IVF stimulation protocols and outcomes in women

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<p>Best Practice & Research Clinical Obstetrics & Gynaecology 92 (2024) 102429</p><p>Available online 22 November 2023</p><p>1521-6934/© 2023 Elsevier Ltd. All rights reserved.</p><p>IVF stimulation protocols and outcomes in women</p><p>with endometriosis</p><p>Eduardo Goyri a,*, Graciela Kohls a, Juan Garcia-Velasco a</p><p>a IVI Madrid, Madrid, Spain</p><p>A R T I C L E I N F O</p><p>Keywords:</p><p>Endometriosis</p><p>Ovarian stimulation protocols</p><p>Fertility preservation</p><p>Ovarian surgery</p><p>A B S T R A C T</p><p>Endometriosis is a complex medical condition with a high prevalence in women of reproductive</p><p>age. Fertility is compromised in patients with endometriosis, and success in IVF treatments has</p><p>been a challenge leading to evaluation of different stimulation protocols. The long-standing</p><p>debate between GnRH agonist long protocols and short GnRH antagonist protocols is being</p><p>resolved in favor of the latter, since in addition to presenting equivalent results with respect to the</p><p>traditional option, they have the additional benefit of safety. The good results derived from</p><p>vitrification techniques have led to the development of new stimulation strategies, such as</p><p>progestin-primed ovarian stimulation (PPOS), with a greater degree of approval among patients.</p><p>None of the stimulation protocols currently applied in women with endometriosis has been shown</p><p>to be superior, so early intervention with an Assisted Reproduction treatment, regardless of the</p><p>chosen protocol, can provide these women with good chances of motherhood. Women with</p><p>endometrioma should be counseled for fertility preservation before planned ovarian endome-</p><p>trioma excision. The number of cryopreserved oocytes or embryos can be increased by repeated</p><p>cycles.</p><p>1. General overview about endometriosis</p><p>Endometriosis is a chronic medical condition that can significantly impact quality of life and is characterized by the presence of</p><p>functional endometrium growing outside the uterus. This tissue, known as endometrial implants, typically appears in the pelvic cavity</p><p>but can also affect other organs in the abdomen. It can cause a wide range of symptoms, such as pelvic pain, painful menstrual periods,</p><p>and dyspareunia. In some cases, it can also lead to infertility. Therefore, it is imperative to seek medical management to alleviate its</p><p>symptoms [1].</p><p>Several theories have been proposed to explain endometriosis development. A combination of genetic, hormonal, and environ-</p><p>mental factors likely contributes to the development of this condition. Some leading theories and potential causes of endometriosis</p><p>include retrograde menstruation, genetic and hormonal factors, immune system dysfunction, surgical or obstetric history, and envi-</p><p>ronmental factors [2]. It is important to note that, while these premises provide insights into the potential causes of endometriosis, the</p><p>condition’s exact origin remains a subject of ongoing research. Many individuals with endometriosis have multiple risk factors, and</p><p>symptoms and severity can be significatively diverse.</p><p>Endometriosis is a relatively common gynecological condition, and its prevalence varies among different populations and age</p><p>groups. Globally, endometriosis is estimated to affect around 10 % of women of reproductive age; this figure can change depending on</p><p>* Corresponding author.</p><p>E-mail address: eduardo.goyri@ivirma.com (E. Goyri).</p><p>Contents lists available at ScienceDirect</p><p>Best Practice & Research Clinical</p><p>Obstetrics & Gynaecology</p><p>journal homepage: www.elsevier.com/locate/bpobgyn</p><p>https://doi.org/10.1016/j.bpobgyn.2023.102429</p><p>Received 31 October 2023; Accepted 10 November 2023</p><p>mailto:eduardo.goyri@ivirma.com</p><p>www.sciencedirect.com/science/journal/15216934</p><p>https://www.elsevier.com/locate/bpobgyn</p><p>https://doi.org/10.1016/j.bpobgyn.2023.102429</p><p>https://doi.org/10.1016/j.bpobgyn.2023.102429</p><p>http://crossmark.crossref.org/dialog/?doi=10.1016/j.bpobgyn.2023.102429&domain=pdf</p><p>https://doi.org/10.1016/j.bpobgyn.2023.102429</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 92 (2024) 102429</p><p>2</p><p>the population studied and the criteria used for diagnosis. Endometriosis can be challenging to diagnose because symptoms can vary</p><p>widely, and some individuals may have the condition without experiencing significant symptoms [3]. The medical evaluation typically</p><p>involves a combination of medical history, physical examination, and in most cases, a surgical procedure for confirmation.