Should intrauterine inseminations still be proposed in cases of unexplained infertility? Retrospective study and literature review.

OBJECTIVE: Unexplained infertility is defined by the absence of identifiable causes of infertility. The results of randomized studies and meta-analysis regarding the treatment of unexplained infertility are discordant due to methodological problems. DESIGN: The aim of this study is to compare the clinical pregnancy rate per cycle (CPR/c) in IUI and IVF/ICSI in cases of unexplained infertility, according to the woman's age group and to identify the factors which predict success. INTERVENTIONS: We performed a retrospective study in two ART centers, comparing overall clinical pregnancy, ongoing pregnancy and live birth rates in IVF/ICSI and IUI. We also compared pregnancy and birth rates according to different female age groups. RESULTS: 855 IVF/ICSI and 804 IUI cycles were compared. We found a significant difference (p < 0.001) in the pregnancy and live birth rates per cycle between IUI and IVF/ICSI, overall and in the different female age groups, except in women aged 40 and over. The greatest chances of pregnancy with IUI are found in women with secondary unexplained infertility, during the first two cycles and with a bi-follicular response to stimulation. In IVF/ICSI, pregnancy rates are higher in women with secondary unexplained infertility, in the first two cycles, in IVF and in women receiving a transfer of two embryos regardless of the embryonic stage. CONCLUSION: We recommend IVF/ICSI treatment rather than IUI for unexplained infertility (OR CPR/c 4.20 with 95% CI [3.72-4.68]). This is in accordance with NICE, which advises the use of IVF after 2 years.

Impact of Endocrine Disruptors upon Non-Genetic Inheritance.

Similar to environmental factors, EDCs (endocrine-disrupting chemicals) can influence gene expression without modifying the DNA sequence. It is commonly accepted that the transgenerational inheritance of parentally acquired traits is conveyed by epigenetic alterations also known as "epimutations". DNA methylation, acetylation, histone modification, RNA-mediated effects and extracellular vesicle effects are the mechanisms that have been described so far to be responsible for these epimutations. They may lead to the transgenerational inheritance of diverse phenotypes in the progeny when they occur in the germ cells of an affected individual. While EDC-induced health effects have dramatically increased over the past decade, limited effects on sperm epigenetics have been described. However, there has been a gain of interest in this issue in recent years. The gametes (sperm and oocyte) represent targets for EDCs and thus a route for environmentally induced changes over several generations. This review aims at providing an overview of the epigenetic mechanisms that might be implicated in this transgenerational inheritance.

Endometrium Immunomodulation to Prevent Recurrent Implantation Failure in Assisted Reproductive Technology.

After more than four decades of assisted reproductive technology (ART) practice worldwide, today more than 60% of women undergoing in vitro fertilization (IVF) treatments fail to become pregnant after the first embryo transfer and nearly 20% of patients are suffering from unexplained recurrent implantation failures (RIFs) and repeated pregnancy loss (RPL). The literature reported different causes of RIF-RPL, mainly multifactorial, endometrial and idiopathic. RIF remains a black box because of the complicated categorization and causes of this physio-pathological dysregulation of implantation and pregnancy process after ovarian stimulation. Many options were suggested as solutions to treat RIF-RPL with controversial results on their usefulness. In this article, we reviewed different possible therapeutic options to improve implantation rates and clinical outcomes. Based on our experience we believe that endometrium immunomodulation after intrauterine insemination of activated autologous peripheral blood mononuclear cells (PBMCs) or platelet-rich plasma (PRP) can be a promising therapeutic solution. On the other hand, peripheral lymphocyte balance typing, specific cytokines and interleukins profiling can be proposed as predictive biomarkers of implantation before embryo transfer.

Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player.

Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50-70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20-100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.

Seminal cell-free DNA and sperm characteristic's: An added biomarker for male infertility investigation.

