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Endometriosis: HELP
Articles by Ivo A. Brosens
Based on 47 articles published since 2008
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Between 2008 and 2019, I. Brosens wrote the following 47 articles about Endometriosis.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Progress in the diagnosis and management of adolescent endometriosis: an opinion. 2018

Benagiano, Giuseppe / Guo, Sun-Wei / Puttemans, Patrick / Gordts, Stephan / Brosens, Ivo. ·Department of Gynaecology, Obstetrics and Urology, 'Sapienza' University, Viale del Policlinico 155, 00161, Rome, Italy. · Department of Gynecology, Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai 2000011, China. · Leuven Institute for Fertility and Embryology, Leuven, Belgium. · Leuven Institute for Fertility and Embryology, Leuven, Belgium. Electronic address: ivo.brosens@med.kuleuven.be. ·Reprod Biomed Online · Pubmed #29174167.

ABSTRACT: Increasing evidence indicates that early onset endometriosis (EOE), starting around menarche or early adolescence, may have an origin different from the adult variant, originating from neonatal uterine bleeding (NUB). This implies seeding of naïve endometrial progenitor cells into the pelvic cavity with NUB; these can then activate around thelarche. It has its own pathophysiology, symptomatology and risk factors, warranting critical management re-evaluation. It can also be progressive, endangering future reproductive capacity. This variant seems to be characterized by the presence of ovarian endometrioma. Today, the diagnosis of endometriosis in young patients is often delayed for years; if rapidly progressive, it can severely affect pelvic organs, even in the absence of serious symptoms. Given the predicament, great attention must be paid to symptomatology that is often non-specific, justifying a search for new, simple, non-invasive markers of increased risk. Better use of modern imaging techniques will aid considerably in screening for the presence of EOE. Traditional laparoscopy should be limited to cases in which imaging gives rise to suspicion of severity and a stepwise, minimally invasive approach should be used, followed by medical treatment to prevent recurrence. In conclusion, EOE represents a condition necessitating early diagnosis and stepwise management, including medical treatment.

2 Review Müllerianosis, Endocervicosis, and Endosalpingiosis of the Urinary Tract: A Literature Review. 2018

Habiba, Marwan / Brosens, Ivo / Benagiano, Giuseppe. ·1 Department of Health Sciences, University of Leicester, Women and Perinatal Services, University Hospitals of Leicester, Leicester, United Kingdom. · 2 Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium. · 3 Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy. ·Reprod Sci · Pubmed #29739266.

ABSTRACT: INTRODUCTION AND HYPOTHESIS: We reviewed reported cases of endocervicosis, endosalpingiosis, and müllerianosis of the bladder or ureters in women in order to highlight these conditions as distinct from endometriosis or adenomyosis. METHODS: Medline and Scopus searches of all cases published till the October 1, 2017. All retrieved references were searched manually to identify relevant articles. RESULTS: Twenty-six articles reported endocervicosis. These included 37 cases described by the authors as endocervicosis of the bladder. We identified 7 case reports of bladder endosalpingiosis. There were 26 publications including 27 cases of müllerianosis of the bladder and 3 cases affecting the lower ureter. Literature descriptions are limited but available accounts do not point to features that uniquely distinguished these conditions. Affected women tended to be older, and in many cases, there was a possible relation to past surgery and particularly to hysterectomy and caesarean sections. Many cases were reported in postmenopausal women. Local excision was sufficient in most cases. CONCLUSION: The etiology of these conditions remains speculative, but case reports raise a possible link to pelvic surgery. There is a need for more detailed accounts of these lesions, which should be considered in the differential diagnosis of pre- and postmenopausal women with pelvic pain, dyspareunia, lower abdominal pain or discomfort, dysuria, frequency, or hematuria.

3 Review Pathogenesis of deep endometriosis. 2017

Gordts, Stephan / Koninckx, Philippe / Brosens, Ivo. ·Leuven Institute for Fertility & Embryology, Leuven, Belgium. Electronic address: stephan.gordts@lifeexpertcentre.be. · Department of Obstetrics and Gynecology, Catholic University Leuven, University Hospital, Gasthuisberg, Leuven, Belgium; Gruppo Italo Belga, Villa del Rosario and Gemelli Hospitals Università Cattolica, Rome, Italy. · Leuven Institute for Fertility & Embryology, Leuven, Belgium. ·Fertil Steril · Pubmed #29100623.

ABSTRACT: The pathophysiology of (deep) endometriosis is still unclear. As originally suggested by Cullen, change the definition "deeper than 5 mm" to "adenomyosis externa." With the discovery of the old European literature on uterine bleeding in 5%-10% of the neonates and histologic evidence that the bleeding represents decidual shedding, it is postulated/hypothesized that endometrial stem/progenitor cells, implanted in the pelvic cavity after birth, may be at the origin of adolescent and even the occasionally premenarcheal pelvic endometriosis. Endometriosis in the adolescent is characterized by angiogenic and hemorrhagic peritoneal and ovarian lesions. The development of deep endometriosis at a later age suggests that deep infiltrating endometriosis is a delayed stage of endometriosis. Another hypothesis is that the endometriotic cell has undergone genetic or epigenetic changes and those specific changes determine the development into deep endometriosis. This is compatible with the hereditary aspects, and with the clonality of deep and cystic ovarian endometriosis. It explains the predisposition and an eventual causal effect by dioxin or radiation. Specific genetic/epigenetic changes could explain the various expressions and thus typical, cystic, and deep endometriosis become three different diseases. Subtle lesions are not a disease until epi(genetic) changes occur. A classification should reflect that deep endometriosis is a specific disease. In conclusion the pathophysiology of deep endometriosis remains debated and the mechanisms of disease progression, as well as the role of genetics and epigenetics in the process, still needs to be unraveled.