</p><p>Endometriosis treatment aims to reduce symptoms, control pain, and improve quality of life. The treatment choice should consider</p><p>the severity of the symptoms, the individual’s age, reproductive goals, and the extent of the disease. The choice of treatment should be</p><p>tailored to each woman’s specific needs and objectives, and it often involves a multidisciplinary approach involving gynecologists,</p><p>pain specialists, and fertility specialists.</p><p>2. Endometriosis and infertility</p><p>Endometriosis can have a significant impact on fertility for some women. While not all people with endometriosis will experience</p><p>infertility, the condition is a known cause of fertility problems in some cases. Studies have shown that about 30–50 % of women with</p><p>endometriosis have infertility, and about 20–50 % of infertility patients have endometriosis.</p><p>Despite the clinically recognized association between endometriosis and infertility, the exact mechanism involved in developing</p><p>this link are not fully understood. Endometriosis is a systemic and multifactorial disease that directly and indirectly affects repro-</p><p>duction. The population of infertile patients with endometriosis is quite heterogenous, and the different phenotypes observed in a</p><p>clinical context make it more complicated to establish a precise diagnosis and a single mechanism by which endometriosis can lead to</p><p>infertility [3].</p><p>Endometriosis can predispose the formation of adhesions; these adhesions directly alter pelvic anatomy by binding pelvic organs</p><p>together, including the ovaries, Fallopian tubes, and uterus [4]. Other proposed pathological mechanisms include chronic inflam-</p><p>mation and oxidative damage leading to impaired fertilization process by altering the interactions between the sperm and the oocyte,</p><p>decreased ovarian function due to the endometriotic lesions within the ovary, abnormal receptivity of the eutopic endometrium, less</p><p>frequency of sexual intercourse due to painful intercourse, and possible surgical damage to the ovary after ovarian endometrioma</p><p>excision [5].</p><p>Clinical management of infertility due to endometriosis is challenging due to the heterogeneity in the population of women affected</p><p>by the disease, the lack of good-quality scientific evidence and the controversy between available guidelines [6]. From the patient’s</p><p>point of view, an informed and shared decision is mandatory since choosing between different treatment options has clinical and</p><p>personal implications. Treatment should be individualized according to the clinical situation and potential to deteriorate. Factors such</p><p>as a woman’s age, ovarian reserve, duration of infertility, and indications for an Assisted Reproductive treatment must be considered as</p><p>they will influence the treatment choice, and consequences.</p><p>3. Endometriosis: ovarian reserve, oocyte, and embryo quality</p><p>The ovary is the most common location of endometriosis. Ovarian reserve is one of the main prognostic factors concerning fertility</p><p>and is closely related to a woman’s age. Currently, the pathophysiological mechanism of decreased ovarian reserve in cases of</p><p>endometriosis remains diffuse. However, increasing histological, molecular, and morphological evidence demonstrates that endo-</p><p>metriomas have a detrimental effect on ovarian function.</p><p>The analysis of reproductive results in women with an endometrioma who had not undergone adnexal surgery suggested a decrease</p><p>in the ovarian response as a higher cancellation rate and fewer oocytes and embryos were observed [7,8]. Despite this global effect, it is</p><p>essential to highlight two issues</p><p>concerning endometrioma such as its size and bilaterality. Women with unilateral endometriomas</p><p>undergoing an in vitro fertilization [IVF] cycle showed that the affected ovary and the healthy one had a similar number of codominant</p><p>follicles and oocytes [9,10]. On the other hand, women with bilateral endometriomas have an even lower ovarian response; however,</p><p>pregnancy rates per transfer are not affected [11]. Cumulative livebirth rate may be lower due to the poorer ovarian response,</p><p>demonstrating the quantitative impact of the disease on fertility.</p><p>While it has not been statistically proven that endometriosis causes poor oocyte quality, some studies have shown that patients with</p><p>endometriosis tend to have impaired morphological features such as dark and granular ooplasm. As a result, they may have lower-</p><p>quality embryos and worse IVF outcomes [12–14]. Moreover, it has been shown that oocytes from women with ovarian endometri-</p><p>osis exhibited a different transcriptomic profile compared to oocytes from healthy donors [15]. Ther are impaired molecular mech-</p><p>anisms in oocytes of patients with endometriosis; treatments targeting these mechanisms could be therapeutic alternatives to improve</p><p>IFV outcomes for these patients [14].