{"paper_id":"263a7674-b26c-4a12-a1f2-1918c598e837","body_text":"Although endometriosis was described in the late 1800s, we\nstill do not fully understand why this progressive disease, characterized by the\nappearance of endometrial tissue – glands and stroma – outside the endometrial cavity,\nis present only in some women and not in others. Its huge clinical variability in\nsymptoms and technical difficulty to diagnose precisely in its early stages makes\ndiagnosis only possible when the disease is quite advanced and already producing pelvic\npain and/or infertility in patients [ 1 ].\nStill today, there is a 5- to 10-year\ndelay from the onset of symptoms to the clinical diagnosis of endometriosis [ 2 ]. It\naffects around 10-15% of women of fertile age, so it is not an uncommon disease that may\nbe present in women from menarche to menopause, and even in women beyond menopause, in\nsome exceptional cases [ 3 ]. Unfortunately, early stages of the disease will cause very\nunspecific symptoms, mainly pelvic pain. It represents one of the most common causes of\nchronic pelvic pain, dysmenorrhea, and infertility [ 4 ]. This pain may impair the quality\nof life of affected women, especially with their partners, their families, and at work.\nEndometriotic lesions will grow within the peritoneum and ovaries, and the fibrosis\ninduced by this will affect nerve fibers causing pain. These endometriotic lesions are\ninfluenced by the menstrual cycle, as they have both endometrial glands and stroma.\nThus, in each menstruation the lesions may bleed, causing inflammation and fibrosis in\nthe nearby tissues, such as ovaries, pelvic organs (ureter, bladder, bowel, and\nintestines), pelvic peritoneum, and/or rectovaginal septum [ 4 ]. Thus, endometriosis can\nbe divided into three main types:  peritoneal ,  deep\ninfiltrating , and  ovarian , and these frequently coexist [ 5 ].\nBut, unless the physician has endometriosis in their differential diagnosis of pelvic\npain in young women, the patient will be treated with pain killers, non-steroidal\nanti-inflammatory drugs (NSAIDs), or even oral contraceptive pills (OCPs), in order to\nminimize pelvic pain and dysmenorrhea.\nMedical therapy is aimed at alleviating\nthe symptoms and reducing the size of the lesions, thus improving the patient’s quality\nof life [ 6 ]. Although many drugs and minimally invasive techniques with different\nside-effects have been tried to date, no agent has been found to be objectively superior\nto the rest. In fact, given that most interfere with estradiol secretion and ovulation,\nthey may interfere with fertility as well.\nA very common practice was to\nadminister a depot of gonadotropin releasing hormone (GnRH) agonist, leading to\ndown-regulation of GnRH receptors and generating a hypogonadotropic hypogonadism state\nin the body, hence improving the endometriotic lesions due to low estradiol levels [ 6 ].\nNew oral GnRH antagonists, which do not completely suppress estradiol secretion, may be\nan alternative with less side effects than the agonists [ 7 ].\nOral Contraceptive\n(OC) pills have been shown to have beneficial effects due to their suppressive action\n[ 8 ]. Progestins are also an option in patients with endometriosis due to their\nanti-proliferative and anti-inflammatory properties [ 8 ]. Resveratrol, among other\nnatural remedies, is a natural phytoalexin synthesized by plants in response to\nultraviolet radiation and fungal infections which has been proposed as potential\ntreatment for endometriosis due to its anti-inflammatory, anti-oxidative, and\nanti-angiogenic properties [ 8 ].\nFinally, minimally invasive surgery is usually\nthe best option for women with extensive endometriosis and excruciating pain [ 3 , 9 ].\nCareful laparoscopic excision of the endometriotic lesions and scar tissue, avoiding\ndamage to the surrounding tissues, will in most cases, reduce pain and improve quality\nof life. Special care should be taken when removing lesions from the ovaries in order to\navoid reducing the ovarian reserve in young women. In fact, spontaneous pregnancy after\nsurgery in a population of women with severe endometriosis may be up to 73% [ 3 ], but\nthis may not be exactly the same in infertile women with\nendometriosis.\n\nIt is important to note that not all women with endometriosis\nsuffer from infertility. However, the prevalence of the disease is much higher in\ninfertile women (around 30-40%) than in the fertile population (10-15%) [ 10 ]. This does\nnot mean that all women with endometriosis will have difficulty having children, and\nvice versa, not all infertile women have endometriosis. In fact, young women with\nendometriotic ovarian cysts showed a similar ovulation rate in the healthy ovary than in\nthe affected ovary (49.7 vs 50.3%, p=ns), and a spontaneous pregnancy rate of 43% in 4\nyears [ 11 ]. The problem, most of the time, is that women/couples do not want to wait so\nlong to get pregnant, or that due to their advanced age, this may not be\nadvisable.