from other specialties who may be involved in the operation. It is precisely these complex surgeries that expose patients to a higher risk of post-operative complications, such as terrifying digestive fistulas requiring a temporary stoma, urinary disorders treated by self-catheterization several times a day, or various functional sequelae.
The risk of complications depends on the location of the lesions and the procedure performed, so the only person who can estimate the risk is the surgeon himself. For example, the risk of fistula requiring a stoma is close to 0% for deep endometriosis that does not infiltrate the rectum; on the other hand, for digestive endometriosis treated by resection, the same risk varies from 1% for nodules in the sigmoid colon, to 2-3% for nodules in the upper rectum, and up to 10% for nodules in the lower rectum close to the anus. Consequently, without knowing the precise location of the deep endometriosis and the type of surgery performed, it is impossible to give an accurate assessment of the risk of this complication.
The risk of these complications, often wrongly associated with less complex surgery, often leads to a refusal of surgery, both on the part of patients and certain doctors. Fear and ignorance combine, leading to a default decision to opt for an alternative hormonal treatment, perceived as offering a better benefit-risk balance (1). Nonetheless, it is clear that delaying surgery exposes the patient to the risk of lesion progression, sometimes despite hormonal treatment, or in connection with assisted reproductive management, which further increases postoperative risks. Previously performing one or more incomplete surgeries further increases the risk of complications, and reinforces the conviction of detractors of surgical treatment of endometriosis.
Nevertheless, the occurrence of a post-operative complication or a result different from the one hoped for leads to the same question "Could I have made another choice than surgery?" and the answer is sometimes "I would have done better not to have had the operation".
In the majority of cases, patients do not ask themselves this question, as the beneficial effects of surgery are immediate, and concern pain, functional and urinary disorders, or fertility. In a randomized study carried out at Rouen University Hospital on patients operated on for severe rectal endometriosis and followed for 10 years, the recurrence rate in the rectum was 5%, the improvement in symptoms was significant and constant over the years, while 80% of women who had wanted a pregnancy after surgery achieved it, most by natural conception. (2,3)
Given that the origin of endometriosis and its mechanisms of progression are still obscure, surgery is not a definitive cure either. A complex surgical procedure performed on a 25-year-old patient cannot guarantee that the endometriosis lesions will not recur in the 25 years between now and menopause. To date, the only means of preventing post-operative recurrence is hormonal amenorrhea, with interruptions justified by the desire to become pregnant.
In a study of over 1,000 patients who had undergone complete removal of endometriosis lesions at Rouen University Hospital, it was estimated that the risk of having further endometriosis-related surgery was around 28% at 10 after the initial surgery. However, the risk of having a new surgery justified by the return of pain was only 10% under conditions of widespread prescription of postoperative hormonal treatment to prevent recurrence. Hysterectomy for adenomyosis was the procedure most frequently performed within 10 years of the initial surgery, particularly in women who had achieved one or more pregnancies in the meantime (4).
It is generally accepted that the risks of surgery and associated general anaesthesia are more frequent than those of medical treatment, and this belief is the primary justification for the recommendation to always begin endometriosis treatment with continuous pill intake, and to reserve surgery for well-elected patients. Overall, the risks of major complications associated with surgery are of the order of %, while those associated with drug treatments are of the order of ‰. This argument may seem hard to accept to a patient with a severe complication related to medical treatment, such as meningioma, stroke or pulmonary embolism, but it may seem fair to another patient with a troublesome functional sequela following surgery.
Expectative
Recent years have seen an explosion in endometriosis-related treatments, with more or less consistent scientific support. Whereas 15 years ago, endometriosis was a great unknown to the general public and to most carers, today patients with endometriosis have a wide choice of complementary or supportive therapies on offer or even specifically recommended.
Supportive care, starting with anti-inflammatory diets, relaxation therapies, sports coaching, naturopathy and spa treatments, has a clear effect on patients' well-being, by improving certain painful or digestive symptoms, and overall by helping them to cope with the daily constraints associated with this painful, chronic disease. However, their impact on the endometriosis lesions themselves has not been demonstrated. More specifically, it has not been proven that the anti-inflammatory diet, despite a perceived favorable effect on digestive disorders, can have any effect on reducing inflammation of endometriosis lesions.
In everyday practice, many women adopt this attitude, refusing hormone treatments and avoiding surgery. They often describe a state of well-being, without the undesirable effects of hormonal treatments, and the satisfaction of having chosen the right path. What's more, repeated ultrasound or MRI examinations of the pelvis sometimes reveal no new lesions, despite the absence of menstrual braking. This is not very surprising, as endometriosis can have different evolutionary paths, and the crossroads between these paths is probably found in late adolescence, around the age of 20. It is possible that, at this point in their lives, women will either embark on the path of deep endometriosis, or on that of minimal or moderate endometriosis. A study by the Rouen University Hospital team showed that the majority of surgeries for colorectal endometriosis, the most frequent form of complex endometriosis, are performed around the age of 30, meaning that the evolution of these severe forms began around the age of 20 (5). On the other hand, in clinical practice, we observe that patients operated on at the same age, 30, for minimal endometriosis are likely to recur, if at all, always in the form of minimal endometriosis, and not in the form of complex endometriosis. It is therefore highly likely that patients with minimal endometriosis who adopt an expectant attitude will expose themselves to recurrence of lesions that remain minimal, and therefore difficult to reveal by imaging examinations.