4 Review Spontaneous hemoperitoneum in pregnancy (SHiP) and endometriosis - A systematic review of the recent literature. 2017

Lier, Marit C I / Malik, Romana F / Ket, Johannes C F / Lambalk, Cornelis B / Brosens, Ivo A / Mijatovic, Velja. ·VU University Medical Center, Endometriosis Center VUmc, Amsterdam, The Netherlands. Electronic address: ma.lier@vumc.nl. · VU University Medical Center, Endometriosis Center VUmc, Amsterdam, The Netherlands. · Vrije Universiteit Amsterdam, Medical Library, Amsterdam, The Netherlands. · Leuven Institute for Fertility and Embryology, Leuven, Belgium. ·Eur J Obstet Gynecol Reprod Biol · Pubmed #29054042.

ABSTRACT: Spontaneous Hemoperitoneum in Pregnancy (SHiP), an unprovoked (nontraumatic) intraperitoneal bleeding in pregnancy (up to 42days postpartum), is associated with serious adverse pregnancy outcomes. To evaluate the clinical consequences of SHiP and its association with endometriosis, a systematic review was conducted according to the PRISMA guidelines. PubMed, Embase.com and Thomson Reuters/Web of Science were searched for articles published since the latest review (August 2008) until September 2016. After assessment for eligibility, forty-four articles were included in this systematic review, describing 59 cases of SHiP. Endometriosis was present in 33/59 cases (55.9%), most often diagnosed prior to pregnancy. An association between the severity of SHiP and the stage of endometriosis could not be found. In the majority of cases, SHiP occurred in the third trimester of pregnancy (30/59 cases (50.8%)); women presented with (sub)acute abdominal pain (56/59 cases (94.9%)), hypovolemic shock (28/59 cases (47.5%)) and/or a decreased level of hemoglobin (37/59 cases (62.7%)). Signs of fetal distress were observed in 24/59 cases (40.7%). Imaging confirmed free peritoneal fluid in (37/59 cases (62.7%)). At time of surgery active bleeding was revealed in 51/56 cases (91,1%), originating from endometriotic implants (11/51 cases (21.6%)), ruptured utero-ovarian vessels (29/51 cases (56.8%)), hemorrhagic nodules of decidualized cells (1/51 cases (2.0%)) or a combination (10/51 cases (19.6%)). Median amount of hemoperitoneum was 1600mL (IQR 1000mL-2500mL). From the 45/59 cases (76.3%) in which surgical interventions was carried out during pregnancy, 7/45 cases (15.6%) reported a successful continuation of pregnancy. 5/59 cases reported recurrence of SHiP (recurrence rate 8.5%). The perinatal mortality rate was 26.9% (18/67 fetus), one maternal death was reported (1/59 cases (1,7%)). In conclusion, SHiP is a very serious complication of pregnancy, highly associated with adverse pregnancy outcomes and particularly relevant to women with endometriosis. Currently preventive measures are lacking, therefore increasing the awareness and recognition of SHiP is crucial to improve pregnancy outcomes.

5 Review Decidual Bleeding as a Cause of Spontaneous Hemoperitoneum in Pregnancy and Risk of Preterm Birth. 2017

Lier, Marit C I / Brosens, Ivo A / Mijatovic, Velja / Habiba, Marwan / Benagiano, Giuseppe. ·VU University Medical Centre, Endometriosis Centre VUmc, Department of Reproductive Medicine, Amsterdam, The Netherlands. ·Gynecol Obstet Invest · Pubmed #28351025.

ABSTRACT: BACKGROUND: Spontaneous hemoperitoneum in pregnancy (SHiP) is a rare, life-threatening event, particularly relevant to women with endometriosis or deciduosis. METHODS: To determine the type of lesions leading to SHiP, a literature search was conducted among all published SHiP cases. From a total of 1,339 publications, information on pathological findings at the bleeding site with histological data was found in 24 case reports (16 pregnant, 8 postpartum). RESULTS: Among pregnant women (81% primigravida), 75% had a diagnosis of endometriosis and 25% of deciduosis. Among postpartum women (38% primiparous), 63% had a diagnosis of deciduosis and 25% of endometriosis. In all cases except one, decidual cells, with or without glandular structures, were present at the bleeding site. Decidual vessels were described in 7 cases and all exhibited vascular changes, including distension of the lumen, medial disorganization, or loss of vascular integrity. These vessels were significantly different from arteries seen in the secretory endometrium, showing that structural modifications take place during the initial stage of the remodelling of placental bed spiral arteries. CONCLUSIONS: During pregnancy, a link seems to exist between ectopic decidualization, particularly that occurring in endometriotic foci, and occurrence of SHiP. In addition, subclinical decidual bleeding may be a potential risk factor for preterm labour.

6 Review Promoting awareness of neonatal menstruation. 2017

Bianchi, Paola / Benagiano, Giuseppe / Brosens, Ivo. ·a Department of Medical and Surgical Sciences and Traslational Medicine , Sapienza University of Rome , Roma , Italy. · b Gynaecology, Obstetrics and Urology, Sapienza University of Rome, Policlinico Umberto I , Rome , Italy , and. · c Leuven Institute for Fertility and Embryology , Leuven , Belgium. ·Gynecol Endocrinol · Pubmed #28079409.

