PGE2 and PGF2α concentrations in human endometrial fluid as biomarkers for embryonic implantation.

BACKGROUND: Prostaglandin (PG) signaling has been implicated in embryonic implantation in several animal species including humans; however, this knowledge has not yet been clinically translated. The objective of this work is to investigate whether PGE2 and PGF2α in endometrial fluid (EF) can be used as biomarkers of human embryonic implantation. PATIENTS AND METHODS: Lipidomic profile of human EF (n = 173) obtained through natural cycles, hormonal replacement therapy, controlled ovarian stimulation, and refractory endometrium induced by the insertion of an intrauterine device was analyzed by liquid chromatography and tandem mass spectrometry. Immunohistochemistry, Western blotting, immunolocalization of PG receptors on mouse embryos, embryo adhesion assay, pharmacological interventions, and statistical analysis were conducted. RESULTS: PGE2 and PGF2α concentrations increased significantly in the human EF during the window of implantation in natural cycles and assisted reproductive technologies patients undergoing in vitro fertilization and ovum donation. This profile was abrogated in the refractory endometrium. We also demonstrated that PGE2 and PGF2α synthases are located in the endometrial epithelium being hormonally regulated during the window of implantation, and PG receptors are expressed in the trophoectoderm and inner cell mass of mouse blastocysts. Using an in vitro model of embryo adhesion, we demonstrated that inhibition of PGE2 and PGF2α or PG receptors (EP2 and FP) prevents embryo adhesion, which can be overcome by adding these molecules back or using their agonists. Finally, in a pilot study, we demonstrated that PGE2 and PGF2α levels from EF 24 hours prior to embryo transfer could predict pregnancy outcome. CONCLUSIONS: Our results suggest that PGE2 and PGF2α concentrations 24 hours prior to embryo transfer are potential noninvasive biomarkers of endometrial receptivity.

The follicular hormonal profile in low-responder patients undergoing unstimulated cycles: Is it hypoandrogenic?

STUDY QUESTION: What is the final hormonal milieu of pre-ovulatory follicles of low-responder (LR) patients undergoing unstimulated cycles? SUMMARY ANSWER: Neither androgen secretion nor LH was impaired in pre-ovulatory follicles of LR women. WHAT IS KNOWN ALREADY: Therapies currently used to improve ovarian response in LR women have an impact on the final hormonal follicular milieu, and these changes are believed to be partially responsible for determining the success rate in these women. Surprisingly, as far as we know, there is no report of the final hormonal profile of LR women undergoing unstimulated cycles or evidence that follicular androgen secretion in LR women is impaired. STUDY DESIGN, SIZE AND DURATION: A prospective case-control study including 94 women, 36 normal controls and 58 LR patients (19 Young ≤ 35 years LR and 39 Aged >35 years LR) from 2009 to 2011. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Fifty-eight LR women were divided into two groups: Young LR (age ≤ 35; n = 19) and Aged LR (ALR; age >35; n = 39). The control group (group C) comprised 36 egg donors undergoing an unstimulated cycle in our IVF unit. Serum and follicular fluid hormonal concentrations for estradiol (E2), progesterone, testosterone and androstendione were measured. The spindle parameters of metaphase II oocytes generated from these groups were also analysed. MAIN RESULTS AND THE ROLE OF CHANCE: Pre-ovulatory follicles from LR patients had similar androgenic and LH concentrations to those observed in the control group. However, higher intrafollicular concentrations of FSH and progesterone were observed in ALR. Moreover, no differences were found for the spindle evaluation of oocytes between groups by the Oosight technology. LIMITATIONS, REASONS FOR CAUTION: The controls were younger and had a lower BMI than the LR women. The sample size available restricted statistical power. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that the problem with LR women is not the final pre-ovulatory follicular androgen concentration since this is similar to normal responders, but in the ability to respond to controlled ovarian stimulation protocols. Therefore, efforts should be focused on long-interval androgen priming to potentially increase the recruitment of small antral follicles rather than increasing the intraovarian androgen levels within the current cycle. STUDY FUNDING/COMPETING INTEREST: The present project has been supported by the R+D programme from the Generalitat Valenciana (Regional Valencian Government) IMPIVA MIDTF/2010/95. The authors have no conflict of interest to declare.

Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis.