</p><p>Numerous investigations have been conducted to examine the quality of embryos that originate from oocytes of females with</p><p>endometriosis to determine if endometriosis affects embryo quality. As per a study of 235 human embryos, nuclear and cytoplasmic</p><p>impairment, cytoplasmic fragmentation, and uneven cleavage were observed to be more prevalent in embryos derived from oocytes of</p><p>females with endometriosis than those derived from patients with other forms of infertility [16].</p><p>Endometriosis may increase embryo aneuploidy due to alteration to the meiotic spindle, leading to poor IVF outcomes [17].</p><p>However, a study by Juneau et al. [18] demonstrated no difference in aneuploidy rate between endometriosis patients and healthy</p><p>women after IVF cycles. Aneuploidy rates were higher in older women, but no differences were observed between endometriosis</p><p>patients and those without endometriosis when aneuploidy rates were stratified by age.</p><p>E. Goyri et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 92 (2024) 102429</p><p>3</p><p>4. Endometriosis and assisted reproductive treatments</p><p>In patients with endometriosis-related infertility, Assisted Reproductive treatments are an appropriate option to achieve preg-</p><p>nancy. Assisted Reproduction treatments can circumvent the inflammatory processes limited to the pelvic cavity [4]. However, as</p><p>described in previous section and summarized in Fig. 1, there are many special features in patients with endometriosis which impact in</p><p>reproductive treatment has been a reason of debate and continuous research.</p><p>Intrauterine insemination is not considered an effective treatment to overcome detrimental effect of endometriosis in reproduction,</p><p>considering it could not reduce negative effect of oocyte quality, ovarian reserve, and tubal function among others. Moreover, it has</p><p>been associated with higher cumulative rate of recurrence [19].</p><p>In vitro fertilization with embryo transfer (IVF-ET) has gradually become an important treatment for patients with infertility and</p><p>endometriosis. Despite its high implementation, the influence of this disease on pregnancy rates after fertility treatment and the</p><p>effectiveness of Reproductive Medicine in these women continue to be a subject of great debate. The evidence regarding the outcomes</p><p>of patients with endometriosis is conflicting. While some studies have shown lower pregnancy rates in individuals with endometriosis</p><p>compared to those with other infertility causes who undergo IVF-ET, a comparison of data from assisted reproductive treatments in</p><p>women with and without endometriosis has not revealed significant differences in livebirth rates [20]. It is important to note that the</p><p>presence of ovarian endometriomas can affect the ovarian response during controlled ovarian stimulation. Compared to what happens</p><p>in women without endometriosis, those with ovarian endometriomas may have higher cancellation rates [21].</p><p>Current scientific evidence for IVF, egg donation treatments and transcriptomic analysis of endometrium indicate that endometrial</p><p>receptivity is not affected by the presence of the disease or its clinical stage. Impaired implantation rates in patients with endometriosis</p><p>are currently assumed to be due to oocyte and consequent embryo quality [22].</p><p>5. Down regulation pre-treatment for endometriosis</p><p>Considering that altered steroidogenesis in cases of endometriosis may be associated with infertility, the use of hormonal sup-</p><p>pression treatment has been investigated. Current scientific recommendations [23,24] indicate that ovarian suppression with danazol,</p><p>GnRH agonists or contraceptives should not be offered alone or in combination with surgery, as there is no evidence that it improves</p><p>pregnancy outcomes [25]. Furthermore, the results of a Cochrane review comparing the effectiveness of different periods of hormonal</p><p>suppression in a surgical context for endometriosis, concluded that post-surgical care with placebo or no drugs increased pregnancy</p><p>rates and reduced disease recurrence [26]; therefore, this indication would only apply to women who are not seeking pregnancy</p><p>immediately after surgery.