Mol Med Rep. 2018 Mar 29. doi: 10.3892/mmr.2018.8823. [Epub ahead of print] Zearalenone regulates endometrial stromal…
Obstet Gynecol Sci. 2016 Jul;59(4):286-94
Preoperative risk factors in recurrent endometrioma after primary conservative surgery.
Endometriosis is a common gynecological disorder caused by ectopic implantation of endometrial glandular and stromal cells outside the uterine cavity. Among several types of endometriosis, endometrioma is the only subtype that could be determined preoperatively using pelvic ultrasonography, and guidelines recommend pathologic confirmation of endometrioma greater than 3 cm in diameter. However, although surgery is performed in cases of endometrioma, endometrioma has a high cumulative rate of recurrence. Therefore, because determining the possibility of recurrence before performance of initial surgery is important, we examined preoperative factors associated with recurrent endometrioma.
This was a retrospective, comparative study including 236 patients who visited the outpatient clinic between January 2009 and December 2011. Patients who were pathologically diagnosed with endometrioma were included in this study. They were followed up postoperatively and were divided into two groups according to presence of recurrent endometrioma.
We examined associations between baseline factors and recurrent endometrioma. In multivariate analysis, dysmenorrhea and cyst septation were statistically significant after adjusting with age, parity, surgical staging and postoperative management. We examined cumulative recurrence free survival within cases of recurrent endometriosis, based on the presence of inner cyst septation. The cumulative recurrence free survival was lower in cases with septation.
Our study found that recurrent endometrioma is more likely in patients with inner cyst septation and the recurrence occurred within a shorter duration of time than in patients without inner cyst septation on preoperative ultrasonography. Therefore intensive caution and postoperative long term medical therapy would be appropriate in patients with inner cyst septation on preoperative ultrasonography before undergoing primary surgery for endometrioma.
Obstet Gynecol Sci. 2016 Jul;59(4):295-302.
Analysis of falsely elevated risk of ovarian malignancy algorithm in women with ovarian endometrioma.
To estimate the incidence of falsely elevated risk of ovarian malignancy algorithm (ROMA) in a group of women with pathologically confirmed endometrioma and to investigate the associated factors.
One hundred premenopausal women surgically diagnosed with ovarian endometrioma were selected. Preoperative clinical, laboratory, and surgical characteristics were compared between the elevated-risk group (ROMA-premenopausal value, ≥7.4%) and normal-risk group (ROMA-premenopausal value, <7.4%).
Elevated ROMA was observed in 15 women (false positive rate, 15%). Excluding one woman with known chronic renal failure, we compared the characteristics of 99 women between the elevated-risk group (n=14) and the normalrisk group (n=85). None of the clinical and surgical variables distinguished the two groups. Serum level of CA 125 >82.3 U/mL and serum level of human epididymis protein 4 (HE4) >46 pmol/L could predict an elevated ROMA test with a statistical significance. When serum level of HE4 ≤46 pmol/L, none of the women showed an elevated ROMA test, regardless of serum level of CA 125; however, 55.6% of the women showed an elevated ROMA test when serum level of HE4 >46 pmol/L and CA 125 ≤82.3 U/mL and all women showed an elevated ROMA test when serum level of HE4 >46 pmol/L and CA 125 >82.3 U/mL.
The incidence of falsely elevated ROMA was 15% in the group of women with pathologically confirmed endometrioma. Interpretation of the ROMA results should be cautious when serum level of HE4 >46 pmol/L and CA 125 >82.3 U/mL in women with suspicious ovarian endometrioma.
Obstet Gynecol Sci. 2016 Jul;59(4):323-7.
A case of advanced-stage endometrial stromal sarcoma of the ovary arising from endometriosis.
Endometrial stromal sarcoma (ESS) is a rare malignancy. Development of extrauterine ESS form endometriosis is particularly rare. The majority of extrauterine ESS occurs in areas with preexisting endometriosis. The most common site is the ovary. We experienced a case of ESS of the ovary that arose from endometriosis with multiple disseminated lesions. This disease was managed by total abdominal hysterectomy, bilateral salpingo-oophorectomy, both pelvic lymph nodes dissection, omentectomy, and appendectomy followed by postoperative high-dose progesterone therapy. Here, we report this case with literature review.
Sex Dev. 2016;10(4):191-199.
NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations.
Mutations in the NR5A1 gene, which encodes the steroidogenic factor 1 (SF1), are responsible for different phenotypes of disorders of sex development (DSD), such as bilateral anorchia and hypospadias. Furthermore, they can be associated with primary amenorrhea, premature ovarian failure, male infertility, adrenal tumors, and endometriosis. Direct sequencing of the 7 NR5A1 exons including ∼1,000 bp of the 5′-upstream and 3′-downstream regions and all intron-exon boundaries was performed in patients with DSD. Three different in silico tools were used to assess the consequences of a splice site mutation. As a result, 3 novel NR5A1 mutations were identified in 3 patients with 46,XY partial gonadal dysgenesis: p.Lys38* and p.Leu80Trpfs*8 lead to premature translation termination codons within the SF1 DNA-binding domain, and the intronic nucleotide substitution c.1138+1G>T at the intron 6 donor splice site is considered to modify correct splicing. We assume that the anomalous mRNA produced as a result of p.Lys38* and p.Leu80Trpfs*8 will be degraded by nonsense-mediated mRNA decay even before translation, leading to SF1 haploinsufficiency. The c.1138+1G>T mutation is expected to produce a truncated protein. Heterozygous SF1 loss-of-function mutations in these cases resulted in mild DSD manifestations, such as dysgenetic testes, spontaneous puberty, and preserved adrenal function.
Aust N Z J Obstet Gynaecol. 2016 Oct;56(5):518-522
Diagnostic laparoscopy in pre-surgical planning for higher stage endometriosis: Is it still relevant?
It has become necessary to re – examine the relevance of diagnostic laparoscopy in the two-stage approach to surgical management of symptomatic women with higher stage endometriosis following emerging evidence demonstrating acceptable diagnostic performance of alternative less invasive and less expensive imaging modalities. We highlight the relative merits of these presurgical diagnostic imaging modalities and propose strategies that address the challenge of transitioning to a new diagnostic paradigm in the management of symptomatic women with higher stage endometriosis.
Zhonghua Fu Chan Ke Za Zhi. 2016 Jul 25;51(7):503-9.
Clinical analysis of efficacy and quality of life of segmental bowel resection for bowel endometriosis.
To evaluate the efficacy and quality of life of segmental bowel resection for bowel endometriosis.
Totally 62 symptomatic patients with bowel endometriosis undergoing segmental bowel resection were recruited. A visual analogue scale(VAS)and the 36-item short form health survey(SF-36)questionnaire were administered before and at least 1 year after surgery, respectively. Pregnancy rates were also recorded.
Sixty-two patients in total underwent follow-up ranging from 12 to 74 months. All patients complained of obvious pain symptoms, including dysmenorrhea, dyspareunia, pain on defecation and chronic pelvic pain. The relief of dysmenorrhea(2.9 ± 2.2 versus 7.5 ± 2.9), dyspareunia(0.7 ± 0.5 versus 4.3 ± 2.2)and pain on defecation(1.6 ± 0.7 versus 7.3 ± 1.9)after surgery was statistically significant(all P<0.01). The scores for all 8 domains of the SF-36 questionnaire were significant improved after segmental bowel resection(all P<0.01). The complication rate was 45%(28/62), including 18 cases of urinary retention, 4 rectovaginal fistulas, 2 cases of vaginal dehiscence, and 1 case each of thrombogenesis, pelvic abscess and general peritonitis. All of the patients with complications recovered well throughout follow-up. The postoperative pregnancy rate of the previous infertile patients was 6/10. Among the 6 gestational cases, 2 had labour, 2 underwent caesarean sections, one had a spontaneous natural abortion, and one underwent uterine curettage.
