Gynecol Endocrinol. 2015 Oct;31(10):751-4.
Transient psychosis in women on clomiphene, bromocriptine, domperidone and related endocrine drugs.
There have been reports of transient psychosis in women medicated for gynecologic conditions.
The aim of this paper was to explore this literature.
The PubMed and Google Scholar databases were searched for relevant case reports Results: The following reports were found: psychosis induced by gonadotropin-releasing hormone in the treatment of endometriosis, by clomiphene treatment for infertility, by bromocriptine treatment for milk suppression and by the withdrawal of domperidone prescribed as a galactologue as well as by the withdrawal of estrogen replacement therapy.
In susceptible women, psychotic symptoms can result from treatments that reduce estrogen levels, such as leuprolide acetate or clomiphene, or treatments that increase dopamine levels (bromocriptine). Psychosis can also be caused indirectly when estrogen treatment is discontinued or dopamine antagonism (e.g. domperidone) withdrawn. Estrogen-reducing and dopamine-increasing treatments used in gynecology need to be carefully monitored.
J Steroid Biochem Mol Biol. 2015 Sep;153:144-50.
Reprint of “Steroid receptor coactivators as therapeutic targets in the female reproductive system”.
The steroid receptor coactivators (SRCs/p160/NCOA) are a family of three transcriptional coregulators initially discovered to transactivate the transcriptional potency of steroid hormone receptors. Even though SRCs were also found to modulate the activity of multiple other transcription factors, their function is still strongly associated with regulation of steroid hormone action and many studies have found that they are critical for the regulation of reproductive biology. In the case of the female reproductive tract, SRCs have been found to play crucial roles in its physiology, ranging from ovulation, implantation, to parturition. Not surprisingly, SRCs’ action has been linked to numerous abnormalities and debilitating disorders of female reproductive tissues, including infertility, cancer, and endometriosis. Many of these pathologies are still in critical need of therapeutic intervention and “proof-of-principle” studies have found that SRCs are excellent targets in pathological states. Therefore, small molecule modulators of SRCs’ activity could be applied in the future in the treatment of many diseases of the female reproductive system.
Clin Anat. 2015 Nov;28(8):1029-38.
Neural involvement in endometriosis: Review of anatomic distribution and mechanisms.
Endometriosis (EM) is an infrequent cause of peripheral neuropathy, most commonly sciatic. Perineural spread has recently been introduced as an alternate explanation for cases of lumbosacral or sciatic nerve EM. We performed a literature review to collect all reported cases of peripheral and central nervous system EM in search of anatomic patterns of involvement; potentially to support the perineural spread theory. If available, intraneural invasion and presence of peritoneal EM were recorded. The search revealed 83 articles describing 365 cases of somatic peripheral nervous EM and 13 cases of central nervous EM. The most frequently involved site was the sacral plexus (57%, n = 211), followed by the sciatic nerve (39%, n = 140). Other nerves were reported in significantly smaller numbers. Ninety seven percent (97%, n = 355) of peripheral nerve cases presented with pain, 20% (n = 72) reported weakness and 31% (n = 114), numbness. Thirty four percent (34%, n = 38) had solely intraneural EM of which 89% (n = 33) had no peritoneal EM (percentage based on available information). In the central nervous system, the conus medullaris and/or cauda equina constituted the majority of cases with 54% (n = 7). Apart from perineural spread, other discussed mechanisms include retrograde menstruation with peritoneal seeding, hematogenous and lymphogenous spread, stem cell implantation either hematogenously or via retrograde menstruation with subsequent EM differentiation, and coelomic or Müllerian duct metaplasia. We believe this literature review supports perineural spread as an alternate mechanism for EM of nerve, particularly the subgroup with intraneural EM and without peritoneal disease.
Semin Ultrasound CT MR. 2015 Aug;36(4):385-93
Pelvic Endometriosis: Spectrum of Magnetic Resonance Imaging Findings.
Endometriosis is defined as the presence of endometrial tissue outside the uterus. It is a common cause of pelvic pain and infertility among reproductive age women. Although laparoscopy remains the reference standard for diagnosis, this invasive procedure provides little information on subperitoneal extent of disease or areas hidden by adhesions. In contrast, magnetic resonance imaging (MRI) provides a comprehensive, noninvasive survey of the pelvis with simultaneous tissue characterization. In this article, we review the spectrum of MRI findings in pelvic endometriosis and discuss common complications associated with the disease. Radiologists should be familiar with the spectrum of MRI findings of pelvic endometriosis so that they can provide meaningful information that will guide treatment and future laparoscopic examinations.
Laparoscopy in ART?.
The use of laparoscopy in infertility is currently controversial. However, laparoscopic treatment of tubal and peritoneal disease, or endometriosis improves natural fecundity and ART results. The use of laparoscopy in unexplained infertility can be considered because of underestimated pelvic pathology. The result of laparoscopy may help the practitioner for choosing spontaneous pregnancy or ART postoperative management. Although there is a lack of randomized study, laparoscopy is useful for a high overall pregnancy rate (surgery and ART treatment). Rather than opposing ART and laparoscopy, the integrated approach seems better for personal management.
Gynecol Obstet Fertil. 2015 Sep;43(9):604-11
Evaluation of the potential therapeutic effects of a double-stranded RNA mimic complexed with polycations in an experimental mouse model of endometriosis.
To assess the therapeutic potential of polyinosine-polycytidylic acid, a double-stranded RNA molecule with selective proapoptotic and antiangiogenic activity, complexed with polyethyleneimine (pIC(PEI)) in treating endometriosis.
A heterologous mouse model of endometriosis was created by injecting human endometrial fragments into the peritoneum. Endometrial fragments were engineered to express the fluorescent protein mCherry as a reporter to monitor status over the course of the 4-week study.
University-affiliated infertility center.
Ovariectomized and hormone-replaced nude mice (n = 30) injected with fluorescent-labeled human endometrial fragments at 4-6 weeks of age.
Animals (n = 10 per group) were injected with vehicle (control), the anti-VEGF compound CBO-P11 (0.6 mg/kg), or pIC(PEI) (0.6 mg/kg) twice weekly over the course of 4 weeks.
MAIN OUTCOME MEASURE(S):
Variations in the size of endometriotic implants were estimated by quantifying the expression of mCherry throughout the course of the experiment. Neovascularization, cellular proliferation, and apoptosis were estimated by quantitative immunofluorescence detection of PECAM, α-SMA, Ki67, and TUNEL.
pIC(PEI) promoted a significant increase in apoptosis and a decrease in neovascularization in human fragments, but did not reduce the size of endometriotic implants.
While pIC(PEI) treatment had significant antiangiogenic and pro-apoptotic effects in this setting, longer periods of exposure than the ones supported by our heterologous model and/or assays in homologous mouse models of endometriosis may be necessary to detect an effect of this compound on lesion size.
Fertil Steril. 2015 Nov;104(5):1202-9.
Nuclear magnetic resonancemetabolomic profiling of urine provides a noninvasive alternative to the identification of biomarkers associated with endometriosis.
To investigate whether urine metabolomic profile can be used to identify biomarkers associated to endometriosis.
Prospective study. For each subject, a urine sample was collected after overnight fasting and before surgery.
University medical center.
The clinical cohort included 45 endometriosis patients, diagnosed at early (n = 6) and advanced (n = 39) stages of the disease, and 36 healthy women. All women underwent diagnostic laparoscopy to visually confirm the presence or absence of endometriotic lesions.
Metabolomic profiling of urine samples based on (1)H-nuclear magnetic resonance (NMR) spectroscopy in combination with statistical approaches.
MAIN OUTCOME MEASURE(S):
Comparative identification of metabolites present in urine from endometriosispatients and healthy women.
The urine metabolomic profile of endometriosis patients exhibited higher concentrations of N(1)-methyl-4-pyridone-5-carboxamide, guanidinosuccinate, creatinine, taurine, valine, and 2-hydroxyisovalerate and decreased concentrations of lysine compared with healthy women. Most of these metabolites are involved in inflammation and oxidative stress processes. These pathophysiologic events had been previously described to be present in ectopic endometrial proliferation foci.
Overall, the results demonstrate the potential of (1)H-NMR-based metabolomics, a rapid and noninvasive approach, to identify metabolic changes associated to endometriosis in urine samples. This information could be useful to get a better understanding of the pathogenesis of endometriosis, thus providing support to the noninvasive diagnosis of this pathology.