Cell-free DNA (Cf-DNA) fragments may constitute an easy-to-measure molecular tool for guiding the choice of care provided to infertile couples who benefit assisted reproductive technology (ART) programmes. Data on Cf-DNA levels in the seminal plasma of men with sperm alterations are scarce. The objective of the present study was to quantify the presence of Cf-DNA in semen by using a quantitative real-time PCR. We compared men with abnormal sperm characteristics (n = 21) with normospermic controls (n = 21). The PCR assay evidenced significantly higher mean Cf-DNA levels in patients with sperm abnormalities than in controls (2.09 versus 1.18 µg/ml, respectively; p = .0003). The Cf-DNA levels were notably higher in men with azoospermia (3.65 µg/ml, versus 1.34 µg/ml in matched controls; p = .03) and men with teratozoospermia (1.80 µg/ml, versus 1.29 µg/ml in matched controls; p = .008). Our data report a significant association between elevated Cf-DNA levels and sperm abnormalities. These results may open up new diagnostic and prognostic perspectives in male infertility.

Pregnancy after oocyte donation in a patient with NLRP7 gene mutations and recurrent molar hydatidiform pregnancies.

Molar pregnancies are benign trophoblastic diseases associated with a risk of malignant transformation. If aetiology remains mostly unknown, the risk of recurrent molar pregnancy is around 1.5% after one molar pregnancy and around 25% after 2 molar pregnancies. In the later situation, genetic mutations have been described, increasing hugely this risk. In case of mutations, probability to obtain a normal pregnancy is estimated around 1.8%. We report the case of a Caucasian 30-year-old woman whose previous five spontaneous pregnancies had a negative outcome: a spontaneous miscarriage and then 4 complete hydatidiform moles. Genetic testing revealed that the patient carried two heterozygous mutations in the NLRP7 gene (c.2982-2A > G and Y318CfsX7). According to this, counselling was conducted to advocate for oocyte donation in order to obtain a normal pregnancy. This technique enabled a complication-free, singleton pregnancy that resulted in a healthy term live birth of a 2900 g female. Few months after delivery, the patient presented a new complete hydatidiform mole. Women presented with mutations in the NLRP7, KHDC3L or PADI6 genes are unlikely to obtain normal pregnancies, with a major risk of reproductive failure. In such a context, oocyte donation may be the best option. Only 4 normal pregnancies and deliveries have been published in this situation through this technique to our knowledge.

New intragenic rearrangements in non-Finnish mulibrey nanism.

Prenatal growth is a complex dynamic process controlled by various genetic and environmental factors. Among genetic syndromes characterized by growth restriction, MULIBREY nanism represents a rare autosomal recessive condition presenting with severe pre- and post-natal growth failure, characteristic dysmorphic features but normal neurological development. The phenotype of MULIBREY nanism is variable and overlaps with others such as the Silver-Russell syndrome. We report here three patients in two distinct non-Finnish families from North France who were first suspected to have Silver-Russell syndrome which failed to be confirmed on molecular analyses. Clinical features in the three patients led us to also consider the diagnosis of MULIBREY nanism. Sequencing of the TRIM37 gene showed the three patients shared a novel nonsense mutation (c.181 C>T p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the deletions were localized in Alu sequences. Given the high number of Alu repeats, which predispose to gene rearrangements, one should always consider such genetic rearrangements in the molecular diagnosis of non-Finnish MULIBREY nanism patients. Early diagnosis of the disease would prompt careful cardiac follow up of such patients as cardiological complication is a characteristic feature of the MULIBREY nanism as described in this report.

[Intrauterine insemination]. / Une étape nécessaire dans la prise en charge du couple infertile: Inséminations intra-utérines.

The intrauterine insemination with husband's sperm is an assisted reproductive technologie, as proposed in the case of cervical infertility, moderate male infertility, dysovulation, mild or moderate endometriosis or unexplained infertility. In the last three indications the ovarian stimulation is necessary. The couple demographic criteria (age of both partners, lifestyle, duration of infertility) and the results of the infertility evaluation (ovarian reserve, uterus, spermogram-spermocytogram) increase the chances of pregnancy by intrauterine insemination with husband's sperm and reduce the risk of multiple pregnancies. Pregnancy rates observed ranged from 8 to 20% per cycle according to indications.

Human papillomavirus carriage in the semen of men consulting for infertility: prevalence and correlations with sperm characteristics.

