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Facts Views Vis Obgyn. 2014;6(4):219-27

Recurrence of endometriosis after hysterectomy.

Rizk B1Fischer AS2Lotfy HA3Turki R4Zahed HA5Malik R6Holliday CP1Glass A1Fishel H1Soliman MY1Herrera D7.




Persistent or recurrent pain after hysterectomy is one of the most frustrating clinical scenarios in benign gynaecology. We attempt to review the current evidence regarding the recurrence of pelvic pain after hysterectomy for endometriosis. The impact of ovarian conservation, type of hysterectomy and the extent of surgical excision were analysed.


Peer reviewed published manuscripts in the English language in the period between 1980 and 2014 were reviewed using Pubmed and science direct regarding the incidence, causes and recurrence of endometriosis.


Sixty-seven articles were identified. Incomplete excision of endometriosis is the most predominant reason in the literature for the recurrence of endometriosis, and the type of Hysterectomy affects the recurrent symptoms mainly by impacting the extent of excision of the lesion. Ovarian cyst drainage is associated with the highest rate of ovarian cyst reformation within three to six months after surgery. The use of hormone replacement therapy is associated with recurrence of pelvic pain in 3.5% of cases. No studies addressed the recurrence of endometriosis after standard vs robotic assisted hysterectomy.


A high recurrence rate of 62% is reported in advanced stages of endometriosis in which the ovaries were conserved. Ovarian conservation carries a 6 fold risk of recurrent pain and 8 folds risk of reoperation. The decision has to be weighed taking into consideration the patient’s age and the impact of early menopause on her life style. The recurrence of endometriosis symptoms and pelvic pain are directly correlated to the surgical precision and removal of peritoneal and deeply infiltrated disease. Surgical effort should always aim to eradicate the endometriotic lesions completely to keep the risk of recurrence as low as possible.




Front Surg. 2014 May 8;1:14.

Endometriosis and ovarian cancer risk: a systematic review of epidemiological studies.

Zafrakas M1Grimbizis G2Timologou A2Tarlatzis BC2.




A possible etiological association between endometriosis and ovarian cancer has been repeatedly reported in the literature.


Our aim was to evaluate published epidemiological data on this issue.


We conducted an extensive search of the literature in MEDLINE, of articles ever published until February 2014, using the key-words “endometriosis” and “ovarian” and one of the following terms in the title: “cancer” or “malignancy” or “malignant” or “tumor” or “neoplasia” or “neoplasm” or “transformation.” Retrieved papers were checked for further relevant publications.


Overall, our search yielded 1 prospective cohort study, 10 retrospective cohort, and 5 case-control studies. A meta-analysis of these studies was not considered to be appropriate, due to differences in data reporting, study design, and adjustment for confounding factors.


The main limitation of studies found, with one exception, was the lack of operative confirmation of endometriosis.


An association of endometriosis with clear-cell and endometrioid ovarian cancer was a consistent finding in most studies. On the other hand, existing epidemiological evidence linking endometriosis with ovarian cancer is insufficient to change current clinical practice. Prospective cohort studies, with prior laparoscopic confirmation, localization, and staging of endometriosis are needed, in order to further clarify this issue.



Front Surg. 2014 May 27;1:16.

Endometriosis: a new cellular and molecular genetic approach for understanding the pathogenesis and evolutivity.

Bouquet De Jolinière J1Ayoubi JM2Gianaroli L3Dubuisson JB4Gogusev J5Feki A4.



Endometriosis is a benign disease with high prevalence in women of reproductive age estimated between 10 and 15% and is associated with considerable morbidity. Its etiology and pathogenesis are controversial but it is believed to involve multiple genetic, environmental, immunological, angiogenic, and endocrine processes. Altered expressions of growth factors, cytokines, adhesion molecules, matrix metalloproteinases, and enzymes for estrogen synthesis and metabolism have been frequently observed in this condition. The possibility of genetic basis of endometriosis is demonstrated in studies of familial disease, in which the incidence of endometriosis is higher for first-degree relatives of probands as compared to controls. This review describes mainly the cellular, cytochemical, cytogenetic, and molecular genetic features of endometriotic lesions and cultured endometriotic cells. In attempts to identify candidate gene (s) involved in the pathogenesis of endometriosis, a tissue-based approaches including conventional cytogenetics (RHG-banding), loss of heterozygosity (LOH), and comparative genomic hybridization (CGH) were employed. In addition to the karyotypic anomalies, consistent chromosome instability was confirmed by CGH and fluorescence in situ hybridization (FISH). The nature and significance of the molecular genetic aberrations in relation to the locations and function of oncogenes and tumor suppressor genes will be discussed. At last, a possible pathogenic role of embryonic duct remnants was observed in seven female fetal reproductive tract in endometriosis and may induce a discussion about the beginning of ovarian tumors and malignant proliferations.



Front Surg. 2014 Jul 2;1:24.

Endometriosis and infertility: how and when to treat?

Fadhlaoui A1Bouquet de la Jolinière J1Feki A1.



Endometriosis is defined as the presence of endometrial-like tissue (glands or stroma) outside the uterus, which induces a chronic inflammatory reaction. Although endometriosis impairs fertility, it does not usually completely prevent conception. The question of evidence based-medicine guidelines in endometriosis-associated infertility is weak in many situations. Therefore, we will highlight in this issue where the challenges are.



Front Surg. 2015 Jan 6;1:51.

Somatic stem cells and their dysfunction in endometriosis.

Djokovic D1Calhaz-Jorge C2.



Emerging evidence indicates that somatic stem cells (SSCs) of different types prominently contribute to endometrium-associated disorders such as endometriosis. We reviewed the pertinent studies available on PubMed, published in English language until December 2014 and focused on the involvement of SSCs in the pathogenesis of this common gynecological disease. A concise summary of the data obtained from in vitro experiments, animal models, and human tissue analyses provides insights into the SSC dysregulation in endometriotic lesions. In addition, a set of research results is presented supporting that SSC-targeting, in combination with hormonal therapy, may result in improved control of the disease, while a more in-depth characterization of endometriosis SSCs may contribute to the development of early-disease diagnostic tests with increased sensitivity and specificity. Key message: Seemingly essential for the establishment and progression of endometriotic lesions, dysregulated SSCs, and associated molecular alterations hold a promise as potential endometriosis markers and therapeutic targets.



Int Surg. 2015 Jan;100(1):109-11.

Endometriosis in a spigelian hernia sac: an unexpected finding.

Moris D1Michalinos AVernadakis S.



Describes the existence of endometrioma in a spigelian hernia sac. Spigelian Hernia is a rare ventral hernia, presenting difficulties in diagnosis and carrying a high incarceration and obstruction risk. Endometriomas occur due to implantation of endometrial cells into a surgical wound, most often after a cesarean delivery. A 37-year-old woman presented to our department with persistent abdominal pain, exacerbating during menses, and vomiting for 2 days. Physical examination revealed a mass-like lesion in the border between the left-upper and left-lower quadrant. Ultrasound examination was inconclusive and a computed tomography scan of the abdomen revealed an abdominal wall mass. During surgery, a spigelian hernia was found 5 to 7 cm above a previous cesarean incision. Tissue like “chocolate cysts” was present at the hernia sac. Hernia was repaired while tissue was excised and sent for histological examination that confirmed the diagnosis. Spigelian hernia is a hernia presenting difficulties in diagnosis and treatment. Endometrioma in a spigelian hernia sac is a rare diagnosis, confirmed only histologically. Clinical suspicion can be posed only through symptoms and thorough investigation.



Gynecol Obstet Fertil. 2015 Feb;43(2):109-16.

Surgery for deep infiltrating endometriosis before in vitro fertilization: no benefit for fertility?.

Capelle A1Lepage J2Langlois C3Lefebvre C4Dewailly D4Collinet P5Rubod C5.




Does surgery for deep infiltrating endometriosis (DIE) before in vitro fertilization (IVF) improve pregnancy and birth rate?