</p><p>The role of down-regulation with GnRH agonists before an Assisted Reproductive treatment has been intensely debated since the</p><p>1990s, when it was suggested that long-term down regulation with GnRH agonists could improve the reproductive possibilities in</p><p>women with endometriosis. International guidelines fully supported this treatment thanks to a Cochrane review published in 2006</p><p>[27]; however, a second Cochrane meta-analysis in 2017 that superseded the 2006 review concluded that data are insufficient to</p><p>establish whether long-term GnRH agonist therapy affects the livebirth rate or the complication rate in women with endometriosis</p><p>undergoing standard IVF/ICSI. Similarly, it is unclear whether this therapy impacts the clinical pregnancy rate, multiple pregnancy</p><p>rate, miscarriage rate, mean number of oocytes, and mean number of embryos [28].</p><p>Due to their hypoestrogenic effects, GnRH agonists have been shown to be effective in the treatment of pelvic pain associated with</p><p>endometriosis. However, apart from their therapeutic effects on this pathology, these interventions have numerous side effects among</p><p>which we can highlight vasomotor symptoms, vaginal dryness, headache, or osteopenia. Add-back therapies are successfully used to</p><p>alleviate this undesirable symptomatology [29]. These are based on the re-administration of natural or synthetic steroid hormones, in</p><p>situations in which circulating levels have decreased as consequence of pituitary suppression. The main objective of the add-back</p><p>therapy is to normalize estradiol levels to values at which hypoestrogenic effects can be minimized but remain low enough to</p><p>Fig. 1. Proposed mechanisms of endometriosis-related infertility.</p><p>E. Goyri et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 92 (2024) 102429</p><p>4</p><p>prevent disease progression, in what is known as “the estrogen threshold hypothesis” [30]. Currently, the FDA has approved a single</p><p>add-back therapy treatment, which combines the use of a depot preparation of leuprolide acetate with 5 mg daily of norethindrone, a</p><p>potent oral progestin related to the metabolism of ethynyl-estradiol [31].</p><p>6. IVF ovarian stimulation protocols</p><p>In recent years, the debate</p><p>has intensified regarding the best ovarian stimulation protocol for patients with endometriosis un-</p><p>dergoing an Assisted Reproductive treatment. These women classically used to have prior to their IVF cycle the surgical procedure to</p><p>remove their endometriotic cysts, which can affect their ovarian reserve [4], but this paradigm has changed completely, leaving</p><p>surgery as a final option [1]. Optimizing treatments and finding the best protocol to achieve an adequate number of oocytes and</p><p>embryos is essential to achieve reproductive success. We describe different strategies to improve outcomes summarized in Fig. 2.</p><p>Natural or modified natural cycle. The clinical relevance is questionable, but this method can be a cheap and safe alternative</p><p>compared to conventional stimulated IVF cycles. However, it is extremely inefficient and rarely used.</p><p>GnRH agonists. They were introduced into stimulation protocols in early reproductive medicine. Its physiological activity is based</p><p>on the desensitization of pituitary receptors to control follicular synchrony and reduce the risks of premature LH surge. As mentioned</p><p>previously, hormonal suppression with GnRH agonists before an IVF cycle has no significant differences in terms of the number of</p><p>oocytes and embryos as well as clinical results [28].</p><p>A recent study conducted by Cao et al. [32], compared the effectiveness of three different protocols that involve administering</p><p>GnRH agonists: ultra-long, long, and short protocols. The study revealed that the ultra-long protocol was more effective in improving</p><p>pregnancy rates in randomized controlled trials [RCTs] compared to the long protocol- However, this improvement was not observed</p><p>in non-RCT trials.</p><p>Furthermore, in the randomized studies, the improvement observed with the ultra-long protocol was only evident in the most</p><p>severe cases of endometriosis (III/IV) stages. In contrast, the same effect was not observed in the mild modalities (I/II) stages. This fact</p><p>could be explained because the changes in pelvic anatomy, inflammatory response and the imbalance of endometrial microenvi-</p><p>ronment were heavier in women with severe pathology, so more time and more doses were needed to inhibit the inflammatory process</p><p>and restore the pelvic microenvironment. These results initially confirmed previous studies [33]. However, they were subsequently</p><p>refuted by two more recent RCTs [34,35], which did not demonstrate any benefit of the ultra-long protocol in terms of embryo quality</p><p>or gestational outcomes.