ABSTRACT: We aim to study the semen carriage of human papillomavirus (HPV) and evaluate its association with patient characteristics. We conduct a single-center cohort study at Amiens University Hospital Center (Amiens, France). From May 1 to October 31, 2021, 461 men consulting for infertility and with semen analysis data were included. Each participant gave his written informed consent for the use of laboratory, demographic, clinical, and lifestyle data. A proportion of the semen samples were sent to a virology laboratory for HPV screening in a polymerase chain reaction (PCR) assay. In univariate and multivariate analyses with a logistic regression model, HPV + and HPV - groups were compared with regard to semen characteristics (including the DNA fragmentation index and the sperm decondensation index) and demographic, clinical, and lifestyle variables. Semen HPV carriage was detected in 22.3% of the patients. High-oncogenic-risk HPV genotypes were predominant (57.6%). Multivariate analysis showed that HPV carriage was significantly associated with the presence of at least one abnormal spermogram dinging (according to the 6 th World Health Organization criteria), with an adjusted odds ratio (OR) of 4.10 (95% confidence interval [CI]: 2.32-7.25, P < 0.001). A statistically significant association was also found for the type of infertility (OR: 1.61, 95% CI: 1.00-2.57, P = 0.05), the presence of varicocele (OR: 3.99, 95% CI: 1.48-10.71, P = 0.01), and a history of cryptorchidism, testicular ectopia, or monorchidism (OR: 3.54, 95% CI: 1.07-11.66, P = 0.04). Infection with a single HPV genotype or multiple HPV genotypes was significantly associated with at least one abnormal spermogram finding for all HPV oncogenic risk groups (OR: 3.93, 95% CI: 2.08-7.41, P < 0.001; and OR: 4.11, 95% CI: 1.58-10.68, P = 0.01, respectively). The association between sperm HPV carriage and the risk of infertility was statistically significant in a multivariate analysis (OR: 5.63, 95% CI: 3.16-10.01, P < 0.001) and after adjustment for the propensity score (OR: 6.10, 95% CI: 3.33-11.21, P < 0.001). Our results suggest that semen HPV carriage has an impact on male fertility. Sperm screening for HPV might be a useful addition to the work-up for male infertility.

Genome and Epigenome Disorders and Male Infertility: Feedback from 15 Years of Clinical and Research Experience.

Infertility affects around 20% of couples of reproductive age; however, in some societies, as many as one-third of couples are unable to conceive. Different factors contribute to the decline of male fertility, such us environmental and professional exposure to endocrine disruptors, oxidative stress, and life habits with the risk of de novo epigenetics dysregulation. Since the fantastic development of new "omes and omics" technologies, the contribution of inherited or de novo genomes and epigenome disorders to male infertility have been further elucidated. Many other techniques have become available to andrology laboratories for the investigation of genome and epigenome integrity and the maturation and the competency of spermatozoa. All these new methods of assessment are highlighting the importance of genetics and epigenetics investigation for assisted reproduction pathology and for supporting professionals in counselling patients and proposing different management strategies for male infertility. This aims to improve clinical outcomes while minimizing the risk of genetics or health problems at birth.

Paternal Age Matters: Association with Sperm Criteria's- Spermatozoa DNA Integrity and Methylation Profile.

Advanced age has been reported to negatively affect sperm parameters and spermatozoa DNA integrity. A decline in sperm criteria was also associated with altered epigenetic marks such as DNA methylation with a potential downstream impact on in vitro fertilization success and clinical outcomes. The aim of the present retrospective study was to clarify the association between advanced paternal age (APA) and sperm parameters, DNA integrity and DNA methylation profile. A total of 671 patients consulting for infertility underwent sperm analysis, sperm DNA integrity assessment and methylation level measurement. The principal finding was that individuals over 40 years of age exhibit a significant increase in DNA fragmentation levels compared to the younger group (15% versus 9%, respectively, p = 0.04). However, there was no significant difference in DNA decondensation and sperm parameters in association with APA. In addition, a drop in the global methylation level was also found in men over 40 years (6% in the young group versus 2% in the old group, p = 0.03). As a conclusion, men over 40 years are at higher risk of elevated sperm DNA fragmentation and lower methylation level. Based on these observations, it is recommended that the assessment of sperm DNA fragmentation should be taken into consideration particularly after the age of 40. Our findings support the idea that paternal age is a crucial factor that should not be neglected during fertility evaluation and treatment since it is associated with epigenetics changes in sperm. Although the underlying mechanism remains to be clarified, we believe that environmental and professional exposure factors are likely involved in the process.

