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Previous evidence seems to support the more common presence of certain pigmentation types in women with endometriosis. The aim of this study was to assess the association of certain somatic phenotypes with specific localizations of the disease. The genetic makeup of those somatic traits may will help in better define the disease pathogenesis.Multicentric, retrospective study of women aged 18 to 45 with histologically confirmed endometriosis. 575 patients were recruited at eleven different Italian endometriosis clinics from March 2015 to January 2021. Data regarding clinical and surgical features were recorded following the self-administered endometriosis patient questionnaire and the surgical standard of reports approved by the World Endometriosis Research Foundation (WERF). Pigmentation types/somatic phenotypes frequencies among endometriosis localizations were reported. A logistic regression analysis was performed to determine somatic types independently associated with disease' localizations.Having green eyes increased by ∼4 folds (OR 3.7; 95% CI: 1.42-9.61; p = 0.007) the risk of having a ureteral nodule, whereas brown/black eyes decreased this risk (OR 0.34; 95% CI: 0.13-0.87; p = 0.025). Consistently, the combination of green eyes and blonde/light brown hairs increased the odds of ureteral endometriosis by more than 5 folds (OR 5.40; 95%CI: 2.02-14.49; p = 0.001), even after correction for anthropometric confounders (aOR 5.85; 95% CI: 2.13-16.09; p 0.001).The association between endometriosis and pigmentary traits has been herein confirmed, with the novel finding of the possible predisposition of ureteral endometriosis in patients with green eyes and blonde/light brown hairs. Further investigation on the genetic makeup of somatic traits may provide new inroads also into the molecular aspects of endometriosis leading to a better understanding of this complex disease.

Background Although endometriosis may benefit from primary prevention measures, the epidemiological risk factors identified are equivocal. Two genome-wide association studies (GWAS) have been conducted for endometriosis in two different ethnic populations but results are still to be replicated consistently and across various ethnicities. To confirm the association of GWAS-derived susceptibility loci, we conducted a replication Italian case-control study and a meta-analysis. Methods An independent set of 305 laparoscopically-proven endometriosis patients and 2710 controls were recruited. Four SNPs— CDKN2BAS rs1333049, rs7521902 close to WNT4 , rs12700667 in an inter-genic region on 7p15.2 and fibronectin 1 rs1250248—were selected for this association study. Results Rs1333049 risk allele G frequency resulted significantly higher in endometriosis patients compared with controls (OR 1.32, 95% CI 1.11 to 1.57), confirming the role of this locus also in the Caucasian population. The meta-analysis showed that rs7521902 was associated with endometriosis at a genome-wide significance (pmeta=2.23×10−9) while for rs1250248, a genome-wide significant pmeta value of 3.89×10−9 was detected only in association with severe forms. An epistatic interaction between rs7521902 and rs1250248 (OR 1.56, p=1.19×10−2) was found especially in presence of ovarian disease (OR=2.15, p=3.12×10−4). Conclusions We confirm WNT4 , CDKN2BAS and FN1 as the first identified common loci for endometriosis.

Patients with Cushing's disease are known to present a variable secretory response to stimulatory and inhibitory challenges. Evaluation of the secretory behaviour of pituitary adrenocorticotrophic hormone (ACTH)-secreting adenomas in vitro aids in the comprehension of its behaviour in vivo; however, given the small size of these tumours and the consequent paucity of material available to in vitro studies, a comprehensive study on the secretory behaviour of human corticotroph tumours has not yet been performed. The present study aimed to assess the spectrum of responses to the two main corticotroph modulators, corticotrophin-releasing hormone (CRH) and dexamethasone, in a large series of human ACTH-secreting pituitary tumours. Seventy-two ACTH-secreting pituitary tumours were collected during surgery and established in culture. Specimens were incubated with 10nm CRH and/or 10nm dexamethasone for 4h and 24h. Secretion in unstimulated, control wells was set at 100% and changes in ACTH concentrations by at least 20% were considered as responses. Parallel experiments in 12 rat anterior pituitary primary cultures were evaluated. A marked ACTH increase was observed during incubation with CRH in 70% of tumoural specimens at 4h (range 124-3500% of control wells) and in 57% at 24h (range 122-3323%). Dexamethasone reduced ACTH secretion in almost 50% of tumours (range 78-2% of control at 4h; 76-3% at 24h), whereas it did not affect ACTH medium levels in 30% of specimens and induced a paradoxical ACTH increase in 20% of tumours (range 130-327% of control at 4h; 156-348% at 24h). By comparison, CRH uniformly increased ACTH levels in rat anterior pituitary primary cultures (mean 745±84% at 4h; 347±25% at 24h), whereas dexamethasone decreased ACTH levels by 40-50% in all experiments. In conclusion, the present study of a large series of human ACTH-secreting pituitary tumours in vitro revealed a considerable variability in the responses to CRH and dexamethasone. This finding indicates the existence of multiple corticotroph tumoural phenotypes and may account for the different responses to physiological and pharmacological modulators in vivo. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