BACKGROUND: Elevated serum progesterone levels at the end of the follicular phase in controlled ovarian stimulation (COS) leads to a poorer ongoing pregnancy rate in IVF cycles due to reduced endometrial receptivity. The objective of this study was to use microarray technology to compare endometrial gene expression profiles at the window of implantation according to the levels of circulating progesterone. METHODS: For this prospective cohort study, microarray data were obtained from endometrial biopsies from 12 young healthy oocyte donors undergoing COS with pituitary suppression by either gonadotrophin-releasing hormone (GnRH) agonists or antagonists, and recombinant FSH. On the day of recombinant chorionic gonadotrophin (rCG) administration, six women had serum progesterone levels (P) >1.5 ng/ml (study group) and six had serum P levels <1.5 ng/ml (control group). Endometrial samples were collected using a Pipelle catheter 7 days after the rCG injection. RESULTS: Using the parametric test, we identified 140 genes significantly dysregulated (64 up- and 76 down-regulated) in the study group endometria compared with the control endometria, regardless of the GnRH analogue employed. These genes are related to cell adhesion, developmental processes, the immune system and others, which are all required for normal endometrial function development. Of the 25 gene targets previously proposed as markers for endometrial receptivity, 13 appeared over-regulated in the study group. CONCLUSIONS: Our results reveal that elevated progesterone levels on the day of rCG administration can induce significant alterations in the gene expression profile of the endometrium.

GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study.

The use of gonadotrophin-releasing hormone (GnRH) agonists for triggering ovulation remains controversial. The primary objective of this study was to evaluate the incidence of ovarian hyperstimulation syndrome (OHSS) following GnRH agonist versus recombinant human chorionic gonadotrophin (HCG) as methods for triggering ovulation. A second aim was to compare the clinical outcome and embryo quality according to the two procedures. The cycle characteristics of 100 oocyte donors undergoing ovarian stimulation and IVF outcomes of their 100 oocyte recipients were analysed. Donors were prospectively randomized into two groups on the last day of ovarian stimulation: Group I received a single bolus of 0.2 mg of triptorelin and Group II received 250 microg of recombinant HCG. No differences were observed in the number of oocytes retrieved or in the proportion of metaphase II oocytes between the groups. The OHSS rate was higher in donors that received recombinant HCG ( P = 0.003). Moreover, there was no significant difference between IVF parameters and outcome in the two groups. In conclusion, a GnRH agonist effectively triggers the final oocyte maturation in oocyte donors without negatively affecting implantation, pregnancy or miscarriage rates. Moreover, this regime effectively eliminates the risk of OHSS in this group of women.

Fresh human orthotopic ovarian cortex transplantation: long-term results.

BACKGROUND: Ovarian orthotopic transplantation in patients with premature ovarian failure is reported to result in full-term pregnancies. Ischaemia and freezing/thawing are potentially injurious for tissues. This study was designed to analyse the effect of ischaemia on long-term ovarian function in humans. METHODS: Prospective case-control study. Subjects were 12 premenopausal women undergoing hysterectomy and fresh orthotopic transplantation of the entire ovarian cortex plus a control group of five patients undergoing hysterectomy only. Follow-up lasted 2 years. Serum FSH and anti-Müllerian hormone (AMH) were recorded, and ovulatory cycles were determined by vaginal ultrasound and serum progesterone levels. RESULTS: Follow-up showed that ovulation was restored in 11 of the 12 patients who received grafts over the duration of the study (9.3 +/- 1.73 ovulations versus 12.0 +/- 0.86 in controls, NS), and 9 of 12 patients remained ovulatory after 2 years. We identified four patterns of FSH secretion during the study, 5 of 12 (41.7%) women having the same pattern as controls. There was a trend for serum AMH levels 7 days after surgery (0.16 +/- 0.02 microg/l) to be lower than pre-surgery levels (0.38 +/- 0.09 microg/l, P = 0.07) and higher in women whose FSH patterns suggested normal ovarian function, but the results did not reach significance. After transplantation, FSH correlated more closely (r = -0.639, P = 0.02) with normal ovarian function than AMH (r = 0.465, P = 0.12). CONCLUSIONS: Fresh orthotopic ovarian cortex transplantation is a viable procedure. It maintains normal ovarian function after 2 years in 75% of cases and preserves ovarian function against ischaemia in 41.7% of patients.

Transobturator tape procedure outcome: a clinical and quality of life analysis of a 1-year follow-up.