ABSTRACT: Neonatal uterine bleeding (NUB) has been carefully studied in the past through case reports, small series, clinical cohort studies, pathology investigations of fetal and neonatal. Following a historical recount, this review summarizes biological mechanisms conditioning NUB, starting from the persistence till birth of an 'ontogenetic progesterone resistance' (OPR), causing decreased responsiveness of target tissues to bioavailable progesterone. Several pregnancy-related conditions, such as preeclampsia, fetal growth restriction, prematurity, post-maturity and even Rhesus or ABO incompatibility, influence the occurrence of NUB. It seems therefore that the phenomenon is precipitated by chronic fetal distress. When present, OPR may persists until telarche; as a consequence, if pregnancy occurs in early teenage, the disorder known as "defective deep placentation" may ensue, increasing the risk of obstetrical syndromes. In the presence of NUB, retrograde shedding into the peritoneal cavity of endometrial stem/progenitor and niche cells may occur. There, given the right environment, these cells can survive and become activated at the time of telarche, causing the specific phenotype of early-onset endometriosis. In conclusion, neonatal menstruation is a fetal distress indicator and can alter the incidence of a variety of pathological conditions later in life. For this reason, it should be carefully recorded and the parents informed.

7 Review Neonatal uterine bleeding as a biomarker for reproductive disorders during adolescence: a worldwide call for systematic registration by nurse midwife. 2017

Puttemans, Patrick / Benagiano, Giuseppe / Gargett, Caroline / Romero, Roberto / Guo, Sun-Wei / Brosens, Ivo. ·a Leuven Institute for Fertility and Embryology , Leuven , Belgium. · b Department of Obstetrics and Gynecology , Catholic University of Leuven , Leuven , Belgium. · c Department of Gynecology , Obstetrics and Urology, Sapienza, University of Rome , Rome , Italy. · d Department of Obstetrics and Gynecology , Monash University , Clayton , Victoria , Australia. · e NICHD, NIH, DHHS, Perinatology Research Branch, Center for Molecular Medicine and Genetics, Wayne State University , Detroit , MI , USA , and. · f Shanghai Obstetrics and Gynecology Hospital, Fudan University , Shanghai , China. ·J Matern Fetal Neonatal Med · Pubmed #27454348.

ABSTRACT: Neonatal uterine bleeding (NUB) occurs in approximately 5% of newborns and is generally considered to be of little clinical significance. However, the real clinical importance of this condition and its long-term implications remain to be determined. The reason why NUB is rare despite high circulating levels of progesterone can be attributed to a progesterone resistance present in a majority of neonates. Recent work indicates that NUB represents a significant biomarker for events that can occur later-on during adolescence. Indeed, clinical studies have shown that "neonatal menstruation" constitutes a sign of fetal distress during late pregnancy, reflecting a stage of endometrium development that may subsequently have an impact on the reproductive life of the adolescent and the young adult. Via retrograde flow, NUB can cause endometrial stem/progenitor cells to arrive into the pelvic cavity and survive there, dormant underneath the peritoneal surface, until menarche activates them. Indeed, there is both clinical and epidemiological evidence of a link between NUB and adolescent endometriosis. In addition, if progesterone resistance persists till the onset of menarche, in case of an early teen pregnancy, it can result in a disorder of deep placentation. Therefore, we propose that NUB should be carefully recorded so that prospective studies can examine its links with reproductive disorders in adolescence and beyond.

8 Review Pharmacologic treatment of the ovarian endometrioma. 2016

Benagiano, Giuseppe / Guo, Sun-Wei / Bianchi, Paola / Puttemans, Patrick / Gordts, Stephan / Petraglia, Felice / Brosens, Ivo. ·a Department of Gynaecology, Obstetrics and Urology , Sapienza University of Rome , Rome , Italy. · b Department of Gynecology, Shanghai Obstetrics and Gynecology Hospital , Fudan University , Shanghai , People's Republic of China. · c Department of Surgical and Medical Sciences and Traslational Medicine, Sant'Andrea Hospital, Faculty of Medicine and Psychology , Sapienza University of Rome , Rome , Italy. · d Leuven Institute for Fertility and Embryology , Leuven , Belgium. · e Department of Molecular and Developmental Medicine, Obstetrics and Gynecology , University of Siena , Siena , Italy. · f Department of Obstetrics and Gynaecology , Catholic University of Leuven , Leuven , Belgium. ·Expert Opin Pharmacother · Pubmed #27615386.

ABSTRACT: INTRODUCTION: Treatment of ovarian endometriomas is commonly achieved through laparoscopic surgery and this can be effective in eliminating the disease, although a majority of recent trials documented an adverse effect of surgery on ovarian reserve markers. With the advancement in imaging techniques, ovarian endometriomas are increasingly diagnosed at an earlier stage when the endometrioma may be smaller, less fibrotic and more responsive to medical treatment, making an evaluation of medical options critically important. AREAS COVERED: The review focuses on currently utilized pharmacologic therapies for endometrioma (oral contraceptives, the levonorgestrel-releasing IUS, the hormone-releasing subdermal implant, Implanon); experimental and future treatments are also mentioned (GnRH antagonists, progesterone receptor modulators, antioestrogens, newer subdermal implants and intracystic administration of pharmacologic agents). Finally, the usefulness of post-operative adjuvant medical treatments is discussed Expert opinion: Today, reliable, non-invasive diagnostic procedures of an ovarian endometrioma are available and should be utilized to identify its presence and type of pathology. In a young patient, classic medical therapies such as oral contraceptives and synthetic progestins should be tried first to alleviate symptoms. Only when these regimens fail, should a minimally invasive surgery be envisaged. Following endoscopic surgery, adjuvant medical treatment may reduce recurrence of both symptoms and the lesion.