Cohort study of 177 consecutive patients with DIE related infertility and receiving IVF. Patients were divided into 3 groups according to surgical management decided during multidisciplinary team meeting. Group no surgery (NS) (n=65), group complete surgery (CS) with complete resection of all lesions (n=49) and group incomplete surgery (IS) with gestures improving ovaries accessibility for IVF and/or facilitating embryonic implantation (n=63). Pre-surgery clinical, MRI lesion locations, and history of IVF characteristics were analyzed with logistic regression.


There was no significant difference in general and IVF characteristics and in the severity of endometriosis among the three groups (P=0.43). Overall pregnancy and birth rates after IVF were 45.8% and 33.3%, respectively and were not different among the 3 groups (P=0.59 and P=0.49). Four major complications during oocytes retrievals were observed in NS group, one in IS group and none in CS group. Presence of an inter-utero-rectal lesion at MRI decreased the rate of pregnancy (OR=0.49 [0.25, 0.97]).


Surgery for deep infiltrating endometriosis does not improve pregnancy and birth rates before IVF. This inter-utero-rectal extensive lesion might explain IVF failures by ovarian difficult access and difficulties in embryonic transfers. Further studies should explore the impact of surgical excision of inter-utero-rectal lesion on oocyte retrieval and embryonic transfer.



Diabetologia. 2015 Apr;58(4):707-15.

History of infertility and risk of type 2 diabetes mellitus: a prospective cohort study.

Tobias DK1Gaskins AJMissmer SAHu FBManson JEBuck Louis GMZhang CChavarro JE.




We sought to evaluate the relationship between delayed conception and type 2 diabetes risk, given that there are plausible underlying mechanisms linking the two, including inflammation and insulin resistance.


Participants of the Nurses’ Health Study II prospective cohort were included if they were free of chronic disease (cardiovascular disease, type 2 diabetes, cancer) at baseline. Biennial questionnaires updated information on infertility status (>12 months attempted pregnancy), lifestyle characteristics and several health-related outcomes. Self-reported cases of diabetes were confirmed using a follow-up questionnaire. Multivariable Cox proportional hazards models were used to compute the HRs and 95% CIs.


Incident type 2 diabetes occurred in 5,993 of the 112,106 participants over 24 years of follow-up (1989-2013). A history of infertility was reported in 27,774 (24.8%) women and was associated with a 20% greater risk of developing diabetes, compared with those never reporting infertility (HR 1.20 [95% CI 1.14, 1.28]), after adjusting for age, lifestyle factors, marital status, oral contraceptive use, family history of diabetes and BMI. Compared with women without a history of infertility, the causes of infertility associated with a higher diabetes risk were ovulation disorders (HR 1.43 [95% CI 1.29, 1.58]) and tubal factor (HR 1.34 [95% CI 1.13, 1.58]). Cervical factor (HR 1.06 [95% CI 0.81, 1.40]) and endometriosis (HR 1.06 [95% CI 0.89, 1.27]) were not associated, while male factor infertility was associated with a modestly higher diabetes risk (HR 1.15 [95% CI 1.00, 1.33]).


These novel findings suggest a history of infertility, particularly that related to ovulation disorders and tubal blockage, is significantly associated with a higher risk of type 2 diabetes.



Eur J Obstet Gynecol Reprod Biol. 2015 Mar;186:22-5.

Hysterosalpingo-contrast-sonography (HyCoSy) in the assessment of tubal patency in endometriosis patients.

Moro F1Tropea A2Selvaggi L2Scarinci E2Lanzone A2Apa R2.




Tubal patency in women with endometriosis has traditionally been evaluated by laparoscopy. The aim of this study was to investigate the accuracy of hysterosalpingo-contrast-sonography (HyCoSy) in the assessment of tubal patency in these women.


A retrospective study was conducted at Physiopathology of Human Reproduction Unit. Infertile women who underwent HyCoSy and then a laparoscopy (dye test) within 6 months from the HyCoSy were included. Tubal patency was assessed by HyCoSy and the findings were compared with the results of laparoscopy, which was considered the gold standard for assessment of tubal patency. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) and positive and negative likelihood ratios (Lh+, Lh-) were calculated including the 95% confidence interval (CI).


A total of 1452 women underwent HyCoSy and 126 of them received a laparoscopy within 6 months from the HyCoSy. Of the 126 women, 42 (33.3%) had a diagnosis of pelvic endometriosis and 84 (66.7%) had no endometriosis. In the endometriosis population, HyCoSy showed a sensitivity, specificity, PPV, NPV, Lh+ and Lh- of 85% (95% CI 62-96), 93% (95% CI 82-97), 81% (95% CI 58-94), 94% (95% CI 84-98), 12.6 (95% CI 4.8-33) and 0.15 (95% CI 0.05-0.4) respectively. In the non-endometriosis group, HyCoSy showed a sensitivity, specificity, PPV, NPV, LR+ and LR- of 85% (95% CI 65-95), 93% (95% CI 87-96), 71% (95% CI 53-85), 97% (95% CI 92-99), 13.2 (95% CI 6.9-25) and 0.15 (95% CI 0.06-0.3) respectively. The diagnostic accuracy of HyCoSy was 91% in the endometriosis group and 92% in the non-endometriosis patients.


HyCoSy showed high accuracy in evaluating tubal patency in infertile non-endometriosis women and in those affected by endometriosis.



J Minim Access Surg. 2015 Jan-Mar;11(1):50-9

Robotic surgery in gynecology.

Sinha R1Sanjay M1Rupa B1Kumari S1.



FDA approved Da Vinci Surgical System in 2005 for gynecological surgery. It has been rapidly adopted and it has already assumed an important position at various centers where this is available. It comprises of three components: A surgeon’s console, a patient-side cart with four robotic arms and a high-definition three-dimensional (3D) vision system. In this review we have discussed various robotic-assisted laparoscopic benign gynecological procedures like myomectomy, hysterectomy, endometriosis, tubal anastomosis and sacrocolpopexy. A PubMed search was done and relevant published studies were reviewed. Surgeries that can have future applications are also mentioned. At present most studies do not give significant advantage over conventional laparoscopic surgery in benign gynecological disease. However robotics do give an edge in more complex surgeries. The conversion rate to open surgery is lesser with robotic assistance when compared to laparoscopy. For myomectomy surgery, Endo wrist movement of robotic instrument allows better and precise suturing than conventional straight stick laparoscopy. The robotic platform is a logical step forward to laparoscopy and if cost considerations are addressed may become popular among gynecological surgeons world over.



Clin Exp Reprod Med. 2014 Dec;41(4):151-7.

Association of the neutrophil-to-lymphocyte ratio and CA 125 with the endometriosis score.

Kim SK1Park JY2Jee BC1Suh CS1Kim SH3.




To evaluate the association between the severity of endometriosis and the preoperative neutrophil-to-lymphocyte ratio (NLR) and serum level of cancer antigen 125 (CA 125).


Data were obtained from the medical records of 419 patients who underwent laparoscopic conservative surgery for ovarian endometrioma between April 2005 and March 2013. Each patient’s preoperative complete blood count was recorded and the endometriosis score was assessed.


The endometriosis score was not associated with either the NLR or the serum level of CA 125. The endometriosis score was negatively related to preoperative hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. The only positive association was between NLR and the patients’ age. NLR and preoperative serum anti-Müllerian hormone level were found to be negatively related.


The severity of endometriosis was not associated with the serum level of CA 125 or the NLR. The presence of a negative correlation between the severity of endometriosis and red blood cell dynamics needs further investigation.



Pain. 2015 Mar;156(3):528-39.

Oxidation-sensitive nociception involved in endometriosis-associated pain.

Ray K1Fahrmann JMitchell BPaul DKing HCrain CCook CGolovko MBrose SGolovko SSantanam N.