\nThis spontaneously reduced fertility in women with endometriosis may\nbe due to different pathomechanisms [ 12 ]. If there are major mechanical distortions of\nthe pelvis with extensive disease and pelvic adhesions that may even embed the ovaries,\nmechanical occlusion of the fallopian tubes may be the main reason. However, alternative\nmechanisms should be considered in the absence of major pelvic disease. Possible causes\nfor reduced fertility in these women might be minor adhesions, chronic intraperitoneal\ninflammation – a characteristic feature of endometriosis, disturbed folliculogenesis,\nluteal phase defects, the interesting theory of progesterone resistance due to a reduced\nexpression of progesterone receptors in the endometrium, dysfunctional uterotubal\nmotility, and differences in immunological changes. Changes including anti-endometrial\nantibodies and increased concentrations of interleukin 1b, 6, 8 and 10, and TNF-a, which\nmay contribute to sperm DNA damage, interfere in sperm-oocyte interactions and embryo\ndevelopment, and compromise implantation [ 12 ].\nAccording to the American Society\nfor Reproductive Medicine (ASRM) classification, which created a score system based on\nextension of the disease, endometriosis is classified in four stages: minimal, mild,\nmoderate, or severe [ 13 ]. Despite this being the most accepted classification for\nendometriosis, it unfortunately does not show a good correlation with fertility: some\npatients with mild disease have difficulties having children whereas women in stage IV\n(severe disease) may still be fertile. So, in 2010, Adamson  et al . [ 14 ]\ncreated the Endometriosis Fertility Index (EFI), a much more precise and robust staging\nsystem to estimate fertility in women with endometriosis. It does require laparoscopy –\nas the ASRM classification does – but also takes into consideration the ASRM stage plus\nthe function of the fallopian tubes, fimbria, and ovaries, the age of the patient the\nduration of infertility, and if the patient has had prior pregnancies. An EFI score of\n10 suggests a 75% pregnancy rate after 36 months, but only 5-10% if their EFI score was\n1. This index is helpful for developing treatment plans in infertile patients with\nendometriosis. With the EFI score and the prognosis regarding spontaneous pregnancy in\nthe coming years that it provides, the doctor can discuss with their patients the plan\nfor the next coming months: how long it would be reasonable to wait prior to initiating\nfertility treatments, if pregnancy does not happen, when to start and how (ovarian\nstimulation, timed intercourse, intrauterine insemination…), what to expect for these\ntreatments and success rates, and when, if needed, would be reasonable to move to\nIVF.\nMany infertile women with endometriosis require assisted reproductive\ntreatment (ART) to get pregnant, and this has been a great learning tool to understand\nhow endometriosis affects fertility.\nThis disease may affect the reproductive\nprocess in almost all aspects ( Figure 1 ), but we will focus on those where the evidence\nis convincing enough to prove a causal relationship.\n\nOne of the main prognostic factors regarding fertility is the woman’s\nage. In fact, this is the only qualitative marker. Generally speaking, women under 35\nyears old have fairly good fertility, from 35 to 40 years of age, fertility starts to\ndecline rapidly, and after 40 it is extremely difficult to have a child [ 15 ]. Maternal\nage is probably the best qualitative marker of oocyte quality and fertility. With the\nrecent trend to postpone maternity and start families at a later age, it becomes crucial\nto have a quantitative marker as well. Today, the best quantitative markers of ovarian\nreserve are antral follicle count (AFC), done by transvaginal ultrasound and\nAnti-Müllerian hormone (AMH), evaluated in serum [ 16 ].\nEndometriosis mainly\naffects the ovaries, reducing the healthy tissue as it grows into the ovaries, even\nthough it is a benign but progressive disease. This will reduce the ovarian reserve of\nthe patient. There is plenty of data showing that women with endometriosis have a lower\novarian reserve, lower AFC and lower AMH concentrations, especially in advanced disease\n( i.e.  when bilateral ovarian cysts – endometriosis – are present)\n[ 17 , 18 ].\n\nThe old paradigm “when in doubt, cut it out” does not work in\nendometriosis. Classically, if an ovarian endometriotic cyst was visible in ultrasound,\nand the patient had infertility, surgery was the first approach [ 19 ]. The cyst was\nremoved, but also a safety margin around the cyst, reducing even more the healthy tissue\navailable, and consequently, reducing the ovarian response to ovarian stimulation. Using\nwomen who had unilateral endometriotic cyst removed by laparoscopy as a model, several\nstudies have shown operated ovaries having a lower AFC, lower number of developing\nfollicles, and a significantly higher risk of no response to the ovarian stimulation\nwhen compared to the contralateral healthy ovary [ 20 - 22 ]. In a pioneering work combining\ndata from Yale University and our group IVI in Spain, we demonstrated that surgery prior\nto ART did not improve the chances of pregnancy, increased the costs, increased the time\nto pregnancy, reduced the ovarian reserve even more, and exposed the patient to surgical\nrisks [ 23 ]. Surgery should only be considered if the patient is symptomatic (pain), the\ncyst has suspicious malignant characteristics in the ultrasound (rapid growth,\nvascularization, etc.), or she is very young and has at least one year to consider\nspontaneous pregnancy [ 24 ]. In addition, if the patient has already had ovarian surgery\ndue to endometriosis and needs another surgery (recurrence of cysts, pelvic pain\nrefractory to medical treatment, etc.), the ovarian reserve will be affected even\nfurther [ 25 ]. In fact, today, the European guidelines suggest advising women who undergo\novarian surgery for endometriosis about the impact on the ovarian reserve before\nperforming the surgery [ 26 ]. Therefore, when discussing surgery in women with\nendometriosis, we could summarize with the saying “less is\nmore”.