Segmental bowel resection could significantly relieve pain and improve quality of life for patients with bowel endometriosis.
Int J Gynecol Cancer. 2016 Oct;26(8):1461-4
Testosterone Aromatization to Estradiol in Course of Ovarian Functioning Brenner Tumor Associated With Endometrial Carcinoma and Endometriosis (Roncati-Manenti Triad).
Aromatization is the biochemical process in which aromatase catalyzes the conversion of testosterone into estradiol, the fundamental pathway for the synthesis of estrogens. When enhanced, it can lead to hyperestrogenism, a well-known risk factor for gynecological cancers.
The surgical specimens, coming from 2 postmenopausal women with hyperestrogenism on pap smear and bioptic diagnosis of endometrial endometrioid carcinoma, were fixed in 10% neutral buffered formalin, paraffin embedded, and then submitted for routine hematoxylin/eosin staining and immunohistochemical characterization for antiestrogen, antiprogesterone, antitesterone, anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6.
The presence of an undescribed triad represented by ovarian functioning Brenner tumor, endometrial carcinoma, and pelvic endometriosis has been ascertained. The immunohistochemical investigation proved a normal expression of the DNA mismatch repair proteins and revealed a bimodal hormonal status in the pathological tissues, that is, the Brenner tumor cells showed a high expression of testosterone, contrariwise endometrioid carcinoma and endometriosis a high estrogen and progesterone immunolabeling.
This synchronous triad underlines the importance of aromatization and hyperestrogenism in the development of gynecological malignancies in which the immunohistochemical detection of an active source of hormone production – to always keep in consideration during synchronous diseases – can guide subsequent antihormone chemotherapy based on aromatase inhibitors.
J Zoo Wildl Med. 2016 Jun;47(2):614-7.
MANAGEMENT OF ENDOMETRIOSIS IN TWO CAPTIVE MANDRILLS (MANDRILLUS SPHINX).
Endometriosis has been reported in humans, great apes, and Old World monkeys. Although cases are noted anecdotally in Mandrillus spp., and a previously reported case was noted on postmortem examination, to the authors’ knowledge, no previous reports of case management have been published in the peer-reviewed literature. This paper describes the medical and surgical management of endometriosis in two mandrills (Mandrillus sphinx).
Reprod Sci. 2017 Jun;24(6):803-811.
Genes Linked to Endometriosis by GWAS Are Integral to Cytoskeleton Regulation and Suggests That Mesothelial Barrier Homeostasis Is a Factor in the Pathogenesis of Endometriosis.
Endometriosis, defined by the presence of ectopic endometrial lesions, is a common disease in reproductive-age women that profoundly affects patients’ quality of life. Various pathogenic models have been proposed, but the origin of endometriosis remains elusive. In this article, we propose that the mesothelial barrier, which protects the underlying stroma from endometrial transplants present in retrograde menstrual fluid, can be compromised by activation of the epithelial to mesenchymal transition (EMT) repair mechanism that lead to temporary loss of barrier integrity. Absent of the mesothelial barrier, endometrial cells can more readily adhere to the underlying peritoneal stroma and establish endometrial lesions. The hypothesis is based on the clinical and experimental observations that correlate the location of endometrial lesions with areas of mesothelial damage, together with genetic evidence that 4 genes associated with endometriosis are direct regulators of the actin-cytoskeleton, which coordinates mesothelial barrier integrity. It supports past observations that implicate the peritoneum in the pathogenesis of endometriosis and unifies previously disparate theories that endometriosis may be triggered by infection, mechanical damage, and inflammation since each of these mechanisms can induce EMT in the mesothelium. If the hypothesis is correct, inhibition of EMT in the mesothelial barrier provides a novel paradigm for the prevention and treatment of endometriosis.
Homeopathy. 2016 Aug;105(3):240-249
Protocol of randomized controlled trial of potentized estrogen in homeopathic treatment of chronic pelvic pain associated with endometriosis.
Endometriosis is a chronic inflammatory disease that causes difficult-to-treat pelvic pain. Thus being, many patients seek help in complementary and alternative medicine, including homeopathy. The effectiveness of homeopathic treatment for endometriosis is controversial due to the lack of evidences in the literature. The aim of the present randomized controlled trial is to assess the efficacy of potentized estrogen compared to placebo in the treatment of chronic pelvic pain associated with endometriosis.
The present is a randomized, double-blind, placebo-controlled trial of a homeopathic medicine individualized according to program ‘New Homeopathic Medicines: use of modern drugs according to the principle of similitude’ (http://newhomeopathicmedicines.com). Women with endometriosis, chronic pelvic pain and a set of signs and symptoms similar to the adverse events caused by estrogen were recruited at the Endometriosis Unit of Division of Clinical Gynecology, Clinical Hospital, School of Medicine, University of São Paulo (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo – HCFMUSP). The participants were selected based on the analysis of their medical records and the application of self-report structured questionnaires. A total of 50 women meeting the eligibility criteria will be randomly allocated to receive potentized estrogen or placebo. The primary clinical outcome measure will be severity of chronic pelvic pain. Statistical analysis will be performed on the intention-to-treat and per-protocol approaches comparing the effect of the homeopathic medicine versus placebo after 24 weeks of intervention.
The present study was approved by the research ethics committee of HCFMUSP and the results are expected in 2016.
Ann Pathol. 2016 Aug;36(4):282-5.
Vaginal adenosis: A case report and literature review.
We report a case of vaginal adenosis in a woman of 42years. This is a rare congenital disorder since cessation of use of diethylstilbestrol (DES), usually of benign course, not to ignore in its tubo-endometrial histological form which may progress to atypical adenosis precursor of vaginal clear cell adenocarcinoma in patients exposed in utero to DES.
Fertil Steril. 2016 Nov;106(6):1420-1431.
Immune-inflammation gene signatures in endometriosis patients.
To determine if the molecular profiles of endometriotic lesions contain informative measures of inflammation and immune dysfunction that may contribute to better understanding of the interplay between immune dysfunction and inflammation and their contribution to endometriosis pathogenesis.
Immune and inflammation transcriptomic analysis with the use of the Nanostring nCounter GX Human Immunology V2 platform (579 human immune and inflammation-related genes and 15 housekeeping genes).
Academic university and teaching hospital.
Stage III-IV endometriosis patients with infertility (n = 8) and fertile disease-free control women undergoing tubal ligation (n = 8). Menstrual stage was matched to secretory phase in all participants.
MAIN OUTCOME MEASURE(S):
Immune and inflammation transcriptomics quantification from ectopic endometriotic lesions and matched eutopic endometrium from patients. Endometria of fertile women served as control subjects.
Our results displayed endometriotic lesions as molecularly distinct entities compared with eutopic endometrium and endometrium of control samples; 396 out of 579 screened immune and inflammation-related genes were significantly different in ectopic tissues compared with control endometrium. Most importantly, eutopic endometrium of the patients displayed a unique molecular profile compared with the control endometrium (91/579 genes were significantly different), particularly of genes involved in regulation of cell apoptosis and decidualization.
We characterize differential expression of immune-inflammation genes in endometriosis patients, and show molecular distinction of eutopic endometrium of patients compared with control fertile women.
Int J Gynaecol Obstet. 2016 Nov;135(2):135-139.
Effects of low-dose combined drospirenone-ethinylestradiol on perimenstrual symptoms experienced by women with endometriosis.
To determine the effectiveness of a 24/4-day regimen of a low-dose combination drospirenone-ethinylestradiol oral contraceptive in alleviating perimenstrual symptoms among Japanese women with endometriosis.
The present prospective, non-randomized study enrolled women diagnosed with endometriosis radiographically or surgically at the Kyoto Prefectural University of Medicine hospital, Japan, between December 1, 2010 and August 31, 2013. Patients received treatment with oral drospirenone-ethinylestradiol for six treatment cycles. Dysmenorrhea, chronic pelvic pain, and dyspareunia severity were assessed using visual analog scale scores after three and six treatment cycles, and changes in perimenstrual symptoms were assessed using the menstrual distress questionnaire (MDQ) scores.
