Reprod Sci. 2013 Jun;20(6):675-9. doi: 10.1177/1933719112463253. Epub 2012 Nov 19.

Follistatin is induced by IL-1β and TNF-α in stromal cells from endometrioma.

Akiyama I1Yoshino OOsuga YIzumi GUrata YHirota YHirata THarada MKoga KOgawa KKozuma S.

 

Abstract

The aim of this study is to examine the regulation of follistatin, an activin-binding protein, in endometriosis. Endometrioma stromal cells (EoSCs) were obtained from 9 patients undergoing laparoscopy of the ovarian endometrioma. In cultured EoSCs, interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α), which could induce activin-A, also induced follistatin messenger RNA (mRNA) and protein. The cystic fluid of endometrioma from 8 patients was obtained to measure the concentration of activin-A and follistatin by enzyme-linked immunosorbent assay (ELISA). Also, activin activity in the fluid was examined by erythroid differentiation assay using mouse erythroleukemia F5-5.fl cells. In the cystic fluid of endometrioma, the mean values of activin-A and follistatin concentration were 36.8 ng/mL and 4.0 ng/mL, respectively. In a bioassay, all 8 samples exhibited activin activity, which was equivalent to recombinant activin-A activity of 12.8 ± 1.4 ng/mL. Although follistatin was present in the cystic fluid of endometrioma, the activity of activin, which is an exacerbation factor of endometriosis, was predominant in vivo.

 

 

Reprod Sci. 2013 Jun;20(6):639-45. doi: 10.1177/1933719112461188. Epub 2012 Nov 19.

Somatostatin analogs regress endometriotic implants in rats by decreasing implant levels of vascular endothelial growth factor and matrix metaloproteinase 9.

Sevket O1Sevket AMolla TBuyukpınarbasılı NUysal OYılmaz BDane BKelekcı S.

Abstract

OBJECTIVE:

To examine the effect of somatostatin analogs on surgically induced endometriosis in rat models.

STUDY DESIGN:

Endometrial tissue was implanted onto the abdominal peritoneum of 26 rats that were randomized into 3 groups. The rats in group 1(n = 9) were subcutaneously administered with 0.02 mg/kg/d of octreotide (a short-acting analog)for 28 days . The rats in group 2 (n = 8) were subcutaneously injected with 20 mg/kg of a single dose of a long-acting analogue lanreotide The rats in group 3 were given no medication and served as controls (n = 9).

RESULTS:

Mean volume and histologic score of implants in groups 1 (P < .01 and P < .05, respectively) and 2 (P < .01and P < .05, respectively) were significantly lower than that in group 3. There were significant reductions in vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) immunoreactivities in group 1 (0.67 ± 0.50 and 1.22 ± 0.44, respectively; both P < .01) and group 2 (0.71 ± 0.48 and 0.86 ± 0.69, respectively; both P < .01) when compared with the control group (1.78 ± 0.83 and 2.11 ± 0.78, respectively).

CONCLUSION:

Somatostatin analogs has regressed significantly the size of the endometriotic implants and caused atrophy of these lesions in rats by decreasing explant levels of VEGF and MMP-9.

 

 

Reprod Sci. 2013 May;20(5):557-62. doi: 10.1177/1933719112459234. Epub 2012 Nov 20.

Increased circulating MMP-2 levels in infertile patients with moderate and severe pelvic endometriosis.

Malvezzi H1Aguiar VGPaz CCTanus-Santos JEPenna IANavarro PA.

 

Abstract

The current study compares the levels of matrix metalloproteinase (MMP)-2 and MMP-9 in the follicular fluid (FF) of infertile patients with and without endometriosis submitted to ovarian stimulation for in vitro fertilization and the levels of MMP-2 in the serum of the same patients. We also evaluated whether the severity of endometriosis can influence serum and/or FF concentration of these metalloproteinases. A cross-sectional study was conducted on 30 patients: stage I/II endometriosis (n = 10), stage III/IV endometriosis (n = 10), and control (infertility due to tubal and/or male factor; n = 10). Blood samples for the analysis of MMP-2 levels were obtained during the early follicular phase of the menstrual cycle. The FF samples for the analysis of MMP-2 and MMP-9 were obtained on the day of oocyte retrieval. The concentrations of MMP-2 and MMP-9 were determined by zymography. No intragroup or intergroup difference was observed in MMP-2 or MMP-9 levels in FF. Significantly higher MMP-2 levels were detected in the serum of infertile women with stage III/IV endometriosis compared to women with stage I/II endometriosis. In conclusion, no differences were observed in the follicular levels of MMP-2 and MMP-9 between infertile patients with and without endometriosis. However, the levels of MMP-2 were significantly higher in the serum of infertile women with advanced stages of endometriosis. Taken together, the present results demonstrate that advanced pelvic endometriosis severity is related to higher serum MMP-2 levels but does not influence follicular MMP-2 or MMP-9 levels in periovulatory follicles obtained from stimulated cycles.

 

 

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2012 Aug;32(8):1112-6.

Comparison of the effects of sanjie zhentong capsule and danazol on the endometriosis rats.

Zou J1Guan ZZhang WY.

Abstract

OBJECTIVE:

To compare the effects of sanjie zhentong capsule (SZC) and danazol on rats with endometriosis (EMT).

METHODS:

Totally 48 adult female Lewis rats were selected, 12 as the blank control group, and the rest 36 rats in the estrus cycle were used to establish the EMT model. After modeling they were randomly divided into 3 groups, i.e., the model control group, the SZC treatment group, and the danazol treatment group, 12 in each group. Four weeks later the focus was measured by a second laparotomy. The normal saline at 1 mL/day was administered to rats in the model control group, SZC at 86.4 mg/day to those in the SZC treatment group, and danazol at 7.2 mg/day to those in the danazol treatment group. All the treatment lasted for 4 weeks. At the end of the treatment, a third laparotomy was performed to measure the size of focus. The expression of proliferating cell nuclear antigen (PCNA) was detected using immunohistochemical assay. The cell apoptosis rate was detected using terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick-end labeling (TUNEL). The concentration of prostaglandin E2 (PGE2) in the peritoneal fluid and the serum were detected using ELISA.

RESULTS:

There was statistical difference in the change of the focus volume between the SZC treatment group (-23.27 +/- 18.18) and the danazol treatment group (-12.28 +/- 10.04) and the model control group (13.97 +/- 7.54, P < 0.01). The expression of ectopic PCNA significantly decreased and the positive expression rate of TUNEL obviously increased in the two treatment groups when compared with the model control group (P < 0.05, P < 0.01). The expression of ectopic PCNA decreased and the positive expression rate of TUNEL increased more obviously in the SZC treatment group than in the danazol treatment group (P < 0.01). The concentration of PGE2 in the peritoneal fluid and the serum was significantly lower in the two treatment group when compared with the model control group (P < 0.01). The concentration of PGE2 in the peritoneal fluid and the serum was significantly lower in the SZC treatment group than in the danazol treatment group (P < 0.01).

CONCLUSIONS:

SZC and danazol both could inhibit the focus growth in EMT rats. SZC showed better effects. It was an effective drug for treating EMT.

 

Surg Clin North Am. 2013 Feb;93(1):45-59. doi: 10.1016/j.suc.2012.09.008. Epub 2012 Oct 22.

Unexpected intra-operative findings.

Hall JF1Stein SL.

 

Abstract

Abdominal surgeons are often asked to manage challenging pathologic conditions with limited preoperative information. As such, unexpected intraoperative findings are commonly encountered. Often, there is little peer-reviewed evidence on which to base management decisions. This article reviews common unexpected surgical challenges and provides recommendations based on the latest available literature.

 

 

Reprod Biomed Online. 2013 Jan;26(1):93-8. doi: 10.1016/j.rbmo.2012.09.007. Epub 2012 Sep 22.

Association of an oestrogen receptor gene polymorphism in Chinese Han women with endometriosis and endometriosis-related infertility.

Wang W1Li YMaitituoheti MYang RWu ZWang TMa DWang S.

 

Abstract

Endometriosis is a steroid-dependent complex disease. The oestrogen receptor plays an important role by mediating oestrogen action and eutopic or ectopic endometrium development. This study investigated whether single-nucleotide polymorphisms in the genes for oestrogen receptor 1 (ESR1) and oestrogen receptor 2 (ESR2) are associated with endometriosis and endometriosis-related infertility. The participants included 157 infertile and 155 fertile endometriosis women as well as 92 women with primary infertility and 265 fertile women as controls. The iPLEX Gold system (MassARRAY system, Sequenom) was used for genotyping of ESR1 and ESR2. Statistical analysis showed that ESR1 (rs3798573 A/G) was significantly associated with endometriosis and endometriosis-related infertility (P=0.011, P=0.009). No association was found with ESR1 (rs1159327 A/G, rs3020348 A/C) and ESR2 (rs17179740 A/G) either for endometriosis or endometriosis-related infertility. According to the revised American Fertility Society classification, all of the detected single-nucleotide polymorphisms had no association with endometriosis in stage I-II or in stage III-IV. The results suggest that the ESR1 polymorphism rs3798573 A/G is associated with increased risk of endometriosis and endometriosis-related infertility in Han women from central China. Endometriosis is an oestrogen-dependent complex disease, which is one of the most common causes of infertility. Oestrogen receptors (ESR), which mediate oestrogen actions, are considered to play an essential role in the pathogenesis of endometriosis. Therefore, ESR may also play an important role in endometriosis-related infertility. To investigate the association between ESR and endometriosis or endometriosis-related infertility, detection of ESR polymorphisms have been carried out in several populations by other researchers; however, the results remain controversial. In a previous study of ours, through a pooling-based genome-wide scan of endometriosis and controls, we obtained two highly ranked single-nucleotide polymorphisms (SNP) that were individually located in introns of the genes ESR1 and ESR2. To find more evidence of a relationship between ESR and endometriosis or endometriosis-related infertility, the current study selected for genotyping another two ESR1 SNP from a Japanese genome-wide association study in endometriosis. According to the genotypes and the patients’ histories, we found that the ESR1 polymorphism rs3798573 A/G was associated with risk of endometriosis and infertile endometriosis in Han women from central China.