9 Review Severe spontaneous hemoperitoneum in pregnancy may be linked to in vitro fertilization in patients with endometriosis: a systematic review. 2016

Brosens, Ivo A / Lier, Marit C / Mijatovic, Velja / Habiba, Marwan / Benagiano, Giuseppe. ·Leuven Institute for Fertility and Embryology, Leuven, Belgium. Electronic address: ivo.brosens@med.kuleuven.be. · Endometriosis Center VUmc, Department of Reproductive Medicine, VU University Medical Center, Amsterdam, the Netherlands. · Department of Obstetrics and Gynecology, Leicester Royal Infirmary, University Hospitals of Leicester, Leicester, United Kingdom. · Department of Gynecology, Obstetrics, and Urology, Sapienza, University of Rome, Rome, Italy. ·Fertil Steril · Pubmed #27336207.

ABSTRACT: OBJECTIVE: To evaluate existing evidence of a possible association in women with endometriosis between controlled ovarian hyperstimulation plus embryo transfer (COH-ET) and the occurrence of spontaneous hemoperitoneum in pregnancy (SHiP). DESIGN: Comprehensive review. SETTING: Not applicable. PATIENT(S): None. INTERVENTION(S): An electronic literature search up to February 2016 was conducted using Scopus and PubMed. MAIN OUTCOME MEASURE(S): The role of COH-ET in SHiP. RESULT(S): Controlled ovarian hyperstimulation plus embryo transfer may increase the severity or incidence of the rare condition known as SHiP. An analysis of published cases shows that bleeding often occurs from multiple or diffuse sites, mainly situated in the posterior pelvic cavity, making it difficult to control without interfering with the pregnancy itself. Spontaneous hemoperitoneum in pregnancy is linked to adverse perinatal outcomes, including stillbirth, neonatal mortality, and very low or low birth weight. In 14 cases a biopsy of the bleeding site was obtained, and in all cases, even in the absence of visible endometriosis, decidualization was documented. At present, the relatively small number of cases published prevents firm conclusions, although they are highly suggestive of a link between COH-ET in women with endometriosis and the occurrence and seriousness of SHiP. CONCLUSION(S): Spontaneous hemoperitoneum in pregnancy is a rare but potentially fatal complication for the pregnant woman and her unborn child. In vitro fertilization in women with severe endometriosis may be a risk factor for SHiP.

10 Review A new approach to the management of ovarian endometrioma to prevent tissue damage and recurrence. 2016

Benagiano, Giuseppe / Petraglia, Felice / Gordts, Stephan / Brosens, Ivo. ·Department of Obstetrics, Gynaecology and Urology, Sapienza University of Rome, Policlinico Umberto I, 00161 Roma, Italy. · Department of Molecular and Developmental Medicine, Obstetrics and Gynaecology, University of Siena, via Aldo Moro, 2, 53100 Siena, Italy. · Leuven Institute for Fertility & Embryology, Tiensevest 168, 3000 Leuven, Belgium. · Leuven Institute for Fertility & Embryology, Tiensevest 168, 3000 Leuven, Belgium. Electronic address: ivo.brosens@med.kuleuven.be. ·Reprod Biomed Online · Pubmed #27037156.

ABSTRACT: Management of ovarian endometrioma is a matter of debate between those advocating early treatment and those believing that cysts less than 3 cm in diameter should not be submitted to surgery. To explore a new approach to its management capable of preserving future fertility, the molecular pathology of ovarian endometrioma is reviewed and mechanisms by which the endometrioma progressively affects the ovary during reproductive life are summarized. The scope of new therapeutic modalities includes restoring the progesterone receptor ratio using progestin or progesterone receptor modulators and decreasing local oestrogen production through an aromatase inhibitor. In addition, free radical production can be blocked by antioxidants and the autophagic process by increasing apoptosis. Finally, metalloproteinases and relaxin activity, as well as the inflammatory process can be controlled. Many of these pharmacological treatments lend themselves to local administration and can be applied through intracystic drug administration; in fact, the intracystic route has already been tried with recombinant interleukin-2, methotrexate and ethanol; the latter to obtain sclerotization. Specifically, it is proposed that endometrial growth in the endometrioma is suppressed by intra-cystic application of synthetic progestins, such as levonorgestrel or danazol, selective progesterone receptor modulators, such as mifepristone, ulipristal or asoprisnil, without affecting ovarian activity.

11 Review Origins and Progression of Adolescent Endometriosis. 2016

Brosens, Ivo / Gargett, Caroline E / Guo, Sun-Wei / Puttemans, Patrick / Gordts, Stephan / Brosens, Jan J / Benagiano, Giuseppe. ·Leuven Institute for Fertility and Embryology, Leuven, Belgium ivo.brosens@med.kuleuven.be. · The Ritchie Centre, Hudson Institute of Medical Research and Department of Obstetrics and Gynaecology Monash University, Clayton, Australia. · Department of Gynecology, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, People's Republic of China. · Leuven Institute for Fertility and Embryology, Leuven, Belgium. · Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom. · Department of Gynaecology, Obstetrics and Urology, "Sapienza" University, Rome, Italy. ·Reprod Sci · Pubmed #27036950.