In total, 46 patients were recruited for the study. Dysmenorrhea, chronic pelvic pain, and dyspareunia were all significantly reduced after both three and six treatment cycles in comparison with baseline (P<0.001 for all comparisons). After six treatment cycles, significant reductions were observed for all menstrual MDQ measures and for the premenstrual water retention and negative-effect MDQ measures (all P<0.05).
Combination drospirenone-ethinylestradiol was effective in the treatment of dysmenorrhea, chronic pelvic pain, dyspareunia, and somatic/psychological symptoms in Japanese women with endometriosis.
J Minim Invasive Gynecol. 2017 Feb;24(2):196-197.
Single-Port Total Laparoscopic Hysterectomy in a Patient With Deep Infiltrating Endometriosis.
To present the feasibility of single-port laparoscopic surgery at patients with deep infiltrating endometriosis.
Step by step explanation of the surgery using videos (Canadian Task Force classification III-c).
Single-port laparoscopic surgery is an emerging technique and an option for improving the benefits of laparoscopic surgery. The goals of single-port laparoscopic surgery is to further enhance the cosmetic benefits of minimally invasive surgery and minimize the potential risk and morbidity associated with multiport surgery [1,2]. This procedure is not without challenges, however, such as instrument crowding and clashing, ergonomic difficulties, loss of instrument triangulation, and the need for advanced laparoscopic skills [1,2]. Despite these challenges, technical advances in optics and instrumentation have led to the widespread use of single-port laparoscopic surgery to treat such gynecologic disorders as endometriosis, uterine myomas, and cancers [2,3].
A 42-year-old woman was admitted to our clinic with a complaint of chronic pelvic pain dysmenorrhea and deep dyspareunia. Her medical history revealed a cesarean section delivery and a diagnosis of endometriosis. Despite treatment of her endometriosis with dienogest, there has been no decline at her complaints. Ultrasound examination performed at admission revealed a 6 × 6 cm right adnexal mass compatible with endometrioma, with a normal left ovary and uterus. Rectovaginal examination detected no endometriotic nodules. Although all treatment options were explained and discussed and laparoscopic excision of right ovarian endometrioma was recommended, the patient strongly desired removal of the uterus and the ovaries to avoid recurrence of endometriosis and related complaints. Thus, laparoscopic hysterectomy and bilateral salpingo-oophorectomy were planned. Under general anesthesia and endotracheal intubation, the patient was placed in low lithotomy position with the arms tucked. An orogastric tube and a Foley catheter were placed. Abdominal access was performed following an open Hasson technique with a 2.0- to 2.5-cm vertical umbilical incision and a 4-channel (with two 10-mm and two 5-mm channels) access port was placed into the peritoneal cavity. On pelvic examination, a 6 × 6-cm right ovarian endometrioma adherent to the pelvic sidewall was detected, along with severe adhesions on the left side between the left adnex and the pelvic sidewall. The uterus was normal. The adhesion on the left side was released using a Harmonic scalpel (Ethicon Endosurgery, Cinncinnati, OH). The pelvic sidewall peritoneum was opened, and the ureters were identified and isolated at the pelvic brim and followed toward the true pelvis. The internal iliac artery, uterine and obliterated umbilical artery, and infundibulopelvic ligament were dissected and identified. The paravesical, pararectal, and rectouterine spaces were opened. Deep infiltrating endometriosis implants on the right side located in the uterosacral ligment and pararectal space were dissected and excised. After restoration of pelvic anatomy, hysterectomy and bilateral salpingo-oophorectomy were performed. The vaginal cuff was closed with intracorporeal knots. The patient was discharged on postoperative day 1, and reported no problems at follow-up.
Single-port laparoscopic hysterectomy appears to be a safe and feasible option in patients with deep infiltrating endometriosis, especially when performed by well-experienced surgeons.
Eur J Pharm Sci. 2016 Oct 10;93:132-40.
Effects of cisplatin and letrozole on surgically induced endometriosis and comparison of the two medications in a rat model.
This study was to investigate the effects of cisplatin (CDDP) and letrozole on surgically induced endometriosis and comparison of the two drugs in a rat model. Endometriosis was surgically induced by autologous transplantation of endometrial pieces. Thirty model rats were divided into three groups, randomly. Group 1 (n=10) served as control and received no medication. Group 2 (n=10) received 0.2mg/kg/day of oral letrozole. Group 3 (n=10) received 35mg/m(2) CDDP via peritoneal perfusion every four days. All the rats were treated for 24days. The growth and histologic score of the implants were evaluated. The proliferation- and angiogenesis-associated proteins were assessed using immunohistochemistry and western blotting. The serum sex hormones were assayed using ELISA. After the medication, the growth and histologic score of the implants were significantly lower in the 2 and 3 groups than in the control group. The protein expressions of vascular endothelial growth factor (VEGF), aromatase P450 (P450arom), transforming growth factor-beta (TGF-β), and matrix metalloproteinase (MMP)-2, were significantly lower in groups 2 and 3 than in the control group. Further, the P450arom level was lower in the letrozole group than in the CDDP group. The TGF-β and MMP-2 levels were lower in the CDDP group than in the letrozole group. Serum T level was significantly higher in the letrozole group, and serum E2 level was lower in the letrozole group. In conclusion, cisplatin and letrozole caused similar regression of the implants in the endometriosis model rats. But their effects on the proliferation- and angiogenesis-associated protein expressions and the serum sex hormone levels were different. Cisplatin and letrozole might cause the effects in the endometriotic foci through different mechanism.
Int J Immunogenet. 2016 Oct;43(5):297-302.
Association of interleukin-16 polymorphisms with disease progression and susceptibility in endometriosis.
Interleukin-16 (IL-16) is a multifunctional pro-inflammatory cytokine that was previously found in association with complex disorders, and it is now cleared that this cytokine plays a critical role in regulation of cellular functions such as homoeostasis. Due to the complexity of endometriosis and its resemblance to cancer, we designed present case-control study to determine the effects of genetic polymorphisms of the human IL-16 gene on Iranian women’s susceptibility to endometriosis. A total of 126 patients with endometriosis (stages I-IV) and 144 healthy women as control group were recruited to the study. We genotyped four single nucleotide polymorphisms of IL-16 gene (rs11556218 T>G, rs4778889 T>C, rs4072111 C>T and rs1131445 C>T). Genotyping was performed using PCR and restriction fragment length polymorphism. Our results showed that genotype distribution in two exonic polymorphisms including rs11556218 and rs4072111 was significantly different between Endometriosis patients and healthy individuals (P < 0.05). We have also found an association between rs4072111 and rs1131445 with progression to the severe stages (III-IV) of endometriosis (P < 0.05). Finally, we may conclude that IL-16 gene polymorphisms are highly associated with increased risk of endometriosis and could be considered as a susceptibility factor for endometriosis.
Chin J Integr Med. 2017 Apr;23(4):245-252.
Chinese medicine as complementary therapy for female infertility.
Chinese medicine (CM) has been used in clinical treatment for thousands of years in China, Japan, Korea, and other countries. CM is at present attracting many attentions around the world for reproductive health care and disease prevention, including treatment of female infertility. This review focuses on the CM treatment for female infertility patients, and supplies a summary on the efficacy, safety, and mechanism of some Chinese herbal medicines, herbal medicine-derived active compounds, and acupuncture. A large number of researches have reported that CM could alleviate or even cure female infertility by regulating hormone, improving reproductive outcome of in vivo fertilization, affecting embryonic implantation, curing polycystic ovarian syndrome, endometriosis, pelvic inflammatory disease, relieving mental stress, and regulating immune system. Meanwhile, a few studies claimed that there was little adverse reaction of CM in randomized controlled trials. However, up to present there is a lack of adequate evidences with molecular mechanistic researches and randomized controlled trials to prove the CM as an effective and safe treatment for infertility. Thus, utility of CM as a complementary medicine will be a feasible method to improve the outcome of female infertility treatment.