 

 

Gynecol Obstet Fertil. 2012 Dec;40(12):787-96. doi: 10.1016/j.gyobfe.2012.09.032. Epub 2012 Nov 21.

Oxidative stress and fertility: false evidence and bad recipes.

Ménézo Y1Entezami FLichtblau ICohen MBelloc SBrack M.

 

Abstract

Worldwide statistics agree that at least one out of six couples has fertility problems. If the male gamete is the origin of this problem, it is generally admitted that the oxidative stress is involved. Modern life has obviously increased fertility problems through pesticides, xenoestrogenes, endocrine disrupting chemicals involved in plastic technology such as polychlorinated bisphenyls, bisphenol A, phthalates and alkylphenols… and other cosmetic additives. An important part of these compounds increases oxidative stress, at least in part. Oxidative stress is more than probably at the origin or recurrent increasing pathologies such as endometriosis. If the oocyte is theoretically able to repair oxidative stress linked decays such as DNA fragmentation and oxidation of bases, its capacity is finite and decreasing with age. In order to decrease DNA repair charge, reducing or even avoiding the generation of DNA damages related to reactive oxygen species through consumption of antioxidants compounds is often tempting: however Reasons will be provided to break from current treatments given haphazardly in the population in the age of reproduction, as well as the potential risks of over-exposure. Furthermore recommended treatments, in relation with the new concepts in oxidative stress, will be specified.

 

 

 

Steroids. 2013 Feb;78(2):255-67. doi: 10.1016/j.steroids.2012.09.010. Epub 2012 Nov 21.

Synthesis and biological evaluation of partially fluorinated antiprogestins and mesoprogestins.

Nickisch K1Elger WCessac JKesavaram NDas BGarfield RShi SQAmelkina OMeister R.

 

Abstract

A series of antiprogestins have been synthesized by partially fluorinating the steroid molecule in positions relevant for receptor binding. By introducing fluorine at the exo-methylene of the 17 spirofuran ring, we obtained partial agonists (mesoprogestins) with significant applications for antiproliferative and antiovulatory treatment strategies in gynecological therapy such as uterine fibroids, endometriosis and heavy menstrual bleeding. Compared to the standard drug RU486, our synthesized compounds exhibited considerable dissociation between antiprogestational and antiglucocorticoid PR receptors. Furthermore, our studies have shown that pure antiprogestins can be generated by partially fluorinating the 17 propenyl and propynl group or by substituting the 4′ acetyl phenyl group in the 11 position using trifluromethyl group.

 

 

Arch Gynecol Obstet. 2013 Apr;287(4):723-8. doi: 10.1007/s00404-012-2630-x. Epub 2012 Nov 20.

The relation of pelvic pain and dense adhesions to Doppler ultrasound findings in patients with ovarian endometriomas.

Seckin B1Oruc ASTurkcapar FUgur M.

Abstract

PURPOSE:

To study the relation of pelvic pain symptoms and pelvic adhesions to Doppler ultrasound findings in patients with ovarian endometriomas.

METHODS:

62 patients who underwent laparoscopic surgery for endometrioma were divided into two groups according to their pelvic pain symptoms. Group 1 (n = 27) included patients with pelvic pain, group 2 (n = 35) asymptomatic patients. Patients were evaluated for the vascularization of endometrioma by transvaginal color and power Doppler ultrasonography before the surgery. The presence and amount of blood flow reported in terms of a color scale, pulsed Doppler indices, and dense pelvic adhesions were compared between the groups. The relation of Doppler ultrasound findings to the dense pelvic adhesions was also analyzed.

RESULTS:

Blood flow was present in 74.1 % (n = 20) of patients in group 1 and 68.6 % (n = 24) in group 2 (p = 0.63). The volume and vascularization of the endometriomas, pulsed Doppler indices, stage of endometriosis, and the presence of dense pelvic adhesions were also similar. Patients with dense pelvic adhesions had significantly higher amount of blood flow compared to patients without adhesions (p = 0.006), but the mean pulsatility index and resistance index were not different between the groups (p = 0.55 and 0.59, respectively).

CONCLUSIONS:

Pelvic pain symptoms were not found to be related to endometrioma vascularization. On the other hand, we observed an association between higher vascularized endometrioma and the presence of dense pelvic adhesions.

 

 

Womens Health (Lond). 2012 Nov;8(6):647-58. doi: 10.2217/whe.12.52. Review.

Role of inflammation and aromatase expression in the eutopic endometrium and its relationship with the development of endometriosis.

Maia H Jr1Haddad CCoelho GCasoy J.

 

Abstract

Epigenetic changes favoring the transcription of the aromatase gene in the endometrium allow endometrial cells to survive in ectopic locations by producing estrogens that spare them from destruction through activated macrophages. Local estrogen production hastens prostaglandin synthesis by stimulating COX-2 activity, thus creating a self-perpetuating sequence of augmented estrogen formation and enhanced inflammation. Repetitive retrograde menstruation reintroduces aromatase-positive endometrial cells endowed with the capacity to implant and invade the peritoneum. In order to control endometriosis, an effective medication must inhibit aromatase, block COX-2, decrease fibrosis and induce amenorrhea. Within this framework, progestins, either alone or in the form of oral contraceptives, appear as first-line treatment for endometriosis owing to their capacity to block enzymes such as aromatase and COX-2.

 

 

 

Obstet Gynecol Clin North Am. 2012 Dec;39(4):535-49. doi: 10.1016/j.ogc.2012.10.002.

Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility.

Macer ML1Taylor HS.

 

Abstract

Endometriois has been associated with infertility; however, the mechanisms by which it affects fertility are still not fully understood. This article reviews the proposed mechanisms of endometriosis pathogenesis, its effects on fertility, and treatments of endometriosis-associated infertility. Theories on the cause of the disease include retrograde menstruation, coelomic metaplasia, altered immunity, stem cells, and genetics. Endometriosisaffects gametes and embryos, the fallopian tubes and embryo transport, and the eutopic endometrium; these abnormalities likely all impact fertility. Current treatment options of endometriosis-associated infertility include surgery, superovulation with intrauterine insemination, and in vitro fertilization. We also discuss potential future treatments for endometriosis-related infertility.

 

 

 

 

Chem Biol Interact. 2013 Feb 25;202(1-3):218-25. doi: 10.1016/j.cbi.2012.10.028. Epub 2012 Nov 23.

Progestin effects on expression of AKR1C1-AKR1C3, SRD5A1 and PGR in the Z-12 endometriotic epithelial cell line.

Beranič N1Lanišnik Rižner T.

 

Abstract

Endometriosis is defined as the presence of endometrial glands and stroma outside the uterine cavity. This disease is associated with diminished protective effects of progesterone, which are usually explained by inadequate activation of progesterone receptors and also enhanced pre-receptor metabolism of progesterone. Endometriosis is often treated with progestins, which act as progesterone receptor agonists, although their exact mechanisms of action are not completely understood. The aim of the present study was to investigate how the progestins medroxyprogesterone acetate, dydrogesterone and dienogest, as well as progesterone, impact on the expression of genes of pre-receptor progesterone metabolism in Z-12 epithelial cell line, a model system of peritoneal endometriosis. Our data demonstrate that these progestins affect local pre-receptor metabolism to a different extent. The most favorable effects were seen for dydrogesterone and dienogest, where the first, dydrogesterone, significantly reduced SRD5A1, AKR1C2 and AKR1C3 expression, and additionally had a nonsignificant impact on progesterone receptor B (PR-B) protein levels. This might slow down the first step of pre-receptor metabolism, the conversion of progesterone to 5α-dihydroprogestrone by SRD5A1, and it might also affect further reduction of 3-keto and 20-keto groups catalyzed by AKR1C2 and AKR1C3. Similarly favorable effects were seen for dienogest, which promoted significant reduction of AKR1C1 and AKR1C2 expression and also showed no effect on PR-B protein levels. Different effects were seen for progesterone, which significantly decreased SRD5A1, PR-B and HSD17B2 protein levels. In contrast, treatment with medroxyprogesterone acetate resulted in increased AKR1C1 expression and decreased levels of PR-B, which might lead to enhanced progesterone metabolism and reduced signaling through progesterone receptors. Altogether, our data in this Z-12 cell model suggest that the beneficial effects of treatment with progestin observed in endometriosis patients might arise from decreased pre-receptor metabolism of the protective progesterone by the SRD5A1 and AKR1C enzymes.

 

 

 

 

 

Mol Hum Reprod. 2013 Mar;19(3):160-8. doi: 10.1093/molehr/gas055. Epub 2012 Nov 25.