Fertil Steril. 2015 Nov;104(5):1145-52.e1-5.
Gonadotropin dose is negatively correlated with live birth rate: analysis of more than 650,000 assisted reproductive technology cycles.
To evaluate the correlation between total gonadotropin dose and live birth rate.
A total of 658,519 fresh autologous cycles of in vitro fertilization (IVF) reported to the Society for Assisted Reproductive Technology from 2004 to 2012.
MAIN OUTCOME MEASURE(S):
Logistic regression models were fitted to live birth rates with the use of categorized values for total FSH dose and number of oocytes retrieved as the primary predictor variables. To reduce the effect of the most significant confounders that may lead physicians to prescribe higher doses of FSH, additional analyses were performed limited to good-prognosis patients (<35 years of age, body mass index <30 kg/m(2), and no diagnosis of diminished ovarian reserve, endometriosis, or ovulatory disorder) and including duration of gonadotropin treatment.
Live birth rate significantly decreased with increasing FSH dose, regardless of the number of oocytes retrieved. The statistically significant decrease in live birth rate with increasing FSH dose remained in patients with good prognosis, and regardless of female age, except for women aged ≥ 35 years with 1-5 oocytes retrieved.
This analysis suggests that physicians may wish to avoid prescribing a high dose of FSH. However, the results of this study do not justify the use of minimal-stimulation or natural-cycle IVF.
Maturitas. 2015 Nov;82(3):282-3.
Uterine stem cells–promise and possibilities.
A fraction of cells residing in the uterine endometrium exhibit functional pluripotent potential, allowing them to be classified as adult stem cells. While the physiological relevance of this cell population is mostly conjectural at this juncture, uterine endometrial stem cells (UESC’s) may underline pathogenesis of certain common gynecological disorders, such as endometriosis and adenomyosis. The ease of access and harvesting of UESC’s and the diverse differentiation potential of this cell population has identified the uterine endometrium as a valuable source of autologous stem cells that can be harnessed through judicious application of principals of regenerative medicine. This mini review offers a glimpse into the journey, and an introduction to the spectrum of disorders that UESC’s have the potential of impacting.
Ann N Y Acad Sci. 2015 Sep;1350:52-60
Estrogen receptor-β in mitochondria: implications for mitochondrial bioenergetics and tumorigenesis.
Estrogen enhances mitochondrial function by enhancing mitochondrial biogenesis and sustaining mitochondrial energy-transducing capacity. Shifts in mitochondrial bioenergetic pathways from oxidative phosphorylation to glycolysis have been hypothesized to be involved in estrogen-induced tumorigenesis. Studies have shown that mitochondria are an important target of estrogen. Estrogen receptor-β (ERβ) has been shown to localize to mitochondria in a ligand-dependent or -independent manner and can affect mitochondrial bioenergetics and anti-apoptotic signaling. However, the functional role of mitochondrial ERβ in tumorigenesis remains unclear. Clinical studies of ERβ-related tumorigenesis have shown that ERβ stimulates mitochondrial metabolism to meet the high energy demands of processes such as cell proliferation, cell survival, and transformation. Thus, in elucidating the precise role of mitochondrial ERβ in cell transformation and tumorigenesis, it will be particularly valuable to explore new approaches for the development of medical treatments targeting mitochondrial ERβ-mediated mitochondrial function and preventing apoptosis.
Asian J Endosc Surg. 2015 Aug;8(3):337-9
Appendiceal submucosal mass as presentation of intestinal endometriosis.
Submucosal lesions are mass-like protuberances into the gastrointestinal lumen covered by normal mucosa. Making a definitive diagnosis is difficult because of the number of benign and malignant lesions and extrinsic compression. Here we report the case of a 42-year-old woman referred for colon polypectomy. Colonoscopy revealed a polypoid formation with externalization from the appendicular orifice covered by normal mucosa and another formation at the sigmoid colon. The histopathology of both lesions was normal. Endoscopic ultrasound showed a hypoechoic lesion that was slightly heterogeneous in the fourth layer, and CT colonography confirmed the findings. Surgical therapy with ileocolic resection and resection of the sigmoid lesion was performed. Surgical specimens revealed an appendicular intussusception by endometriosis and endometrial foci in the sigmoid. Intestinal endometriosis may have several presentations, but it should always be considered in the differential diagnosis of a submucosal lesion in the colon.
Endocrinology. 2015 Nov;156(11):4214-25
The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle.
Women’s health disorders such as uterine fibroids and endometriosis are currently treated by GnRH modulators that effectively suppress the hypothalamic-pituitary-gonadal axis. The neurokinin-3 receptor (NK3R) is an alternative target with an important role in the modulation of this axis. In this report, we demonstrate that systemic administration of an NK3R antagonist (ESN364) prolongs the LH interpulse interval in ovarectomized ewes and significantly lowers plasma LH and FSH concentrations in castrated nonhuman primates (Macaca fascicularis). Moreover, daily oral dosing of ESN364 throughout the menstrual cycle in M fascicularis lowered plasma estradiol levels in a dose-dependent manner, although nadir levels of estradiol were maintained well above menopausal levels. Nevertheless, estradiol levels during the follicular phase were sufficiently inhibited at all doses to preclude the triggering of ovulation as evidenced by the absence of the LH surge and failure of a subsequent luteal phase rise in plasma progesterone concentrations, consistent with the absence of normal cycle changes in the uterus. Apart from the point at surge, FSH levels were not altered over the course of the menstrual cycle. These effects of ESN364 were reversible upon cessation of drug treatment. Together these data support the proposed role of neurokinin B-NK3R signaling in the control of pulsatile GnRH secretion. Furthermore, in contrast to GnRH antagonists, NK3R antagonists induce a partial suppression of estradiol and thereby offer a viable therapeutic approach to the treatment of ovarian sex hormone disorders with a mitigated risk of menopausal-like adverse events in response to long-term drug exposure.
Ned Tijdschr Geneeskd. 2015;159:
Impending caecal blowout due to endometriosis.
Endometrial tissue is present outside the uterine cavity in 6-10% of fertile women. Associated symptoms such as dysmenorrhoea, dyspareunia and abdominal discomfort are non-specific. For this reason, endometriosis is not always considered in women with abdominal symptoms. Endometriosis can also manifest itself as an acute surgical emergency such as an intestinal obstruction.
A 29-year-old woman was admitted to our hospital with acute lower abdominal pain and vomiting. On rectal examination a firm mass was palpable. CT scan of the abdomen showed the loops of colon to be extremely dilated. As a caecal blowout seemed imminent we carried out a laparotomy which revealed an obstruction of the rectum caused by severe endometriosis.
In fertile women presenting with signs of acute bowel obstruction, endometriosis should be included in the differential diagnosis and an early gynaecological consultation is indicated.
Respirology. 2015 Nov;20(8):1272-6.
Clinical characteristics of catamenial and non-catamenial thoracic endometriosis-related pneumothorax.
BACKGROUND AND OBJECTIVE:
A major pathogenic factor for catamenial pneumothorax is thoracic endometriosis. However, thoracic endometriosis-related pneumothorax (TERP) can develop as either catamenial or non-catamenial pneumothorax (CP). Therefore, the aim of this study was to elucidate the clinical differences between catamenial and non-catamenial TERP.
The clinical and pathological data in female patients who underwent video-assisted thoracoscopic surgery at the Pneumothorax Research Center during an 8-year period were retrospectively reviewed. This study included 150 female patients with surgico-pathologically confirmed TERP. The subjects were divided into two groups, those having all of the pneumothorax episodes in the catamenial period (CP group) and those who did not (non-CP group). We compared the clinical characteristics and surgico-pathological findings between these two groups.
Of the 150 TERP patients, 55 (36.7%) were classified in the CP group, and 95 (63.3%) in the non-CP group. In regard to the locations of endometriosis, all TERP patients had diaphragmatic endometriosis, while pleural implantation was recognized in 34 of the 55 (61.8%) patients in the CP group and 42 of the 95 (44.2%) patients in the non-CP group (P < 0.05).
A significant difference in the proportion of patients with pleural endometriosis was observed between catamenial and non-catamenial TERP. The ectopic sites of the endometriosis may be responsible for the timing of the pneumothorax episodes.