ABSTRACT: Accumulating evidence indicates that adolescent endometriosis is common and often severe. Here we explore the possibility that seeding of naive endometrial progenitor cells into the pelvic cavity early in life, that is, at the time of neonatal uterine bleeding or soon after the menarche, results in more florid and progressive disease, characterized by highly angiogenic implants, recurrent ectopic bleeding, and endometrioma formation. We discuss the potential intergenerational risk factors associated with early-onset endometriosis and explore the molecular drivers of disease progression. Taken together, the available data suggest that an increased focus on early-life events may help to identify young women at risk of severe, progressive endometriosis.

12 Review The endometrium from the neonate to the adolescent. 2016

Brosens, Ivo / Benagiano, Giuseppe. ·a Institute for Fertility and Embryology , Leuven , Belgium and. · b Department of Gynecology , Obstetrics and Urology, Sapienza University , Rome , Italy. ·J Matern Fetal Neonatal Med · Pubmed #25958988.

ABSTRACT: BACKGROUND: Scientific data on the phenomenon of uterine bleeding in the neonate (NUB) began to appear over a century ago when angiogenesis and petechial haemorrhages in the endometrium of newborn female infants, as well as fluid blood within the uterine cavity, were first described. METHODS: A thorough search of the 20th century literature was carried out to identify studies reporting data on NUB. RESULTS: The neonatal endometrium, although not identical to the adult, shows cellular responses of the same type, and at birth the endometrium is proliferative in 2/3 of all newborns with the residual 1/3 showing secretory, decidual or menstrual features. In the latter neonates, the presence of a functional cervical obstruction may expose them to menstrual regurgitation including neonatal mesenchymal stem-like cells. This can represent the origin of early-onset endometriosis. At menarche, partial or full ontogenic progesterone resistance can occur in the majority. If persisting, adolescent pregnancy may be exposed to major obstetrical syndromes including preeclampsia and fetal growth restriction. CONCLUSIONS: Increasing evidence indicates that the origin of major reproductive disorders in adolescents may lie in the degree of progesterone response in the neonate. The spectrum of progesterone response from resistance till decidualisation may explain the early occurrence of major obstetrical syndromes and endometriosis, respectively.

13 Review The perinatal origins of major reproductive disorders in the adolescent: Research avenues. 2015

Brosens, I / Ćurčić, A / Vejnović, T / Gargett, C E / Brosens, J J / Benagiano, G. ·Leuven Institute for Fertility and Embryology, Tiensevest 168, B-3000 Leuven, Belgium. Electronic address: ivo.brosens@med.kuleuven.be. · Department of Gynecology and Obstetrics, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia. · The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton 3168, Australia; Department of Obstetrics and Gynecology, Monash University, Clayton 3168, Australia. · The Division of Reproductive Health, Warwick Medical School, Coventry CV2 2DX, United Kingdom. · Department of Gynecology, Obstetrics and Urology, Sapienza, University of Rome, Rome, Italy. ·Placenta · Pubmed #25637411.

ABSTRACT: The fetal endometrium becomes responsive to steroid hormones around the fourth month of pregnancy starting with an oestrogenic phase, which is followed late in pregnancy by a secretory phase. Based on post-mortem studies, the endometrium at birth is secretory in only one-third of neonates and proliferative in the remaining cases. Decidual or menstrual changes are rare in fetal endometrium despite high circulating steroid hormone levels, which drop rapidly after birth. Hence, acquisition of progesterone responsiveness appears to be dependent on endometrial maturation and relative immaturity may persist in a majority of girls until the menarche and early adolescence. Two major reproductive disorders have been linked with either advanced or delayed endometrial maturation. First, early-onset endometriosis may be caused by menstruation-like bleeding in the neonate, leading to tubal reflux and ectopic implantation of endometrial stem/progenitor cells. Second, persistence of partial progesterone resistance in adolescent girls may compromise deep placentation and account for the increased risk of major obstetrical syndromes, including preeclampsia, fetal growth retardation and preterm birth. The concept of neonatal origins of common reproductive disorders poses important research challenges but also subsumes potential new preventative strategies.

14 Review Selective progesterone receptor modulators: an update. 2014

Benagiano, Giuseppe / Bastianelli, Carlo / Farris, Manuela / Brosens, Ivo. ·University of Rome, 'Sapienza', Department of Gynaecology, Obstetrics and Urology , C/O AIED Via Toscana 30, 00187 Rome , Italy Manuela.farris@uniroma1.it. ·Expert Opin Pharmacother · Pubmed #24787486.

ABSTRACT: INTRODUCTION: Several selective progesterone receptor modulators (SPRMs) show promise in several areas of medicine and this work has been summarized by us in 2008. AREAS COVERED: Since the publication of our reviews, several developments have taken place in the field of reproductive medicine. The first is emergency contraception (EC). Two SPRMs are clinically utilized today: mifepristone (MFP) and ulipristal acetate (UPA). MFP is available for EC in up to 120 h following unprotected intercourse. A dose of 10 mg is significantly more effective than levonorgestrel (LNG). In a metanalysis of the use of UPA versus LNG up to 72 h after unprotected intercourse, failure rates of 1.4 versus 2.2% were reported. The second is contraception. A daily dose of 2 mg MFP can block ovulation and several MFP regimens are being tested, including a vaginal ring releasing MFP. The third is the preoperative administration in women harboring leiomyomas, where clinical testing of several SPRM has shown that they can decrease uterine leiomyomas' size and substantially reduce uterine bleeding. SPRM can induce unusual, specific endometrial appearances. Many believe that these changes should not cause concern, but the issue remains controversial. EXPERT OPINION: SPRMs are very effective in EC and for the preoperative treatment of uterine leiomyomas.