Endometriosis is a disease characterized by the growth of endometrial tissue outside the uterus and is associated with chronic pelvic pain. Peritoneal fluid (PF) of women with endometriosis is a dynamic milieu and is rich in inflammatory markers, pain-inducing prostaglandins prostaglandin E2 and prostaglandin F2α, and lipid peroxides; and the endometriotic tissue is innervated with nociceptors. Our clinical study showed that the abundance of oxidatively modified lipoproteins in the PF of women with endometriosis and the ability of antioxidant supplementation to alleviate endometriosis-associated pain. We hypothesized that oxidatively modified lipoproteins present in the PF are the major source of nociceptive molecules that play a key role in endometriosis-associated pain. In this study, PF obtained from women with endometriosis or control women were used for (1) the detection of lipoprotein-derived oxidation-sensitive pain molecules, (2) the ability of such molecules to induce nociception, and (3) the ability of antioxidants to suppress this nociception. LC-MS/MS showed the generation of eicosanoids by oxidized-lipoproteins to be similar to that seen in the PF. Oxidatively modified lipoproteins induced hypothermia (intracerebroventricular) in CD-1 mice and nociception in the Hargreaves paw withdrawal latency assay in Sprague-Dawley rats. Antioxidants, vitamin E and N-acetylcysteine, and the nonsteroidal anti-inflammatory drug indomethacin suppressed the pain-inducing ability of oxidatively modified lipoproteins. Treatment of human endometrial cells with oxidatively modified lipoproteins or PF from women with endometriosis showed upregulation of similar genes belonging to opioid and inflammatory pathways. Our finding that oxidatively modified lipoproteins can induce nociception has a broader impact not only on the treatment of endometriosis-associated pain but also on other diseases associated with chronic pain.



Reprod Biomed Online. 2015 Mar;30(3):220-32.

Adenomyosis: a life-cycle approach.

Benagiano G1Brosens I2Habiba M3.



The life-cycle approach to endometriosis highlighted unexpected features of the condition; the same approach was therefore applied to gain insight into the clinical features of adenomyosis and to draw a comparison with endometriosis. This is possible today thanks to new imaging techniques enabling non-invasive diagnosis of adenomyosis. The specificity and sensitivity of magnetic resonance imaging and transvaginal ultrasound remain uncertain. Unlike endometriosis, little information is available on the presence of classic adenomyosis in adolescents, except for rare cystic forms that may not represent the true disease. Adenomyosis is most likely to affect adult women, although most reported incidences are still based on post-hysterectomy studies, and are affected by diligence in histopathologic diagnosis and the adopted cut-off point. The traditionally accepted associations of adult adenomyosis, such as multiparity, a link to infertility and its effect on pregnancy are uncertain. Active adenomyosis has been found in pre- and peri-menopausal women and in postmenopausal women receiving tamoxifen. In conclusion, major diagnostic limitations and the systematic bias of hysterectomy make it difficult to draw firm conclusions from existing evidence. In addition, no information is available on the natural history of adenomyosis and no study has systematically evaluated its existence in adolescents.


JAMA. 2015 Jan 20;313(3):296-7.

An overview of treatments for endometriosis.

Brown J1Farquhar C2.




What treatments are associated with improved outcomes for women with endometriosis?


The levonorgestrel-releasing intrauterine system (LNG-IUD), gonadotropin-releasing hormone analogues (GnRHa; nafarelin, leuprolide, buserelin, goserelin, triptorelin), laparoscopic ablation, and excision are associated with relief of pain due to endometriosis. Gonadotropin-releasing hormone analogues and laparoscopic ablation or excision are associated with increased clinical pregnancy rates in women with endometriosis. Gonadotropin-releasing hormone analogues, danazol, and depot progestagens are associated with a higher incidence of adverse events.



Eur J Radiol. 2015 Apr;84(4):568-74.

Detection and localization of deep endometriosis by means of MRI and correlation with the ENZIAN score.

Di Paola V1Manfredi R2Castelli F2Negrelli R2Mehrabi S2Pozzi Mucelli R2.




To determine the accuracy of ENZIAN score, as detected on MR imaging, compared to surgical-pathologic findings.


This retrospective study was approved by the investigational review board and the requirement for informed patient consent was waived. 115 patients were included according to following criteria: tubo-ovarian and/or deep endometriosis suspected at physical examination and transvaginal ultrasound; availability of MR examination; histopathological results from laparoscopic or surgical treatment.


lack of available MR examination, and/or (b) lack of a definitive histopathological results. Histopathological findings from bioptic specimens obtained during laparoscopic or laparotomic treatment were considered as reference standard. For all detected lesions a score according to ENZIAN score (revised 2010) was assigned both for MRI and histopathological findings. By comparing MRI-ENZIAN score and histopathological-ENZIAN score the overall sensitivity, specificity, accuracy, positive and negative predictive values in relation to presence/absence of deep endometriosis in each patient were calculated. k-Cohen to evaluate the degree of concordance between MRI-ENZIAN score and histopathological-ENZIAN score was also measured. Moreover the sensitivity, specificity, accuracy, positive and negative predictive values for each specific localization provided by ENZIAN score were also calculated.


At histopathology, the diagnosis of deep endometriosis was confirmed in 82/115 (71.3%) patients. The sensitivity, specificity, accuracy, PPV and NPV of MRI were 94%, 97%, 95%, 99%, 86%, respectively. The highest accuracy was for adenomyosis (100%) and endometriosis of utero-sacral ligaments (USLs) (98%), slightly lower for vagina-rectovaginal septum an colo-rectal walls (96%), and the lowest for bladder endometriosis (92%). The concordance between histopathological and MRI ENZIAN score was excellent (k=0.824); in particular it was 0.812 for lesions in vagina-rectovaginal space, 0.890 for lesions in USL, 0.822 for lesions in rectum-sigmoid colon, 1.000 for uterine adenomyosis, and 0.367 for lesions located in the bladder wall.


MRI correlates with the ENZIAN score and has an accuracy of 95% in the detection and localization of deep endometriosis, allowing to minimize false negative results (4%) in patients with deep endometriosis and to obtain a correct preoperative staging.



Clin Obstet Gynecol. 2015 Mar;58(1):3-27.

Pathology of the adnexal mass.

Bennett JA1Oliva E.



An “adnexal mass” is a common specimen encountered in the daily pathology practice. Although most are benign, the incidence of malignancy increases with age, and approximately 30% are malignant in postmenopausal females. Herein we describe the salient macroscopic and microscopic features of the most prevalent adnexal masses. The entities are separated based on patients’ age into premenopausal and postmenopausal, with further subdivision into non-neoplastic lesions, benign and malignant neoplasms, and those of uncertain behavior. For each entity, a brief differential diagnosis is discussed and for the malignant neoplasms, tables highlighting the key immunohistochemical differences that may be helpful are provided.




Sci Transl Med. 2015 Jan 21;7(271):27

Dual suppression of estrogenic and inflammatory activities for targeting of endometriosis.

Zhao Y1Gong P1Chen Y1Nwachukwu JC2Srinivasan S2Ko C3Bagchi MK1Taylor RN4Korach KS5Nettles KW2Katzenellenbogen JA6Katzenellenbogen BS7.