Reprod Sci. 2017 Feb;24(2):174-192.
Surgery for Benign Gynecological Disorders Improve Endometrium Receptivity.
Regardless of the anatomical locations, some benign gynecological disorders (BGDs) such as peritoneal endometriosis, ovarian endometrioma, adenomyosis, uterine leiomyomas, endometrial polyps, uterine septum, and hydrosalpinges may lead to implantation failure. Despite progress in medical therapies, surgery remains a mainstay of BGDs treatment. Although our knowledge of endometrial receptivity after BGDs surgery is limited, it has allowed for significant improvement in the treatment of female subfertility. Many researchers studied on pregnancy outcome following BGDs surgery, but they did not investigate the possible impact of surgery on endometrial receptivity. They, therefore, concluded that pregnancy rates improved after BGDs surgery based on clinical observations. Many of these clinicians believe that surgical resection of BGDs leads to removal of local mechanical effect over the endometrium. Moreover, they accept that BGDs surgery may inhibit the detrimental signaling and secretion of some molecules from the BGDSs into the endometrium that may lead to favorable effect on the endometrium. However, so far, data from randomized controlled trials or systematic review or meta-analyses to answer the question whether surgical treatment of BGDs can improve endometrial receptivity are lacking. The purpose of this systematic review was to evaluate the results of available publications dealing with the impact of reproductive surgery for BGDs on endometrial receptivity.
Reprod Sci. 2017 Mar;24(3):413-420.
Panel of Autoimmune Markers for Noninvasive Diagnosis of Minimal-Mild Endometriosis.
Endometriosis, characterized by the presence of endometrial-like tissue at extrauterine sites, is a common, chronic, estrogen-dependent, inflammatory condition associated with pelvic pain, subfertility, dysmenorrhea, and dyspareunia, affecting about 10% of reproductive-age women in any population. The diagnosis of endometriosis is usually delayed on an average by 8 to 11 years leading to significant consequences in terms of disease progression. The current study was aimed to validate enzyme-linked immunosorbent assay based on the epitopes of stomatin-like protein 2, tropomodulin 3 (TMOD3), and tropomyosin 3 (TPM3) for diagnosis of minimal-mild endometriosis (revised American Fertility Society Classification (rAFS) stage I-II) and to compare the performance with the reported markers: cancer antigen (CA) 125, CA19-9, α-enolase, Serine/threonine-protein kinase (PDIK1L), and syntaxin 5. This was a cross-sectional, multicenter study conducted during the year 2012 to 2015. Women with minimal-mild endometriosis (rAFS stage I-II [n = 133]) and healthy controls (n = 104) were screened for 11 novel autoimmune markers and reported markers α-enolase, PDIK1L, syntaxin 5, CA-125, and CA19-9. The sensitivity and diagnostic accuracy of serum antibodies against all the 11 epitopes were higher than that of CA-125, CA19-9, α-enolase, PDIK1L, and syntaxin 5 for diagnosis of rAFS stage I to II endometriosis. The sensitivity of 6 biomarkers (anti-TMOD3b-autoAb, anti-TMOD3c-autoAb, anti-TMOD3d-autoAb, anti-TPM3a-autoAb, anti-TPM3c-autoAb, and anti-TPM3d-autoAb) was higher at the specificity of ≥80% for diagnosis of rAFS stage I to II endometriosis as well as ultrasound-negative endometriosis. Further, logistic regression models of this panel of biomarkers showed increase in sensitivity, specificity, and diagnostic accuracy than individual biomarkers. The panel of 6 autoimmune biomarkers could be useful in setting up of noninvasive diagnostic test for detection of minimal-mild endometriosis.
Biol Reprod. 2016 Sep;95(3):62.
KLF10 Mediated Epigenetic Dysregulation of Epithelial CD40/CD154 Promotes Endometriosis.
Endometriosis is a highly prevalent, chronic, heterogeneous, fibro-inflammatory disease that remains recalcitrant to conventional therapy. We previously showed that loss of KLF11, a transcription factor implicated in uterine disease, results in progression of endometriosis. Despite extensive homology, co-expression, and human disease association, loss of the paralog Klf10 causes a unique inflammatory, cystic endometriosis phenotype in contrast to fibrotic progression seen with loss of Klf11. We identify here for the first time a novel role for KLF10 in endometriosis. In an animal endometriosis model, unlike wild-type controls, Klf10(-/-) animals developed cystic lesions with massive immune infiltrate and minimal peri-lesional fibrosis. The Klf10(-/-) disease progression phenotype also contrasted with prolific fibrosis and minimal immune cell infiltration seen in Klf11(-/-) animals. We further found that lesion genotype rather than that of the host determined each unique disease progression phenotype. Mechanistically, KLF10 regulated CD40/CD154-mediated immune pathways. Both inflammatory as well as fibrotic phenotypes are the commonest clinical manifestations in chronic fibro-inflammatory diseases such as endometriosis. The complementary, paralogous Klf10 and Klf11 models therefore offer novel insights into the mechanisms of inflammation and fibrosis in a disease-relevant context. Our data suggests that divergence in underlying gene dysregulation critically determines disease-phenotype predominance rather than the conventional paradigm of inflammation being precedent to fibrotic scarring. Heterogeneity in clinical progression and treatment response are thus likely from disparate gene regulation profiles. Characterization of disease phenotype-associated gene dysregulation offers novel approaches for developing targeted, individualized therapy for recurrent and recalcitrant chronic disease.
J Assist Reprod Genet. 2016 Oct;33(10):1363-1372.
Intrafollicular interleukin-8, interleukin-12, and adrenomedullin are the promising prognostic markers of oocyte and embryo quality in women with endometriosis.
The study aimed to investigate key intrafollicular prognostic factors among various cytokines and angiogenic molecules for prediction of mature oocytes and good-quality embryos in women with endometriosis undergoing in vitro fertilization (IVF).
Paired follicular fluid and serum samples were collected from 200 women with advanced stage endometriosis and 140 normal ovulating women during oocyte retrieval. The concentrations of cytokines (pro-inflammatory: IL-1β, TNF-α, IL-2, IL-8, IL-12, IFN-γ; anti-inflammatory: IL-4, IL-6, IL-10) and angiogenic molecules (vascular endothelial growth factor (VEGF), adrenomedullin, angiogenin) were determined in follicular fluid and serum using ELISA. Expression of these molecules was subjected to multivariate analysis for the identification of major predictive markers of oocyte and embryo quality. Receiver operating characteristic (ROC) curve was applied to determine the best cutoff point for the discrimination between mature and immature oocytes in these women.
Significant increases in levels of cytokines and angiogenic molecules were observed in women with endometriosis compared to controls (P < 0.001). From the validated partial least squares-discriminant analysis (PLS-DA) model, IL-8, IL-12, and adrenomedullin were identified as the most important factors contributing to endometriosis and were negatively associated with oocyte maturity and embryo quality.
The levels of IL-8, IL-12, and adrenomedullin may be good indicators of embryo and oocyte quality in endometriosis patients undergoing IVF. Further studies are necessary to ascertain the potential of these markers for oocyte and embryo developmental competence which may help improve the chances of a successful IVF in endometriosis patients.
Reprod Domest Anim. 2016 Oct;51(5):751-7.
Distribution of inflammation and association between active and chronic alterations within the endometrium of dairy cows.