Hum Reprod. 2015 Oct;30(10):2292-302.
Peritoneal fluid modifies the microRNA expression profile in endometrial and endometriotic cells from women with endometriosis.
Could peritoneal fluid (PF) from patients with endometriosis alter the microRNA (miRNA) expression profile in endometrial and endometriotic cells from patients?
PF from patients with endometriosis modifies the miRNA expression profile in endometrial cells from patients.
WHAT IS KNOWN ALREADY:
Angiogenesis is a pivotal system in the development of endometriosis, and dysregulated miRNA expression in this disease has been reported. However, to our knowledge, the effect of PF from patients on the miRNA expression profile of patient endometrial cells has not been reported. Moreover, an effect of three miRNAs (miR-16-5p, miR-29c-3p and miR-424-5p) on the regulation of vascular endothelial growth factor (VEGF)-A mRNA translation in endometrial cells from patients with endometriosis has not been demonstrated.
STUDY DESIGN, SIZE, DURATION:
Primary cultures of stromal cells from endometrium from 8 control women (control cells) and 11 patients with endometriosis (eutopic cells) and ovarian endometriomas (ectopic cells) were treated with PF from control women (CPF) and patients (EPF) or not treated (0PF) in order to evaluate the effect of PF on miRNA expression in these cells.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
MiRNA expression arrays (Affymetrix platform) were prepared from cells (control, eutopic, ectopic) treated with CPF, EPF or 0PF. Results from arrays were validated by quantitative reverse transcription-polymerase chain reaction in cultures from 8 control endometrium, 11 eutopic endometrium and 11 ovarian endometriomas. Functional experiments were performed in primary cell cultures using mimics for miRNAs miR-16-5p, miR-29c-3p and miR-424-5p to assess their effect as VEGF-A expression regulators. To confirm a repressive action of miR-29c-3p through forming miRNA:VEGFA duplexes, we performed luciferase expression assays.
MAIN RESULTS AND THE ROLE OF CHANCE:
EPF modified the miRNA expression profile in eutopic cells. A total of 267 miRNAs were modified in response to EPF compared with 0PF in eutopic cells. Nine miRNAs (miR-16-5p, miR-21-5p, miR-29c-3p, miR-106b-5p, miR-130a-5p, miR-149-5p, miR-185-5p, miR-195-5p, miR-424-5p) that were differently expressed in response to EPF, and which were potential targets involved in angiogenesis, proteolysis or endometriosis, were validated in further experiments (control = 8, eutopic = 11, ectopic = 11). Except for miR-149-5p, all validated miRNAs showed significantly lower levels (miR-16-5p, miR-106b-5p, miR-130a-5p; miR-195-5p and miR-424-5p, P < 0.05; miR-21-5p, miR-29c-3p and miR-185-5p, P < 0.01) after EPF treatment in primary cell cultures from eutopic endometrium from patients in comparison with 0PF. Transfection of stromal cells with mimics of miRNAs miR-16-5p, miR-29c-3p and miR-424-5p showed a significant down-regulation of VEGF-A protein expression. However, VEGFA mRNA expression after mimic transfection was not significantly modified, indicating the miRNAs inhibited VEGF-A mRNA translation rather than degrading VEGFA mRNA. Luciferase experiments also corroborated VEGF-A as a target gene of miR-29c-3p.
LIMITATIONS, REASONS FOR CAUTION:
The study was performed in an in vitro model of endometriosis using stromal cells. This model is just a representation to try to elucidate the molecular mechanisms involved in the development of endometriosis. Further studies to identify the pathways involved in this miRNA expression modification in response to PF from patients are needed.
WIDER IMPLICATIONS OF THE FINDINGS:
This is the first study describing a modified miRNA expression profile in eutopic cells from patients in response to PF from patients. These promising results improve the body of knowledge on endometriosis pathogenesis and could open up new therapeutic strategies for the treatment of endometriosis through the use of miRNAs.
Reprod Toxicol. 2015 Dec;58:119-30
Strain-specific induction of endometrial periglandular fibrosis in mice exposed during adulthood to the endocrine disrupting chemical bisphenol A.
The aim of this study was to compare effects of bisphenol A (BPA) on collagen accumulation in uteri of two mouse strains. Adult C57Bl/6N and CD-1 mice were exposed to dietary BPA (0.004-40mg/kg/day) or 17α-ethinyl estradiol (0.00002-0.001mg/kg/day) as effect control. An equine endometrosis-like phenotype with increased gland nesting and periglandular collagen accumulation was characteristic of unexposed C57Bl/6N, but not CD-1, endometrium. BPA non-monotonically increased gland nest density and periglandular collagen accumulation in both strains. Increased collagen I and III expression, decreased matrix metalloproteinase 2 (MMP2) and MMP14 expression, and increased immune response were associated with the endometrosis phenotype in the C57Bl/6N strain and the 30ppm BPA CD-1 group. The association between the pro-collagen shift in increased collagen expression and decreased MMP2 expression and activity implies that strain differences and BPA exposure alter regulation of endometrial remodeling and contribute to increased fibrosis, a component of several human uterine diseases.
Lancet. 2015 Feb 26;385 Suppl 1:S92.
Role of a neurokinin B receptor antagonist in the regulation of ovarian function in healthy women.
Patients with loss-of-function mutation in neurokinin B (NKB) and its receptor show hypogonadotropic hypogonadism characterised by failure to progress through puberty, indicating the involvement of this newly described hypothalamic peptide in human reproduction. However the role of NKB in regulating ovarian function in adult women is unknown. We tested the hypothesis that a NKB antagonist would decrease gonadotropin secretion and inhibit folliculogenesis in healthy women.
Six healthy women with regular menstrual cycles were administered the NKB antagonist AZD4901 (AstraZeneca, London, UK) 40 mg orally twice daily for 5 days from cycle days 4-5. Transvaginal ultrasonography was performed at the end of drug administration, and serum gonadotropins and oestradiol measured. Cycle-day-matched results were compared with seven women who received no treatment (controls). The study received ethics committee approval, and all women gave written informed consent.
The diameter of the largest follicle was significantly smaller in women treated with NKB antagonist than in controls (mean 8·8 mm [SD 1·2] vs 11·9 [2·1], p=0·01). Serum oestradiol concentrations were also significantly reduced in the NKB antagonist group (mean 112·7 pmol/L [SD 56·0] vs 240·1 [73·6], p=0·005): in keeping with this finding endometrial thickness was also reduced (mean 3·5 mm [SD 0·5] vs 6·4 [3·2], p=0·05). Concentrations of luteinising hormone were not significantly altered after 5 days of NKB antagonist (mean pretreatment luteinising hormone 5·2 IU/L [SD 2·1] vs post-treatment 6·7 [3·8], p=0·2) or when compared with control women (6·0 [2·4], p=0·7). One woman had minimal vaginal bleeding; there were no adverse events.
We have shown for the first time, to our knowledge, that NKB antagonist is a potent suppressor of follicle development and oestradiol secretion in women. This effect is likely to be mediated by reduced secretion of gonadotropin-releasing hormone and our results support the involvement of NKB in the control of human reproduction: further analysis will explore in detail effects on secretion of follicle-stimulating hormone and luteinising hormone. Our findings have potential for translational application, for example in endometriosis and contraception.
Womens Health (Lond). 2015 Aug;11(5):587-95.
Stem cells in endometrium and endometriosis.
Endometriosis is a common chronic gynecological disease that is classically defined by the presence of endometrial stromal and glandular tissues outside the uterine cavity. Pelvic pain and infertility are the nonspecific but the most common symptoms of the disease; however, no currently definitive treatment has been developed since its pathogenesis has not been completely understood. Currently, none of the proposed conventional theories can explain all aspects of endometriosis. Recent evidence supports the presence of endometrial stem/progenitor cells and their possible involvement in endometrial regeneration and differentiation. The stem cell theory is a new hypothesis which may clarify the underlying pathophysiologic mechanisms of endometriosis. However, this theory could not only account for an alternative pathogenic mechanism of endometriosis but could also be involved in all conventional theories. This article will review the evidence for the presence of endometrial stem/progenitor cells, their possible sources and their possible involvement in the pathogenesis of endometriosis.