Endocrine disrupting chemicals and male fertility: from physiological to molecular effects.

The deleterious effects of chemical or non-chemical endocrine disruptors (EDs) on male fertility potential is well documented but still not fully elucidated. For example, the detection of industrial chemicals' metabolites in seminal plasma and follicular fluid can affect efficiency of the gametogenesis, the maturation and competency of gametes and has guided scientists to hypothesize that endocrine disrupting chemicals (EDCs) may disrupt hormonal homoeostasis by leading to a wide range of hormonal control impairments. The effects of EDCs exposure on reproductive health are highly dependent on factors including the type of EDCs, the duration of exposure, individual susceptibility, and the presence of other co-factors. Research and scientists continue to study these complex interactions. The aim of this review is to summarize the literature to better understand the potential reproductive health risks of EDCs in France.

Effect of pesticide exposure on human sperm characteristics, genome integrity, and methylation profile analysis.

According to the United Nations' Food and Agriculture Organization, the quantities of pesticide used around the world have increased regularly since the 1990s. Given that pesticides may be classified as carcinogenic, mutagenic, neurotoxic, or toxic for reproduction, some have endocrine-disrupting properties that might be associated with a decline in sperm parameters in general and sperm DNA integrity in particular. These days, a sperm analysis is not enough to determine the etiology of male infertility. Genome integrity analysis is a key step in clarifying a large proportion of cases of male infertility. The objective of the present retrospective study was to assess the impact of self-reported pesticide exposure on sperm parameters and sperm DNA integrity in men consulting for infertility. In a retrospective study, a population of 671 men living in the Picardy region of France were assessed in a conventional sperm parameter analysis, Shorr staining, a DNA fragmentation assay (terminal deoxynucleotidyl transferase-mediated dUDP nick-end labelling), and chromatin decondensation with aniline blue staining. The exposed and the non-exposed groups did not differ significantly in some of the conventional sperm parameters (including volume, sperm count, and percent typical forms). However, vitality, progressive motility, and non-progressive motility were significantly lower in the exposed group. Levels of DNA fragmentation and chromatin decondensation were moderately higher in the exposed group.

Growth hormone replacement improved oocyte quality in a patient with hypopituitarism: A study of follicular fluid.

BACKGROUND: Growth hormone (GH) is known to be involved in ovarian folliculogenesis and oocyte maturation. In patients with poor ovarian response without growth hormone deficiency (GHD), adjuvant GH treatment improves in-vitro fertilization (IVF) results. Improvement of oocyte quality in IVF by GH replacement was reported in only a few patients with GHD. We report on a new case with study of follicular fluid. METHODS: A 29-year-old patient with hypopituitarism was referred to our infertility center. She was undergoing hormonal replacement for hypogonadotropic hypogonadism and diabetes insipidus, and did not consider at first GH replacement. Four IVF procedures were performed between 2011 and 2014. Growth hormone replacement (somatotropin 1.1mg/day) was initiated before the fourth IVF procedure and unmasked central hypothyroidism; levothyroxine (75mg/day) was introduced. It took 10 months to reach the treatment objectives for insulin-like growth factor 1 (IGF1), free triiodothyronine (fT3) and free thyroxine (fT4). GH, IGF1 and thyroid hormones were measured in the blood and follicular fluid before and after GH and thyroid hormone replacement. Oocyte and embryo quality were also compared. RESULTS: The first 3 IVF procedures were performed without GH replacement. 62% to 100% of mature oocytes presented one or more morphologic abnormalities: diffuse cytoplasmic granularity, large perivitelline space with fragments, fragmentation of the first polar body, ovoid shape, or difficult denudation. Embryo quality was moderate to poor (grade B to D), and no pregnancy was obtained after embryo transfer. After GH replacement, hormones levels increased in follicular fluid: GH [7.68 vs. 1.39 mIU/L], IGF1 [109 vs. <25ng/mL], fT3 [3.7 vs. 2.5pmol/L] and fT4 [1.45 vs. 0.84ng/mL]. Concomitantly, there was dramatic improvement in oocyte quality (no abnormal morphologies) and embryo quality (grade A), allowing an embryo transfer with successful pregnancy. CONCLUSIONS: This is the first report illustrating changes in hormonal levels in follicular fluid and the beneficial effect of GH replacement on oocyte and embryo quality during an IVF procedure in a patient with hypopituitarism. These results suggest that GH replacement is beneficial for oocyte quality in patients with GHD.