\n\nThere is plenty of\nevidence from animal models that clearly show a lower oocyte quality in women with\nendometriosis. When mice oocytes are exposed to peritoneal fluid from women with\nendometriosis, chromosome misalignment and spindle aberrations were observed with\nconfocal microscopy, having a higher impact as the stage of the disease advanced [ 27 ].\nSimilarly, when endometriosis is induced in mice models, these mice showed a lower\nproportion of normal oocytes (61 vs 83%, p<0.001), with a higher percentage of\nspindle abnormalities, and incomplete extrusion of 1 st  polar body. They also\nshowed a lower number of zygotes per mouse (21 vs 35.5, p=0.02), but similar embryo\nquality, suggesting a lower oocyte quality and, thus, a lower embryo number\n[ 28 ].\nWhen looking into the follicular milieu of these patients, women with\nendometriosis showed a pro-oxidative shift in their oxidative stress system, and a\npro-inflammatory status [ 29 ]. Electron microscopy showed abnormal mitochondria\nstructures, decreased mitochondrial mass, and a lower mitochondrial DNA copy number\n[ 30 ]. Similarly, cumulus cells from women with endometriosis produced a significantly\nlower amount of ATP per total DNA. This suggests that reduced energy production has a\nrole in the decrease of oocyte quality [ 31 ].\nA recent contribution to this debate\nabout the questionable oocyte quality in women with endometriosis showed that oocytes\nfrom women with endometriosis display a different transcriptome behavior, with\ndifferentially expressed genes when they were compared with women without endometriosis\n[ 32 ]. Pathways involved included key biological processes and molecular functions\nrelated to steroid metabolism, response to oxidative stress and cell growth regulation,\nwhich might explain this reduced oocyte quality.\nAll this basic information\nprovides a rationale to consider that women with endometriosis have a lower oocyte\nquality. However, this does not seem to have a clear clinical impact based on two\nrelevant pieces of information. First, when considering large registries of assisted\nreproductive treatment from the ASRM, after reviewing around 350,000 cycles, it was\nshown that women with endometriosis do have a lower oocyte yield (lower response to\nmedication), but not a lower success rate, suggesting a quantitative rather than\nqualitative damage of the disease on the ovaries [ 33 ]. On the other hand, we are all\naware that embryo aneuploidy is the major cause for failed IVF cycles: our group\nrecently demonstrated that women with endometriosis do not have a higher incidence of\naneuploidy when compared with healthy women across all age strata, again suggesting a\nquantitative impact only [ 34 ].\n\nOne of\nthe reasons why endometriosis affects fertility could be by generating endometrial\nchanges that can hamper embryo implantation, as it is a steroid based disease. Early\nbasic studies identified molecular differences in the endometrium of these women:\ndifferences in transcriptomic signature revealed an upregulation of genes related with\nDNA synthesis and cellular mitosis, which would fit it in a chronic, progressive\ndisease; and downregulation of genes related with progesterone response, which would\nmake sense within the context of the “progesterone resistance” theory [ 35 ].\nBut\nthen again, clinical data suggested otherwise. On one hand, the oocyte donation model\nshowed that patients with severe endometriosis who receive donated oocytes from a\nhealthy donor had comparable success rates as recipients without endometriosis,\nconfirming that it is the oocyte but not the endometrium that may be affected in\nendometriosis [ 36 ]. On the other hand, a transcriptomic analysis of the endometrium in\nwomen with endometriosis, focusing on the days of peak receptivity, and analyzing 238\ngenes directly implicated in embryo implantation, did not show any difference between\nwomen with or without endometriosis [ 37 ].\n\nAs this disease is estrogen dependent, it may seem\nreasonable to think that ovarian stimulation for fertility treatment may induce disease\nprogression, cyst growth, and consequently, a deterioration of the quality of life of\npatients. Nonetheless, data is reassuring regarding patient safety. Indeed, it has been\nshown that ovarian endometriotic cysts do grow during the ovarian stimulation cycle;\nhowever, such a short duration of hormonal stimulation (7 to 10 days) induces a minimal\ngrowth (22.2ml at the beginning of the cycle vs 24.9 at the time of the trigger), so\ndifferences are clinically irrelevant [ 38 ]. Even more convincing is the work done in\nBelgium by D’Hooghe  et al . [ 39 ] doing a laparoscopy at the beginning of\nthe fertility treatments and another laparoscopy when treatments were finalized. No\ndeleterious impact of ovarian stimulation for IVF using the ASRM classification of the\ndisease was found in this study.