The situation is completely different for patients with complex endometriosis. The Rouen University Hospital team showed that, in patients with rectal endometriosis lesions, a 3-year wait-and-see attitude, without any hormonal treatment, was followed by obvious growth of deep lesions in 40% of cases; in the same study, in women who had continuous hormonal treatment without menstruation, the dimensions of rectal nodules did not change after 3 years (6). This study gives a fairly accurate idea of the medium-term evolution of women with deep rectal endometriosis who do not undergo surgery or take hormone therapy. This is exactly the case for women in whom the discovery of a meningioma definitively contraindicates hormonal treatment.
Contraindications to hormone therapy in women with endometriosis
How will endometriosis be treated from now on?
The sudden appearance of a contraindication to hormonal treatments, such as the discovery of an intracranial tumor of the meningioma type, the occurrence of a pulmonary embolism or hormone-dependent cancer, is an event that completely disrupts the lives of patients being treated for endometriosis. The entire management strategy must be rethought in the light of this new disease, which in most cases suddenly relegates endometriosis to the background.
The case of meningiomas is typical and topical in France (7). Even if the causal relationship with drug treatments cannot be established with certainty in all cases, particularly in patients who have not previously been treated with cyproterone acetate, chlormadinone or nomegestrol, the appearance of a meningioma is in most cases a definitive contraindication to hormonal treatments with macroprogestins. In some women with asymptomatic meningiomas, hormone therapy can be continued after multidisciplinary consultation with a gynecologist and neurosurgeon, under strict supervision. However, women's motivation to continue taking hormones is generally severely tested.
In these cases, surgical excision is a good therapeutic alternative, as it enables all endometriosis lesions to be removed, with a highly probable improvement in symptoms and quality of life. There is, of course, a risk of recurrence, but as previously shown, this is acceptable after complete surgery, especially as the women in whom meningiomas are discovered are often close to forty. In women who no longer wish to become pregnant, hysterectomy may be proposed in cases of adenomyosis associated with endometriosis, in order to achieve better long-term control of pelvic pain. Finally, in women nearing menopause, bilateral oophorectomy can eliminate the risk of postoperative recurrence.
The routine use of brain MRI scans in patients treated with certain macroprogestins has recently led to the diagnosis of intracranial meningiomas in many women undergoing treatment for endometriosis. Gynecologists need to adapt their practices to this new situation, in terms of choosing therapeutic strategies and alternatives, providing information on adverse effects, and monitoring patients over the long term. To date, all drug treatments capable of slowing disease progression are hormonal. The prospect of discovering a non-hormonal, non-contraceptive treatment that would specifically target endometriosis cells while sparing normal cells is not immediate, and will probably not concern the patients we are currently treating for endometriosis.
Bibliography :
- Canis M, Guo SW. In the thicket of fears, doubts, and murky facts: some reflections on treatment modalities for endometriosis-associated pain. Hum Reprod. 2023 Apr 6:dead061. doi: 10.1093/humrep/dead061.
- Roman H, Huet E, Bridoux V, Khalil H, Hennetier C, Bubenheim M, Braund S, Tuech JJ. Long-term Outcomes Following Surgical Management of Rectal Endometriosis: Seven-year Follow-up of Patients Enrolled in a Randomized Trial. J Minim Invasive Gynecol. 2022 Jun;29(6):767-775.
- Roman H, Chanavaz-Lacheray I, Ballester M, Bendifallah S, Touleimat S, Tuech JJ, Farella M, Merlot B. High postoperative fertility rate following surgical management of colorectal endometriosis. Hum Reprod. 2018 Sep 1;33(9):1669-1676.
- Roman H, Chanavaz-Lacheray I, Hennetier C, Tuech JJ, Dennis T, Verspyck E, Merlot B. Long-term risk of repeated surgeries in women managed for endometriosis. A 1,092 patient-series. Fertil Steril 2023, In press.
- Stochino-Loi E, Millochau JC, Angioni S, Touleimat S, Abo C, Chanavaz-Lacheray I, Hennetier C, Roman H. Relationship between Patient Age and Disease Features in a Prospective Cohort of 1560 Women Affected by Endometriosis. J Minim Invasive Gynecol. 2020 Jul-Aug;27(5):1158-1166.
- Netter A, d'Avout-Fourdinier P, Agostini A, Chanavaz-Lacheray I, Lampika M, Farella M, Hennetier C, Roman H. Progression of deep infiltrating rectosigmoid endometriotic nodules. Hum Reprod. 2019 Nov 1;34(11):2144-2152.
- Meningiomas and progesterone-derived drugs, amavea.org, 2023.
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