Follicular GH and IGF1 Levels Are Associated With Oocyte Cohort Quality: A Pilot Study.

Introduction: Oocyte quality contributes to the development of an optimal embryo and thus a successful pregnancy. The objective of this study was to analyse the association between oocyte cohort quality and the follicular levels of growth hormone (GH), insulin-like growth factor 1 (IGF1), 25-hydroxy vitamin D (25OHD), thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4) and antithyroid antibodies, as a function of intracytoplasmic sperm injection (ICSI) outcomes. Material and methods: We conducted a prospective comparative pilot study from January 2013 to December 2017. 59 ICSI cycles constituted an abnormal oocyte cohort (n=34 cycles, in which more than 50% of oocytes presented at least one morphological abnormality) and a normal oocyte cohort (n=25 cycles, in which 50% or less of the oocytes presented at least one morphological abnormality). GH, IGF1, 25OHD, TSH, fT3, fT4 and antithyroid antibodies were measured in follicular fluid. Results: The fertilisation rate was lower in the abnormal oocyte cohort (65.5% vs. 80%, respectively, p=0.012). Oocytes' proportion with at least one abnormality was 79.4% in the abnormal oocyte cohort and 29.0% in the normal oocyte cohort. The mean number of morphological abnormalities per oocyte was significantly higher in the abnormal oocyte cohort. The follicular levels of GH (4.98 vs. 2.75 mIU/L, respectively; p <0.01) and IGF1 (72.1 vs. 54.2 ng/mL, respectively; p=0.05) were higher in the normal oocyte cohort. There was no association with follicular levels of TSH, fT3, fT4, antithyroid antibodies, or 25OHD. Conclusion: Oocyte cohort quality appears to be associated with follicular levels of GH and IGF1.

Can Ratios Between Prognostic Factors Predict the Clinical Pregnancy Rate in an IVF/ICSI Program with a GnRH Agonist-FSH/hMG Protocol? An Assessment of 2421 Embryo Transfers, and a Review of the Literature.

None of the models developed in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) is sufficiently good predictors of pregnancy. The aim of this study was to determine whether ratios between prognostic factors could predict the clinical pregnancy rate in IVF/ICSI. We analyzed IVF/ICSI cycles (based on long GnRH agonist-FSH protocols) at two ART centers (the second to validate externally the data). The ratios studied were (i) the total FSH dose divided by the serum estradiol level on the hCG trigger day, (ii) the total FSH dose divided by the number of mature oocytes, (iii) the serum estradiol level on the trigger day divided by the number of mature oocytes, (iv) the serum estradiol level on the trigger day divided by the endometrial thickness on the trigger day, (v) the serum estradiol level on the trigger day divided by the number of mature oocytes and then by the number of grade 1 or 2 embryos obtained, and (vi) the serum estradiol level on the trigger day divided by the endometrial thickness on the trigger day and then by the number of grade 1 or 2 embryos obtained. The analysis covered 2421 IVF/ICSI cycles with an embryo transfer, leading to 753 clinical pregnancies (31.1% per transfer). Four ratios were significantly predictive in both centers; their discriminant power remained moderate (area under the receiver operating characteristic curve between 0.574 and 0.610). In contrast, the models' calibration was excellent (coefficients: 0.943-0.978; p < 0.001). Our ratios were no better than existing models in IVF/ICSI programs. In fact, a strongly discriminant predictive model will be probably never be obtained, given the many factors that influence the occurrence of a pregnancy.

Fertility preservation and sperm donation in transgender individuals: The current situation within the French CECOS network.