The incidence of endometriosis in middle-aged women is not minimal compared to that in the reproductive age group. The treatment of affected women after childbearing age to the natural transition toward menopause has received considerably poor attention. Disease management is problematic for these women due to increased contraindications regarding hormonal treatment and the possibility for malignant transformation, considering the increased cancer risk in patients with a long-standing history of the disease. This state-of-the-art review aims for the first time to assess the benefits of the available therapies to help guide treatment decisions for the care of endometriosis in women approaching menopause. Progestins are proven effective in reducing pain and should be preferred in these women. According to the international guidelines that lack precise recommendations, hysterectomy with bilateral salpingo-oophorectomy should be the definitive therapy in women who have completed their reproductive arc, if medical therapy has failed. Strict surveillance or surgery with removal of affected gonads should be considered in cases of long-standing or recurrent endometriomas, especially in the presence of modifications of ultrasonographic cyst patterns. Although rare, malignant transformation of various tissues in endometriosis patients has been described, and management is herein discussed.

Background An increased incidence of imprint-associated disorders has been reported in babies born from assisted reproductive technology (ART). However, previous studies supporting an association between ART and an altered DNA methylation status of the conceived babies have been often conducted on a limited number of methylation sites and without correction for critical potential confounders. Moreover, all the previous studies focused on the identification of methylation changes shared among subjects while an evaluation of stochastic differences has never been conducted. This study aims to evaluate the effect of ART and other common behavioral or environmental factors associated with pregnancy on stochastic epigenetic variability using a multivariate approach. Results DNA methylation levels of cord blood from 23 in vitro and 41 naturally conceived children were analyzed using the Infinium HumanMethylation450 BeadChips. After multiple testing correction, no statistically significant difference emerged in the number of cord blood stochastic epigenetic variations or in the methylation levels between in vitro- and in vivo-conceived babies. Conversely, four multiple factor analysis dimensions summarizing common phenotypic, behavioral, or environmental factors (cord blood cell composition, pre or post conception supplementation of folates, birth percentiles, gestational age, cesarean section, pre-gestational mother’s weight, parents’ BMI and obesity status, presence of adverse pregnancy outcomes, mother’s smoking status, and season of birth) were significantly associated with stochastic epigenetic variability. The stochastic epigenetic variation analysis allowed the identification of a rare imprinting defect in the locus GNAS in one of the babies belonging to the control population, which would not have emerged using a classical case-control association analysis. Conclusions We confirmed the effect of several common behavioral or environmental factors on the epigenome of newborns and described for the first time an epigenetic effect related to season of birth. Children born after ART did not appear to have an increased risk of genome-wide changes in DNA methylation either at specific loci or randomly scattered throughout the genome. The inability to identify differences between cases and controls suggests that the number of stochastic epigenetic variations potentially induced by ART was not greater than that naturally produced in response to maternal behavior or other common environmental factors.