15 Review Potential role of endometrial stem/progenitor cells in the pathogenesis of early-onset endometriosis. 2014

Gargett, C E / Schwab, K E / Brosens, J J / Puttemans, P / Benagiano, G / Brosens, I. ·The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton 3168, Australia Department of Obstetrics and Gynecology, Monash University, Clayton 3168, Australia caroline.gargett@monash.edu. · The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton 3168, Australia. · Division of Reproductive Health, Warwick Medical School, University of Warwick, Coventry CV4 7Al, UK. · Leuven Institute for Fertility and Embryology, Leuven B-3000, Belgium. · Department of Gynecology, Obstetrics and Urology, Sapienza University, 00161 Rome, Italy. ·Mol Hum Reprod · Pubmed #24674992.

ABSTRACT: The pathogenesis of early-onset endometriosis has recently been revisited, sparked by the discovery of endometrial stem/progenitor cells and their possible role in endometriosis, and because maternal pregnancy hormone withdrawal following delivery induces uterine bleeding in the neonate. The neonatal uterus has a large cervix to corpus ratio which is functionally blocked with mucous, supporting the concept of retrograde shedding of neonatal endometrium. Only 5% show overt bleeding. Furthermore, the presence of endometriosis in pre-menarcheal girls and even in severe stage in adolescents supports the theory that early-onset endometriosis may originate from retrograde uterine bleeding soon after birth. Endometrial stem/progenitor cells have been identified in menstrual blood suggesting that they may also be shed during neonatal uterine bleeding. Thus, we hypothesized that stem/progenitor cells present in shedding endometrium may have a role in the pathogenesis of early-onset endometriosis through retrograde neonatal uterine bleeding. During the neonatal and pre-pubertal period, shed endometrial stem/progenitor cells are postulated to survive in the pelvic cavity in the absence of circulating estrogens supported by niche cells also shed during neonatal uterine bleeding. According to this hypothesis, during thelarche, under the influence of rising estrogen levels, endometrial stem/progenitor cells proliferate and establish ectopic endometrial lesions characteristic of endometriosis. This New Research Horizon review builds on recent discussions on the pathogenesis of early-onset endometriosis and raises new avenues for research into this costly condition.

16 Review Structural and molecular features of the endomyometrium in endometriosis and adenomyosis. 2014

Benagiano, Giuseppe / Brosens, Ivo / Habiba, Marwan. ·Department of Gynaecology, Obstetrics and Urology, Sapienza University, 00161 Rome, Italy. ·Hum Reprod Update · Pubmed #24140719.

ABSTRACT: BACKGROUND Adenomyosis and endometriosis were initially described as 'adenomyoma'. When the retrograde menstruation theory became widely accepted to explain the pathogenesis of endometriosis, since it does not explain adenomyosis, the two conditions came to be seen as distinct entities. However, emerging evidence suggests that both diseases may be linked to changes in the inner portion of the myometrium. In addition, similar anomalies were found in the eutopic endometrium of the two conditions and the debate has re-opened. A common origin for both adenomyosis and endometriosis would have relevance not only for understanding uterine function and pathophysiology, but also for clinical management and treatment. METHODS The Scopus and Medline databases were searched for all original articles published in English up to the end of 2012. Search terms included 'adenomyosis'; 'endometriosis'; 'endometrium'; 'eutopic endometrium'; 'inner myometrium'; 'junctional zone'. Special attention was paid to articles comparing features of eutopic endometrium in the two conditions. RESULTS A number of similarities exist between adenomyosis and endometriosis and, by using magnetic resonance and laparoscopy, it was found that, at least in some subgroups, the two conditions often coexist. In both situations the inner myometrium (or junctional zone) is altered, although alterations are much more marked in adenomyosis where a thickness >12 mm is today considered sufficient for diagnosis. Research has shown differences between the eutopic endometrium of women with both diseases when compared with controls. There is an immune dysfunction and there are alterations of adhesion molecules, cell proliferation and apoptosis. An increase in cytokines and inflammatory mediators has also been observed. Finally, the presence of oxidative stress and anomalies in free-radical metabolism may alter uterine receptivity. When the two conditions were compared, dissimilarities were also observed in the extent of apoptosis inhibition and in the expression of some inflammatory mediators. It is not clear if observed differences are primarily related to presenting symptoms. Finally, both conditions are steroid dependent and research suggests a role for epigenetic mechanisms. The analysis indicates that much of the published research may have been influenced by the method of diagnosis and/or has not been controlled for the presenting symptoms, the concomitant presence of both diseases or full consideration of fluctuations within cycle phase. CONCLUSIONS It is difficult to draw firm conclusions from existing evidence since major diagnostic limitations still exist and there is a systematic bias in clinical presentation. In addition, scanty information is available on the natural history of endometriosis and no studies exist on the natural history of adenomyosis. Notwithstanding these limitations, a number of similarities, but also some differences have been found between the eutopic endometrium in the two diseases. These findings need to be taken with considerable caution as the few instances where the research was repeated yielded conflicting results.

17 Review In utero exposure and endometriosis. 2014

Benagiano, Giuseppe / Brosens, Ivo. ·Department of Gynecology, Obstetrics and Urology, Sapienza, University of Rome , Rome , Italy and. ·J Matern Fetal Neonatal Med · Pubmed #23819685.