Womens Health (Lond). 2015 Aug;11(5):611-8.
The importance of pelvic nerve fibers in endometriosis.
Several lines of recent evidence suggest that pelvic innervation is altered in endometriosis-affected women, and there is a strong presumption that nerve fibers demonstrated in eutopic endometrium (of women with endometriosis) and in endometriotic lesions play roles in the generation of chronic pelvic pain. The recent observation of sensory C, sensory A-delta, sympathetic and parasympathetic nerve fibers in the functional layer of endometrium of most women affected by endometriosis, but not demonstrated in most women who do not have endometriosis, was a surprise. Nerve fiber densities were also greatly increased in myometrium of women with endometriosis and in endometriotic lesions compared with normal peritoneum. Chronic pelvic pain is complex, and endometriosis is only one condition which contributes to this pain. The relationship between the presence of certain nerve fibers and the potential for local pain generation requires much future research. This paper reviews current knowledge concerning nerve fibers in endometrium, myometrium and endometriotic lesions, and discusses avenues of research that may improve our knowledge and lead to enriched understanding and management of endometriotic pain symptoms.
Womens Health (Lond). 2015 Aug;11(5):653-64.
Experimental treatments of endometriosis.
Endometriosis is defined as the presence of endometrial gland and stroma outside the uterine cavity. It is an estrogen-dependent disease and is associated with chronic pelvic pain, dysmenorrhea, dyspareunia and infertility. The treatment of endometriosis is conservative or radical surgery, medical therapies or their combination. All currently used hormonally active treatments are effective in the treatment of endometriosis; however, the adverse effects of these hormonal treatments limit their long-term use. Moreover, recurrence rates are high after cessation of therapy, and the treatments have no benefit in endometriosis-associated infertility. Therefore, researchers are working on new treatment modalities with improved side effects, mainly focusing on the molecular targets involved in etiopathogenesis of endometriosis. Here we summarized these novel treatments modalities.
Womens Health (Lond). 2015 Aug;11(5):677-83.
Pearls and pitfalls in surgery for endometrioma.
Endometrioma surgery should be planned and executed very carefully as it is associated with risks that may hamper future reproductive potential. Symptoms, age, risk of malignancy, bilaterality, ovarian reserve, and desire to have children should all be taken into account prior to surgical intervention. Cyclic and noncyclic severe pain may be an indicator or deep infiltrating diseases. Laparoscopic surgery is the gold standard, however, the issue of resection versus ablation should be further studied.
Womens Health (Lond). 2015 Aug;11(5):685-92.
Complications and their management in endometriosis surgery.
Endometriosis is a common chronic disease mostly seen in young women. Endometriosis surgery may be considered as rather challenging in gynecology. In this article, we tried to emphasize on basic concepts of endometriosis surgery, the best surgical method that should be applied and the complications and the management of the complications.
Womens Health (Lond). 2015 Aug;11(5):705-9
Endometriosis in teenagers.
Endometriosis affects a significant proportion of teenagers. Published studies suggest that laparoscopically confirmed endometriosis could be found in over 60% of adolescent girls undergoing laparoscopic investigation for pain, in 75% of girls with chronic pelvic pain resistant to treatment and in 70% of girls with dysmenorrhea and in approximately 50% of girls with chronic pelvic pain not necessarily resistant to treatment. Both early and advanced forms, including deep endometriosis have been reported to be present in teenagers. It has recently been claimed that deep endometriosis has its roots in teenage years. Risk factors include obstructive mullerian anomalies, family history, early menarche and early onset dysmenorrhea. Both surgical and medical treatment approaches are used for treatment in this age group, but care should be taken when treatment with GnRHa and progestins is being considered due to their potential impact on bone formation. Further studies are urgently needed to determine whether early diagnosis and treatment of teenage endometriosis lead to better long term outcomes or simply increase number of interventions without preventing progression of the disease.
Cytokine. 2015 Dec;76(2):117-122.
Peripheral blood proinflammatory response in women during menstrual cycle and endometriosis.
The aim of this study was to evaluate differences in levels of serum and monocyte derived interleukin (IL)-1, IL-6 and neopterin (NPT) in women with normal or abnormal menstrual cycles and women with endometriosis. The women participating in this study were divided into 4 groups: 25 women with normal menstrual cycle; 25 women taking oral contraception (OC); 20 postmenopausal women and 25 endometriosis patients. IL-1beta, IL-6 and NPT levels in serum and monocyte culture media were measured with ELISA methods. The data collected showed the lowest serum NPT levels in women with follicular menstrual cycles. The levels of both types of interleukins in serum were the lowest in women using OC. In contrast, the highest concentrations of all cytokines were found in the serum of women with endometriosis. The lowest monocyte activity was observed in women with a follicular menstrual cycle phase and the highest in endometriosis. Monocytes from women using OC secreted similar amounts of cytokines to the cells during the follicular menstrual cycle phase. Changes occurring at the time of contraception, after menopause and during endometriosis, are followed by changed proinflammatory monocyte activity, which is associated with different secretion of cytokines. OC can inhibit inflammatory monocyte properties. Lower serum concentration of cytokines compared to cell secretion may suggest some control mechanisms of monocyte activity.
Acta Radiol. 2016 Jul;57(7):878-85.
Susceptibility-weighted magnetic resonance imaging for the evaluation of deep infiltrating endometriosis: preliminary results.
Knowledge of the precise sites of deep infiltrating endometriosis (DIE) lesions is essential for preoperative workup and treatment. Susceptibility-weighted imaging (SWI) has high sensitivity for blood products and have recently been applied in abdominal imaging.
To determine the value of SWI in the diagnosis of DIE.
MATERIAL AND METHODS:
Forty-three clinically suspected DIE patients with sonographically diagnosed ovarian endometriomas who had tenderness or palpable nodule(s) on rectovaginal examination were referred to pelvic magnetic resonance imaging (MRI) including SWI. Two patients were excluded from the study because of low quality of SWI series. Twenty-eight patients who were offered laparoscopic endometriosis surgery (LES) preferred medical treatment over surgical approach. Thirteen out of 41 participants had LES. Lesions were evaluated for their locations, signal intensities on T1-weighted (T1W) and T2-weighted (T2W) images, and presence of signal voids on SWI using 3T MRI and correlated with LES findings.
A total of 18 endometriosis foci were laparoscopically removed from 13 patients. DIE lesions removed at laparoscopy were located at the uterosacral ligament (9/18), rectovaginal region (4/18), retrocervical region (2/18), and fallopian tubes (3/18). Eleven out of 18 (61%) DIE foci were detected by their high-signal intensities on T1W images whereas 16 out of 18 (89%) DIE foci were detected by signal voids on SWI.
SWI imaging with its high sensitivity to blood products, contributes to the diagnosis of DIE by depicting different phases of hemorrhage not seen by conventional MRI sequences.
Biol Reprod. 2015 Oct;93(4):84.
Endometrial side population cells: potential adult stem/progenitor cells in endometrium.
Uterine endometrium is one of the most important organs for species preservation. However, the physiology of human endometrium remains poorly understood, because the human endometrium undergoes rapid and large changes during each menstrual cycle and it is very difficult to investigate human endometrium as one organ. This remarkable regenerative capacity of human endometrium strongly suggests the existence of adult stem cells, and physiology of endometrium cannot be explained without adult stem cells. Therefore, investigating endometrial stem/progenitor cells should lead to a breakthrough in understanding the normal endometrial physiology and the pathophysiology of endometrial neoplastic disorders, such as endometriosis and endometrial cancer. Several cell populations have been discovered as putative endometrial stem/progenitor cells. Emerging evidence reveals that the endometrial side population (SP) is one of the potential endometrial stem/progenitor populations. Of all the endometrial stem/progenitor cell candidates, the endometrial SP (ESP) is best investigated in vitro and in vivo, and has the largest number of references. In this review, we provide an overview of the accumulating evidence for the ESP cells, both directly from human endometria and from cultured endometrial cells. Furthermore, SP cells are compared to other potential stem/progenitor cells, and we discuss their stem cell properties. We also discuss the difficulties and unsolved issues in endometrial stem cell biology.
Redox Rep. 2016 May;21(3):119-26.
Potential scenarios leading to ovarian cancer arising from endometriosis.
The aim of this review was to highlight recent advances in our understanding of the pathogenesis of malignant transformation of endometriosis.