Leptin receptor is induced in endometriosis and leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways.

Oh HK1Choi YSYang YIKim JHLeung PCChoi JH.

 

Abstract

Leptin acts as a potential growth stimulator in several normal and neoplastic cells. Recent studies have shown the presence of increased levels of leptin in the peritoneal fluid of patients with endometriosis, implicating leptin in the pathogenesis of endometriosis. However, the specific function of leptin in the induction of mitogenesis in endometriosis is not known. This study investigated the expression of the leptin receptor (ObR) in endometrioma tissues and immortalized endometriotic cells, and the effect of leptin on cell growth. ObR expression was higher in endometriomas than in the normal endometrium, and it was detected in 74% of epithelial and 30% of stromal endometrioma tissues. In addition, human endometriotic epithelial cells (11Z and 12Z) showed a high level of ObR when compared with endometrial cells and endometriotic stromal cells (22B). Furthermore, leptin treatment stimulated the growth of 11Z and 12Z cells, but not that of 22B cells. Knockdown of the ObR in 11Z and 12Z cells impaired the ability of leptin to induce cell growth. Leptin induced the activation of Janus Kinases 2 (JAK2), signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) in endometriotic epithelial cells. Moreover, pretreatment with the JAK2/STAT3 inhibitor AG490 and the ERK inhibitor PD98059 significantly inhibited leptin-induced cell growth. The present results show that the ObR is induced in endometriosis, and that leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways.

 

 

Hum Reprod. 2013 Feb;28(2):315-21. doi: 10.1093/humrep/des411. Epub 2012 Nov 27.

Plasma adipokines and endometriosis risk: a prospective nested case-control investigation from the Nurses’ Health Study II.

Shah DK1Correia KFHarris HRMissmer SA.

Abstract

STUDY QUESTION:

Do higher leptin levels and lower adiponectin levels predict subsequent development of endometriosis?

SUMMARY ANSWER:

Plasma leptin and adiponectin levels were not associated with laparoscopically confirmed endometriosis when collected prior to disease diagnosis.

WHAT IS KNOWN ALREADY:

Case-control studies have identified altered levels of the inflammatory adipokines leptin and adiponectin in women with endometriosis, but it remains unclear whether inflammation results in endometriosis or whether the presence of endometriosis creates an inflammatory state.

STUDY DESIGN, SIZE, DURATION:

Nested, matched, case-control study within the prospective Nurses’ Health Study II (NHS II) cohort. Blood samples were collected between 1996 and 1999 from 29 611 female nurses within the cohort. Women who reported endometriosis before blood collection were excluded.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Plasma leptin and adiponectin levels were assayed by ELISA. Three hundred and fifty cases of laparoscopically confirmed endometriosis were matched 1:2 with 694 controls of comparable race, age, infertility history, menopausal status and time of blood draw. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression models adjusting for matching factors and BMI.

MAIN RESULTS AND THE ROLE OF CHANCE:

After adjusting for BMI, there were no statistically significant associations between endometriosis and leptin [RR = 1.2; 95% CI = 0.7-2.0; P-value, test for linear trend (P(trend)) = 0.72], adiponectin (RR = 0.8; 95% CI = 0.5-1.2; P(trend) = 0.48) or the leptin to adiponectin ratio (RR = 0.8; 95% CI = 0.4-1.4; P(trend) = 0.14) when comparing the upper with the lower quartile. Results were unaltered when analyses were stratified by BMI or restricted to cases diagnosed ≥ 4 years after blood draw. To evaluate statistical significance and limit the role of chance to the gold standard of 5%, we present 95% CIs about the RRs, and for P-values calculated for linear tests of trend and tests of heterogeneity, we have set the α-level to be 0.05 (i.e. <0.05 is considered to be statistically significant).

LIMITATIONS AND REASONS FOR CAUTION:

A limitation of this study is the inability to differentiate the time of endometriosis ‘diagnosis’ from the time of disease ‘onset’ due to the impossibility in identifying a precise time point at which the disease process was first initiated at a molecular or cellular level. Additional limitations include lack of information regarding stage of endometriosis and the possibility of asymptomatic disease in the control population.

WIDER IMPLICATIONS OF THE FINDINGS:

The mean age at diagnosis of endometriosis in the study population is 41.7, ≈ 10 years older than the mean age of diagnosis in the general population. While this may limit the generalizability of the results, there is no reason to suspect that the association between adipokines and endometriosis risk should differ at a younger age of diagnosis in an adult population.

 

 

 

Hum Mol Genet. 2013 Feb 15;22(4):832-41. doi: 10.1093/hmg/dds491. Epub 2012 Nov 28.

Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer’s disease, multiple sclerosis and endometriosis.

Lee SH1Harold DNyholt DRANZGene ConsortiumInternational Endogene ConsortiumGenetic and Environmental Risk for Alzheimer’s disease ConsortiumGoddard MEZondervan KTWilliams JMontgomery GWWray NRVisscher PM.

Collaborators (115)

 

Abstract

Common diseases such as endometriosis (ED), Alzheimer’s disease (AD) and multiple sclerosis (MS) account for a significant proportion of the health care burden in many countries. Genome-wide association studies (GWASs) for these diseases have identified a number of individual genetic variants contributing to the risk of those diseases. However, the effect size for most variants is small and collectively the known variants explain only a small proportion of the estimated heritability. We used a linear mixed model to fit all single nucleotide polymorphisms (SNPs) simultaneously, and estimated genetic variances on the liability scale using SNPs from GWASs in unrelated individuals for these three diseases. For each of the three diseases, case and control samples were not all genotyped in the same laboratory. We demonstrate that a careful analysis can obtain robust estimates, but also that insufficient quality control (QC) of SNPs can lead to spurious results and that too stringent QC is likely to remove real genetic signals. Our estimates show that common SNPs on commercially available genotyping chips capture significant variation contributing to liability for all three diseases. The estimated proportion of total variation tagged by all SNPs was 0.26 (SE 0.04) for ED, 0.24 (SE 0.03) for AD and 0.30 (SE 0.03) for MS. Further, we partitioned the genetic variance explained into five categories by a minor allele frequency (MAF), by chromosomes and gene annotation. We provide strong evidence that a substantial proportion of variation in liability is explained by common SNPs, and thereby give insights into the genetic architecture of the diseases.

 

 

Balkan Med J. 2012 Dec;29(4):410-3. doi: 10.5152/balkanmedj.2012.042. Epub 2012 Dec 1.

Uterine junctional zone thickness, cervical length and bioelectrical impedance analysis of body composition in women with endometriosis.

Ayas S1Bayraktar M1Gürbüz A1Alkan A1Eren S1.

Abstract

OBJECTIVE:

We aimed to evaluate uterine junctional zone thickness, cervical length and bioelectrical impedance analysis of body composition in women with endometriosis.

MATERIAL AND METHODS:

This is a prospective study conducted in a tertiary teaching hospital. A total of 73 patients were included in the study. Endometriosis was surgically diagnosed in 36 patients (study group). The control group included 37 patients.

MAIN OUTCOME MEASURE(S):

Bioelectrical impedance analysis was used to measure body composition. Uterine junctional zone thickness and cervical length were measured by transvaginal ultrasonography.

RESULTS:

Patients’ characteristics (age, gravida, parity, live baby, age of menarche, lengths of menstrual cycle, percentage of patients with dysmenorrhea, positive family history), body mass index (BMI) (kg/m(2)), amount of body fat (kg), percentage of body fat were not statistically different between the two groups (p>0.05). The length of menstruation and cervical length were longer in women with endometriosis. Similarly, the inner myometrium was thicker in women with endometriosis than the control group.

CONCLUSION:

The relation between endometriosis and demographic features such as age, gravida, parity, gravida, BMI, lengths of the menstrual cycle, age of menarche are controversial. Longer cervical length and thicker inner myometrial layer may be important in the etiopathogenesis of endometriosis.

 

 

Geburtshilfe Frauenheilkd. 2012 Dec;72(12):1092-1098.

Chronic Pain Syndromes in Gynaecological Practice: Endometriosis and Fibromyalgia.

Siedentopf F1.

 

Abstract

in EnglishGerman

As gynaecologists frequently function as “general practitioners” for women, gynaecologists are frequently confronted with questions which initially appear to have only a tenuous connection to their field. Chronic pain syndromes represent a particular challenge, especially as pain syndromes are often associated with severe psychosocial stress for the affected woman. This article discusses some of the psychometric aspects of chronic pain in endometriosis and fibromyalgia together with practical therapeutic approaches.

 

 

 

J Robot Surg. 2012 Dec;6(4):317-22. doi: 10.1007/s11701-011-0314-3. Epub 2011 Oct 2.

Peri-operative outcomes of patients with stage IV endometriosisundergoing robotic-assisted laparoscopic surgery.

Brudie LA1Gaia G2Ahmad S3Finkler NJ3Bigsby GE 4th3Ghurani GB3Kendrick JE 4th3Rakowski JA3Groton JH3Holloway RW3.