Objectives of this study were twofold: (i) to assess the association between polymorphonuclear (PMN) counts and chronic alterations within the bovine endometrium and (ii) to determine the distribution of inflammation throughout the endometrium of clinically healthy dairy cows. Holstein-Friesian cows (n = 32) from a single dairy farm were selected for this experiment. Before slaughtering, a complete reproductive examination was performed to discard any type of clinical disease. After slaughtering, reproductive tracts were collected, and the endometrium was sampled at 8 pre-defined locations. At each location, endometrial biopsies (EBs) and cytology (CY) samples were harvested. Histopathology samples were stained with haematoxylin-eosin (EB-HE) and naphthol-AS-D-chloroacetate-esterase (EB-naphthol), while CY samples were stained with Wright-Giemsa. In the EB-HE samples, parameters assessed were epithelium height, mononuclear cells infiltration, lymphocytic aggregates, periglandular fibrosis, angiosclerosis and haemorrhage. In EB-naphthol and CY slides, PMNs counts were evaluated. Binomial logistic regression was used to assess the association between the number of PMNs present in both the EB-naphthol and CY samples and alterations identified in the EB-HE samples and to analyse the distribution of the histopathological alterations (EB-HE). A Poisson mixed-effect model was used to analyse the distribution of PMNs within the endometrium. A significant positive association was found between the PMN counts and the mononuclear cells infiltration. The presence of erythrocytes was associated with higher odds to detect PMNs in the stratum compactum. Significantly, higher infiltration of PMNs and mononuclear cells were detected in the uterine body and the right horn region. Concluding, CY is a technique that allows the evaluation of PMN counts and therefore only evaluates active inflammation. A complete assessment of endometrial health can only be obtained using EB. To optimize the sensitivity to diagnose endometrial inflammation in cows, adjacencies of the corpus uteri should be considered as the preferred region to harvest samples.
JSLS. 2016 Jul-Sep;20(3)
Robotic Trachelectomy After Supracervical Hysterectomy for Benign Gynecologic Disease.
BACKGROUND AND OBJECTIVES:
A renewed interest in the supra cervical approach to hysterectomy has created a cohort of patients with a retained cervix at risk of persistent symptoms requiring a subsequent trachelectomy. The objective of this study was to evaluate the efficacy of robotic trachelectomy after a previous supracervical hysterectomy.
This is a retrospective chart review of women who had robotic trachelectomy after supracervical hysterectomy for benign gynecologic disease from January 2009 through October 2014.
Eleven patients underwent robotic trachelectomy for benign conditions during the observed period. Prior supracervical hysterectomy had been performed for pelvic pain (8/11, 73%), abnormal uterine bleeding (7/11, 64%), and dysmenorrhea (5/11, 45%). In 10 of 11 patients, the symptoms leading to robotic trachelectomy were the same as those leading to supracervical hysterectomy. The time from hysterectomy to recurrence of symptoms ranged from 0.5 to 26 months (median, 6), whereas the time interval from previous surgery to robotic trachelectomy ranged from 1 to 57 months (median, 26). Mean age and body mass index at robotic trachelectomy were 42 ± 5.4 years and 32 ± 6.1 kg/m(2). Mean length of surgery was 218 ± 88 minutes (range, 100-405). There was 1 major postoperative complication involving bladder perforation and subsequent vesicovaginal fistula (VVF). Endometriosis was seen in 27% of pathologic specimens and cervicitis in another 27%; 45% showed normal tissue histology. In 6 (55%) cases, symptoms leading to trachelectomy resolved completely after surgery, and the other 5 (45%) patients reported a significant improvement.
Although trachelectomy can be a challenging surgery, our experience suggests that the robotic approach may be a valuable means of achieving safe and reproducible outcomes.
Med J Islam Repub Iran. 2016 May 17;30:371.
Outcomes of assisted reproduction treatment after dopamine agonist -cabergoline- for prevention of ovarian hyper stimulation syndrome.
Release of vascular endothelial growth factor (VEGF) by ovaries in response to HCG administration is one of the main mechanisms of ovarian hyper stimulation syndrome. Since Dopamine/dopamine receptor2 (Dp-r2) pathway activity -mediated by VEGF/ Vascular endothelial growth factor receptor 2 (VEGFR- 2) signaling-, is associated with angiogenic events, dopamine agonists were used for the management of severe forms of OHSS. In order to assess the effects of Cabergoline on angiogenesis in the human endometrium, and subsequently its impacts on the implantation rate this study was conducted.
This historical cohort study was conducted based on existing data of 115 patients (20-40 years) whom underwent assisted reproductive treatment (ART) and with a high probability for developing OHSS between March 2007 and September 2008. Forty five cases received Cabergoline were compared to 70 control subjects. The statistical methods used were: Unpaired t-test for continuous variables and the chi-square test (or Fisher’s exact test if required) for categorical variables.
None of the patients (treatment or control group) developed OHSS. The etiologies of infertility and administration of GnRH agonist or antagonist protocols were similar in two groups (p>0.2). Number of transferred embryos and zygote intra-fallopian transfer (ZIFT) did not differ between the two groups (p≥0.06). Implantation rate in treatment (3.1%) and control (6.6%) subjects was similar (p=0.4). No significant difference was observed in fertilization rate, chemical, clinical and ongoing pregnancies between the two groups (p>0.5).
Cabergoline can be safely administered in ART protocols to prevent OHSS, without compromising ART outcomes.
Visc Med. 2016 Jun;32(3):211-3.
Intussusception of the Appendix and Ileum Endometriosis: A Case Report.
Intussusception of the appendix is a very rare condition. It may clinically mimic acute or chronic abdominal diseases or can be asymptomatic.
This paper describes our experience with intussusception of the appendix. We report a case of a female with appendiceal intussusception and ileum endometriosis.
It is important to know about such a rare condition in order to avoid mistaking it with other abdominal diseases. However, diagnosis is rarely made preoperatively.
BMJ Case Rep. 2016 Aug 5;2016.
Transanal endoscopic microsurgery in the management of rectal wall endometriosis.
A 29-year-old woman with known history of endometriosis was referred to colorectal outpatient clinic from gynaecology with a history of intermittent rectal bleeding and no associated bowel symptoms. Flexible sigmoidoscopy in concordance with pelvic MRI revealed a 3×2×2 cm sessile lesion in the anterior rectal wall. The lesion was also palpable as a firm mass on digital rectal examination. From the gynaecological point of view no intra-abdominal exploration was required; the sole rectal wall lesion was removed with the minimally invasive surgical technique of transanal endoscopic microsurgery. Full thickness rectal wall excision sample was reported to be histologically complete and confirmed endometriosis. No recurrence was detected at endoscopic follow-up at 6 months. The patient remained symptom free. Therefore, we demonstrated a case of minimally invasive removal of a rectal wall large endometriosis nodule in a fertile woman with a complete, symptomatic, uneventful recovery.
Med J Malaysia. 2016 Jun;71(3):144-6.
Polypoid endometriosis of post vaginal fornix: utility of MRI imaging of pelvis with diffusion weighted imaging for diagnosis.
Polypoid endometriosis is an uncommon variant of endometriosis which can mimic malignancy due to its presentation as masses. We present a case of polypoid endometriosis which simulated cervical malignancy both on clinical examination and on computed tomography (CT) scanning and discuss how magnetic resonance (MR) imaging, in particular Diffusion Weighted Imaging (DWI), can help to distinguish this condition from true malignancy and avoid invasive surgery.
Am J Obstet Gynecol. 2017 Jan;216(1):40.e1-40
First evidence of a menstruating rodent: the spiny mouse (Acomys cahirinus).
Advances in research relating to menstruation and associated disorders (eg, endometriosis and premenstrual syndrome) have been hindered by the lack of an appropriate animal model. Menstruation, the cyclical shedding of the decidualized endometrium in the absence of pregnancy, is believed to be limited to 78 higher-order primates (human beings and Old World monkeys), 4 species of bat, and the elephant shrew. This represents only 1.5% of the known 5502 mammalian species and <0.09% of these are nonprimates. Thus, many aspects of menstruation remain poorly understood, limiting the development of effective treatments for women with menstrual disorders. Menstruation occurs as a consequence of progesterone priming of the endometrial stroma and a spontaneous decidual reaction. At the end of each infertile cycle as progesterone levels decline the uterus is unable to maintain this terminally differentiated stroma and the superficial endometrium is shed. True menstruation has never been reported in rodents.