</p><p>GnRH antagonists. Protocols with GnRH antagonists are characterized by an immediate interruption of pituitary activity right</p><p>after their administration. They are equally effective as GnRH agonists but with some advantages such as shorter treatment time,</p><p>decreased risk of OHSS, lower consumption of gonadotropin doses and greater patient acceptance [36]. Thus, no protocol that stands</p><p>out in the treatment of endometriosis; this is one of the reasons why the interest in GnRH antagonists has grown over the last years,</p><p>since they have proven to be just as beneficial as other “classical” drugs available [37].</p><p>Currently, two oral GnRH antagonists are available: elagolix and relugolix, both of which are approved by the FDA. Elagolix has</p><p>two fundamental advantages over GnRH agonists: it is administered orally and has a shorter half-life, allowing for more rapid elim-</p><p>ination from the system. Moreover, elagolix does not entirely block the pituitary gland, so the residual levels of estrogens can exert</p><p>their protective function and avoid secondary effects due to low estrogen levels, as opposed to the effect of GnRH agonists, which</p><p>completely down regulate estrogen production [38]. Clinical studies developed so far showed a dose-dependent reduction in</p><p>dysmenorrhea and non-menstrual pelvic pain compared to women who received a placebo; furthermore, it has been shown that</p><p>relugolix was non-inferior to leuprorelina for treating endometriosis-associated pelvic pain. Recent clinical evidence establishes that</p><p>oral GnRH antagonists are as effective as injected antagonists for pituitary suppression in controlled ovarian stimulation protocols [39,</p><p>Fig. 2. Described strategies to improve outcomes in reproductive treatments.</p><p>E. Goyri et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 92 (2024) 102429</p><p>5</p><p>40].</p><p>GnRH agonists vs. GnRH antagonists. Different studies have previously shown a higher number of retrieved oocytes and live</p><p>birth rates in protocols using GnRH agonists; however, to date, no prospective study has demonstrated significant differences between</p><p>them, so both are considered equally effective in daily clinical practice [41]. These studies are characterized by not discriminating</p><p>between fresh and frozen embryo transfers, except de work from Kolasnka et al. [42], which reversed this trend and concluded that</p><p>GnRH agonist protocols led to a significant improvement in pregnancy rates in patients with endometriosis; the authors relied on the</p><p>action of antagonists on endometrial receptivity rather than in the ovarian function to explain these data. In summary, despite the</p><p>hypothetical effect of GnRH antagonists on the endometrium, that have not been shown in other studies, pregnancy, and livebirth rates</p><p>in patients with endometriosis are similar between both treatment options [43–45]. So, we could conclude that endometriosis,</p><p>regarding ovarian stimulation, is not different from any other stimulated cycle. We should consider AMH, antral follicle count, body</p><p>mass index, and previous ovarian response-if any- and discuss with the patient the protocol to be considered, as GnRH antagonists are</p><p>equally effective but shorter in duration.</p><p>Progestin-primed ovarian stimulation [PPOS] protocol Initially aimed at fertility preservation for oncological reasons, this</p><p>protocol has seen relatively few studies in endometriosis. The reason for using progestins is that they are just as effective as GnRH</p><p>antagonists in preventing premature LH surge. Recently [46], it was investigated whether prolonged suppression with dienogest, a</p><p>highly selective progestin for the progesterone receptor improved reproductive results before an IVF. Authors showed that women</p><p>under prolonged suppression with progestins retrieved significantly fewer oocytes, directly affecting pregnancy rates compared to the</p><p>results derived from long GnRH agonist protocols.</p><p>Subsequently, two non-randomized studies comparing PPOS vs. GnRH antagonist protocols reported similar number of retrieved</p><p>oocytes in both study groups [47,48], concluding that the PPOS protocol could be a good alternative in women with endometriosis</p><p>when a fresh embryo transfer is not planned. Finally, although more studies are needed to draw robust evidence on the applicability of</p><p>PPOS protocol in endometriosis, it is not possible to anticipate that progestins other than medroxyprogesterone acetate or dydro-</p><p>gesterone would report different rates. From a pragmatic point of view, a woman who is already being treated with a progestin to</p><p>control her symptoms could start gonadotropin stimulation right away and continue taking the same progestin [49].