This study reviewed the English-language literature concerning basic science studies of the potential promotion of carcinogenesis.
Repeated episodes of hemorrhage occur in endometriosis at the onset of menstruation. Extracellular hemoglobin, heme, and iron derivatives in endometriosis cause DNA damage and mutations, which create increased cellular susceptibility to oxidant-mediated cell killing. Excess DNA damage and mutations are linked to cell death, but not carcinogenesis. In response to an oxidative and inflammatory microenvironment, endometriotic cells and macrophages secrete antioxidants that control excess oxidative stress in the surrounding environment. Exposure of endometriotic cells to a sublethal level of oxidative stress may lead to carcinogenesis. Macrophages also secrete immunosuppressive factors that lead to promotion of malignant transformation.
At least two potential scenarios could result in ovarian cancer arising from endometriosis. The first step: extracellular hemoglobin, heme, and iron cause cellular oxidative damage by promoting reactive oxygen species formation, which results in DNA damage and mutations (ovarian cancer initiation from endometriosis). The second step: cancer progression may be associated with persistent antioxidant production favoring a protumoral microenvironment.
BMC Immunol. 2015 Aug 29;16:51
Exogenous activated NK cells enhance trafficking of endogenous NK cells to endometriotic lesions.
Endometriosis is defined as the presence of endometrial glands and stroma at ectopic locations. Although the prevalence of endometriosis is as high as 35%-50%, its pathogenesis remains controversial. An increasing number of studies suggest that changes in immune reactivity may be primarily involved in the development of endometriosis development. In this sense, it has been strongly suggested that a fundamental part of immunologic system, the natural killer cells (NK cells), are an important part of this process. NK cells, a component of the innate immune system, have been extensively studied for their ability to defend the organism against infections and malignancy. Recent studies have shown that IL-2-activated NK (A-NK) cells are able to attack and destroy tumors in lungs and livers of mice, demonstrating the therapeutic potential of these cells. Similarly to metastatic tumor cells, endometrial cells are able to adhere, infiltrate and proliferate at ectopic locations. Therefore, in this study, we evaluated the ability of adoptively transferred and endogenous NK cells to infiltrate endometriosis lesions.
As NK cells donors were used C57BL/6 B6. PL- Thy 1.1 female mice. As uterine horns donors were used C57/BL6+GFP female mice and as endometriosis recipients C57BL/6 Thy1.2 female mice. Endometriosisinduction was made by injection of endometrial tissue fragments. After 4 weeks, necessary for endometriosislesions establishment the animals were divided in 3 experimental groups with 10 animals each. Group 1 received i.v doses of 5×106 A-NK in 200μl RPMI; Group 2 received i.p dose of 5×106 A-NK in 200μl RPMI and Group 3 received i.p dose of IL2 (0.5 mL RPMI containing 5.000U of IL2).
Our data show that exogenous A-NK cells injected via ip combined with endogenous A-NK cells seems to be the most efficient way for activated NK cells track and infiltrate endometriosis.
For the first time, it was shown that both endogenous as exogenous A-NK cells are able to track, migrate and infiltrate endometriosis lesion. This seems to be a promising result, and if confirmed the efficiency of A-NK cells in killing endometriosis lesions, maybe in the future we could use this approach as an alternative treatment for women with endometriosis.
Eur J Obstet Gynecol Reprod Biol. 2015 Nov;194:1-6.
Effectiveness of complementary pain treatment for women with deep endometriosis through Transcutaneous Electrical Nerve Stimulation (TENS): randomized controlled trial.
Evaluate TENS effectiveness as a complementary treatment of chronic pelvic pain and deep dyspareunia in women with deep endometriosis.
This randomized controlled trial was performed in a tertiary health care center, including twenty-two women with deep endometriosis undergoing hormone therapy with persistent pelvic pain and/or deep dyspareunia. This study was registered in the Brazilian Record of Clinical Trials (ReBEC), under n RBR-3rndh6. TENS application for 8 weeks followed a randomized allocation into two groups: Group 1 – acupuncture-like TENS (Frequency: 8Hz, pulse duration: 250μs) – VIF (n=11) and Group 2 – self-applied TENS (Frequency: 85Hz, pulse duration: 75μs) (n=11). The intensity applied was “strong, but comfortable”. We evaluated patients before and after treatment by the use of the Visual Analogue Scale, Deep Dyspareunia Scale and Endometriosis Quality of Life Questionnaire. We used the Wilcoxon and Mann-Whitney tests to compare before and after treatment conditions.
Despite the use of hormone therapy for 1.65±2.08 years, the 22 women with deep endometriosissustained pelvic pain complaints (VAS=5.95±2.13 and 2.45±2.42, p<.001) and/or deep dyspareunia (DDS=2.29±0.46 and 1.20±1.01, p=.001). We observed significant improvement for chronic pelvic pain, deep dyspareunia and quality of life by the use of TENS. Both application types of TENS were effective for improving the evaluated types of pain.
Both resources (acupuncture-like TENS and self-applied TENS) demonstrated effectiveness as a complementary treatment of pelvic pain and deep dyspareunia, improving quality of life in women with deep endometriosis regardless of the device used for treatment.
Eur J Obstet Gynecol Reprod Biol. 2015 Nov;194:30-3.
Analysis of psychopathological comorbidity behind the common symptoms and signs of endometriosis.
The present study was aimed to investigate quality of life, negative emotions, such as anger, anxiety and depression, and possible psychopathological comorbidity in patients affected by endometriosis.
We undertook a prospective, cohort study between October 2013 and February 2014. We selected patients with histologically confirmed ovarian endometriosis (Endometriosis Group) and with other benign adnexal diseases (Control Group) who underwent laparoscopic surgery. Participants underwent a psychometric assessment using the following self-report instruments: Symptom Checklist-90-R, State-Trait Anger Expression Inventory-2, Self-Rating Anxiety Scale, Self-Rating Depression Scale, Quality of Life Index.
The Endometriosis Group was formed by 166 patients (mean age: 36±6 yrs) matched with 48 controls (mean age: 38.4±12.8 yrs). Somatization (p=0.02), depression (p=0.01), sensitivity (p=0.04) and phobic anxiety (p=0.04) were higher in Endometriosis Group than in Control Group. Endometriosis Group was further characterized by significantly higher levels of anxiety than Control Group (p=0.03) as assessed by Self-Rating Anxiety Scale. Regarding Quality of Life Index, a significant health decline in Endometriosis Group compared with Control Group (p=0.008) was found.
Higher levels of somatization, depression, sensitivity and anxiety were found in EndometriosisGroup compared with Control Group.
Life Sci. 2015 Oct 15;139:166-74.
Effect of SKI2670, a novel, orally active, non-peptide GnRH antagonist, on hypothalamic-pituitary-gonadal axis.
Suppression of the hypothalamic-pituitary-gonadal axis has been widely utilized for the management of gonadal-hormone-dependent diseases such as endometriosis. Efforts to develop orally available gonadotropin-releasing hormone (GnRH) antagonists for the treatment of gonadal-hormone-dependent diseases led to the discovery of SKI2670, a novel non-peptide GnRH antagonist. The present study was undertaken to pharmacologically characterize SKI2670 in vitro and in vivo.
We measured binding affinity and antagonistic activity of SKI2670 for the GnRH receptors. Immediate suppression of gonadotropins by single dosing of SKI2670 was examined in castrated monkeys. Subsequently, influence on gonadal hormones by prolonged administration of SKI2670 was assessed in naive female monkeys. To investigate in vivo efficacy of SKI2670, regression of ectopic implants by repeated administration of SKI2670 was examined in a rat endometriosis model.
SKI2670 is a potent functional antagonist for the human GnRH receptor, with subnanomolar binding affinity. In castrated monkeys, single administration of SKI2670 lowered serum luteinizing hormone (LH) levels stronger with longer duration when compared to elagolix at equivalent doses. Moreover, repeated dosing of SKI2670 suppressed serum levels of gonadotropins and gonadal hormones in intact female monkeys while elagolix suppressed serum LH levels only. Finally, it exhibited regressive effects on ectopic implants in a rat endometriosis model without bone loss.