 

Abstract

We analyzed peri-operative outcomes of 80 patients who underwent robotic-assisted laparoscopic surgery and were diagnosed with stage IV endometriosis (revised American Society for Reproductive Medicine) between January 2007 and December 2010 at a tertiary gynecologic oncology referral center with a fellowship training program. Eligible women had a combination of one or more factors: pelvic mass, sub-acute or chronic pelvic pain, dysmenorrhea, dyspareunia, elevated serum CA-125, diagnosed with stage IV endometriosis at surgery with robotic-assisted gynecologic procedures using the da Vinci(®) Surgical System. The mean age was 43.7 ± 7.0 years, body mass index 27.5 ± 7.4 kg/m(2), and 23 (28.9%) patients had prior endometriosissurgery. Presenting symptoms included: chronic pelvic pain (48.8%), dysmenorrhea (40.3%), and dyspareunia (33.8%). Sixty-nine (86%) patients had pelvic masses (43 unilateral and 26 bilateral). Thirty-seven (46.3%) had elevated CA-125 levels (mean 97.9 ± 71.6 U/ml). Forty-eight (60%) underwent robotic-assisted laparoscopic hysterectomy (RALH)/bilateral salpingo-oophorectomy (BSO), 9 (11.3%) RALH/unilateral salpingo-oophorectomy (USO), 5 (6.3%) modified radical hysterectomy, and 10 (13%) USO or BSO only. Four (5%) had ovarian cystectomies with excision of endometriotic implants. Three (3.8%) underwent appendectomy and no patient required bowel resection. Four (5%) patients required conversion to laparotomy during the first 15 cases of this series [dense adhesions (3) and ureteral injury (1)]. Mean operative time was 115 ± 46 min, blood loss 88 ± 67 ml, and length of stay 1.0 ± 0.4 days. There were four (5%) complications (ureteral injury, cuff abscess, cuff hematoma, re-admission for nausea and vomiting secondary to narcotics) and no transfusions. One (1.3%) patient underwent a second surgery for pain (dyspareunia). Robotic-assisted surgery for stage IV endometriosis resulted in excellent pain relief, with few laparotomy conversions or complications during a robotic learning-curve experience.

 

 

Acta Obstet Gynecol Scand. 2013 Mar;92(3):278-84. doi: 10.1111/aogs.12051. Epub 2013 Jan 21.

Clinicopathologic risk factors for recurrence of ovarian endometrioma following laparoscopic cystectomy.

Sengoku K1Miyamoto THorikawa MKatayama HNishiwaki KKato YKawanishi YSaijo Y.

Abstract

OBJECTIVE:

To identify epidemiologic risk factors and investigate whether the characteristics of removed ovarian tissue during surgery influence the recurrence of endometriomas.

DESIGN:

Retrospective cohort study.

SETTING:

Medical university hospital.

POPULATION:

248 women with endometriomas.

METHODS:

All women who had a minimum of 2 years of follow-up after the laparoscopic excision of endometriomas were analysed retrospectively. Specimens were analysed histologically.

MAIN OUTCOME MEASURES:

Sixteen epidemiologic variables were analysed as possible risk factors for recurrence. The association between the characteristics of removed ovarian tissue (the thickness of the cyst wall, the thickness of ovarian tissue, and the morphological features) and endometrioma recurrence was investigated.

RESULTS:

The cumulative incidence of endometriomas reached 42% at 60 months after surgery. We identified only a younger age at surgery as a risk factor, and postoperative pregnancy as a preventive factor. There were no differences in the mean thickness of the cyst wall and the removed ovarian tissue between patients with and without recurrence. No statistically significant associations were found between the morphologic characteristics of removed cyst wall, ovarian tissue, graded on a semi-quantitative basis, and recurrence.

CONCLUSIONS:

These results suggest that the rate of endometrioma recurrence had a significant relation to patient age and postoperative pregnancy; however, there was no association between the histological characteristics of the excised tissue and recurrence.

 

 

Brain Behav Immun. 2013 Aug;32:1-8. doi: 10.1016/j.bbi.2012.11.006. Epub 2012 Nov 27.

IL-1 receptor 2 (IL-1R2) and its role in immune regulation.

Peters VA1Joesting JJFreund GG.

 

Abstract

The cytokine IL-1 is critical to the pathogenesis of a variety of human conditions and diseases. Unlike most other cytokines, IL-1 is counterbalanced by two endogenous inhibitors. The functional significance of IL-1 receptor antagonist (IL-1RA) is well documented due to the clinical utilization of the recombinant human IL-1RA analog, anakinra. In contrast, much less is known about the type 2 IL-1 receptor (IL-1R2), which acts as a decoy receptor for IL-1. While IL-1R2 is structurally similar to the type 1 IL-1 receptor (IL-1R1) responsible for IL-1 signal transduction, its truncated cytoplasmic domain and lack of Toll-IL-1 receptor (TIR) region renders IL-1R2 incapable of transmembrane signaling. IL-1R2 competes with IL-1R1 for ligands and for the IL-1R1 co-receptor, IL-1 receptor accessory protein (IL-1RAP). Additionally, IL-1R2 exists in both a membrane bound and soluble form (sIL-1R2) that has biological properties similar to both a decoy receptor and a binding protein. Thus far, IL-1R2 has been implicated in arthritis, endometriosis, organ transplantation, sepsis/sickness behavior, diabetes, atherosclerosis, autoimmune inner ear disease (AIED), Alzheimer’s disease and ulcerative colitis. In this review, we will detail the functional properties of IL-1R2 and examine its role in human disease.

 

 

Rev Bras Ginecol Obstet. 2012 Sep;34(9):420-4. Portuguese.

Association between ovarian endometrioma and deep infiltrating endometriosis.

Kondo W1Ribeiro RTrippia CHZomer MT.

Abstract

PURPOSE:

To evaluate the association between ovarian endometrioma and the presence of deep infiltrating endometriosis (DIE) lesions in a sample of women of the South of Brazil.

METHODS:

A retrospective study was conducted in all women undergoing surgical treatment of endometriosisfrom January 2010 to June 2012. Patients were divided into 2 groups according to the presence or not of ovarian endometrioma. Patients presenting an ovarian endometrioma were subsequently divided into 2 groups according to the diameter of the endometrioma (<40 and ≥40 mm). The following parameters were compared between the groups: cancer antigen (CA) 125 level, size of the endometrioma, presence and number of deep lesions. The statistical analysis was performed with Statistica version 8.0 using Fisher’s exact test, Student’s t-test and Mann-Whitney test, when needed. The p values of <0.05 were considered statistically significant.

RESULTS:

During the study period, a total of 201 women underwent laparoscopic surgical treatment of endometriosis. Fifty-five patients (27.9%) presented ovarian endometrioma and 180 patients (89.5%) presented DIE confirmed by pathologic examination. Women presenting an ovarian endometrioma had higher CA 125 levels (39.5 versus 24.1 U/mL; p<0.01) and stronger association with the presence of DIE lesions (98.2 versus 86.2%; p=0.01) and intestinal DIE (57.1 versus 37.9%; p=0.01). There was no difference between the groups with endometriomas <40 and ≥40 mm.

 

 

 

J Mol Med (Berl). 2013 May;91(5):613-23. doi: 10.1007/s00109-012-0977-x. Epub 2012 Nov 30.

Inhibition of aquaporin-1 dependent angiogenesis impairs tumour growth in a mouse model of melanoma.

Nicchia GP1Stigliano CSparaneo ARossi AFrigeri ASvelto M.

 

Abstract

Prohibiting angiogenesis is an important therapeutic approach for fighting cancer and other angiogenic related diseases. Research focused on proteins that regulate abnormal angiogenesis has attracted intense interest in both academia and industry. Such proteins are able to target several angiogenic factors concurrently, thereby increasing the possibility of therapeutic success. Aquaporin-1 (AQP1) is a water channel membrane protein that promotes tumour angiogenesis by allowing faster endothelial cell migration. In this study we test the hypothesis that AQP1 inhibition impairs tumour growth in a mouse model of melanoma. After validating the inhibitor efficacy of two different AQP1 specific siRNAs in cell cultures, RNA interference experiments were performed by intratumoural injections of AQP1 siRNAs in mice. After 6 days of treatment, AQP1 siRNA treated tumours showed a 75 % reduction in volume when compared to controls. AQP1 protein level, in AQP1 knockdown tumours, was around 75 % that of the controls and was associated with a significant 40 % reduced expression of the endothelial marker, Factor VIII. Immunofluorescence analysis of AQP1 siRNA treated tumours showed a significantly lower microvessel density. Time course experiments demonstrated that repeated injections of AQP1 siRNA over time are effective in sustaining the inhibition of tumour growth. Finally, we have confirmed the role of AQP1 in sustaining an active endothelium during angiogenesis and we have shown that AQP1 reduction causes an increase in VEGF levels. In conclusion, this study validates AQP1 as a pro-angiogenic protein, relevant for the therapy of cancer and other angiogenic-related diseases such as psoriasis, endometriosis, arthritis and atherosclerosis.

 

 

Clin Anat. 2013 Jan;26(1):89-96. doi: 10.1002/ca.22188. Epub 2012 Nov 30.

Role of female pelvic anatomy in infertility.

Harris-Glocker M1McLaren JF.

 

Abstract

Infertility is defined as a couple’s failure to achieve pregnancy after one year of regular, unprotected intercourse. The etiology of infertility can be due to female factors, male factors, combined male and female factors, or have an unknown etiology. This review focuses on the role of female pelvic anatomy in infertility. Normal anatomy and the physiology of reproduction will be discussed, as well as the anatomic and pathophysiologic processes that cause infertility including ovulatory disorders, endometriosis, pelvic adhesions, tubal blockage, mullerian anomalies, and abnormalities affecting the uterine cavity such as leiomyomata and endometrial polyps.