Estrogenic and inflammatory components play key roles in a broad range of diseases including endometriosis, a common estrogen-dependent gynecological disorder in which endometrial tissue creates inflammatory lesions at extrauterine sites, causing pelvic pain and reduced fertility. Current medical therapies focus primarily on reducing systemic levels of estrogens, but these are of limited effectiveness and have considerable side effects. We developed estrogen receptor (ER) ligands, chloroindazole (CLI) and oxabicycloheptene sulfonate (OBHS), which showed strong ER-dependent anti-inflammatory activity in a preclinical model of endometriosis that recapitulates the estrogen dependence and inflammatory responses of the disease in immunocompetent mice and in primary human endometriotic stromal cells in culture. Estrogen-dependent phenomena, including cell proliferation, cyst formation, vascularization, and lesion growth, were all arrested by CLI or OBHS, which prevented lesion expansion and also elicited regression of established lesions, suppressed inflammation, angiogenesis, and neurogenesis in the lesions, and interrupted crosstalk between lesion cells and infiltrating macrophages. Studies in ERα or ERβ knockout mice indicated that ERα is the major mediator of OBHS effectiveness and ERβ is dominant in CLI actions, implying involvement of both ERs in endometriosis. Neither ligand altered estrous cycling or fertility at doses that were effective for suppression of endometriosis. Hence, CLI and OBHS are able to restrain endometriosis by dual suppression of the estrogen-inflammatory axis. Our findings suggest that these compounds have the desired characteristics of preventive and therapeutic agents for clinical endometriosis and possibly other estrogen-driven and inflammation-promoted disorders.






Int J Hyperthermia. 2015 May;31(3):280-4.

Ultrasound-guided high intensity focused ultrasound for the treatment of gynaecological diseases: A review of safety and efficacy.

Zhang L1Zhang WOrsi FChen WWang Z.



As a non-surgical treatment, high intensity focused ultrasound (HIFU) has received increasing interest for the treatment of gynaecological diseases over the last 10 years. Many studies have shown that HIFU is safe and effective in treating patients with uterine fibroids, adenomyosis, cervicitis or vulvar diseases. Both magnetic resonance imaging-guided HIFU (MRgHIFU) and ultrasound-guided HIFU (USgHIFU) can offer gynaecologists non-invasive techniques to treat patients with uterine benign diseases. Focused ultrasound therapy can also be used effectively to treat cervicitis and vulvar diseases. As gynaecologists gain more experience with this technology, the rate of severe adverse effects has been lowered with the development of this non-invasive technique. In this paper we review the literature available regarding the utilisation of magnetic resonance imaging-guided focused ultrasound/MRgHIFU or USgHIFU and new findings from our group in the treatment of gynaecological diseases: uterine fibroids, adenomyosis, cervicitis, vulvar diseases, caesarean scar pregnancies, and abdominal wall endometriosis.



Case Rep Obstet Gynecol. 2014;

Endometriosis in a patient with mayer-rokitansky-küster-hauser syndrome.

Troncon JK1Zani AC1Vieira AD1Poli-Neto OB1Nogueira AA1Rosa-E-Silva JC1.



Objective. To report a case of Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) in which there were two nonfunctional rudimentary uteruses with the presence of ovarian endometrioma, corroborating that there are valid alternative theories to the existence of endometriosis, rather than Sampson’s theory alone, such as the coelomic metaplasia theory. Design. A case report. Setting. A tertiary referral center, which is also a university hospital. Patient. A fifteen-year-old patient with MRKH syndrome and endometriosis. Intervention. Laparoscopic approach for diagnostic confirmation and treatment of the endometrioma. Results. Evidence of endometriosis in a patient with no functional uterus. Conclusions. This case report and a few others that are available in the literature reinforce the possibility that coelomic metaplasia could be the origin of endometriosis. Patients with müllerian agenesis and pelvic pain should be carefully evaluated, and the presence of pelvic endometriosis should not be excluded.


Hum Reprod Update. 2015 May-Jun;21(3):329-39.

Deep endometriosis infiltrating the recto-sigmoid: critical factors to consider before management.

Abrão MS1Petraglia F2Falcone T3Keckstein J4Osuga Y5Chapron C6.




Deep endometriosis invading the bowel constitutes a major challenge for the gynecologist. In addition to the greater impact on pain, the high incidence of surgical morbidity involved with bowel endometriosisposes a therapeutic dilemma for the surgeon. Intestinal involvement by deep endometriotic nodules has been estimated to occur in 8-12% of women with endometriosis. Individual and clinical factors, pre-operative morphologic characteristics from imaging, surgical considerations and impact on quality of life are critical variables that should be considered in determining the best therapeutic strategy for a patient with deep endometriosis involving the sigmoid and/or the rectum. Pre-operative planning is fundamental for defining the optimal therapeutic strategy; patient counseling of treatment options, and when surgery is indicated, involvement of a multidisciplinary surgical team is required.


The PubMed and Cochrane database were searched for all original and review articles published in English, French and Italian, until June 2014. Search terms included ‘deep endometriosis’, ‘surgical and clinical approach’, ‘bowel disease’, ‘quality of life’, ‘management of deep endometriosis’. Special attention was paid to articles comparing features of discoid and segmental resection.


The rationale for the best therapeutic options for patients with deep endometriosis has been shown and an evidence-based treatment algorithm for determining when and which surgical intervention may be required is proposed. In deciding the best treatment option for patients with deep endometriosis involving the sigmoid and rectum, it is important to understand how the different clinical factors and pre-operative morphologic imaging affect the algorithm. Surgery is not indicated in all patients with deep endometriosis, but, when surgery is chosen, a complete resection by the most appropriate surgical team is required in order to achieve the best patient outcome.


In women with deep endometriosis, surgery is the therapy of choice for symptomatic patients when deep lesions do not improve with a medical treatment.



Int Urogynecol J. 2015 Jun;26(6):921-3.

Cystoscopic findings: a video tutorial.

Lenherr SM1Crosby ECCameron AP.




Cystoscopy is frequently performed by gynecologists to ensure ureteral patency and to prevent bladder injury when performing concomitant gynecological procedures. Generally, there are no additional findings on cystoscopy; however, when abnormalities arise, they may require either observation or intervention. Our aim was to create a visual library of benign, malignant, and foreign-body pathological conditions incidentally encountered on cystoscopy.


Cystoscopic findings were videotaped at the time of routine surgical care. Regarding Institutional Review Board approval, individual consent was waived as the videos were de-identified and collected for educational purposes.


Benign pathological conditions: squamous metaplasia, duplicated ureteral orifice, ureterocele, Hutch diverticulum, bladder trabeculation, urachal cyst, interstitial cystitis with and without Hunner’s lesion, endometriosis in the bladder, port-wine stain due to Klippel-Trénaunay-Weber syndrome, nephrogenic (mesonephric) metaplasia, and cystitis glandularis (intestinal metaplasia). Malignant pathological conditions: papillary urothelial neoplasm of low malignant potential (PUNLMP), carcinoma in situ (CIS), high-grade urothelial carcinoma, and urachal cancer. Foreign-body pathological conditions: edema from ureteral stents and stone-encrusted mesh.


This video is intended to educate the audience on some incidental bladder findings seen on female cystoscopy. Many pathological conditions can be biopsied or treated immediately during the procedure; hence, early urology consultation is encouraged for most abnormalities.



Oncol Lett. 2015 Feb;9(2):717-720.

Leiomyomatosis peritonealis disseminata associated with endometriosis: A case report and review of the literature.

Yang R1Xu T1Fu Y1Cui S1Yang S1Cui M1.



Leiomyomatosis peritonealis disseminata (LPD) is a specific type of leiomyomatosis with an unclear pathogenesis that is rarely diagnosed by clinical evaluation. To date, <200 cases have been reported. The majority of the patients have a medical history of laparoscopic myomectomy for uterine fibroids. The use of laparoscopic power morcellation may be a contributor to the development of LPD, therefore, the specific surgical approach used in laparoscopic myomectomy should be carefully considered, and protective measures should be taken to prevent myoma fragments spreading if laparoscopic power morcellation is used. The present study reviewed and analyzed the medical history, diagnostic process and treatment strategy of a case of LPD to improve our understanding of the disease. In this report, the case of a 34 year-old female who underwent laparoscopic myomectomy to remove a uterine fibroid is presented. During the surgery, a myoma was resected using morcellators. Three years after surgery, exploratory laparotomy was performed due to uterine fibroid recurrence. During surgery, myoma was identified at the uterine bladder peritoneal reflection, where several unequally sized leiomyoma tubercles were identified on the uterine surface. Subsequently, myomectomy was performed. Postoperative pathology diagnosed leiomyoma. Two years later, gynecological ultrasound revealed a mass in the abdomen. Exploratory laparotomy was subsequently performed. During surgery, compact myoma tubercle-like cysts were identified on the surface of the intestine and mesentery, and an endometriotic cyst was identified on the left ovary. As the myomas were too compact to remove completely, the majority of leiomyoma on the intestine and mesentery was resected. The endometriotic cyst on the left ovary was also resected. Considering the patient’s medical history, observations during surgery and pathological results, the final diagnosis was LPD. Following surgery, the patient was treated with the gonadotropin-releasing hormone agonist, triptorelin acetate (3.5 mg, once every four weeks), for three months and followed-up every six months. In October 2014, a gynecological sonography examination revealed no abnormalities and at the time of writing, the patient remains alive and well.