Study question Does CO2 laser vaporization offer better results in treating endometrioma in terms of ovarian reserve preservation compared to traditional cystectomy? Summary answer Assessing both antral follicle count (AFC) and serum anti-Mullerian hormone (AMH) levels as measures of ovarian reserve, the results suggest that CO2 technology may be an alternative treatment for endometrioma, causing minimal damage to adjacent healthy ovarian tissue. What is known already Excisional surgery has been questioned as an ideal surgical approach for endometriomas because it is associated with potential reduction of ovarian reserve. Recently, vaporization with CO2 laser in-line-of-sight, according to the 'three-step procedure', has been proposed as the best method to preserve ovarian function. However, no randomized controlled trials have been conducted to compare cystectomy and 'one-step' CO2 fiber laser vaporization (without GnRH agonist therapy) with respect to the ovarian reserve. Study design, size, duration A multicentre randomized clinical trial including 60 patients was performed between July 2017 and February 2018. Computerized randomization was conducted to allocate them in a proportion of 1:1 either to Group 1 (laparoscopic stripping: cystectomy) or Group 2 (CO2 laser vaporization). Patients in Group 1 underwent a standardized laparoscopic stripping technique; patients in Group 2 underwent drainage of the cyst content, biopsy and vaporization of the internal wall with a CO2 fiber laser. Patients underwent pelvic ultrasound examination to determine the AFC and blood sampling to determine AMH levels before surgery and at 1- and 3-month follow-up. Participants/materials, setting, methods Patients undergoing surgery for symptomatic endometriomas (infertility and/or pelvic pain) larger than 3 cm were randomized in two groups according to the surgical technique. Patients aged ≥40 years, or with deep infiltrating endometriosis/adenomyosis, or previously submitted to surgical procedures on the ovaries or to hysterectomy were excluded from the study. The primary endpoint was the comparison of intra-group AFC changes before and after surgery (ΔAFC) between the two groups (ΔAFC Group 1 versus ΔAFC Group 2). The secondary endpoint was the modification of serum AMH before and after surgery (ΔAMH) between the two groups (ΔAMH Group 1 versus ΔAMH Group 2). Main results and the role of chance The AFC of the operated ovary was significantly increased in Group 2 (laser vaporization) compared with Group 1 (cystectomy) after surgery (Group 1: from 4.1 ± 2.2 [mean ± SD] at baseline to 6.3 ± 3.5 at 3-month follow-up; 95% CI: 0.9-4; Group 2: from 3.6 ± 1.9 at baseline to 8.6 ± 4.2 at 3-month follow-up; 95% CI: 2.8-7.1; P = 0.016); serum AMH levels were significantly reduced at 3 months in Group 1 (from 2.6 ± 1.4 ng/mL at baseline to 1.8 ± 0.8 ng/mL at 3-month follow-up; 95% CI: -1.3 to -0.2; P = 0.012) compared with no reduction in Group 2 (from 2.3 ± 1.1 ng/mL at baseline to 1.9 ± 0.9 ng/mL at 3-month follow-up; 95% CI: -1 to -0.2; P = 0.09). Limitations, reason for caution The key limitations of the trial were the low accuracy of AFC in estimating the ovarian reserve in ovaries with endometriomas, the limited study size and the relatively short follow-up, which do not allow us to draw definitive conclusions. Wider implications of the findings The present study suggests that CO2 technology may treat endometrioma with minimal damage to the adjacent healthy ovarian tissue; however, this study should be considered as a preliminary clinical trial, intended to stimulate future larger trials to address this clinically relevant issue. Study funding/competing interest(s) None. Trial registration number ClinicalTrials.gov NCT03227640. Trial registration date 9 July 2017. Date of first patient’s enrollment 24 July 2017.

A panel of experts in the field of endometriosis expressed their opinions on management options in a 28-year-old patient, attempting pregnancy for 1 year, with severe cyclic pelvic pain and with clinical examination and imaging techniques suggestive of adenomyosis. Many questions this paradigmatic patient may pose to the clinician are addressed, and all clinical scenarios are discussed. A decision algorithm derived from this discussion is also proposed.

Background Endometriosis is inherited as a complex genetic trait, and the single nucleotide polymorphism (SNP) rs61764370 within the KRAS gene on chromosome subband 12p12.1 has been proposed as a potential candidate gene. By disrupting a binding site for microinterference RNA (miRNA) let-7, the rs61764370 SNP variation site may increase activation of KRAS and favor disease development. Conflicting evidence, however, has emerged on the association between the rs61764370 SNP and endometriosis. Due to the potential implications of this issue for the diagnosis and treatment of endometriosis, we sought to replicate the sequencing of the KRAS rs61764370 SNP in a population of cases and controls and to perform a meta-analysis encompassing all currently available studies as well as our novel replication. Methods We sought to replicate for the first time the sequencing of KRAS rs61764370 SNP in a highly selected population of 86 cases of women with laparoscopically proven endometriosis and 72 healthy controls, and to perform a meta-analysis encompassing currently available studies and including affected subjects (n = 2,225) and controls (n = 1,923). Results The rs61764370 minor allele was observed in 12 of 86 women with endometriosis (14.0%) and in 15 of 72 controls (20.8%) (odds ratio [OR] = 0.76, 95% confidence interval [95% CI], 0.36-1.60, p = 0.48). The meta-analysis failed to identify any significant association (OR = 1.03, 95% CI, 0.89-1.20, p = 0.67, phet = 0.46). Conclusions KRAS variation site rs61764370 is unlikely related to disease development, and other loci with potential implications for diagnosis or treatment for endometriosis should be identified.

Cycles with progesterone elevation during controlled ovarian stimulation (COS) for IVF/ICSI are commonly managed with a "freeze-all" strategy, due to a well-recognized detrimental effect of high progesterone levels on endometrial receptivity. However, also a detrimental effect of elevated progesterone on day-3 embryo quality has recently been found with regards to top quality embryo formation rate. Because blastocyst culture and cryopreservation are largely adopted, we deemed relevant to determine whether this detrimental effect is also seen on blastocyst quality on day 5-6. This issue was investigated through a large two-center retrospective study including 986 GnRH antagonist IVF/ICSI cycles and using top quality blastocyst formation rate as the main outcome. Results showed that on multivariate analysis sperm motility (p1.49 ng/ml as the best cut-off for identification of patients at risk for the absence of top quality blastocysts (AUC 0.55, p