 

 

 

Case Rep Obstet Gynecol. 2012;2012:687510. doi: 10.1155/2012/687510. Epub 2012 Nov 6.

A case of endometrial stromal sarcoma with synchronous bilateral adenocarcinoma of ovary.

Caramelo O1Marinho CRebelo TAmaral NMota FXavier da Cunha FTorgal I.

 

Abstract

Endometrial stromal tumor is a rare mesenchymal uterine tumor. We report the case of a patient with endometrial stromal sarcoma and concomitant bilateral endometrioid adenocarcinoma of the ovary in the context of pelvic endometriosis. The patient underwent a complete cytoreduction including total hysterectomy and bilateral adnexectomy, pelvic lymphadenectomy, appendicectomy, infracolic omentectomy, and pelvic peritonectomy. This is the first report to our knowledge that describes a synchronous endometrial stromal sarcoma and bilateral endometrioid adenocarcinoma of the ovary.

 

 

J Med Primatol. 2013 Feb;42(1):39-45. doi: 10.1111/jmp.12027. Epub 2012 Dec 1.

Pleuro-pulmonary endometriosis in baboons (Papio spp.): insights into pathogenesis.

Jagirdar J1Sirohi DDick EJ JrHubbard G.

Abstract

BACKGROUND:

Human pleuro-pulmonary endometriosis (PPE) is rare. Recently, we identified several cases of abdominal endometriosis in baboons that developed PPE.

MATERIALS AND METHODS:

Ten cases of PPE and four of intra-abdominal endometriosis (three simultaneous) were identified at necropsy in baboons (Papio spp.) found dead due to natural causes. The endometriotic lesions were evaluated using immunohistochemistry.

RESULTS:

The stromal (CD10+) and epithelial cells in intra-abdominal cases were estrogen and progesterone receptor (ER/PR) positive and thyroid transcription factor 1 (TTF-1) negative similar to that seen in humans. In contrast, the PPE cases displayed TTF-1-positive epithelium lining the cystic spaces, while the stroma was ER/PR positive similar to that in abdominal endometriosis. Both lymph nodes and spindle cell rests in lung interstitium contained ER/PR-positive stromal cells.

CONCLUSIONS:

The lung lesions were different from the abdominal lesions in having a TTF-1-positive lining epithelium. The deep pulmonary interstitial and lymph node endometrial stromal rests probably arrive via lymphatic route. The endometrial stroma is the driving force in PPE upon which the lung-specific epithelium condenses and may require a novel approach to therapy.

 

 

 

Am J Obstet Gynecol. 2013 May;208(5):360-5. doi: 10.1016/j.ajog.2012.11.030. Epub 2012 Nov 27.

Phenotyping clinical disorders: lessons learned from pelvic organ prolapse.

Wu JM1Ward RMAllen-Brady KLEdwards TLNorton PAHartmann KEHauser ERVelez Edwards DR

 

Abstract

Genetic epidemiology, the study of genetic contributions to risk for disease, is an innovative area in medicine. Although research in this arena has advanced in other disciplines, few genetic epidemiological studies have been conducted in obstetrics and gynecology. It is crucial that we study the genetic susceptibility for issues in women’s health because this information will shape the new frontier of personalized medicine. To date, preterm birth may be one of the best examples of genetic susceptibility in obstetrics and gynecology, but many areas are being evaluated including endometriosis, fibroids, polycystic ovarian syndrome, and pelvic floor disorders. An essential component to genetic epidemiological studies is to characterize, or phenotype, the disorder to identify genetic effects. Given the growing importance of genomics and genetic epidemiology, we discuss the importance of accurate phenotyping of clinical disorders and highlight critical considerations and opportunities in phenotyping, using pelvic organ prolapse as a clinical example.

 

 

 

Int J Gynecol Pathol. 2013 Jan;32(1):3-14. doi: 10.1097/PGP.0b013e31825554e9.

Clear cell carcinomas of the ovary: a multi-institutional study of 129 cases in Korea with prognostic significance of Emi1 and Galectin-3.

Min KW1Park MHHong SRLee HKwon SYHong SHJoo HJPark IAAn HJSuh KSOh HKYoo CWKim MJChang HKJun SYYoon HKChang EDKim DWKim IGynecologic Pathology Study Group of the Korean Society of Pathologists.

 

Abstract

Accurate diagnosis of ovarian clear cell carcinoma (CCC) is important because of its poor prognosis with chemoresistance and a high recurrent rate. The clinicopathologic characteristics and prognostic significance of the cell cycle regulator [early mitotic inhibitor-1 (Emi1)] and galactoside-binding protein (Galectin-3) were evaluated. Among 155 CCCs from 18 hospitals in Korea between 1995 and 2006, 129 pure CCCs were selected with consensus using immunohistochemical stains for hepatocyte nuclear factor-1β, Wilms’ tumor protein, and estrogen receptor. The expressions of Emi1, Galectin-3, p53, and Ki-67 labeling index were analyzed with clinicopathologic parameters and the patient’s survival. The mean age of the patients was 49.6 yr; the tumors were bilateral in 10.9%, and the average size was 12 cm. Adenofibromatous component was found in 7%, and endometriosis in 48.1% of the cases. Psammoma body was seen in 16.3%. Disease-free survival and overall survival rates were 78.3% and 79.1%, respectively. The International Federation of Obstetrics and Gynecology (FIGO) stage was the most important prognostic indicator. Emi1 expression (>5%) was seen in 23.3% of CCCs, and associated with high FIGO grades and poor overall survival (P<0.05). High Galectin-3 (≥80%) expression was seen in 59.7% of CCCs, and associated with FIGO stages III and IV, and high Ki-67 labeling index. High Ki-67 labeling index (≥50%) and p53 expression (≥50%) were seen in 27.1% and 18.6% of CCCs, respectively, but there was no clinicopathologic and prognostic significance. On the basis of the fact that the expression of Emi1 in CCC was correlated with a high histologic grade and worse overall survival, target therapy using inhibitors of Emi1 may be tried in the management of CCC patients with Emi1 expression.

 

 

Hum Reprod. 2013 Feb;28(2):322-30. doi: 10.1093/humrep/des413. Epub 2012 Nov 30.

Plasma miR-17-5p, miR-20a and miR-22 are down-regulated in women with endometriosis.

Jia SZ1Yang YLang JSun PLeng J.

Abstract

STUDY QUESTION:

Can plasma microRNAs be used as a non-invasive diagnostic test for the detection of endometriosis?

SUMMARY ANSWER:

Plasma miR-17-5p, miR-20a and miR-22 are down-regulated in women with endometriosis compared with those without endometriosis in mainland China.

WHAT IS KNOWN ALREADY:

There is currently a pressing need to develop a non-invasive diagnostic test for endometriosis. Altered circulating microRNA profiles have already been linked to various disease states.

STUDY DESIGN, SIZE, AND DURATION:

This was a prospective laboratory study in a tertiary-referral university hospital in Beijing, PR China, between January 2012 and May 2012. Twenty-three women with histologically proven endometriosis and 23 endometriosis-free controls were enrolled in this study.

PARTICIPANTS/MATERIALS, SETTING, AND METHODS:

Laparoscopic inspection of the abdominopelvic cavity was performed for each patient, and peripheral blood samples were collected before laparoscopy. Microarray-based microRNA expression profiling was used to identify differentially expressed microRNAs in plasma samples between women with and without endometriosis, and quantification of selected microRNAs was performed using quantitative RT-PCR.

MAIN RESULTS AND THE ROLE OF CHANCE:

Twenty-seven microRNAs were differentially expressed between women with and without endometriosis, of which six microRNAs (miR-15b-5p, miR-17-5p, miR-20a, miR-21, miR-22 and miR-26a) were selected for validation. MiR-17-5p, miR-20a and miR-22 were significantly down-regulated in women with endometriosis compared with controls (P = 0.011, 0.0020 and 0.0002, respectively), yielding an area under the receiver operator characteristics curve of 0.74 [95% confidence interval (CI): 0.58-0.90], 0.79 (95% CI: 0.65-0.93) and 0.85 (95% CI: 0.71-0.98) in discriminating endometriosis from controls, respectively.

LIMITATIONS AND REASONS FOR CAUTION:

Our sample size was small and all cases were rAFS stage III-IV, which may limit generalization of plasma microRNAs for early diagnosis of endometriosis. Moreover, only six microRNAs were selected for validation.

WIDER IMPLICATIONS OF THE FINDINGS:

Plasma microRNAs provide a promising opportunity for detection of endometriosis.

 

 

 

J Int Med Res. 2012;40(5):1840-9.

Endostatin gene therapy for endometriosis in rats.

Zhang TT1Fang XLGang J.

Abstract

OBJECTIVE:

Endostatin gene therapy for endometriosis was studied in an experimental autotransplantation model in rats.

METHODS:

Endometriotic lesions were transfected by intralesional injection of the plasmid lipofectamine-endostatin-pBud (group 1), lipofectamine-pBud (empty vector; group 2) or phosphate-buffered saline (group 3). Endostatin mRNA and protein levels in lesions were evaluated by quantitative real-time reverse transcription-polymerase chain reaction and Western blot analysis. Endostatin and vascular endothelial growth factor (VEGF) protein levels in serum, and microvessel density (MVD) and matrix metalloproteinase (MMP)-2 protein levels in endometriotic lesions, were also determined.