Our findings demonstrate robust GnRH antagonistic efficacy of SKI2670 in animal models, suggesting that SKI2670-induced suppression of the hypothalamic-pituitary-gonadal axis may be beneficial for the treatment of gonadal-hormone-dependent diseases such as endometriosis in humans.
Eur J Med Chem. 2015 Oct 20;103:56-68.
Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme.
17β-Estradiol (E2), the most potent human estrogen, is known to be involved in the etiology of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step of E2 biosynthesis and is thus a promising target for the treatment of EDD. The previously described bicyclic substituted hydroxyphenylmethanones (BSHs) display high inhibitory potency towards human 17β-HSD1, but marginal activity towards rodent 17β-HSD1, precluding a proof of principle study in an animal endometriosis model. The aim of this work was to perform structural optimizations in the BSHs class to enhance inhibitory activity against rodent (mouse and rat) 17β-HSD1 while maintaining activity against the human enzyme. The introduction of fluorine atoms on the benzoyl moiety resulted in compounds with the desired properties. Molecular docking and homology modeling were applied to elucidate the binding mode and interspecies differences in activity. Compound 33 is the most potent inhibitor of both human and rat 17β-HSD1 up to date (IC₅₀ = 2 nM and 97 nM, respectively).
Neurosurg Focus. 2015 Sep;39(3)
Magnetic resonance imaging evidence for perineural spread of endometriosisto the lumbosacral plexus: report of 2 cases.
Sciatic nerve endometriosis (EM) is a rare presentation of retroperitoneal EM. The authors present 2 cases of catamenial sciatica diagnosed as sciatic nerve EM. They propose that both cases can be explained by perineural spread of EM from the uterus to the sacral plexus along the pelvic autonomie nerves and then further distally to the sciatic nerve or proximally to the spinal nerves. This explanation is supported by MRI evidence in both cases. As a proof of concept, the authors retrieved and analyzed the original MRI studies of a case reported in the literature and found a similar pattern of spread. They believe that the imaging evidence of their institutional cases together with the outside case is a very compelling indication for perineural spread as a mechanism of EM of the nerve.
J Psychosom Obstet Gynaecol. 2015;36(4):135-41.
Impact of endometriosis on quality of life and mental health: pelvic pain makes the difference.
No prior study of endometriosis has investigated the psychological impact of having asymptomatic endometriosis versus endometriosis with pelvic pain in a systematic way. This study aimed at examining the impact of endometriosis on quality of life, anxiety and depression by comparing asymptomatic endometriosis, endometriosis with pelvic pain, and healthy, pain-free controls. The psychological impact of different types of endometriosis pain was also tested.
One hundred and ten patients with surgically diagnosed endometriosis (78 with pelvic pain and 32 without pain symptoms) and 61 healthy controls completed two psychometric tests assessing quality of life, anxiety and depression. Endometriosis participants indicated on a numerical rating scale the intensity of four types of pain (dysmenorrhea, dyspareunia, non-menstrual pelvic pain and dyschezia).
Endometriosis patients with pelvic pain had poorer quality of life and mental health as compared with those with asymptomatic endometriosis and the healthy controls. No significant differences were found between asymptomatic endometriosis and the control group. Dysmenorrhea had significant effects only on physical quality of life; non-menstrual pelvic pain affected all the variables; no significant effects were found for dyspareunia and dyschezia.
Pain significantly affects women’s experience of endometriosis. The medical treatment of endometriosis with pain may not be sufficient and psychological intervention is recommended.
Arch Gynecol Obstet. 2016 Feb;293(2):439-45.
Association between chronic pelvic pain symptoms and the presence of endometriosis.
The link between endometriosis and the presence or intensity of pain is controversial. The aim of the present study was to assess the relationship between chronic pelvic pain (CPP) and severity of endometriosisand the effectiveness of laparoscopic treatment in a 6-month follow-up.
Prospective observational study in a referral unit. 144 women had laparoscopy to investigate CPP. Symptoms were assessed by a 10-point visual analog scale. The main outcome measure was the frequency and intensity of CPP.
No difference in pain was found between women with and without endometriosis. Advanced endometriosis was associated with dysmenorrhea, deep endometriosis with dyspareunia and rectovaginal disease with dyschezia. Laparoscopic treatment improves symptoms.
Women with severe endometriosis are more likely to report severe dysmenorrhoea. Furthermore location of endometriosis in the rectovaginal space is associated with dyschezia and deep endometriosis with dyspareunia. However, the association between presence and stage of endometriosis and severity of symptoms is marginal.
Eur J Public Health. 2016 Feb;26(1):76-83.
Toward a multi-country monitoring system of reproductive health in the context of endocrine disrupting chemical exposure.
Worrying trends regarding human reproductive endpoints (e.g. semen quality, reproductive cancers) have been reported and there is growing circumstantial evidence for a possible causal link between these trends and exposure to endocrine disrupting chemicals (EDCs). However, there is a striking lack of human data to fill the current knowledge gaps. To answer the crucial questions raised on human reproductive health, there is an urgent need for a reproductive surveillance system to be shared across countries.
A multidisciplinary network named HUman Reproductive health and Global ENvironment Network (HURGENT) was created aiming at designing a European monitoring system for reproductive health indicators. Collaborative work allowed setting up the available knowledge to design such a system. Furthermore we conducted an overview of 23 potential indicators, based upon a weight of evidence (WoE) approach according to their potential relation with EDC exposure.
The framework and purposes of the surveillance system are settled as well as the approach to select suitable reproductive indicators. The indicators found with the highest scores according to the WoE approach are prostate and breast cancer incidence, sex ratio, endometriosis and uterine fibroid incidence, indicators related to the testicular dysgenesis syndrome, precocious puberty incidence and reproductive hormone levels.
Not only sentinel health endpoints, but also diseases with high burdens in public health are highlighted as prior indicators in the context of EDC exposure. Our work can serve as a basis to construct, as soon as possible, the first multi-country reproductive monitoring system.
Inflamm Bowel Dis. 2016 Jan;22(1):159-63
Impact of Concomitant Endometriosis on Phenotype and Natural History of Inflammatory Bowel Disease.
Inflammatory bowel disease (IBD) and endometriosis are immune-mediated chronic inflammatory disorders affecting young women. The clinical significance of concomitant endometriosis on the course of IBD has not been previously studied. The aim of this study was to determine whether women with concomitant endometriosis and IBD have a unique phenotype and worse prognosis of IBD.
This was a case-control study performed at a tertiary referral center. Cases were women with diagnoses of both endometriosis and IBD. Two random IBD controls without endometriosis were selected for each case, frequency matched for age and IBD type, Crohn’s disease (CD) or ulcerative colitis. Primary outcomes included disease phenotype; the use of immunomodulators, antiTNF agents, or combination therapy and the need for IBD-related surgery.
We identified 51 cases with endometriosis and IBD (28 CD, 23 ulcerative colitis). There was no difference in race, age at IBD diagnosis, and mean duration of IBD between endometriosis-IBD cases and controls. Among endometriosis-CD patients whose endometriosis was surgically verified, there was a higher risk for stricturing disease compared with CD controls (odds ratio, 11.8; 95% confidence interval, 2.03-69.0). There was no difference in phenotype in endometriosis-ulcerative colitis patients. There were no significant differences in IBD-related medication use or surgeries overall or when stratified by IBD type.
Patients with CD and endometriosis, which was surgically diagnosed, were more likely to have stricturing CD. Concomitant endometriosis did not impact the natural history of IBD.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2015 Aug;40(8):872-8.
Expression of G protein-coupled estrogen receptor and Gankyrin protein in ovarian endometriosis and its pathological significance.
To examine the expression of G protein-coupled estrogen receptor (GPER) and Gankyrin in ovarian endometriosis (OEM) and to evaluate its clinicopathological significance.
Immunohistochemistry was conducted to determine the expression and distribution of GPER and Gankyrin in matched ectopic and eutopic endometrium of OEM and the normal endometrium. The association of these two proteins with the stages of OEM was also investigated.