ABSTRACT: Adverse living and nutritional conditions in utero and in early infancy may influence the risk of diseases in adult life, because fetal growth seems determined by interactions between the environment and the fetal genome and these interactions may determine the risk of postnatal disease and the capacity to react to and cope with the postnatal environment. It has been proven that massive fetal exposure to toxic agents causes an increased incidence of negative outcomes in pregnant women; of particular interest is the association between in utero exposure to toxic agents and the occurrence of endometriosis. There is evidence that exposure to dioxins can facilitate short-term survival of endometrial implants in non-human primates, but there is no solid evidence that it may lead to endometriosis in humans. In the case of diethylstilbestrol, an increased risk of developing endometriosis seems well established, although the mechanisms through which diethylstilbestrol can modify endometrial physiology remain uncertain. Finally, evidence that environmental and specific dietary factors may play a role in increasing the incidence of endometriosis and other pathologic conditions has accumulated over the years. Although the hypothesis may be valid, the most recent investigations have failed to find specific, significant correlations.

18 Review Endometriosis: a life cycle approach? 2013

Brosens, Ivo / Puttemans, Patrick / Benagiano, Giuseppe. ·Catholic University Leuven, Leuven, Belgium; Leuven Institute for Fertility and Embryology, Leuven, Belgium. Electronic address: ivo.brosens@med.kuleuven.be. ·Am J Obstet Gynecol · Pubmed #23500453.

ABSTRACT: To improve the still fragmented understanding of endometriosis, a life cycle approach was adopted that revealed unexpected aspects of the natural history of the disease throughout a woman's life. Three age-related stages of endometriosis are distinguished. In premenarcheal and adolescent endometriosis, 2 types can be distinguished: a classic form that can occur before menarche, and a congenital obstructive form that is caused by uterine anomaly and outflow obstruction. The lesions include superficial peritoneal implants, but adhesions and endometrioma can also occur. It is suggested that premenarcheal and possibly adolescent endometriosis develop by activation of resting stem cells shed at the time of neonatal retrograde uterine bleeding. In the adult, endometriosis can be related to uterine preconditioning by cyclic menstruations acting as a priming mechanism for deep placentation. In adult life, the typical lesions are peritoneal, ovarian, and deep or adenomyotic endometriosis. More recently, endometriosis has been associated with endometrial dysfunction and myometrial junctional zone hyperplasia. These uterine changes can be linked with some major obstetrical syndromes. In postmenopause, endometriosis can develop or be reactivated both in the presence or absence of exogenous estrogens and can spread to a variety of organs and structures causing constrictive lesions.

19 Review Defective myometrial spiral artery remodelling as a cause of major obstetrical syndromes in endometriosis and adenomyosis. 2013

Brosens, I / Pijnenborg, R / Benagiano, G. ·Leuven Institute for Fertility and Embryology, Leuven, Belgium. Ivo.Brosens@med.kuleuven.ac.be ·Placenta · Pubmed #23232321.

ABSTRACT: Endometriosis and adenomyosis are characterized by the presence of ectopic endometrium, but are also associated with functional and structural changes in the eutopic endometrium and inner myometrium. Alterations in the inner myometrium occurring in women with endometriosis and adenomyosis may be at the root of a defective remodelling of the myometrial spiral arteries from the onset of decidualization and result in vascular resistance and increased risk of defective deep placentation. The association of major obstetrical syndromes and different types of defective remodelling of the myometrial spiral arteries has been well documented. The possibility of a link between both endometriosis and adenomyosis and some major obstetric syndromes remains controversial because of at least two factors: first, changes of the inner myometrium are frequently present in women with endometriosis but the diagnosis requires high-resolution imaging such as magnetic resonance which is not routinely performed and second, patients with endometriosis are frequently subjected to prolonged hormone suppressive therapy. Indeed, there is evidence that pre-treatment with a Gonadotropin Releasing-Hormone analogue can improve the uterine microenvironment and implantation rate following IVF in infertile patients with endometriosis.

20 Review The pathophysiology of uterine adenomyosis: an update. 2012

Benagiano, Giuseppe / Habiba, Marwan / Brosens, Ivo. ·Department of Gynecology, Obstetrics and Urology, Sapienza, University of Rome, Rome, Italy. ·Fertil Steril · Pubmed #22819188.

ABSTRACT: The diagnosis of adenomyosis using noninvasive techniques such as vaginal ultrasounds and magnetic resonance has clear clinical applications and has renewed the interest in the pathogenesis of uterine adenomyosis. However, the research remains hampered by the lack of consensus on the classification of lesions. Magnetic resonance imaging and transvaginal ultrasound have comparable diagnostic accuracy. Minimal interventional biopsy techniques have recently been introduced. This article reviews human and animal studies and provides an update on the pathophysiology of adenomyosis. Recent views on the pathogenesis and links with endometriosis are discussed.

21 Review The endometrium in adenomyosis. 2012

Benagiano, Giuseppe / Brosens, Ivo. ·Department of Gynecology, Obstetrics & Urology, Sapienza, University of Rome, Rome, Italy. ·Womens Health (Lond) · Pubmed #22554177.