RESULTS:

Lipofectamine-endostatin-pBud injection increased endostatin mRNA and protein levels in lesions. Lesions were significantly smaller, and serum VEGF levels significantly lower, in group 1 versus controls. Serum VEGF was significantly and negatively correlated with serum endostatin. In group 1, MMP-2 levels and MVD were significantly lower versus controls. MMP-2 level was negatively correlated with endostatin.

CONCLUSIONS:

Gene therapy with endostatin appears to be an effective treatment for endometriosis. Restoration of endostatin gene expression by gene transfer in vivo might be a potential gene therapy approach for human endometriosis.

 

 

Fertil Steril. 2013 Mar 1;99(3):871-881.e1. doi: 10.1016/j.fertnstert.2012.10.051. Epub 2012 Nov 30.

Targeting of syndecan-1 by micro-ribonucleic acid miR-10b modulates invasiveness of endometriotic cells via dysregulation of the proteolytic milieu and interleukin-6 secretion.

Schneider C1Kässens NGreve BHassan HSchüring ANStarzinski-Powitz AKiesel LSeidler DGGötte M.

Abstract

OBJECTIVE:

To study the function of syndecan-1 (SDC1) and its potential regulator miR-10b in endometriosis.

DESIGN:

Experimental laboratory study.

SETTING:

University medical center.

PATIENT(S):

Not applicable.

INTERVENTION(S):

The human endometriotic cell line 12Z was transiently transfected with SDC1 small interfering RNA or miR-10b precursors and investigated for changes in cell behavior and gene expression. 12Z and primary eutopic endometrial stroma cells of two American Society for Reproductive Medicine class III endometriosis patients were transfected with miR-10b precursors to investigate posttranscriptional regulation of SDC1.

MAIN OUTCOME MEASURE(S):

Quantitative polymerase chain reaction, Western blotting, flow cytometry, 3′ untranslated region luciferase assays, and zymography were used to measure miR-10b-dependent targeting of SDC1 and SDC1-dependent expression changes of proteases and interleukin-6. Altered cell behavior was monitored by Matrigel invasion assays, cell viability assays, and mitogen-activated protein kinase activation blots.

RESULT(S):

Knockdown of SDC1 inhibited Matrigel invasiveness by >60% but did not affect cell viability. Interleukin-6 secretion, matrix metalloproteinase-9 expression, and matrix metalloproteinase-2 activity were reduced, whereas plasminogen activator inhibitor-1 protein expression was up-regulated. miR-10b overexpression significantly down-regulated SDC1, reduced Matrigel invasiveness by 20% and cell viability by 14%, and decreased mitogen-activated protein kinase activation in response to hepatocyte growth factor.

CONCLUSION(S):

Syndecan-1, a target of miR-10b, inhibits epithelial endometriotic cell invasiveness through down-regulation of metalloproteinase activity and interleukin-6.

 

 

Fertil Steril. 2013 Mar 1;99(3):790-5. doi: 10.1016/j.fertnstert.2012.11.013. Epub 2012 Dec 1.

In utero exposures and endometriosis: the Endometriosis, Natural History, Disease, Outcome (ENDO) Study.

Wolff EF1Sun LHediger MLSundaram RPeterson CMChen ZBuck Louis GM.

Abstract

OBJECTIVE:

To assess in utero exposures and the odds of an endometriosis diagnosis.

DESIGN:

Matched cohort design.

SETTING:

Fourteen participating clinical centers in geographically defined areas in Utah and California.

PATIENT(S):

Operative cohort comprised 473 women undergoing laparoscopy/laparotomy, and an age- and residence-matched population cohort comprising 127 women undergoing pelvic magnetic resonance imaging (MRI), 2007-2009.

INTERVENTION(S):

None.

MAIN OUTCOME MEASURE(S):

Women completed standardized interviews before surgery or MRI regarding in utero exposures: mothers’ lifestyle during the index pregnancy, and the index woman’s gestation and birth size. Endometriosis was defined as visually confirmed disease in the operative cohort, and MRI visualized disease in the population cohort. The odds of an endometriosis diagnosis and corresponding 95% confidence intervals (CI) were estimated for each exposure by cohort using logistic regression and adjusting for current smoking, age at menarche, body mass index, and study site.

RESULT(S):

Endometriosis was diagnosed in 41% and 11% of women in the operative and population cohorts, respectively. In the primary analysis, adjust odds ratios (AORs) were elevated for maternal vitamin usage (1.27; 95% CI, 0.85-1.91), maternal cigarette smoking (1.16; 95% CI = 0.61-2.24), and low birth weight (1.1; 95% CI, 0.92-1.32). Reduced odds were observed for maternal usage of caffeine (0.99; 95% CI, 0.64-1.54), alcohol (0.82; 95% CI, 0.35-1.94), paternal cigarette smoking (0.72; 95% CI, 0.43-1.19), and preterm delivery (0.98; 95% CI, 0.47-2.03). Sensitivity analyses mostly upheld the primary results except for a decreased AOR for preterm birth (0.41; 95% CI, 0.18-0.94) when restricting to visualized and histologically confirmed endometriosis in the operative cohort.

CONCLUSION(S):

In utero exposures were not statistically significantly associated with the odds of an endometriosis diagnosis in either cohort.

 

 

 

Arch Gynecol Obstet. 2013 May;287(5):941-5. doi: 10.1007/s00404-012-2647-1. Epub 2012 Dec 2.

Efficacy of the revised Enzian classification: a retrospective analysis. Does the revised Enzian classification solve the problem of duplicate classification in rASRM and Enzian?

Haas D1Wurm PShamiyeh AShebl OChvatal ROppelt P.

Abstract

PURPOSE:

The most widely accepted classification for endometriosis is the Revised American Society for Reproductive Medicine (rASRM) system, but this does not take deeply infiltrating endometriosis (DIE) into account. The Enzian classification enables clinicians to classify DIE. Due to complexity and partial overlap with rASRM, it was revised for a second time in February 2011. Using both the systems to classify lesions would be inappropriate, as they refer to different locations. The aim of this study was to analyze whether the revised Enzian classification is easier to use and avoids duplicate classifications.

METHODS:

Retrospective study of 460 women admitted for endometriosis.

RESULTS:

One hundred and eighty-seven of 460 patients (41 %) had histologically confirmed DIE based on the revised Enzian classification. Further classification of these 187 patients using Enzian revealed 270 retroperitoneal lesions, as some patients had several DIE-type lesions simultaneously: 66 in compartment A (rectovaginal septum, vagina), 112 in compartment B (sacrouterine ligaments, pelvic wall), 58 in compartment C (bowel), 15 with adenomyosis uteri, 7 with bladder involvement, 8 with intrinsic involvement of the ureter, and 4 with bowel involvement. All 270 lesions were classified using Enzian alone and not with the rASRM score. There were no duplicate classifications (rASRM and Enzian).

CONCLUSIONS:

The revised Enzian classification is an excellent complement to the rASRM score for morphological description of DIE.

 

 

 

Patholog Res Int. 2012;2012:674748. doi: 10.1155/2012/674748. Epub 2012 Nov 1.

Clear cell carcinomas of the mullerian system: does the pathogenesis vary depending on their nuclear grade and their association with endometriosis? An immunohistochemical analysis.

Alduaij A1Hansen KKarim TAZhang CLomme MMSung CJLawrence WDQuddus MR.

Abstract

Clear cell carcinomas (CCC) of the mullerian system are considered high grade tumors, but morphologically, the cells of CCC show both low and high grade features. The aims of the current study were to categorize CCC into low and high nuclear grade types, correlate their association with endometriosis, and then observe possible variations in pathogenesis based on their expression of p53 and Ki-67. We studied 41 pure mullerian CCCs and designated each as either a high (HNG) or low (LNG) nuclear grade tumor. Morphologically, 17 (41%) CCCs were LNG and 24 (59%) were HNG. Nine (38%) HNG and 2 (12%) LNG tumors showed positive immunostaining with p53. Endometriosis was associated with 8 (47%) LNG tumors and 8 (33%) HNG CCCs. Of the 11 cases with p53 alteration, 4 (1 LNG and 3 HNG) were associated with endometriosis.

CONCLUSIONS:

HNG CCCs, irrespective of their association with endometriosis, have alterations of p53. In general, LNG ovarian and endometrial CCCs, irrespective of their association with endometriosis/adenomyosis, are less likely to show p53 alteration. It appears that mullerian CCCs may have variable pathogenesis depending on their nuclear grade and association with endometriosis. A larger study is needed to validate these findings.

 

 

 

Stem Cells Dev. 2013 Mar 15;22(6):964-74. doi: 10.1089/scd.2012.0435. Epub 2013 Jan 29.

Mesenchymal-to-epithelial transition contributes to endometrial regeneration following natural and artificial decidualization.

Patterson AL1Zhang LArango NATeixeira JPru JK.