Here we describe the first observation of menstruation in a rodent, the spiny mouse (Acomys cahirinus).
Virgin female spiny mice (n = 14) aged 12-16 weeks were sampled through daily vaginal lavage for 2 complete reproductive cycles. Stage-specific collection of reproductive tissue and plasma was used for histology, prolactin immunohistochemistry, and enzyme-linked immunosorbent assay of progesterone (n = 4-5/stage of the menstrual cycle). Normally distributed data are reported as the mean ± SE and significant differences calculated using a 1-way analysis of variance. Nonnormal data are displayed as the median values of replicates (with interquartile range) and significant differences calculated using Kruskal-Wallis test.
Mean menstrual cycle length was 8.7 ± 0.4 days with red blood cells observed in the lavages over 3.0 ± 0.2 days. Cyclic endometrial shedding and blood in the vaginal canal concluding with each infertile cycle was confirmed in all virgin females. The endometrium was thickest during the luteal phase at 322.6 μm (254.8, 512.2), when plasma progesterone peaked at 102.1 ng/mL (70.1, 198.6) and the optical density for prolactin immunoreactivity was strongest (0.071 ± 0.01 arbitrary units).
The spiny mouse undergoes spontaneous decidualization, demonstrating for the first time menstruation in a rodent. The spiny mouse provides a readily accessible nonprimate model to study the mechanisms of menstrual shedding and repair, and may therefore be useful in furthering studies of human menstrual and pregnancy-associated disorders.
Eur J Obstet Gynecol Reprod Biol. 2017 Feb;209:61-66.
Hormonal therapy for endometriosis: from molecular research to bedside.
Endometriotic lesions are associated with hormonal imbalance, including increased estrogen synthesis, metabolism and progesterone resistance. These hormonal changes cause increased proliferation, inflammation, pain and infertility. Hormonal imbalances are targets for treatment. Therapeutic strategies and innovations of hormonal drugs for endometriosis are increasing. Acting on estrogen receptors are hormonal drugs decreasing systemic and local estrogen synthesis (GnRH analogs, GnRH antagonists, Aromatase inhibitors) or estrogen activity (selective estrogen receptor modulators). The progesterone resistance is counteracted by progestins (Medroxyprogesterone acetate, Dienogest, Danazol, Levonorgestrel) or by Selective progesterone receptor modulators, a class of drugs under development. The future trend will be to define new drugs to use for prolonged period of time and with poor side effects considering endometriosis a chronic disease.
Reprod Sci. 2017 Mar;24(3):400-406.
Pooling-Based Genome-Wide Association Study Identifies Risk Loci in the Pathogenesis of Ovarian Endometrioma in Chinese Han Women.
Endometriosis, regarded as a complex disease, is influenced by multiple genetic factors. Recent genome-wide association studies (GWASs) in endometriosis have identified several susceptibility loci in Caucasian and Japanese populations. However, the overlapped susceptible loci were few. This case-control study tried to identify risk loci-related genes for ovarian endometrioma in Chinese Han women from central China using DNA pooling-based GWAS. Genome DNA samples were extracted from 3038 participants in central China. Pooling-based genome-wide scan and individual genotyping were performed using Affymetrix Genome-Wide Human SNP Array 6.0 and IPLEX Gold system, which demonstrated 10 ovarian endometrioma-related novel risk loci. There were 3 of them with P value < 5 × 10-06, separately locating in intron of insulin-like growth factor 1 receptor, chromosome 7 open reading frame 50, and Meis homeobox 1. In conclusion, the pooling-based GWAS for ovarian endometrioma identified some novel single-nucleotide polymorphisms in Chinese Han women of central China. Further assessment in other samples will be crucial to confirm the susceptibility of these results and explore the mechanisms of the related genes in the pathogenesis of ovarian endometrioma.
Ann Thorac Cardiovasc Surg. 2017 Apr 20;23(2):108-112.
Left-Sided Catamenial Pneumothorax with Thoracic Endometriosis and Bullae in the Alveolar Wall.
Catamenial pneumothorax (CP) is generally caused by intraperitoneal air leaking from the uterus into the thoracic cavity via a defect in the endometrial tissue of the diaphragm and is usually detected in the right thorax. We report a case of left-sided CP caused by endometriosis in the visceral pleura and with no abnormal findings in the diaphragm. A 33-year-old female patient presented at the end of a course of low-dose contraceptive pills for pelvic endometriosis, with spontaneous pneumothorax in the left chest. Chest CT revealed a bulla in the left upper lung lobe. The patient underwent partial resection of the lung. Immunohistochemistry confirmed the presence of endometrial stromal tissue in the visceral pleura and confirmed this as the cause of pneumothorax since there were no observable abnormalities in the diaphragm. This case suggests that immunohistochemical examination of patients with spontaneous pneumothorax can detect alternative endometrial lesions.
Akush Ginekol (Sofiia). 2016;55 Suppl 1 Pt 2:5-10.
ENDOMETRIOSIS FERTILITY INDEX.
In women suffering from endometriosis and infertility, the decision as to when and how to perform surgical excision and/or fertility treatment is mainly based on clinical guidelines and expert opinions. However, so far data from randomized controlled trials or meta-analyses to answer the question whether surgical treatment of moderate to severe endometriosis can indeed enhance pregnancy rates compared with expectant management are lacking, as not all studies report fertility outcome or supply sufficiently detailed information. The most frequently used staging system for endometriosis is the revised American Fertility Society (rAFS) score (ASRM, 1997). Unfortunately, this classification system has some serious limitations, including not effectively predicting clinical outcomes of treatment, especially pregnancy rates in infertile patients. For this reason, Adamson and Pasta (2010) developed the endometriosis fertility index (EFI). EFI is a scoring system which includes assessment of historical factors at the time of surgery (age, duration of infertility and pregnancy history), of adnexal function at conclusion of surgery (functional score of Fallopian tubes, fimbriae and ovaries bilaterally), and of the extensiveness of endometriosis (rAFS endometriosis lesion score and total rAFS score). The EFI is intended as a clinical tool to counsel patients on the approach towards fertility after surgery.
Semin Reprod Med. 2016 Jul;34(4):242-54
Beyond Endometriosis Genome-Wide Association Study: From Genomics to Phenomics to the Patient.
Endometriosis is a heritable, complex chronic inflammatory disease, for which much of the causal pathogenic mechanism remains unknown. Genome-wide association studies (GWAS) to date have identified 12 single nucleotide polymorphisms at 10 independent genetic loci associated with endometriosis. Most of these were more strongly associated with revised American Fertility Society stage III/IV, rather than stage I/II. The loci are almost all located in intergenic regions that are known to play a role in the regulation of expression of target genes yet to be identified. To identify the target genes and pathways perturbed by the implicated variants, studies are required involving functional genomic annotation of the surrounding chromosomal regions, in terms of transcription factor binding, epigenetic modification (e.g., DNA methylation and histone modification) sites, as well as their correlation with RNA transcription. These studies need to be conducted in tissue types relevant to endometriosis-in particular, endometrium. In addition, to allow biologically and clinically relevant interpretation of molecular profiling data, they need to be combined and correlated with detailed, systematically collected phenotypic information (surgical and clinical). The WERF Endometriosis Phenome and Biobanking Harmonisation Project is a global standardization initiative that has produced consensus data and sample collection protocols for endometriosis research. These now pave the way for collaborative studies integrating phenomic with genomic data, to identify informative subtypes of endometriosis that will enhance understanding of the pathogenic mechanisms of the disease and discovery of novel, targeted treatments.
J Laparoendosc Adv Surg Tech A. 2016 Aug 11.
Laparoscopic Treatment of a Retroduodenopancreatic Endometriotic Cyst Observed Postpartum.