Cancer Epidemiol Biomarkers Prev. 2015 Apr;24(4):671-676.

Population distribution of lifetime risk of ovarian cancer in the United States.

Pearce CL1,2Stram DO2Ness RB3Stram DA2Roman LD4Templeman C4Lee AW2Menon U5Fasching PA6,7McAlpine JN8Doherty JA9Modugno F10,11,12Schildkraut JM13,14Rossing MA15,16Huntsman DG17Wu AH2Berchuck A18Pike MC#2,19Pharoah PDP#20,21.




In U.S. women, lifetime risk of ovarian cancer is 1.37%, but some women are at a substantially lower or higher risk than this average.


We have characterized the distribution of lifetime risk in the general population. Published data on the relative risks and their variances for five well-accepted risk and protective factors for ovarian cancer, oral contraceptive use, parity, tubal ligation, endometriosis, and first-degree family history of ovarian cancer in conjunction with a genetic risk score using genome-wide significant common, low penetrance variants were used. The joint distribution of these factors (i.e., risk/protective factor profiles) was derived using control data from four U.S. population-based studies, providing a broad representation of women in the United States.


A total of 214 combinations of risk/protective factors were observed, and the lifetime risk estimates ranged from 0.35% [95% confidence interval (CI), 0.29-0.42] to 8.78% (95% CI, 7.10-10.9). Among women with lifetime risk ranging from 4% to 9%, 73% had no family history of ovarian cancer; most of these women had a self-reported history of endometriosis.


Profiles including the known modifiable protective factors of oral contraceptive use and tubal ligation were associated with a lower lifetime risk of ovarian cancer. Oral contraceptive use and tubal ligation were essentially absent among the women at 4% to 9% lifetime risk.


This work demonstrates that there are women in the general population who have a much higher than average lifetime risk of ovarian cancer. Preventive strategies are available. Should effective screening become available, higher than average risk women can be identified.



Zhonghua Bing Li Xue Za Zhi. 2014 Dec;43(12):827-30

Cannabinoid receptor 1 controls nerve growth in ectopic cyst in a rat endometriosis model.

Zhao Q1Liang X1Han H2.




To investigate whether cannabinoid receptor 1 (CB1R) is involved in nerve growth in endometriosis-associated ectopic cyst.


The effect of CB1R agonist and antagonist on the expression of pan-neuronal marker protein gene product (PGP) 9.5 in ectopic cyst was examined by immunofluorescence and Western blot in endometriosismodel of 18 rats.


Immunofluorescence revealed that PGP 9.5 was expressed in the nerve fibers and was mainly distributed in the cyst hilum. Western blot revealed that the protein density of either PGP 9.5 (2 week: 0.38 ± 0.05; 4 week: 0.63 ± 0.03; 8 week: 0.80 ± 0.07, P < 0.01) or CB1R (2 week: 0.48 ± 0.04; 4 week: 0.68 ± 0.01; 8 week: 0.80 ± 0.03, P < 0.01) in the ectopic cyst increased with cyst size. In addition, compared to control group (0.75 ± 0.01), PGP 9.5 expression in the ectopic cyst was promoted by CB1R agonist ACPA (0.81 ± 0.01, P < 0.05), and inhibited by CB1R antagonist AM251 (0.67 ± 0.03, P < 0.01).


CB1R was involved in the nerve growth of ectopic cyst associated with endometriosis.



J Clin Oncol. 2015 Mar 10;33(8):930-6.

Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma.

Slomovitz BM1Jiang Y1Yates MS1Soliman PT1Johnston T1Nowakowski M1Levenback C1Zhang Q1Ring K1Munsell MF1Gershenson DM1Lu KH1Coleman RL2.




The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregulated in endometrial cancer (EC). Hormonal manipulation leads to response in some patients with EC, but resistance derived from PI3K pathway activation has been documented. Targeting mammalian target of rapamycin (mTOR) may overcome endocrine resistance. We conducted a two-institution phase II trial of everolimus and letrozole in women with recurrent EC.


Patients were considered incurable, had measurable disease, and were treated with up to two prior cytotoxic regimens. Everolimus was administered orally at 10 mg daily and letrozole was administered orally at 2.5 mg daily. Each cycle consisted of 4 weeks of therapy. Patients were treated until progression, toxicity, or complete response (CR). The primary end point was the clinical benefit rate (CBR), which was defined as CR, partial response, or stable disease (≥ 16 weeks) by RECIST 1.0 criteria. Translational studies were performed to correlate biomarkers with response.


Thirty-eight patients were enrolled (median age, 62 years; range, 24 to 82 years). Thirty-five patients were evaluable for response. The CBR was 40% (14 of 35 patients); the median number of cycles among responders was 15 (range, seven to 29 cycles). The confirmed objective response rate (RR) was 32% (11 of 35 patients; nine CRs and two partial responses; median, 15 cycles; range, eight to 29 cycles). Twenty percent of patients (seven of 35 patients) were taken off treatment after a prolonged CR and at the discretion of the treating clinician. None of the patients discontinued treatment as a result of toxicity. Serous histology was the best predictor of lack of response. Patients with endometrioid histology and CTNNB1 mutations responded well to everolimus and letrozole.


Everolimus plus letrozole results in a high CBR and RR in patients with recurrent EC. Further development of this combination in recurrent endometrioid EC is under way.



J Hum Reprod Sci. 2014 Oct-Dec;7(4):269-71.

Primary umbilical endometriosis: A rarity.

Pramanik SR1Mondal S1Paul S1Joycerani D1.



Endometriosis is a functional endometrial tissue found outside the normal uterine cavity. Primary umbilical endometriosis is defined as the presence of ectopic endometrial glands and stroma within umbilicus, without prior history of pelvic endometriosis. It is a rare presentation in all cases of endometriosis, especially in Asians. Here, a case of primary umbilical endometriosis has been reported in a 33-year-old nulliparous female who presented with the history of cyclical bleeding and pain in an umbilical mass during menstrual cycle. Athough the disease is rare, umbilical endometriosis should be taken into account in differential diagnosis of umbilical disorders even in young nulliparous women with no typical symptoms of pelvic endometriosis. The disease pathogenesis, its symptoms, and treatment modality have been discussed.



Balkan Med J. 2014 Sep;31(3):224-9.

Clinical and pathological features of lipoleiomyoma of the uterine corpus: a review of 76 cases.

Akbulut M1Gündoğan M1Yörükoğlu A1.




Uterine lipoleiomyoma is a rare and specific type of leiomyoma with a considerable amount of adipocytes.


The aim of the study was to investigate the clinical, pathological and immunohistochemical features of lipoleiomyoma of the uterine corpus, and review its histogenesis and differential diagnosis from other neoplastic and non-neoplastic lesions in order to obtain a detailed profile of this somewhat uncommon lesion.


Descriptive study.


This study is a retrospective analysis of 70 consecutive women with 76 lipoleiomyomas, who underwent surgery mainly for uterine leiomyoma and gynecological carcinomas between January 2000 and April 2013. Clinical and pathological information was obtained from medical records. Immunohistochemistry was applied in selected cases. Parametric methods were used to compare clinical and pathologic features.