Objective To analyze the WNT/β-catenin signaling pathway in luteinized granulosa cells from women with and without endometriosis in relation to cellular apoptosis. Design Basic. Setting University hospital. Patient(s) Patients with a laparoscopic diagnosis of endometriosis (n = 30) and women undergoing intracytoplasmic sperm injection for male infertility (control group n = 39). Intervention(s) Isolation of luteinized granulosa cells. Main Outcome Measure(s) Gene expression analysis of components of the WNT/β-catenin pathway, protein expression levels of β-catenin, and cell cycle studies in luteinized granulosa cells. Result(s) Compared with luteinized granulosa cells from control women, cells derived from endometriosis patients had significantly higher transcript levels of the β-catenin–independent molecules WNT4 and WNT5a and lower levels of the β-catenin–dependent molecule WNT1. A decrease of total β-catenin as well as of its dephosphorylated active form, together with an aberrant gene expression of the downstream targets survivin and BMP4, was detected in cells from affected women. Flow cytometry analysis confirmed an enhanced apoptosis of luteinized granulosa cells from patients with endometriosis. Conclusion(s) The concomitant dysregulation of specific members of the WNT pathway and of its pivot molecule β-catenin in granulosa cells characterized by an increased apoptosis suggests that the WNT/β-catenin signaling pathway might be involved in leading to granulosa cell atresia.

Prepro-thyrotrophin-releasing hormone (TRH) (178-199), a 22-amino acid cleavage product of the TRH prohormone, has been postulated to act as an adrenocorticotrophin hormone (ACTH)-release inhibitor. Indeed, although in vitro evidence indicates that this peptide may inhibit basal and stimulated ACTH secretion in rodent anterior pituitary primary cultures and cell lines, not all studies concur and no study has as yet evaluated the effect of this peptide in Cushing's disease. The present study aimed to test the effect of preproTRH(178-199) in human tumoural corticotrophs. Twenty-four human ACTH-secreting pituitary tumours (13 macroadenomas, 11 microadenomas) were collected during surgery and incubated with 10 or 100 n. m preproTRH(178-199). ACTH secretion was assessed after 4 and 24 h of incubation by immunometric assay and expressed relative to levels observed in control, unchallenged wells (= 100%). Parallel experiments were performed in rat anterior pituitary primary cultures. A clear inhibition of ACTH secretion at 4 and 24 h was observed in 12 specimens (for 10 n. m ppTRH: 70 ± 4% control at 4 h and 83 ± 5% control at 24 h; for 100 n. m ppTRH: 70 ± 4% control at 4 h and 85 ± 5% control at 24 h), whereas a mild and short-lasting stimulatory effect was observed in three tumours and no changes in ACTH secretion in the remaining nine tumoural specimens. The inhibitory effect of preproTRH(178-199) was more evident in macroadenomas and significantly correlated with sensitivity to dexamethasone inhibition. Significant inhibition of ACTH secretion by preproTRH(178-199) in rat pituitary cultures was observed after 24 h of incubation. The present study conducted in a large series of human corticotroph tumours shows that preproTRH(178-199) inhibits tumoural ACTH secretion in a sizable proportion of specimens, in close relation to the size of the tumour and its sensitivity to glucocorticoid negative feedback. This appears a promising avenue of research and further studies are warranted to explore the full scope of preproTRH(178-199) as a regulator of ACTH secretion. © 2010 The Authors. Journal Compilation © 2010 Blackwell Publishing Ltd.

STUDY QUESTION Are women with endometriosis who conceive with IVF at increased risk of preterm birth? SUMMARY ANSWER Women with endometriosis who conceive with IVF do not face an increased risk of preterm birth. WHAT IS KNOWN ALREADY The eutopic endometrium of women with endometriosis has been repeatedly shown to present molecular and cellular alterations. On this basis, it has been hypothesized that pregnancy outcome may be altered in affected women. However, to date, available evidence from epidemiological studies is scanty and conflicting. Data tended to be partly consistent only for an increased risk of preterm birth and placenta previa. STUDY DESIGN, SIZE, DURATION Retrospective matched case-control study of women achieving an IVF singleton pregnancy progressing beyond 12 weeks' gestation. PARTICIPANTS/MATERIALS, SETTING, METHODS Women achieving IVF singleton pregnancies that progressed beyond 12 weeks' gestation at two infertility units were reviewed. Cases were women with a history of surgery for endometriosis and/or with a sonographic diagnosis of the disease at the time of the IVF cycle. Controls were women without current or past evidence of endometriosis who were matched to cases by age (± 6 months), type of cycle (fresh or frozen cycle) and study period. Male factor and unexplained infertility were the most common diagnoses in the control group. Two hundred and thirty-nine women with endometriosis and 239 controls were selected. The main outcome of the study was the rate of preterm birth (birth