The positive rate for GPER protein in paired ectopic and eutopic endometrium of OEM and the normal endometrium were 63.6%, 51.5% and 21.2%, respectively. There was significant difference in matched ectopic and eutopic endometrium from OEM compared with the control endometrium (P<0.0125). No statistical significance was found between ectopic and eutopic endometrium from OEM (P>0.0125). The positive rate for Gankyrin protein were 69.7%, 36.4% and 9.1%, respectively. Significant difference in Gankyrin protein was found between ectopic and eutopic endometrium of OEM, ectopic and normal endometrium or eutopic and normal endometrium (P<0.0125). Higher positive expression rate for GPER was also observed in eutopic endometrium from OEM during proliferative phase in comparison to secretory phase (P<0.05). There was no significant difference in Gankyrin between proliferative and secretory phase (P>0.05). These two proteins were positively correlated with the revised American Society for Reproductive Medicine (rASRM) stages of OEM. Both of them were found to be significantly higher in advanced stages (III-IV) compared with those in early stages (I-II, P<0.05). Moreover, a significant positive correlation was found between GPER and Gankyrin proteins in ectopic endometrium of OEM (rs=0.640, P<0.01).
GPER and Gankyrin might be involved in the pathogenesis of OEM, which could possibly facilitate the formation of ectopic lesions.
Medicine (Baltimore). 2015 Sep;94(35):e1168.
Association of FCRL3 Genetic Polymorphisms With Endometriosis-Related Infertility Risk: An Independent Study in Han Chinese.
The Fc receptor-like 3 (FCRL3) gene was reported to be linked to a variety of autoimmune diseases, including endometriosis-related infertility. However, this linkage has not been studied in Chinese population and there has been no meta-analysis on the interrelationship of FCRL3 gene and endometriosis-related infertility. The aim of the study was to investigate the association between FCRL3 genetic polymorphisms and the risk of endometriosis-related infertility in Han Chinese, and a further meta-analysis was conducted to confirm our results.Four single nucleotide polymorphisms (SNPs) (rs7528684 [FCRL3_3], rs11264799 [FCRL3_4], rs945635 [FCRL3_5], and rs3761959 [FCRL3_6]) on FCRL3 gene were genotyped in a case-control cohort composed of 217 patients suffering from endometriosis-related infertility and 220 healthy controls using cleaved amplification polymorphism sequence-tagged sites (polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP). Odds ratio (OR) and its 95% confidence interval (CI) was used to evaluate the association quantitatively. Furthermore, a meta-analysis of previous studies including the present study was implemented through Stata 11.0 (Stata Corporation, College Station, TX).We found an approximately 1.4-fold significantly increased frequency of the FCRL3_3 variant in women with endometriosis-related infertility over the controls (OR = 1.41 [95% CI = 1.08-1.84], P = 0.013). However, no significant difference was found between women with endometriosis-related infertility and controls for FCRL3_4, FCRL3_5, and FCRL3_6. Regardless of the symptoms and the revised classification of the American Society of Reproductive Medicine (rASRM) stage of endometriosis, there was a significant association between FCRL3_3 variant and an increased risk of endometriosis-related infertility. Meta-analysis of previous studies combined with the present study further confirmed the association between FCRL3_3 and the risk of endometriosis-related infertility.In summary, the present study suggested that FCRL3_3 variant was associated with an increased risk of endometriosis-related infertility, regardless of symptoms, and rASRM stage of the patients. Meta-analysis of previous studies combined with the present study further confirmed our results. Further large-scale studies in the future are warranted to explore the association between FCRL3 genetic polymorphisms and endometriosis-related infertility, as well as other human diseases, in Asian and other ethnicities.
Fertil Steril. 2015 Oct;104(4):813-830.
Endometriosis and ovarian cancer: potential benefits and harms of screening and risk-reducing surgery.
Although endometriosis is well recognized as a benign gynecologic condition, its association with ovarian cancer (OVCA) has frequently been reported. Review articles on this topic are voluminous, yet there seems to be no consensus as to whether endometriosis is truly a precursor of OVCA and whether any screening or risk-reducing surgery should be instituted, on the basis of our current knowledge. In this review, published data are compiled and critically appraised. Through this critical appraisal, it seems clear that the strongest evidence seems to come from prevalence data. This type of data also suggests a reduced risk of certain histotypes (mainly type II) of OVCA in women with endometriosis. This may explain the rather moderate increase in risk as shown in epidemiologic studies. Even with this moderate increase in OVCA risk, caution should be exercised because of apparent bias in favor of publication of positive results, extensive heterogeneities among prevalence estimates, and inverse relationship between estimates and sizes of the studies. Many molecular studies are conflicting, and earlier studies showing molecular aberrations involved in genomic instability and mutation that enable malignant transformation are not replicated in later studies. Given the low incidence of OVCA and the rather moderate increase in risk of mostly type I tumors, screening seems to be ill-advised, and risk-reducing surgery such as salpingectomy with or without oophorectomy does not seem to yield any substantial benefit to women with endometriosis.
Reprod Sci. 2016 Jan;23(1):11-23.
Bentamapimod (JNK Inhibitor AS602801) Induces Regression of Endometriotic Lesions in Animal Models.
Endometriosis is an estrogen (ER)-dependent gynecological disease caused by the growth of endometrial tissue at extrauterine sites. Current endocrine therapies address the estrogenic aspect of disease and offer some relief from pain but are associated with significant side effects. Immune dysfunction is also widely believed to be an underlying contributor to the pathogenesis of this disease. This study evaluated an inhibitor of c-Jun N-terminal kinase, bentamapimod (AS602801), which interrupts immune pathways, in 2 rodent endometriosis models. Treatment of nude mice bearing xenografts biopsied from women with endometriosis (BWE) with 30 mg/kg AS602801 caused 29% regression of lesion. Medroxyprogesterone acetate (MPA) or progesterone (PR) alone did not cause regression of BWE lesions, but combining 10 mg/kg AS602801 with MPA caused 38% lesion regression. In human endometrial organ cultures (from healthy women), treatment with AS602801 or MPA reduced matrix metalloproteinase-3 (MMP-3) release into culture medium. In organ cultures established with BWE, PR or MPA failed to inhibit MMP-3 secretion, whereas AS602801 alone or MPA + AS602801 suppressed MMP-3 production. In an autologous rat endometriosis model, AS602801 caused 48% regression of lesions compared to GnRH antagonist Antide (84%). AS602801 reduced inflammatory cytokines in endometriotic lesions, while levels of cytokines in ipsilateral horns were unaffected. Furthermore, AS602801 enhanced natural killer cell activity, without apparent negative effects on uterus. These results indicate that bentamapimod induced regression of endometriotic lesions in endometriosis rodent animal models without suppressing ER action. c-Jun N-terminal kinase inhibition mediated a comprehensive reduction in cytokine secretion and moreover was able to overcome PR resistance.
J Endocrinol Invest. 2015 Nov;38(11):1211-8.
Quality of life and sexual function of women affected by endometriosis-associated pelvic pain when treated with dienogest.
The aim of the study was to evaluate the effects of dienogest (DNG) on quality of life (QoL) and sexual function of women affected by endometriosis pain.
Fifty-four women constituted the study group and were given 2 mg/daily DNG; 48 women were given non-steroidal anti-inflammatory drugs and constitut ed the control group. To define the endometriosis-associated pelvic pain, the Visual Analogic Scale (VAS) was used. The Short Form-36 (SF-36), the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) were used to assess the QoL, the sexual function and the sexual distress, respectively. The study included two follow-ups at 3 and 6 months.
Pain improvement was observed in the study group at 3 (p < 0.05) and 6 months (p < 0.001) of treatment. At the 1st follow-up, women reported QoL improvements in some functions (p < 0.05); at the 2nd follow-up, they reported improvement in all categories (p < 0.001). The FSFI score did not change at the 1st follow-up (p = NS). On the contrary, at the 2nd follow-up, it improved with respect to the baseline (p < 0.05). At the 2nd follow-up, the FSFI score had risen to 27.8 (p < 0.001) and the FSDS score had dropped to 11.3 (p < 0.001). No change was observed in the control group (p = NS).
The progressive reduction of the pain syndrome reported by women over the treatment period could contribute to improve the QoL and sexual life of women on DNG.
Twin Res Hum Genet. 2015 Oct;18(5):518-25.
Independent Replication and Meta-Analysis for Endometriosis Risk Loci.