Endometriosis occurs in 5%-10% of fertile women, usually in the pelvic region, such as the ovaries, uterine ligaments, pelvic peritoneum, and rectovaginal septum. A mesenteric endometriotic cyst is an exceptional observation and difficult to diagnose preoperatively. We report a case of a large mesenteric endometriotic cyst treated by laparoscopy. A 21-year-old Caucasian woman was admitted as an emergency to our Academic Hospital on the 30th day postpartum for abdominal pain and a palpable epigastric mass. A CT scan revealed a mass measuring 7.5 × 5.5 cm showing a fluid content, located below the pancreas. A preoperative diagnosis of mesenteric cyst was made and confirmed by MRI. A dissection of the mass from the inferior vena cava, pancreas, and duodenum was achieved by a laparoscopic approach. During the blunt dissection, avoiding any spillage, the cyst was aspirated to preserve a safe cleavage plane with the lower third of the duodenum showing tenacious adhesions to the mass. Histology revealed an endometriotic cyst of the mesenterium. To our knowledge, this is the first case reported in the literature of laparoscopic treatment of a retroduodenopancreatic endometriotic cyst observed postpartum. In dedicated centers, laparoscopic management could be the gold standard.
J Ovarian Res. 2016 Aug 11;9(1):48.
A case of ovarian adenosquamous carcinoma arising from endometrioid adenocarcinoma: a case report and systematic review.
The aims of this report were to describe a case of ovarian adenosquamous carcinoma and to systematically review the pertinent literature.
We describe a case in which a 57-year-old woman had stage IC ovarian cancer histologically diagnosed as adenosquamous carcinoma. We also systematically reviewed the literature using the PubMed database.
Preoperative computed tomography and magnetic resonance imaging showed a tumor measuring 14 cm in diameter and containing solid areas. Tumor marker levels were as follows: CA125, 42.6 U/mL; CA 19-9, 134.1 U/mL; CEA, 0.9 ng/mL; and SCC, 1.6 ng/mL. The patient underwent multiple surgeries including total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, para-aortic lymph node biopsy, and total omentectomy. Based on the cytological features of the ascitic fluid, the tumor was diagnosed as a squamous cell carcinoma. Histological examination of an excised specimen showed the transition of an endometrioid adenocarcinoma to a squamous cell carcinoma. There was no evidence of any teratomas or endometriosis-related features. We considered the tumor to be an adenosquamous carcinoma, with the squamous cell carcinoma component arising from the endometrioid adenocarcinoma component. After surgery, the patient underwent 6 cycles of paclitaxel and carboplatin chemotherapy. There has been no recurrence to date, 66 months after the initial treatment.
Histologically, the 8 adenosquamous carcinomas reported in the literature either arose from the mature cystic teratoma (4 cases) or endometriosis (3 cases) or were pure adenosquamous carcinomas (1 case). Our literature search uncovered no cases of ovarian adenosquamous carcinomas originating from endometrioid adenocarcinomas.
This is the first reported case of an adenosquamous carcinoma arising from an endometrioid adenocarcinoma. Because such tumors are rare, their standard management is unclear.
Mol Hum Reprod. 2016 Sep;22(9):655-68.
Decreased expression of NR4A nuclear receptors in adenomyosis impairs endometrial decidualization.
How do NR4A receptors drive decidualization of human endometrial stromal cells (hESCs)?
NR4A receptors modulate endometrial decidualization by transcriptional activation of FOXO1A, and in adenomyosis patients, the reduced expression of NR4A receptors in the eutopic endometrium may represent a novel mechanism to explain impaired decidualization and subfertility.
WHAT IS KNOWN ALREADY:
A close relationship between impaired decidualization and subfertility has been established. In human endometrial stromal cells, orphan nuclear receptor NR4A is a novel regulator of decidualization.
STUDY DESIGN, SAMPLES/MATERIALS, METHODS:
Eutopic endometrial tissues and hESCs from fertile controls (n = 56) and adenomyosis patients (n = 27) were collected for in vitro analysis. Primary hESCs isolated from eutopic endometrial tissues were used to evaluate the biological function of NR4A receptors. Adenovirus-mediated overexpression of NR4A and small interfering RNAs targeting NR4A, and FOXO1A were used to investigate the molecular mechanisms. Gene expression regulation was examined by real-time-quantitative PCR, immunostaining, and luciferase reporter assay. Artificial decidualization assay was performed to investigate the role of NR4A1 during decidualization in vivo.
MAIN RESULTS AND THE ROLE OF CHANCE:
NR4A modulates the decidualization of hESCs by upregulating prolactin (PRL) and insulin-like growth factor binding protein-1 (IGFBP-1) expression and transformation in vitro. Loss of uterine Nr4a1 results in female subfertility due to impaired decidualization. Mechanistically, NR4A binds to the nerve growth factor 1B (NGFI-B) -responsive element (NBRE) (-843 to -813) within the FOXO1A promoter region and regulates FOXO1A expression. Loss of FOXO1A significantly inhibits PRL and IGFBP-1 expression, as induced by NR4A. Moreover, the expression of NR4A and FOXO1A was lower in adenomyosis endometrial tissues compared to fertile controls, especially in stroma compartments. Ectopic NR4A expression rescued PRL and IGFBP-1 expression in adenomyotic hESCs to near-normal levels. Furthermore, PI3K/AKT signaling pathway involved in inducing NR4A expression under decidualization stimuli in hESCs and the level of p(Ser473)-AKT was significantly higher in stroma in endometrium from patients with adenomyosis.
LIMITATIONS, REASONS FOR CAUTION:
This is an in vitro study with a small sample size, utilizing stromal cell cultures from endometrial tissues of adenomyosis patients. Furthermore, results obtained should also be confirmed in a larger data set and with adenomyosis mouse models in vivo.
WIDER IMPLICATIONS OF THE FINDINGS:
Identification of a positive agonist of NR4A receptors will be critical for the improved treatment of patients with conditions of insufficient decidualization-associated infertility, such as adenomyosis and endometriosis.
Am J Reprod Immunol. 2016 Oct;76(4):292-8
Progestin suppressed inflammation and cell viability of tumor necrosis factor-α-stimulated endometriotic stromal cells.
Endometriosis is an estrogen-dependent inflammatory disease. Progestins are a first-line treatment for endometriosis via activation of pituitary progesterone receptors and suppression of systemic estrogen: a less than optimal treatment. Increasing evidence is beginning to show that progestins may also influence local endometriotic cells, which may contribute to their clinical efficacy.
METHOD OF STUDY:
Endometrial stromal cells (ESC) isolated from women with endometriosis were cultured with TNF-α to simulate an inflammatory environment. ESC were treated with the progestins, medroxyprogesterone acetate (MPA), norethisterone acetate (NETA), or dienogest (DNG) and cytokine mRNA production, protein secretion, and cell viability measured.
DNG, NETA, and MPA suppressed the secretion of interleukin (IL)-6, IL-8, and monocyte chemotactic protein (MCP)-1 from ESC. DNG and NETA only reduced the TNF-α-stimulated mRNA production. All three progestins suppressed TNF-α-stimulated ESC proliferation.
Progestins may influence endometriotic stromal cells altering the inflammatory microenvironment and their clinical efficacy.
Microsc Microanal. 2016 Aug;22(4):878-86.
Synthetic Hormones and Clot Formation.