ABSTRACT: Eutopic and ectopic endometria of women with adenomyosis show a series of metabolic and molecular abnormalities that increase angiogenesis and proliferation, decrease apoptosis, allow local production of estrogens, create progesterone resistance, and impair cytokine expression. These changes enhance the ability of the endometrium to infiltrate the junctional zone myometrium and the growth of ectopic tissue. In addition, in these subjects several immunological abnormalities have been observed, together with an increased production of 'free radicals' leading to excessive growth of endometrial stromal cells that may facilitate the establishment of adenomyosis. A limiting factor is that these studies have been performed on hysterectomy specimens representing final stages of the disease. This increased knowledge has created new therapeutic options, including the block of local aromatase production through the use of selective estrogen receptor modulators, estrogen-progestin combinations and gonadotropin-releasing hormone super agonists. Also promising are investigations into the mechanism of dysmenorrhea and abnormal uterine bleeding.

22 Review The eutopic endometrium in endometriosis: are the changes of clinical significance? 2012

Brosens, Ivo / Brosens, Jan J / Benagiano, Giuseppe. ·Leuven Institute for Fertility and Embryology, Leuven, Belgium. ivo.brosens@med.kuleuven.be ·Reprod Biomed Online · Pubmed #22417665.

ABSTRACT: The eutopic endometrium in women suffering from endometriosis is different in many ways from that of healthy controls. Both proliferative and secretory eutopic endometria exhibit changes in endometriosis with heterogeneous responses. In addition, nerve fibres appear in the endometrium and myometrium of these women. The endometrium is a rich source of pro-angiogenic factors and vascular events are often disrupted in endometriosis with an overall increase in angiogenesis. A number of investigations have shown that endometriosis is likely the most common cause of endometrial receptivity defects. Endometriosis is also associated with relative 17β-hydroxysteroid dehydrogenase type II deficiency and these molecular aberrations indicate that local oestrogen production sustains ectopic implants. Recently it has been shown that endometriosis, as a chronic inflammatory disorder, disrupts co-ordinated progesterone response throughout the reproductive tract, including the endometrium, leading to a condition of 'progesterone resistance'. Investigators have searched for biomarkers of endometriosis, but these investigations are fraught with methodological difficulties. In conclusion, molecular phenotyping of the endometrium is changing the disease paradigm, from being foremost an oestrogen-dependent disease to a disorder characterized primarily by progesterone resistance. In recent years, research on the pathogenesis of endometriosis has been focused on alterations in the uterus and particularly the eutopic endometrium. The eutopic endometrium in women suffering from endometriosis is different in many ways from that of healthy controls. Both proliferative and secretory eutopic endometria exhibit changes in endometriosis with heterogeneous responses. The endometrium is a rich source of pro-angiogenic factors and vascular events are often disrupted in endometriosis with an overall increase in angiogenesis. A number of investigations have shown that endometriosis is likely the most common cause of endometrial receptivity defects. Recently, it has been shown that endometriosis, as a chronic inflammatory disorder, disrupts co-ordinated progesterone response throughout the reproductive tract, including the endometrium, leading to a condition of 'progesterone resistance'. Investigators have searched for biomarkers of endometriosis, but these investigations are fraught with methodological difficulties. In conclusion, molecular phenotyping of the endometrium is changing the disease paradigm; from being foremost an oestrogen-dependent disease to a disorder characterized primarily by progesterone resistance.

23 Review Risks of adverse pregnancy outcome in endometriosis. 2012

Brosens, Ivo / Brosens, Jan J / Fusi, Luca / Al-Sabbagh, Marwa / Kuroda, Keiji / Benagiano, Giuseppe. ·Leuven Institute of Fertility and Embryology, Leuven, Belgium. ivo.brosens@med.kuleuven.be ·Fertil Steril · Pubmed #22386841.

ABSTRACT: Bleeding from endometriotic implants is now an established cause of acute hemoperitoneum in pregnancy. However, the adverse impact of pelvic endometriosis on uterine function before conception may also interfere with subsequent deep placentation, accounting for the increased risk of obstetrical complications, including preterm birth and antepartum hemorrhage.

24 Review Endometriosis, a modern syndrome. 2011

Brosens, Ivo / Benagiano, Giuseppe. ·Leuven Institute for Fertility & Embryology, Leuven, Belgium . ·Indian J Med Res · Pubmed #21727656.

ABSTRACT: The identification of endometriosis has been a subject of intense debate over the last decade. There is, however, no doubt that Thomas Cullen was the first to describe endometriosis and adenomyosis as one disease characterized by the presence of endometrium-like tissue outside the uterine cavity. With the introduction of laparoscopy in the early 1960s three different clinical presentations of endometriosis were distinguished: peritoneal, deep adenomyotic and cystic ovarian. As soon as synthetic steroids became available, pioneer clinicians started utilizing these in an attempt to replace radical surgery by a medical treatment. While medical therapy may resort in relief, in most cases the current approach consists of a combination of medical and surgical therapy. While the pathogenesis of endometriosis is still enigmatic and complex, there is increasing evidence that endometriosis is part of a uterine reproductive dysfunction syndrome. For prevention of complications, it is very important that diagnosis is made as early as possible in a woman's life.

25 Review Endometriosis is a risk factor for spontaneous hemoperitoneum during pregnancy. 2009

Brosens, Ivo A / Fusi, Luca / Brosens, Jan J. ·Leuven Institute for Fertility and Embryology, Leuven, Belgium. ivo.brosens@med.kuleuven.be ·Fertil Steril · Pubmed #19439293.

ABSTRACT: Spontaneous hemoperitoneum in pregnancy (SHiP) is a rare but dramatic cause of perinatal mortality and morbidity. Emerging evidence suggests that pelvic endometriosis may play an important role in the pathogenesis of SHiP.

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