The patients ranged in age from 34 to 77 years (mean 55.49 years). Lipoleiomyomas ranged from 0.5 to 55 cm in diameter (mean 5.50 cm). Typical macroscopic and microscopic features were noted. Sixty-nine (90.7%) tumors were in the uterine corpus and five (6.5%) were in the cervix. One broad ligament tumor and one retroperitoneal tumor were also studied. No tumors displayed cytologic atypia, mitosis, necrosis, calcification, or other degenerative changes. Immunohistochemically, the adipose tissue element was positive for vimentin, desmin, S100 protein, estrogen (ER), progesterone (PR), and Ki-67. Among patients with lipoleiomyomas, 53 cases (75.7%) had different types of lesions associated with hyperestrogenic status, such as adenomyosis, endometriosis, endometrial hyperplasia, and polyps, complex atypical endometrial hyperplasia, and gynecologic carcinomas. The follow-up period ranged from one to eight years (mean 4.6 years). There were no recurrences or tumor-related fatalities.


In the present study, the lipoleiomyomas were seen more frequently in patients with adenomyosis, endometriosis, endometrial hyperplasia, polyps, and various gynecologic carcinomas. Lipoleiomyoma of the uterus seems to have a benign clinical course.



Int J Mol Med. 2015 Apr;35(4):1119-25.

miR-29c is downregulated in the ectopic endometrium and exerts its effects on endometrial cell proliferation, apoptosis and invasion by targeting c-Jun.

Long M1Wan X2La X1Gong X1Cai X1.



Endometriosis is a prevalent and complex gynecological disease which affects 10% of women of reproductive age. Certain studies have suggested that a substantial number of microRNAs (miRNAs or miRs) are aberrantly or differentially expressed in the ectopic endometrium. To date, to the best of our knowledge, there is no report available on the role of miR-29 in the endometrium. In this study, we investigated the expression of the miR-29 family in the endometrium samples from women without endometriosis, as well as in paired ectopic and eutopic endometrium samples by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results revealed that miR-29c was differentially expressed in the paired eutopic and ectopic endometrium samples. In addition, c-Jun was differentially expressed in the ectopic and eutopic endometrial tissues as determined by western blot analysis. Furthermore, the role of miR-29c in endometrial cell proliferation, invasion and apoptosis was examined in vitro. The results revealed that miR-29c exerted its effects on endometrial cells by suppressing cell proliferation and invasion, as well as promoting cell apoptosis. Furthermore, it was found that c-Jun was a novel target of miR-29c, and c-Jun reversed the effects of miR-29c on the proliferation, invasion and apoptosis of endometrial cells. To the best of our knowledge, this study is the first to identify miR-29c as a suppressor of endometriosis. Taken together, our results suggest that miR-29c exerts its effects on endometrial cell proliferation, apoptosis and invasion by inhibiting the expression of c-Jun. Our data may provide a novel potential therapeutic target for the treatment of endometriosis.



Acta Cir Bras. 2015 Jan;30(1):6-12.

Development of a subcutaneous endometriosis rat model.

Pereira FE1Almeida PR2Dias BH3Vasconcelos PR4Guimarães SB4Medeiros Fd5.




To present a rat model of subcutaneous endometriosis for the study of pathophysiology and the effects of drugs.


Fifty three-month-old female Wistar rats (Rattus norvergicus) were distributed into one control group and four treatment groups: estradiol (2.5; 5; 10 mg/kg s.c.), medroxyprogesterone acetate (0.5; 2; 5 mg/kg s.c.), triptorelin pamoate (0.18; 0.56 mg/kg s.c.) and acetylsalicylic acid (3 mg/kg per os). The animals were autoimplanted subcutaneously with 4×4-mm uterine fragments to induce endometriosis. The endometriomas were measured on days 1, 7, 14 and 21. The relative dry and wet weights of the endometrioma were used to evaluate response to the drug. Endometrial-like tissue was confirmed by histology. The greatest weight gain was observed on day 14 (relative wet weight: 29.1 ± 6.7 mg%, relative dry weight: 5.3 ± 0.9 mg %). Treatments were administered between day 5 and day 14.


The relative wet weight of the hemiuterus in the 10 mg/kg estradiol group differed significantly from control and the other two estradiol groups (p=0.0001). In the medroxyprogesterone acetate group the weight decreased significantly but this decrease was not dose-dependent. Weight reduction was also significant in the triptorelin pamoate and the acetylsalicylic acid groups.


The model of subcutaneous endometriosis is reproducible, low-cost and easy to perform, and suitable for the study of pathophysiology and the effects of drugs.



Obstet Gynecol Sci. 2015 Jan;58(1):53-8

Various anatomic locations of surgically proven endometriosis: A single-center experience.

Lee HJ1Park YM1Jee BC2Kim YB2Suh CS2.




To report the various anatomic locations of surgically and pathologically proven endometriosis.


Pathologic reports (n=1,376) of women who underwent surgeries at a single center between April 2005 and March 2013 were retrieved from the electronic medical record system of the hospital. Pathologic reports were included after performing a search by using the key-words “endometrial cyst,” “endometriotic cyst,” “endometriosis,” or “endometrioma.” Only reports dealing with female patients were selected, and the pathologic reports of 1,350 women (1,374 surgery cases) were included in the analysis.


The predominant location of endometriosis was the ovaries (96.4%), followed by the soft tissue (2.8%), gastrointestinal tract (0.3%) and urinary tract (0.2%). Laparoscopic surgery was the major surgical technique used for the pelvic endometriosis (89.2%). Adrenal gland endometriosis was found in a 55-year-old woman.


We established the various anatomic locations of surgically and pathologically proven endometriosis in Korean women.




J Assist Reprod Genet. 2015 Apr;32(4):495-508.

Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction.

Butler MG1McGuire AManzardo AM.




Obesity is a growing public health concern now reaching epidemic status worldwide for children and adults due to multiple problems impacting on energy intake and expenditure with influences on human reproduction and infertility. A positive family history and genetic factors are known to play a role in obesity by influencing eating behavior, weight and level of physical activity and also contributing to human reproduction and infertility. Recent advances in genetic technology have led to discoveries of new susceptibility genes for obesity and causation of infertility. The goal of our study was to provide an update of clinically relevant candidate and known genes for obesity and infertility using high resolution chromosome ideograms with gene symbols and tabular form.


We used computer-based internet websites including PubMed to search for combinations of key words such as obesity, body mass index, infertility, reproduction, azoospermia, endometriosis, diminished ovarian reserve, estrogen along with genetics, gene mutations or variants to identify evidence for development of a master list of recognized obesity genes in humans and those involved with infertility and reproduction. Gene symbols for known and candidate genes for obesity were plotted on high resolution chromosome ideograms at the 850 band level. Both infertility and obesity genes were listed separately in alphabetical order in tabular form and those highlighted when involved with both conditions.


By searching the medical literature and computer generated websites for key words, we found documented evidence for 370 genes playing a role in obesity and 153 genes for human reproduction or infertility. The obesity genes primarily affected common pathways in lipid metabolism, deposition or transport, eating behavior and food selection, physical activity or energy expenditure. Twenty-one of the obesity genes were also associated with human infertility and reproduction. Gene symbols were plotted on high resolution ideograms and their name, precise chromosome band location and description were summarized in tabular form.


Meaningful correlations in the obesity phenotype and associated human infertility and reproduction are represented with the location of genes on chromosome ideograms along with description of the gene and position in tabular form. These high resolution chromosome ideograms and tables will be useful in genetic awareness and counseling, diagnosis and treatment to improve clinical outcomes.



Arch Gynecol Obstet. 2015 Aug;292(2):429-37.

Endometrial expression of LIF and its receptor and peritoneal fluid levels of IL-1α and IL-6 in women with endometriosis are associated with the probability of pregnancy.

Moberg C1Bourlev VIlyasova NOlovsson M.