 

Abstract

Despite being a histologically dynamic organ, mechanisms coordinating uterine regeneration during the menstrual/estrous cycle and following parturition are poorly understood. In the current study, we hypothesized that endometrial epithelial tissue regeneration is accomplished, in part, by mesenchymal-to-epithelial transition (MET). To test this hypothesis, fate mapping studies were completed using a double transgenic (Tg) reporter strain, Amhr2-Cre; Rosa26-Stop(fl/fl-EYFP) (i.e., flox-stop EYFP reporter). EYFP expression was observed in Müllerian duct mesenchyme-derived stroma and myometrium, but not epithelia in young and peripubertal double Tg female mice. However, mosaic EYFP expression was observed in epithelia of double Tg mice after parturition. To ensure the observed epithelial EYFP expression was not due to leaky Amhr2 promoter activity, resulting in aberrant Cre expression, transgenic mice expressing LacZ under the control of the Amhr2 promoter (Amhr2-LacZ) were used to monitor β-galactosidase (β-Gal) activity within the uterus. β-Gal activity was not detected in luminal or glandular epithelia regardless of age, reproductive status, or degree of damage incurred within the uterus. Lastly, a unique population of transitional cells was identified that expressed the epithelial cell marker, pan-cytokeratin, and the stromal cell marker, vimentin. These cells localized predominantly to the regeneration zone in the mesometrial region of the endometrium. These findings suggest a previously unappreciated role for MET in endometrial regeneration and have important implications for proliferative diseases of the endometrium such as endometriosis.

 

 

Contraception. 2013 Jun;87(6):750-5. doi: 10.1016/j.contraception.2012.10.033. Epub 2012 Dec 4.

Pharmacokinetic study of single and multiple oral administrations of 2 mg dienogest in healthy Korean women.

Shin D1Lee SLim KSPark JSShin SGJang IJYu KS.

Abstract

BACKGROUND:

The progestin dienogest was developed for oral contraception, endometriosis treatment and menopause management. Dienogest’s pharmacokinetics have been primarily studied in Caucasian women. This study evaluated the single- and multiple-dose pharmacokinetics of dienogest in Korean women.

STUDY DESIGN:

Sixteen healthy Korean adult women received a single administration of 2 mg dienogest, followed by multiple once-daily administrations for 14 days. The single-dose administration and the final dose of the multiple administrations were each followed by blood sampling over 60 h.

RESULTS:

The mean (SD) maximum serum concentration after multiple doses of dienogest was slightly increased compared with that after a single dose [from 51.6 (9.6) to 56.6 (11.9) ng/mL], as was the area under the concentration-time curves (AUC)0-24h [from 503 (56.3) to 613 (90.7) ng ∙ h/mL]. The linearity factor calculated by AUCs of single and multiple doses is 1.00 ± 0.14, and the terminal half-life remained unchanged when single dosing and multiple dosing were compared.

CONCLUSIONS:

The present study described the single- and multiple-dose pharmacokinetic profiles of dienogest in Korean women and showed linear pharmacokinetics of dienogest at steady state.

 

 

 

Acta Histochem. 2013 Jun;115(5):434-9. doi: 10.1016/j.acthis.2012.10.006. Epub 2012 Dec 6.

Elevated immunoreactivity of RANTES and CCR1 correlate with the severity of stages and dysmenorrhea in women with deep infiltrating endometriosis.

Yang Y1Zhang XZhou CHuang XLin JXu H.

 

Abstract

Deep infiltrating endometriosis (DIE) is typically characterized by multifocal locations. It has been shown that CCR1, combined highly with RANTES, contributes to the enhanced recruitment of inflammatory cells at endometriotic sites. As an estrogen-dependent disorder, estrogen receptors are also crucial to the growth of endometriotic tissues. In this study we report the immunohistochemical analysis of RANTES, CCR1, ER-α and ER-β in 48 histological lesions prepared from women with DIE undergoing surgery. Immunohistochemical analysis of RANTES, CCR1, ER-α and ER-β was conducted at different sites of DIE lesions. RANTES was immunolocalized in the cytoplasm and CCR1 in cytomembranes of endometriotic cells. ER-α and ER-β extensively immunostained the nuclei of endometrial glandular, and stromal cells. Immunoreactivity in DIE lesions, similar to the widespread ERs, showed higher expression of RANTES and CCR1 in three types of DIE lesions. There was a significant correlation, independent of cyclic changes, between the expression of RANTES/CCR1 and DIE lesions. RANTES/CCR1 increased significantly according to the severity of dysmenorrhea. RANTES and CCR1 together may provide a potential biomarker for DIE-related pain and inflammatory response in endometriotic lesions of patients with DIE.

 

 

Am J Obstet Gynecol. 2013 May;208(5):413.e1-5. doi: 10.1016/j.ajog.2012.12.004. Epub 2012 Dec 5.

Clinical analysis of ovarian epithelial carcinoma with coexisting pelvic endometriosis.

Wang S1Qiu LLang JHShen KYang JXHuang HFPan LYWu M.

Abstract

OBJECTIVES:

To explore the differences between women with endometriosis associated ovarian cancer and typical epithelial ovarian cancer.

STUDY DESIGN:

The medical charts of total 226 patients with epithelial ovarian cancer treated at Peking Union Medical College Hospital between March 2011 and March 2012 were reviewed. Histology evaluation determined endometriosis associated ovarian cancer (n = 17) or non-endometriosis associated ovarian cancer (n = 209).

RESULTS:

Compared with non-endometriosis associated ovarian cancer, patients with endometriosisassociated ovarian cancer were proved: (1) to be younger and more likely to be premenopausal at diagnosis of epithelial ovarian cancer (P = .03 and .005, respectively); (2) to have lower preoperative serum level of Ca125 (mean: 122.9 vs 1377.5 U/mL, P < .001) and more likely to display normal Ca125 level (P < .001); (3) to be identified at the earlier stage (stage I, P < .001); (4) to have completely different distribution of histological subtypes (significant overrepresentation of clear cell and endometrioid carcinoma).

CONCLUSION:

As such, patients with endometriosis associated ovarian cancer differ from non-endomertiosis associated ovarian cancer in many of their critical clinical and biologic characteristics.

 

 

Reprod Sci. 2013 Jul;20(7):762-70. doi: 10.1177/1933719112466307. Epub 2012 Dec 7.

Surgical removal of endometrioma decreases the NF-kB1 (p50/105) and NF-kB p65 (Rel A) expression in the eutopic endometrium during the implantation window.

Celik O1Celik ETurkcuoglu IYilmaz EUlas MSimsek YKaraer ACelik NAydin NEOzerol IUnlu C.

 

Abstract

We aimed to investigate whether the surgical removal of endometrioma alters the nuclear factor-kappa B1 (NF-kB1; p50/105) and NF-kB p65 (Rel A) expression in the eutopic endometrium of infertile women with endometrioma before and after laparoscopic removal of the ovarian endometrioma during the mid-secretory phase. Infertile women with endometrioma (n = 15) were enrolled. Infertile patients with nonendometriotic ovarian cyst (n = 10) and healthy fertile women (n = 10) were recruited as controls. Endometrial samples were obtained before and 3 months after the laparoscopic cystectomy. The NF-kB1 (p50/105) levels were analyzed by enzyme-linked immunosorbent assay (ELISA) in the endometrium of all groups before and after laparoscopic ovarian cystectomy during implantation window. Expression of NF-kB1 (p50/105) in eutopic endometrium was significantly higher in infertile women with endometrioma compared to nonendometriotic cyst and fertile controls (P < .05). Laparoscopic cystectomy resulted in a significant decrease in NF-kB1 expression in women with endometrioma. The NF-kB p65 (Rel A) immunoreactivity of eutopic endometrium decreased significantly subsequent to the surgical removal of the endometrioma. In conclusion, increased endometrial NF-kB expression may contribute to endometriosis-associated infertility.

 

 

Front Physiol. 2012 Dec 3;3:444. doi: 10.3389/fphys.2012.00444. eCollection 2012.

Identification of displaced endometrial glands and embryonic duct remnants in female fetal reproductive tract: possible pathogenetic role in endometriotic and pelvic neoplastic processes.

Bouquet de Jolinière J1Ayoubi JMLesec GValidire PGoguin AGianaroli LDubuisson JBFeki AGogusev J.

Abstract

BACKGROUND:

Recent findings strongly promoted the hypothesis that common pelvic gynecological diseases including endometriosis and ovarian neoplasia may develop de novo from ectopic endometrial-like glands and/or embryonic epithelial remnants. To verify the frequency, the anatomical localization and the phenotype of misplaced endometrial tissue along the fetal female reproductive tract, histological and immunohistochemical analyses of uteri, fallopian tubes, and uterosacral ligaments were performed.

METHODS:

Reproductive organs were collected from seven female fetuses at autopsy, five of them from gestational ages between 18 and 26 weeks and two fetuses with gestational ages of 33 and 36 weeks deceased of placental anomalies. Serial sections from areas containing ectopic glands and embryonic duct residues were analyzed by histological and immunohistochemical procedures.

RESULTS:

Numerous ectopic endometrial glands and stroma were detected in the myometrium in two fetuses with low levels of expression of estrogen receptor-alpha (ER-α) and progesterone receptors (PR). The embryonic ducts were localized in the uterine broad and ovarian ligaments and under the fallopian tube serosa in six fetuses. Low levels of steroid receptors expression were found in the embryonic residues, whereas the carcino-embryonic antigen (CEA) and the tumor marker Ca 125 were not detected. The embryonic residues stromal component strongly expressed the CD 10 and vimentin proteins.

CONCLUSION:

The anatomical and the immunohistochemical features of the ectopic organoid structures identified in fetal female reproductive tract suggest that endometriotic as well as neoplastic disease in adult women may develop on the basis of misplaced endometrial glands and/or embryonic cell remnants.