\nFinally, Benaglia  et al . [ 40 ]\ndid a quality of life assessment in women with endometriosis undergoing fertility\ntreatment. They assessed whether ovarian stimulation had an impact on the symptoms’\nprogression, such as pelvic pain, dyspareunia, dysmenorrhea, etc. They demonstrated that\nsymptoms are not aggravated by the ovarian stimulation, as probably duration is too\nshort to have any impact.\nAn interesting concept is how this disease may affect\npregnancy itself. There has been a long discussion regarding the risk of miscarriage in\nthese patients, and today it seems that this risk is similar to the general population.\nHowever, there is slightly increased obstetrical risk in women with endometriosis [ 41 ].\nFor instance, during pregnancy decidualization of bowel lesions may happen creating\nbowel obstruction. But these severe complications are rare and\nunpredictable.\n\nEndometriosis is a\nprogressive disease, although progression varies among individuals [ 11 ]. As we are\ncurrently unable to predict which patients will have a very aggressive growth of their\ndisease, there is a tendency to treat young women diagnosed with endometriosis with\neither progestins or oral contraceptive pill in a continuous protocol – without placebo\n– in order to avoid the monthly bleeding, and hypothetically, contributing to the\ncontrol of the disease. However, recurrence of the disease may happen even under these\nhormonal treatments [ 42 ].\nFertility preservation is an attractive alternative\nwhich gives women the option of having a child with their own gametes when they are at\nrisk of premature depletion of their ovarian reserve. The first indication for this were\noncological patients, especially those receiving alkylating agents causing high risk of\npremature ovarian failure as a secondary effect [ 43 ].\nToday, fertility\npreservation is discussed prior to their oncological treatment and those who opt to\nfreeing their oocytes, in case they enter premature menopause after the chemotherapy,\ncan have their own children without considering oocyte donation [ 43 ]. Still, the return\nrate – women who froze their oocytes and after failing to conceive at home\nspontaneously, came back to use their oocyte in an IVF cycle – is low: 6 to 12%. Some\nwomen do get pregnant spontaneously, some do not survive the disease, for others it may\nstill be too early for them to use their frozen oocytes, and some will never come back\nto use them [ 43 ].\nAnother indication are women who decide to postpone maternity\nfor many different reasons [ 44 ]. Here also the return rate is still low. Our group\nrecently published the first study on fertility preservation in women with\nendometriosis. Being a progressive disease, women with endometriosis are at risk of\npremature reduced ovarian reserve, so oocyte vitrification is a valid alternative to\nincrease their reproductive chances. We recently analyzed data from 485 women who\nunderwent fertility preservation for endometriosis at our institution [ 45 ]. Mean age was\n35.7 years, and those patients who underwent surgery prior to oocyte freezing had a\nyounger age (33.4 vs 36.7 years, p <0.05). The number of oocytes obtained, as well as\nthe cumulative live birth rate, was significantly higher in women who vitrified their\noocytes before surgery, and not after surgery. In this group of patients, we observed a\nhigher return rate than in oncological patients or social freezers, which could suggest\nthat, in these patients, the vitrification of oocytes was performed as an adjuvant\noption within the treatment of endometriosis-related infertility. Thus, the advantage of\nfertility preservation in young women with endometriosis is that they can obtain a good\nnumber of mature oocytes, and especially if the procedure is done prior to\nsurgery.\n\nEndometriosis has been described for\nmany decades, and it has been often linked to infertility. The impact of endometriosis\non fertility is mainly quantitative damage to the female reproductive tract, reducing\novarian reserve, oocyte and embryo quality, and quality of life, thus interfering with\nfertility. Even though there is a biological rationale for a lower oocyte quality as\nshown in basic research, this does not seem to translate when clinical data is analyzed.\nTreatments should be tailored carefully, as surgery does not improve the results of ART.\nIt should be carefully performed when the patient is symptomatic, as it may further\nreduce their ovarian reserve. Today, fertility preservation could be discussed with the\npatient prior to their surgery so they could vitrify their oocytes and have a valid\nalternative to have children in case surgery and/or disease progression compromises\ntheir ovarian reserve.","source_license":"CC0","license_restricted":false}