Endometriosis is a complex disease that affects 6-10% of women in their reproductive years and 20-50% of women with infertility. Genome-wide and candidate-gene association studies for endometriosis have identified 10 independent risk loci, and of these, nine (rs7521902, rs13394619, rs4141819, rs6542095, rs1519761, rs7739264, rs12700667, rs1537377, and rs10859871) are polymorphic in European populations. Here we investigate the replication of nine SNP loci in 998 laparoscopically and histologically confirmed endometriosis cases and 783 disease-free controls from Belgium. SNPs rs7521902, rs13394619, and rs6542095 show nominally significant (p < .05) associations with endometriosis, while the directions of effect for seven SNPs are consistent with the original reports. Association of rs6542095 at the IL1A locus with ‘All’ (p = .066) and ‘Grade_B’ (p = .01) endometriosis is noteworthy because this is the first successful replication in an independent population. Meta-analysis with the published results yields genome-wide significant evidence for rs7521902, rs13394619, rs6542095, rs12700667, rs7739264, and rs1537377. Notably, three coding variants in GREB1 (near rs13394619) and CDKN2B-AS1 (near rs1537377) also showed nominally significant associations with endometriosis. Overall, this study provides important replication in a uniquely characterized independent population, and indicates that the majority of the original genome-wide association findings are not due to chance alone.
Eur J Obstet Gynecol Reprod Biol. 2015 Nov;194:54-7.
Gynaecological pathology in women with Fowler’s syndrome.
To assess the prevalence of gynaecological pathologies in women with Fowler’s syndrome (FS) which is characterised by chronic urinary retention (CUR) secondary to failure of urethral sphincter to relax and allow normal voiding.
This was a case control study conducted at a tertiary referral centre specialised in managing women with FS. There were 41 patients with FS in the study group with CUR without mechanical obstruction of the urethra or neurological problem. All patients had raised maximum urethral closure pressure on urethral pressure profile, high urethral sphincter volume on ultrasound and complex repetitive discharges on eletromyography of the urethral sphincter. Normal voiding was established in these women after treatment with sacral neuromodulation. Fifty women without voiding dysfunction acted as control group. Data was obtained by using standard questionnaire for both the groups. Information was collected regarding gynaecological pathologies such as endometriosis, polycystic ovarian syndrome, menstrual abnormalities, ovarian cysts and subfertility and also regarding previous pregnancies. Analysis was performed using SPSS software from IBM Corporation.
At least one gynaecological pathology was present in 33 (80%) patients with FS compared to 16 (32%) women from control group (P<0.001). This included a higher incidence of endometriosis (29% versus 6%, P=0.003), PCOS (24% versus 8%, P=0.041) and subfertility (34% versus 8%, P=0.003). The incidence of menstrual abnormalities and ovarian cysts was similar in both groups (P>0.05).
Subfertility was more prevalent in women with FS in our study. Though the prevalence of different pathologies was higher in the FS group compared to the control group, it remained similar to that found in the normal female population in the published literature. Thus, it is not possible to state whether FS is caused by a hormonally based disorder. It took patients many years before they could get right diagnosis and treatment for FS. Early investigation of chronic urinary retention and referral to specialists for appropriate treatment in this small group of women can result in better health and improvement in their quality of life.
Urol J. 2015 Sep 4;12(4):2213-7.
Urinary Tract Endometriosis.
Recently, occurrence of urinary tract endometriosis (UTE) is more frequently diagnosed. According to literature, it refers to approximately 0.3 to even 12% of all women with endometriosis. The pathogenesis of UTE has not been clearly explained so far. The actually proposed hypotheses include embryonic, migration, transplantation, and iatrogenic theory. Most frequently UTE affects bladder, less often ureters and kidneys. One-third of patients remains asymptomatic or exhibits only minor manifestations. In symptomatic patients main complaints include dysuria, urinary urgency, and/or frequency, painful micturition, and burning sensation in the urethra and discomfort in the retropubic area. Treatment of UTE is challenging and can be pharmacological, surgical or can be a combination of both methods. In this paper we present a review of the literature concerning the UTE, its diagnosis and treatment.
Reprod Sci. 2016 Feb;23(2):244-8.
Increased Expression of Interleukin 37 in the Eutopic and Ectopic Endometrium of Patients With Ovarian Endometriosis.
Endometriosis is a chronic inflammatory condition. Interleukin (IL) 37 is a member of the IL-1 family and an anti-inflammatory cytokine. This study investigated the gene and protein expression of IL-37 in the eutopic and ectopic endometrium of women with ovarian endometriosis and in the endometrium of patients without endometriosis.
Eutopic and ectopic endometria (n = 24) were collected from patients with ovarian endometriosis, and control endometria (n = 15) were obtained from women without endometriosis. Quantitative real-time polymerase chain reaction was used to measure the gene expression levels of IL-37, and immunohistochemistry was performed to assess the protein expression levels of IL-37.
The gene and protein expression levels of IL-37 in both eutopic and ectopic endometrium of women with ovarian endometriosis were significantly higher than in the endometrium of patients without endometriosis. Compared to the eutopic endometrium of patients with ovarian endometriosis, IL-37 gene and protein expression levels were significantly higher in the ectopic endometrium.
These findings suggest that increased expression of IL-37 was present in eutopic and ectopic endometrium of women with ovarian endometriosis, which might be involved in the inflammatory process of endometriomas.
Reprod Sci. 2016 Mar;23(3):342-51
N-Acetyl-Cysteine and l-Carnitine Prevent Meiotic Oocyte Damage Induced by Follicular Fluid From Infertile Women With Mild Endometriosis.
This study evaluated the potential protective effect of the antioxidants, l-carnitine (LC) and N-acetyl-cysteine (NAC), in preventing meiotic oocyte damage induced by follicular fluid (FF) from infertile women with mild endometriosis (ME). We performed an experimental study. The FF samples were obtained from 22 infertile women undergoing stimulated cycles for intracytoplasmic sperm injection (11 with ME and 11 without endometriosis). Immature bovine oocytes were submitted to in vitro maturation (IVM) divided into 9 groups: no-FF (No-FF); with FF from control (CFF) or ME (EFF) groups; and with LC (C + LC and E + LC), NAC (C + NAC and E + NAC), or both antioxidants (C + 2Ao and E + 2Ao). After IVM, oocytes were immunostained for visualization of microtubules and chromatin by confocal microscopy. The percentage of meiotically normal metaphase II (MII) oocytes was significantly lower in the EFF group (51.35%) compared to No-FF (86.36%) and CFF (83.52%) groups. The E + NAC (62.22%), E + LC (80.61%), and E + 2Ao (61.40%) groups showed higher percentage of normal MII than EFF group. The E + LC group showed higher percentage of normal MII than E + NAC and E + 2Ao groups and a similar percentage to No-FF and CFF groups. Therefore, FF from infertile women with ME causes meiotic abnormalities in bovine oocytes, and, for the first time, we demonstrated that the use of NAC and LC prevents these damages. Our findings elucidate part of the pathogenic mechanisms involved in infertility associated with ME and open perspectives for further studies investigating whether the use of LC could improve the natural fertility and/or the results of in vitro fertilization of women with ME.
Fertil Steril. 2015 Oct;104(4):764-770.
Treatment of infertility associated with deep endometriosis: definition of therapeutic balances.
Deep endometriosis is a demanding condition that is associated with infertility. However, evidence supporting a direct link between deep endometriosis and infertility is weak. In fact, infertility in affected patients is more likely to be explained by the strong association between deep endometriosis and adhesions, superficial endometriotic implants, ovarian endometriomas, and adenomyosis. The purported beneficial effects of surgery on infertility are mainly based on the 40%-42% pregnancy rate (PR) after surgery observed in published case series. However, this level of evidence is questionable and overestimates the benefits of the intervention. Even if comparative studies are lacking, IVF may be a valid alternative. The procedure may be less effective in affected women compared with other indications and it is not without additional deep endometriosis-related risks. Some case reports suggest that lesions might progress during IVF causing ureteral or intestinal complications or can decidualize during pregnancy causing intestinal perforation, pneumothorax, and pelvic vessels rupture. Finally, in the decision-making process, physicians should also consider that women with a history of deep endometriosismay face an increased risk of pregnancy complications. In conclusion, clear recommendation for the management of infertile women with deep endometriosis cannot be extrapolated from the literature. The therapeutic decision should be based on a comprehensive evaluation that includes clinical history, instrumental findings, pain symptoms, risks of pregnancy complications, and the woman’s wishes.