To investigate whether eutopic endometrial expression of leukaemia inhibitory factor (LIF), LIF receptor (LIFR) and glycoprotein 130 (gp130) in subfertile women with endometriosis and in healthy controls is related to the probability of spontaneous pregnancy. In addition, we aimed to study peritoneal fluid (PF) levels of interleukin (IL)-1α and IL-6 in the same subsets of women.


Eutopic endometrial biopsy and PF samples were taken from patients with rASRM stage I-II endometriosis and healthy controls undergoing laparoscopy. Endometrial LIF, LIFR and gp130 immunostaining and PF levels of IL-1α and IL-6 were assessed. Endometrial biopsy samples were obtained again after postoperative goserelin acetate treatment and on-going pregnancies were registered during a 6-month follow-up period.


Reduced endometrial staining of LIF, LIFR and gp130, unaffected by surgery and goserelin, was seen in endometriosis patients without a recorded pregnancy during the study. Elevated PF levels of IL-6 and, in particular, IL-1α were detected in these patients.


Reduced eutopic endometrial LIF, LIFR and gp130 protein expression may be associated with subfertility in women with minimal-mild endometriosis. Combined surgical and goserelin acetate treatment does not seem to restore the expression of these members of the IL-6 cytokine superfamily. Elevated peritoneal fluid levels of IL-1α and IL-6 may further contribute to the difficulties of achieving pregnancy in these patients.



Gynecol Obstet Invest. 2015;79(2):113-8.

External validation of the endometriosis fertility index (EFI) for predicting spontaneous pregnancy after surgery: further considerations on its validity.

Garavaglia E1Pagliardini LTandoi ISigismondi CViganò PFerrari SCandiani M.




The revised American Society for Reproductive Medicine classification of endometriosishas a limited predictive value for pregnancy after surgery. A tool for predicting spontaneous pregnancy or pregnancy following assisted reproduction technology (ART) represents a clinical need. This study aimed to (i) provide an external validation of the EFI score in predicting pregnancy in infertile Italian endometriosis women; (ii) evaluate the predictive value of EFI score on ART outcome for patients who previously attempted to spontaneously conceive after surgery.


In 104 women with endometriosis, EFI score was calculated based on a prospective database data. Cumulative pregnancy rates curves were calculated using Kaplan-Meier (K-M) product limit estimate and log-rank test was used to evaluate differences between EFI groups. A receiver operating characteristic (ROC) curve was plotted for EFI as a predictor of ART outcome.


Differences in time to non-ART pregnancy for the six EFI groups were statistically significant (log-rank, p = 1.4 × 10(-4)). The area under the curve (AUC) for EFI as ART outcome predictor was 0.75 (95% CI 0.61-0.89, p = 6.2 × 10(-3)), while the best cut-point for pregnancy was 5.5.


The EFI score is a reliable scoring system to predict non-ART and ART pregnancy outcome after surgery for endometriosis.



Gynecol Obstet Invest. 2015;79(2):126-35.

Epithelial ovarian cancers and endometriosis.

Acién P1Velasco IAcién MCapello CVela P.




To determine the prevalence of endometriosis in epithelial ovarian cancers (EOC) and the association among their histological subtypes and with endometrial carcinoma.


An observational cohort study performed in 192 patients operated on for EOC, 30 women with atypical endometriosis and 17 with p53 positive endometriosis. Data on associated endometriosis and endometrial carcinomas, histological subtypes, tumor stage, clinical and pathological characteristics and survival were analyzed.


Twenty cases of EOC (10.4%) had also endometriosis (12.7 in borderline and 9.3% in invasive cases), being a synchronous finding in most cases. Endometriosis associated with serous or mucinous EOC was observed in 2.2 and 2.7% of cases, respectively. However, this association was observed in 50 of endometrioid and 23% of clear cell EOC. Age, parity and tumor stage were lower in endometriosis-associated EOC patients; and all associated cases were type I (Kurman and Shih’s classification) and showed better results in survival rate. Endometrial carcinoma was more frequently associated with endometrioid EOC (25%).


There is a significant association between endometriosis, including atypical forms, and endometrioid and clear cell carcinomas, but not with other EOC histotypes. The presence of endometriosis in EOC suggests a better prognosis and an intermediate stage within the progression endometriosis-carcinoma.



Complement Ther Med. 2015 Feb;23(1):116-28.

Chinese herbal medicine for female infertility: an updated meta-analysis.

Ried K1.




To assess the effect of Traditional Chinese herbal medicine (CHM) in the management of female infertility and on pregnancy rates compared with Western medical (WM) treatment and update previous meta-analyses.


We searched the Medline and Cochrane databases until December 2013 for randomized controlled trials and meta-analyses investigating Chinese herbal medicine therapy for female infertility and compared clinical pregnancy rates achieved with CHM versus WM drug treatment.


Forty RCTs involving 4247 women with infertility were included in our systematic review. Meta-analysis suggested a 1.74 higher probability of achieving a pregnancy with CHM therapy than with WM therapy alone (risk ratio 1.74, 95%CI: 1.56-1.94; p<0.0001; odds ratio 3.14; 95%CI: 2.72-3.62; p<0.0001) in women with infertility. Trials included women with PCOS, endometriosis, anovulation, fallopian tube blockage, or unexplained infertility. Mean pregnancy rates in the CHM group were 60% compared with 33% in the WM group.


Our review suggests that management of female infertility with Chinese herbal medicine can improve pregnancy rates 2-fold within a 3-6 month period compared with Western medical fertility drug therapy. In addition, fertility indicators such as ovulation rates, cervical mucus score, biphasic basal body temperature, and appropriate thickness of the endometrial lining were positively influenced by CHM therapy, indicating an ameliorating physiological effect conducive for a viable pregnancy.



Placenta. 2015 Apr;36(4):341-4.

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

Brosens I1Ćurčić A2Vejnović T2Gargett CE3Brosens JJ4Benagiano G5.



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.



Fertil Steril. 2015 Apr;103(4):1089-1097.

Increased expression of p21-activated kinase 4 in adenomyosis and its regulation of matrix metalloproteinase-2 and -9 in endometrial cells.

Yi KW1Kim SH2Ihm HJ3Oh YS3Chae HD3Kim CH3Kang BM3.




To investigate the expression of p21-activated kinase 4 (Pak4) in both adenomyotic foci and the eutopic endometrium of women with adenomyosis, and whether the activities of matrix metalloproteinases (MMPs)-2 and -9 are regulated by Pak4 in endometrial cells.


Experimental study using human samples and cell lines.


University hospital.


Thirty-nine patients with histologic evidence of adenomyosis, and 34 patients with carcinoma in situ of the uterine cervix without adenomyosis or endometriosis.


Immunohistochemistry, zymography after transfection with Pak4 small interfering RNA (siRNA), and western blot analyses after nuclear factor kappa-B (NF-кB) inhibitor treatment.


The Pak4 immunoreactivity of women with vs. without adenomyosis was compared semiquantitatively. The activities of MMP-2 and -9 were analyzed in eutopic endometrial stromal cells and Ishikawa cells after transfection with Pak4 siRNA. The Pak4 expression was evaluated in endometrial cells after treatment with NF-кB inhibitor.


Pak4 immunoreactivity was increased in adenomyotic foci and in the eutopic endometrium of women with adenomyosis. Transfection of endometrial cells with Pak4 siRNA led to significant decreases of MMP-2 and -9 activities. In vitro treatment of endometrial cells with tumor necrosis factor-alpha caused a significant increase of NF-кB activation and Pak4 expression, which was obviously decreased by the NF-кB inhibitor pyrrolidinedithiocarbamate.


Our results suggest that Pak4 is regulated by NF-кB and that increased Pak4 expression can lead to development of adenomyosis by enhancing the invasiveness of endometrial cells through regulation of MMP-2 and -9 activities.



Fertil Steril. 2015 Mar;103(3):612-25.