</p><p>7. Fertility preservation</p><p>The need for reproductive counselling from a multidisciplinary medical team has become increasingly evident in endometriosis not</p><p>only before surgery but also at the time of diagnosis, based on the premise that fertility can be seriously compromised in this group of</p><p>women [50].</p><p>Endometriosis is a potential indication for fertility preservation. Due to the high clinical heterogeneity of this pathology, the</p><p>challenge lies in defining the groups of patients who can benefit from this technique. Moreover, success depends on ovarian perfor-</p><p>mance and patient’s age at the time of freezing.</p><p>The number of oocytes retrieved in women with endometriosis who undergo an ovarian stimulation process is substantially</p><p>reduced, particularly in the presence of large and bilateral endometriomas [51]. Previous studies have shown that in women with</p><p>endometriosis, fertility preservation treatment is recommended before surgery to increase the number of retrieved oocytes [52,53].</p><p>Nevertheless, it is possible to restore the cumulative livebirth rates in these women when an equivalent number of oocytes can be</p><p>retrieved [53,54].</p><p>In conclusion, it is necessary to raise early counselling in shared decision making with the patients when addressing reproductive</p><p>planning if there is ovarian endometriosis due to the implications it entails ovarian reserve and an increased risk of developing pre-</p><p>mature ovarian insufficiency [55].</p><p>Oocyte vitrification offers women with ovarian endometriomas an effective and reliable option to increase their chances of</p><p>motherhood, mainly when they are young and have large, bilateral endometriomas requiring surgical intervention. The benefit of</p><p>fertility preservation in women with ovarian endometriosis must be recognized.</p><p>8. Summary</p><p>Infertile women with endometriosis undergo an ovarian stimulation process in the context of Assisted Reproduction treatment,</p><p>because of the progressive nature of the disease, with or without surgical intervention.</p><p>The decrease in fertility in women with endometriosis is more related to quantitative than qualitative damage. At first, ovarian</p><p>stimulation was approached with long treatments of pituitary suppression with GnRH agonists, but they were soon replaced by</p><p>treatment with GnRH antagonists due to their advantages in the form of shorter treatment and with fewer doses of gonadotropins.</p><p>Research published up to date support the possibility if using both options interchangeably, since they lead to similar number of</p><p>retrieved oocytes and pregnancy rates. Finally, it is advisable to consider PPOS protocols in those cycles in a which a fresh embryo</p><p>transfer is not intended.</p><p>Since women with endometriosis are at risk of having a compromised ovarian reserve due to both pathological and iatrogenic</p><p>causes, it is necessary to consider fertility preservation as a reproductive treatment option. Approach to fertility preservation must be</p><p>individualized and contemplating age, ovarian reserve and surgical interventions as determining factors in the success of the</p><p>treatment.</p><p>E. Goyri et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 92 (2024) 102429</p><p>6</p><p>Practice points</p><p>1. When treating young patients with endometriosis, it’s important to take a multidisciplinary approach that involves fertility</p><p>specialists.</p><p>2. Encourage fertility preservation, particularly when endometriomas are present.</p><p>3. Pre-treatment with GnRH agonists is not recommended to improve outcomes in fertility treatments.</p><p>4. Stimulation protocols with GnRH antagonists are preferred.</p><p>5. When no fresh transfer is planned, it’s advisable to consider using PPOS as a pituitary suppressor, especially if PPOS are used just</p><p>before stimulation to control symptoms of endometriosis.</p><p>Research agenda</p><p>1. Specific genetic profiles of patients with different features of endometriosis</p><p>2. Patient friendly stimulation protocols in patients with endometriosis</p><p>3. Treatments targeting specific molecular mechanisms of endometriosis-related infertility.</p><p>Role of the founding source</p><p>This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.</p><p>MCQ</p><p>1. About endometriosis and infertility, it is true that:</p><p>a. About 75 % of patients with endometriosis have infertility.</p><p>b. Phenotypes of women affected by endometriosis are homogeneous.</p><p>c. Tubal factor is the only cause of infertility.</p><p>d. Pathological mechanisms include pelvic adhesions, oxidative stress, and chronic inflammation.