 

 

 

 

J Ethnopharmacol. 2013 Feb 13;145(3):767-75. doi: 10.1016/j.jep.2012.12.003. Epub 2012 Dec 8.

Artemisia leaf extract induces apoptosis in human endometriotic cells through regulation of the p38 and NFκB pathways.

Kim JH1Jung SHYang YIAhn JHCho JGLee KTBaek NIChoi JH.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Artemisia leaves have long been used for the treatment of gynecological disorders, including infertility and dysmenorrhea, which can be commonly caused by endometriosis. In the present study, we investigated the effect of Artemisia princeps extract (APE) on the cell growth and apoptosis of human endometriotic cells.

MATERIALS AND METHODS:

MTT assays and FACS analysis using PI and Annexin staining were performed to study cell viability, cell cycle progression, and apoptosis. We also explored the mechanism of APE-induced effects by evaluating the activation of caspases, Akt, p38, and NFκB. The expressions of XIAP, Bcl-2, and Bcl-xL were measured by real-time RT-PCR and Western blot analyses.

RESULTS:

APE significantly inhibited the cell viability of 11Z and 12Z human endometriotic epithelial cells. Interestingly, endometriotic cells were more sensitive to APE treatment than immortalized endometrial cells (HES). Treatment with APE induced apoptosis of 11Z cells in a time-dependent manner, as shown by accumulation of sub G1 and apoptotic cell populations. In addition, treatment with APE stimulated the activation of caspase -3, -8, and -9 in a dose- and time-dependent manner. Furthermore, p38 was activated by APE treatment, and the p38 inhibitor SB203580 markedly inhibited APE-induced cell death in 11Z cells. Moreover, treatment with APE suppressed the activation of NFκB and the expressions of anti-apoptotic factors such as XIAP, Bcl-2, and Bcl-xL.

CONCLUSION:

These results indicate that APE is a potential anti-endometriotic agent, acting to induce apoptosis of endometrial cells through the modulation of the p38 and NFκB pathways.

 

 

 

 

 

Placenta. 2013 Feb;34(2):100-5. doi: 10.1016/j.placenta.2012.11.017. Epub 2012 Dec 8.

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

Brosens I1Pijnenborg RBenagiano G.

 

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.

 

 

 

Adv Anat Pathol. 2013 Jan;20(1):45-52. doi: 10.1097/PAP.0b013e31827bc24d

Pathogenesis and the role of ARID1A mutation in endometriosis-related ovarian neoplasms.

Maeda D1Shih IeM.

 

Abstract

Endometriosis-related ovarian neoplasms (ERONs) are a unique group of tumors as they are associated with endometriosis, especially endometriosis presenting as an ovarian endometriotic cyst (endometrioma). ERONs include clear cell carcinoma, endometrioid carcinoma, and seromucinous borderline tumor. A growing body of evidence from both clinicopathologic and molecular studies suggests that most, if not all, ERONs develop from endometriotic cyst epithelium through different stages of tumor progression. The endometriotic cyst contains abundant iron-induced reactive oxygen species that are thought to be mutagenic, and chronic exposure of cystic epithelium to this microenvironment facilitates the accumulation of somatic mutations that ultimately result in tumor development. Molecular analyses of ERONs, including genome-wide screens, have identified several molecular genetic alterations that lead to aberrant activation or inactivation of pathways involving ARID1A, PI3K, Wnt, and PP2A. Among all molecular genetic changes identified to date, inactivating mutations of the ARID1A tumor suppressor gene are the most common in ERON. Understanding the molecular changes and pathogenesis involved in the development of ERON is fundamental for future translational studies aimed at designing new diagnostic tests for early detection and identifying critical molecular features for targeted therapeutics.

 

 

 

J Clin Ultrasound. 2013 Feb;41(2):69-75. doi: 10.1002/jcu.22018. Epub 2012 Dec 12.

Transvaginal sonography for preoperative assessment of deep endometriosis.

Fratelli N1Scioscia MBassi EMusola MMinelli LTrivella G.

Abstract

PURPOSE:

To determinate transvaginal scan (TVS) accuracy in the preoperative evaluation of deep endometriosis in a large cohort of patients with subsequent laparoscopic assessment.

METHODS:

A retrospective study was performed in a tertiary referral center for endometriosis. Transvaginal scan reports were retrieved from an electronic database of all patients who underwent laparoscopy for pelvic pain or infertility in 2009. The accuracy of TVS was assessed for 10 different sites of pelvic endometriosis.

RESULTS:

Four hundred twenty women were included in the study. Sensitivity and specificity of TVS were 61% and 99%, respectively, for bladder endometriosis, 52% and 96% for endometriosis of rectovaginal septum, 65% and 99% for rectum endometriosis, and 69% and 98% for endometriosis of the sigmoid colon.

CONCLUSIONS:

TVS appears to be useful for the detection of endometriosis located in the bladder and involving the sigmoid colon, the rectovaginal septum, and the rectum.

 

 

 

 

Front Endocrinol (Lausanne). 2012 Nov 28;3:148. doi: 10.3389/fendo.2012.00148. eCollection 2012.

Gonadotropin-inhibitory hormone action in the brain and pituitary.

Ubuka T1Son YLTobari YTsutsui K.

 

Abstract

Gonadotropin-inhibitory hormone (GnIH) was first identified in the Japanese quail as a hypothalamic neuropeptide inhibitor of gonadotropin secretion. Subsequent studies have shown that GnIH is present in the brains of birds including songbirds, and mammals including humans. The identified avian and mammalian GnIH peptides universally possess an LPXRFamide (X = L or Q) motif at their C-termini. Mammalian GnIH peptides are also designated as RFamide-related peptides from their structures. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147), which is thought to be coupled to G(αi) protein. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN) in birds and the dorsomedial hypothalamic area (DMH) in mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function. GPR147 is expressed in the gonadotropes and GnIH suppresses synthesis and release of gonadotropins. It was further shown in immortalized mouse gonadotrope cell line (LβT2 cells) that GnIH inhibits gonadotropin-releasing hormone (GnRH) induced gonadotropin subunit gene transcriptions by inhibiting adenylate cyclase/cAMP/PKA-dependent ERK pathway. GnIH neurons also project to GnRH neurons in the preoptic area, and GnRH neurons express GPR147 in birds and mammals. Accordingly, GnIH may inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as directly acting on the gonadotropes. GnIH also inhibits reproductive behavior possibly by acting within the brain. GnIH expression is regulated by a nocturnal hormone melatonin and stress in birds and mammals. Accordingly, GnIH may play a role in translating environmental information to inhibit reproductive physiology and behavior of birds and mammals. Finally, GnIH has therapeutic potential in the treatment of reproductive cycle and hormone-dependent diseases, such as precocious puberty, endometriosis, uterine fibroids, and prostatic and breast cancers.

 

 

Int J Clin Exp Med. 2013;6(1):67-73. Epub 2012 Nov 30.

Oral continuous combined 0.5 mg estradiol valerate and 5 mg dydrogesterone as daily add-back therapy during post-operative GnRH agonist treatment for endometriosis in Chinese women.

Zou S1Long QZhang SHan YZhang W.

Abstract

OBJECTIVE:

To evaluate the lowest effective dose of combined estrogen and progestogen (E(2)+P) add-back therapy during post-operative gonadotropin-releasing hormone agonist (GnRHa) treatment for endometriosisin Chinese women.

STUDY DESIGN:

The study enrolled 81 patients aged 18 to 50 years with stage III or IV endometriosis, as diagnosed by surgery. All patients were given GnRHa 3.6 mg by subcutaneous injection once every 28 days for a total of three times. Patients were divided into three groups: the first (n = 35; GnRHa only group) received GnRHa only without add-back therapy, the second (n = 35; 0.5 mg E(2)+P add-back group) received GnRHa plus 0.5 mg estradiol valerate and 5 mg dydrogesterone orally every day, and the third (n = 11; 1 mg E(2)+P add-back group) received GnRHa plus 1 mg estradiol valerate and 10 mg dydrogesterone orally every day for the duration of treatment. All patients were required to follow up at our hospital at 4, 8 and 12 weeks after treatment initiation to assess efficacy and levels of serum reproductive hormones.

RESULTS:

Compared with baseline levels, serum levels of the four reproductive hormones assessed (E(2), LH, P(4) and FSH) were significantly decreased in both the GnRHa only and the 0.5 mg E(2)+P add-back groups at 4, 8, and 12 weeks after treatment; and levels reached a stable state at 4 weeks of treatment. In the 1 mg E(2)+P add-back group, LH and FSH serum levels were significantly decreased, while those of E(2) and P were not significantly different at any of the time points assessed. In the 0.5 mg E(2)+P add-back group, E(2) serum levels decreased drastically at first, then gradually over the course of the study. In contrast, pre- and post-treatment E(2) serum levels in the 1 mg E(2)+P add-back group were not significantly different, and these levels were over 45 pg/mL for the entire study duration. Comparison among groups showed that E(2) levels in both add-back groups were significantly higher than in the GnRHa only group at 12 weeks after treatment. Furthermore, E(2) serum levels in the two add-back groups at 8 and 12 weeks after treatment were significantly different.

CONCLUSION:

Oral continuous combined 0.5 mg/d estradiol valerate and 5 mg/d dydrogesterone as immediate add-back therapy during post-operative GnRH agonist treatment for severe endometriosis may be the most suitable regimen for Chinese women.

 

 

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