BACKGROUND: Many studies reported that reproductive desire could be high among transgender individuals. In France, fertility preservation and sperm donation were very little proposed to transgender individuals until recently, mainly because the Bioethics Law allows the use of assisted reproductive technologies only in infertile couples and prohibits surrogacy. OBJECTIVES: To evaluate the distribution of care on the French territory concerning fertility preservation and sperm donation in transgender individuals. MATERIALS AND METHODS: A multicentric national survey was carried out between January 2019 and October 2020 in 28 assisted reproductive technology centres of the French CECOS (Centres d'Etudes et de Conservation des Oeufs et du Sperme) network. Each centre was questioned to find out how many transgender individuals came, were informed and cared for fertility preservation and sperm donation. RESULTS: Concerning fertility preservation, 71.4% of centres received transgender individuals and performed gamete cryopreservation; 581 transgender individuals consulted for fertility preservation. Transgender women were more likely to desire (p < 0.0001) and achieve (p < 0.0001) fertility preservation than transgender men. Concerning sperm donation in couples including a transgender man, 68% of centres offer the complete course from the first consultation to the completion of the assisted reproductive technology cycles; 122 offsprings have been conceived with sperm donation in couples including a transgender man since 1999. DISCUSSION: Our results showed that even if all centres do not propose fertility preservation or sperm donation in transgender individuals, these assisted reproductive technologies are present throughout the French territory. The major point is that both fertility preservation and sperm donation in transgender individuals have grown significantly and that the care of these patients is improving year after year. CONCLUSION: In France, most of CECOS centres can take care of transgender individuals for fertility preservation and sperm donation. The French Bioethics Law allows these latter, and transgender individuals can benefit from a financial support of the national health care insurance for fertility preservation and sperm donation.

The impact of endocrine disruptor chemicals on oocyte/embryo and clinical outcomes in IVF.

The negative impact of endocrine-disrupting pesticides on human fertility is now a key issue in reproductive health. There are much fewer literature data about the impact of pesticide exposure on women than on men and very few studies of women participating in an in vitro fertilization (IVF) programme. In the present review, we found that (1) various pesticides with an endocrine-disrupting action are associated with poor oocyte maturation and competency, embryonic defects and poor IVF outcomes, and (2) some pesticide compounds are linked to specific causes of female infertility, such as premature ovarian insufficiency, polycystic ovarian syndrome, and endometriosis. IVF participants living in agricultural regions should be informed about the fertility decline, low ongoing pregnancy rates, and elevated risk of miscarriage associated with exposure to high doses of pesticides.

It Is Necessary to Purpose an Add-on to the American Classification of Endometriosis? This Disease Can Be Compared to a Malignant Proliferation While Remaining Benign in Most Cases. EndoGram® Is a New Profile Witness of Its Evolutionary Potential.

Endometriosis is a curious pathology that has been the topic of many international publications. Its etiology remains mysterious but seems to have multiple causes. It is a complex disease whose lesions are very heterogeneous in where they can occur (deep endometriosis, superficial, ovarian cyst), extent, associated symptoms, evolution or aggressiveness of the disease, and response to treatments. Furthermore, it evolves in pushes, remains autonomous, and is responsible for both superficial and deep lesions that explain its two most well know challenges: pain and infertility. It has always been classified by the size of its anatomical lesions-Acosta classification (1), revised by the American fertility society (AFS) (2), and the American society of reproductive medicine (ASRM) classification with a description of the disease at different stages: minimal (score of 1 to 5), mild (3-12), moderate (16 to 40), and severe (>40) (13). If this classification provides a complete repertoire of implants (anatomic) (10), the attribution of points is arbitrary. In fact, the size of the lesions is not synonymous with the difficulty to treat them surgically. Their location, if deep, is larger than the size of ovarian endometriomas. In addition, small anatomical but evaluative lesions will have a larger impact than big fibrous and stable lesions (Figure 1). Thus, attempts to explain their inflammatory side effects have been proposed (14, 15). The French classification nodule, ovaries, adhesions, tube, and inflammation (FOATI) (10) has had the merit of taking this phenomenon into account. In our opinion, we must go much further and propose an amendment in this classification, taking into account the evolution of the lesions and their deep molecular biology because in reality, the lesions are not at the same stage.