</p><p>Correct answer: d</p><p>About 30–50 % of patients with endometriosis have infertility. The population of infertile patients with endometriosis is quite</p><p>heterogeneous, and the different phenotypes observed in a clinical context make it more complicated to establish a precise diagnosis</p><p>and a single mechanism by which endometriosis can lead to infertility. Endometriosis can predispose the formation of adhesions; these</p><p>adhesions directly alter pelvic anatomy by binding pelvic organs together, including the ovaries, Fallopian tubes, and uterus. Other</p><p>proposed pathological mechanisms include chronic inflammation and oxidative damage leading to impaired fertilization process.</p><p>2. Endometriosis and ovarian function:</p><p>a. Ovaries are an uncommon location of endometriosis implants.</p><p>b. It is clearly established that endometriosis do not affect oocyte quality.</p><p>c. There are impaired molecular mechanisms and morphological changes in oocytes of patients with endometriosis.</p><p>d. Endometriomas do not affect ovarian reserve.</p><p>Correct answer: c</p><p>The ovary is the most common location of endometriosis. Increasing histological, molecular, and morphological evidence dem-</p><p>onstrates that endometriomas have a detrimental effect on ovarian function. Patients with endometriosis tend to have impaired</p><p>morphological features such as dark and granular ooplasm and impaired molecular mechanisms.</p><p>The analysis of reproductive results in women with an endometrioma who suggested a decrease in the ovarian response as a higher</p><p>cancellation rate and fewer oocytes and embryos were observed.</p><p>3. Studies of In-vitro fertilization treatments of patients with endometriosis-related infertility describe that:</p><p>a. No differences in aneuploidy rates were observed between endometriosis patients and those without endometriosis when aneu-</p><p>ploidy rates were stratified by age.</p><p>b. Endometrial receptivity is affected by the presence of the disease or its clinical stage.</p><p>c. Considering IVF overcomes tubal factor, it is clearly established that patient with endometriosis have the same or better outcomes</p><p>than patients with other causes of infertility.</p><p>d. The presence of endometriomas do not affect ovarian response.</p><p>Correct answer: a</p><p>The evidence regarding the outcomes of patients with endometriosis is conflicting. While some studies have shown lower</p><p>E. Goyri et al.</p><p>Best Practice & Research Clinical Obstetrics & Gynaecology 92 (2024) 102429</p><p>7</p><p>pregnancy rates in individuals with endometriosis compared to those with other infertility causes who undergo IVF-ET, a comparison</p><p>of data from assisted reproductive treatments in women with and without endometriosis has not revealed significant differences in live</p><p>birth rates. It is important to note that the presence of ovarian endometriomas can affect the ovarian response during controlled</p><p>ovarian stimulation. No difference in aneuploidy rate between endometriosis patients and healthy women after IVF cycles. Aneuploidy</p><p>rates were higher in older women, but no differences were observed between endometriosis patients and those without endometriosis</p><p>when aneuploidy rates were stratified by age. Current scientific evidence from IVF, egg donation treatments, and transcriptomic</p><p>analysis of endometrium indicate that endometrial receptivity is not affected by the presence of the disease or its clinical stage.</p><p>4. About strategies to improve outcomes in patients with endometriosis, it is true that:</p><p>a. Pre-treatment with GnRH agonists improves outcomes.</p><p>b. Pituitary suppression with GnRH agonists during ovarian stimulation shows more efficacy and better outcomes than suppression</p><p>with GnRH</p><p>antagonists.</p><p>c. It is demonstrated that excision of endometriomas before IVF, improves outcomes.</p><p>d. In patients with endometriosis, fertility preservation treatment is recommended before surgery to increase the number of retrieved</p><p>oocytes.</p><p>Correct answer d</p><p>Hormonal pituitary suppression with GnRH agonists before an IVF cycle has no significant differences in terms of the number of</p><p>oocytes and embryos as well as clinical results.</p><p>The number of oocytes retrieved in women with endometriosis who undergo an ovarian stimulation process is substantially</p><p>reduced, particularly in the presence of large and bilateral endometriomas. Previous studies have shown that in women with endo-</p><p>metriosis, fertility preservation treatment is recommended before surgery to increase the number of retrieved oocytes.</p><p>Declaration of competing interest</p><p>The authors declare that they have no competing interest.</p><p>References</p><p>[1] Chapron C, Marcellin L, Borghese B, Santulli P. Rethinking mechanisms, diagnosis and management of endometriosis. 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