On-label and off-label drug use in the treatment of endometriosis.

Quaas AM1Weedin EA2Hansen KR2.



Endometriosis, characterized by the presence of endometrial glands and stroma in extrauterine locations, is a significant cause of pelvic pain and infertility, as well as a major health care burden. Although Food and Drug Administration (FDA)-approved treatments are available, the use of “off-label” medications for endometriosis is widespread. In this review, we provide an overview of the current FDA-approved treatments, followed by a detailed review of the major “off-label” treatments being used in the United States and worldwide, including efficacy, side effects, drug interactions, contraindications, and anomaly risks.



Hum Reprod. 2015 Mar;30(3):642-52.

The expression of microRNA-451 in human endometriotic lesions is inversely related to that of macrophage migration inhibitory factor (MIF) and regulates MIF expression and modulation of epithelial cell survival.

Graham A1Falcone T2Nothnick WB3.




What is the role of microRNA-451 (miR-451) in human endometriotic tissue?


miR451 expression was elevated in endometriotic lesion tissue. MiR451 modulated the expression of macrophage migration inhibitory factor and limited cell survival.


microRNAs are post-transcriptional regulators of gene expression which have been reported to be mis-expressed in endometriotic tissue. The exact pattern of expression and role of miR451 in endometriosis is currently unknown.


Thirty women with endometriosis are included in the study.


Matched eutopic (N = 30) and endometriotic lesion tissue (N = 43) were collected. miR-451, macrophage migration inhibitory factor (MIF), cyclin E1 (CCNE) and phosphatase and tensin homolog (PTEN) mRNA expression were examined by quantitative real-time (qRT)-PCR while MIF protein expression was evaluated by western blot analysis. miR-451 regulation of MIF in vitro translation was confirmed by 3’untranslated region (UTR) reporter assays and western blot analysis. The effect of miR-451 on cell survival was assessed using a human endometrial epithelial cell line (HES).


Compared with eutopic endometrium, both MIF mRNA and protein were significantly (P < 0.05) decreased in endometriotic lesions and this was associated with a significant (P < 0.05) increase in miR-451 expression. Transfection of HES cells with luciferase reporter constructs for MIF revealed that miR-451 specifically bound to the 3’UTR to regulate expression. Further, forced expression of miR-451 induced a significant (P < 0.05) down-regulation of both MIF mRNA and protein in HES cells which was associated with a significant (P < 0.05) reduction in cell survival. Inhibition of MIF using a specific antagonist verified that reduction of MIF contributes to HES cell survival.


miR-451 and MIF expression were only examined in tissue from women with endometriosis.


Our data support the hypothesis that miR-451 is elevated in endometriotic tissue and, through regulating MIF expression, may function to limit endometriotic lesion cell survival.


This study was funded by the National Institutes of Health/NICHD by grant NIH HD069043 to W.B.N. The authors have no competing interests.



Recent Pat Endocr Metab Immune Drug Discov. 2015;9(1):15-23.

Recent patents on new steroid agents targeting the steroidogenesis for endocrine cancer treatments.

Poirier D1.



Cancer is a leading cause of death in the population and despite the significant technological advances that have been made over the last years, there is a great need for new and better treatments with fewer side effects. Among the various types, hormone-dependent cancers are stimulated by the presence of certain steroidal hormones such as androgens and estrogens, which act through a nuclear receptor. The use of small molecules to block the biosynthesis (steroidogenesis) or the action of hormones (androgens or estrogens) is a therapeutic approach that has yielded interesting results and whose development continues. This review article emphasizes the patents and patent applications published over the last five years. It deals exclusively with steroid compounds developed as inhibitors of key enzymes (17α-hydroxylase/17,20-lyase, steroid sulfatase, 5α-reductases, aromatase and 17β-hydroxysteroid dehydrogenases) involved in the steroidogenesis and identified as therapeutic targets. Such inhibitors could be used as a drug to reduce the concentration of androgens or estrogens and, consequently, for treating hormone-dependent diseases such as prostate cancer, breast cancer and endometriosis.


Arch Gynecol Obstet. 2015 Jul;292(1):37-43.

Continuous versus cyclic oral contraceptives for the treatment of endometriosis: a systematic review.

Zorbas KA1Economopoulos KPVlahos NF.




Recurrence of endometriosis after conservative surgery has been observed in 40-50 % of patients within the first 5 years. A variety of regimens such as combined oral contraceptives, GnRH agonists, danazol, and progestins have been used postoperatively to reduce recurrence rates. Oral contraceptives (oCP) have been used either in a cyclic or in a continuous (no pill-free interval) fashion. The purpose of this article was to summarize the existing evidence on the efficacy and patient compliance for the use of oCP in a continuous versus cyclic fashion following conservative surgery for endometriosis.


A systematic search of Medline identified four eligible studies. Studies were considered eligible, if they have evaluated oCP therapy, either in a cyclic or continuous regimen, after conservative surgery for endometriosis. Specifically, studies (1) reporting on women with endometriosis who were treated postoperatively with both continuous oCP and cyclic oCP, (2) written in English, (3) with minimum 6 months duration of medical treatment, and (4) with minimum 12 months duration of follow-up were considered eligible for our systematic review. Outcome measures of these eligible studies were tabulated and then analyzed cumulatively. A purely descriptive approach was adopted concerning all variables.


Postoperative use of continuous oCP was associated with a reduction in the recurrence rate of dysmenorrhea, delay in the presentation of dysmenorrhea, reduction in nonspecific pelvic pain, and reduction in the recurrence rate for endometrioma.


Use of oCP in a continuous fashion following conservative surgery for endometriosis is more beneficial to cyclic use.




Menopause. 2015 Aug;22(8):826-34.

Early menopause and other gynecologic risk indicators for chronic fatigue syndrome in women.

Boneva RS1Lin JMUnger ER.




This study aims to examine whether gynecologic conditions are associated with chronic fatigue syndrome (CFS).


This study includes a subset of 157 women from a population-based case-control study in Georgia, United States, conducted in 2004-2009. Gynecologic history was collected using a self-administered questionnaire. Crude odds ratios (ORs) with 95% CIs and ORs adjusted for body mass index and other covariates, where relevant, were estimated for gynecologic conditions between 84 CFS cases and 73 healthy controls.


Cases and controls were of similar age. Women with CFS reported significantly more gynecologic conditions and surgical operations than controls: menopause status (61.9% vs 37.0%; OR, 2.37; 95% CI, 1.21-4.66), earlier mean age at menopause onset (37.6 vs 48.6 y; adjusted OR, 1.22; 95% CI, 1.09-1.36), excessive menstrual bleeding (73.8% vs 42.5%; adjusted OR, 3.33; 95% CI, 1.66-6.70), bleeding between periods (48.8% vs 23.3%; adjusted OR, 3.31; 95% CI, 1.60-6.86), endometriosis (29.8% vs 12.3%; adjusted OR, 3.67; 95% CI, 1.53-8.84), use of noncontraceptive hormonal preparations (57.1% vs 26.0%; adjusted OR, 2.95; 95% CI, 1.36-6.38), nonmenstrual pelvic pain (26.2% vs 2.7%; adjusted OR, 11.98; 95% CI, 2.57-55.81), and gynecologic surgical operation (65.5% vs 31.5%; adjusted OR, 3.33; 95% CI, 1.66-6.67), especially hysterectomy (54.8% vs 19.2%; adjusted OR, 3.23; 95% CI, 1.46-7.17). Hysterectomy and oophorectomy occurred at a significantly younger mean age in the CFS group than in controls and occurred before CFS onset in 71% of women with records of date of surgical operation and date of CFS onset.


Menstrual abnormalities, endometriosis, pelvic pain, hysterectomy, and early/surgical menopause are all associated with CFS. Clinicians should be aware of the association between common gynecologic problems and CFS in women. Further work is warranted to determine whether these conditions contribute to the development and/or perpetuation of CFS in some women.


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