Combined oral contraceptives (COCs), colloquially referred to as “the pill,” have been regarded as a medical breakthrough, as they have improved the lives of countless women, from simplifying family planning to the treatment of acne, endometriosis, polycystic ovarian syndrome, and dysmenorrhea. Unfortunately, COC usage has been associated with an increased occurrence of venous thrombosis and therefore a systemic hypercoagulable state in susceptible females. Here we discuss the health risks of COC usage and use viscoelastic and morphological techniques to investigate the effect of different COC constituents on clot formation, particularly fibrin network packaging and whole blood viscoelasticity. Viscoelastic properties of whole blood showed gender-specific changes while morphological alterations were person-specific, regardless of gender. Using scanning electron microscopy and thromboelastography provides great insight regarding fibrin packaging and the development of a hypercoagulable state in high-risk individuals. We proposed a three-step approach where (1) an individual’s coagulation profile baseline is determined, after which (2) the “ideal” combination of constituents is prescribed, and (3) the coagulation profile of the individual is monitored to assess possible risk of thrombosis. Only in following such an individualized patient-oriented approach will we be able to avoid the many health issues due to COC usage in susceptible females.
Kardiochir Torakochirurgia Pol. 2016 Jun;13(2):117-21.
Catamenial pneumothorax – a review of the literature.
Catamenial pneumothorax should be defined as recurrent accumulation of air in the pleural cavity in reproductive-age women without concomitant respiratory diseases. The sine qua non criterion is the occurrence of the pneumothorax in the period of 72 hours before or after the menses. Additional criteria include characteristic pleural lesions, right-sided occurrence, and coexistence of endometriosis. There are no radiological or pathological conditions allowing an exact confirmation of catamenial pneumothorax. In the case of catamenial pneumothorax, treatment failure most commonly consists in disease recurrence. It may occur even as late as several years after the initial treatment. The recurrence rate in patients undergoing surgery ranges from 8% to 40%. Finding and resecting the visible pleural lesions is of key importance during surgical treatment. Reconstruction of the diaphragm must be performed in every patient in whom diaphragmatic perforations are found. Hormonal therapy seems to be effective in sustaining the effects of surgical treatment.
Biomed Res Int. 2016;
Delivery after Operation for Deeply Infiltrating Endometriosis.
Background. It has been suggested that, during pregnancy, endometriosis can cause a variety of disease-related complications. Objectives. The purpose of the study was to find out if women with histologically confirmed endometriosis do have a higher risk of adverse pregnancy outcome and if they suffer from a higher rate of complications during labor. Study Design. 51 women who underwent surgery because of deeply infiltrating endometriosis in the General Hospital Linz and the Women’s General Hospital Linz and who gave birth in the Women’s General Hospital Linz after the surgery were included in our survey. Results. 31 women (60.8%) had a spontaneous delivery and in 20 women (39.2%) a caesarean section was performed. There were no cases of third- and fourth-degree perineal lacerations. Collectively there were 4 cases (7.8%) of preterm delivery and one case (2.0%) of premature rupture of membranes. In two women (6.5%) a retained placenta was diagnosed. Conclusions. Our study is the first description on delivery modes after surgery for deeply infiltrating endometriosis. We did not find an elevated risk for perineal or vaginal laceration in women with a history of surgery for deeply infiltrating endometriosis, even when a resection of the rectum or of the posterior vaginal wall had been performed.
Reprod Biol Endocrinol. 2016 Aug 12;14(1):43
Localization of TrkB and p75 receptors in peritoneal and deep infiltrating endometriosis: an immunohistochemical study.
The roles of the neurotrophins NGF (Neurotrophic growth factor) and BDNF (brain-derived neurotrophic factor) in neuronal growth and development are already known. Meanwhile, the neurotrophin receptors TrkA (tropomyosin related kinase A), TrkB, and p75 are important for determining the fate of cells. In endometriosis, this complex system has not been fully elucidated yet. The aim of this study was to evaluate the expression and location of these neurotrophins and their receptors in peritoneal (PE) and deep infiltrating endometriotic (DIE) tissues and to measure and compare the density of nerve fibers in the disease subtypes.
PE lesions (n = 20) and DIE lesions (n = 22) were immunostained and analyzed on serial slides with anti-BDNF, -NGF, -TrkA, -TrkB, -p75,-protein gene product 9.5 (PGP9.5, intact nerve fibers) and -tyrosine hydroxylase (TH, sympathetic nerve fibers) antibodies.
There was an equally high percentage (greater than 75 %) of BDNF-positive immunostaining cells in both PE and DIE. TrkB (major BDNF receptor) and p75 showed a higher percentage of immunostaining cells in DIE compared to in PE in stroma only (p < 0.014, p < 0.027, respectively). Both gland and stroma of DIE lesions had a lower percentage of NGF-positive immunostaining cells compared to those in PE lesions (p < 0.01 and p < 0.01, respectively), but there was no significant reduction in immunostaining of TrkA in DIE lesions. There was no difference in the mean density of nerve fibers stained with PGP9.5 between PE (26.27 ± 17.32) and DIE (28.19 ± 33.15, p = 0.8). When we performed sub-group analysis, the density of nerves was significantly higher in the bowel DIE (mean 57.33 ± 43.9) than in PE (mean 26.27 ± 17.32, p < 0.01) and non-bowel DIE (mean 14.6. ± 8.6 p < 0.002).
While the neurotrophin BDNF is equally present in PE and DIE, its receptors TrkB and p75 are more highly expressed in DIE and may have a potential role in the pathophysiology of DIE, especially in promotion of cell growth. BDNF has a stronger binding affinity than NGF to the p75 receptor, likely inducing sympathetic nerve axonal pruning in DIE, resulting in the lower nerve fiber density seen.
Reprod Biomed Online. 2016 Oct;33(4):484-499
Anti-platelet therapy is efficacious in treating endometriosis induced in mouse.
In light of recent findings showing that platelets play important roles in the development of endometriosis in general and in fibrogenesis in particular, this study investigated the efficacy of Ozagrel, a TXA2 synthase inhibitor, in a murine model of endometriosis. In addition, another mouse experiment was conducted to evaluate the effect of timing of platelet depletion and of sequential depletion of platelets and macrophages on the development of endometriosis. It was found that both the Ozagrel treatment and different platelet depletion schemes resulted in significant reduction in lesion growth (all P-values <0.01) along with improved hyperalgesia in mice with induced endometriosis. They also significantly reduced the expression of markers of proliferation, angiogenesis, inflammation and fibrosis as well as decreased macrophage infiltration in endometriotic lesions (all P-values <0.05). Compared with untreated mice, pre-emptive depletion of platelets as well as platelet depletion after induction resulted in significant reduction in lesion weight (both P-values <0.001), while sequential depletion of platelets and macrophages yielded similar reduction. These results, in conjunction with other roles that platelets play in the development of endometriosis, strongly argue for the potential of anti-platelet therapy in treating endometriosis.
Fertil Steril. 2016 Oct;106(5):1011-1017.
Oxidative stress in the pelvic cavity and its role in the pathogenesis of endometriosis.
Endometriosis is a disorder associated with a general inflammatory response in the peritoneal cavity. Oxidative stress is a potential factor involved in the pathophysiology of this disease, and reactive oxygen species (ROS) are implicated in this process. Indeed, in healthy individuals, ROS and antioxidants are in balance, but when balance is tipped toward an overabundance of ROS, oxidative stress occurs and can impact the entire reproductive lifespan of a woman. Reactive oxygen species are intermediaries produced by normal oxygen metabolism but are known to have deleterious effects. Excessive release of ROS induces cellular damage and alters cellular function by regulating protein activity and gene expression, leading to harmful effects. To protect themselves, cells have developed antioxidant systems to limit production of ROS, inactivate them, and repair cell damage. Understanding of the control of hemoglobin, heme, and iron-induced redox balance in endometriosis led us to propose a number of hypotheses to explain why oxidative stress is induced in case of pelvic endometriosis. Erythrocytes, apoptotic endometrial tissue, and cell debris transplanted into the peritoneal cavity by menstrual reflux and macrophages have all been cited as potential inducers of oxidative stress. Erythrocytes are likely to release pro-oxidant and proinflammatory factors, such as hemoglobin and its highly toxic by-products heme and iron, into the peritoneal environment. Iron and heme are essential to living cells, but unless appropriately chelated, free iron, and to a lesser extent heme, play a key role in the formation of deleterious ROS.