To report the results obtained with the transobturator sub-urethral tape (TOT) for the surgical treatment of stress urinary incontinence (SUI) after 1 year follow-up. Ninety-three patients diagnosed with SUI or mixed urinary incontinence (MUI) underwent a TOT procedure associated to prolapse surgery, if necessary. Pre-operative quality of life (QoL) was assessed with the Urogenital Distress Inventory Short Form (UDI-6)/Incontinence Impact Questionnaire Short Form (IIQ-7) questionnaires. Surgical and early complications were monitored. A stress test and an urodynamic test if urge incontinence de novo appeared were performed at 1 year follow-up. UDI-6/IIQ-7 questionnaires and SUI symptoms were recorded. Patients' characteristics, pre-operative quality of life and urodynamic evaluation were similar in the TOT and in the pelvic floor surgery group. From the sample, 15% had post-operative retention and 10% had vaginal erosion. The global rate of objective cure was 97% in both groups. The scores of the QoL questionnaires were worse by 9% and 10% with the procedure, respectively. Patients with urodynamic (MUI) or persistence of SUI symptoms (10%) did not reach a significant improvement, although patients with urge incontinence de novo (10%) did. The TOT procedure is safe and effective. Results showed that the association to pelvic floor surgical techniques did not diminish 1 year later. The stress test outcome assessment can overestimate the results, compared to the QoL assessment. In our report, the MUI did not improve with this surgical approach. Our results highlight the necessary employment of both the objective testing and the patient's opinion of her symptoms during daily life.

Diagnosis, management and prognosis of vaginal erosion after transobturator suburethral tape procedure using a nonwoven thermally bonded polypropylene mesh.

PURPOSE: We studied the diagnosis, management and prognosis of vaginal mesh erosion using a thermally bonded nonwoven polypropylene mesh in a transobturator suburethral tape procedure for the surgical treatment of stress urinary incontinence in women. MATERIALS AND METHODS: A total of 65 patients diagnosed with stress urinary incontinence underwent a transobturator suburethral tape procedure with a fusion welded, nonwoven, nonknitted polypropylene mesh, with or without a central silicone coated section, at our institution. All women were followed and if vaginal erosion was diagnosed, cystoscopy and vaginoscopy were performed, the mesh was partially or completely removed and, if necessary, posterior cough test and urodynamic study were performed. RESULTS: Of the 65 patients 9 (13.8%) were diagnosed with vaginal erosion at the vaginal incision during a relatively long postoperative period (mean 290 days). All presented with vaginal discharge and 1 had a severe complication (obturator abscess). Complete mesh removal was necessary in 8 patients and only 2 (22%) had recurrent stress urinary incontinence. CONCLUSIONS: A 13.8% rate of vaginal mesh erosion using a nonwoven thermally bonded polypropylene mesh was reported. This complication was probably due to the characteristics of the mesh and not to the transobturator approach. Complete removal of the tape is recommended and the continence status prognosis is good (78%).

El pólipo endometrial. ¿Es posible plantear una actitud más conservadora que la resección transhisteroscópica? / Endometrial polyps. Is there a more conservative approach than transhysteroscopic removal?

OBJETIVOS: Establecer si es posible plantear una actitud más conservadora que la resección transhisteroscopica del pólipo endometrial valorando la frecuencia relativa de atipias y adenocarcinoma sobre pólipo. MARCO: Intervenciones de histeroscopia quirúrgica realizadas en la Unidad de Cirugía Sin Ingreso (UCSI). PACIENTES: 149 polipectomías realizadas por histeroscopia quirúrgica en la U.C.S.I. del Hospital Universitario Dr. Peset de Valencia entre los años 2000 y 2002. RESULTADOS: - La frecuencia relativa de hiperplasia sin atipias sobre pólipo ha sido del 34 %. - La frecuencia relativa de hiperplasia con atipias sobre pólipo ha sido del 4 %. - La frecuencia relativa de adenocarcinoma sobre pólipo ha sido del 0.6 %. CONCLUSIONES: A la vista de estos resultados y hasta que otros estudios prospectivos y más amplios aporten datos más concluyentes, debemos continuar con nuestra política de extirpar mediante histeroscopia quirúrgica bajo anetesia general todos aquellos pólipos que no podamos eliminar por histeroscopia en consultorio, por cuanto el potencial riesgo de malignización supera el riesgo de las complicaciones quirúrgicas (AU)

OBJETIVE: To establish whether a more conservative approach other than the transhysteroscopic removal of endometrial polyps is possible, taking into account the relative frequency of atypias and adenocarcinoma on the polyps removed. FRAMEWORK: hysteroscopic surgery undertaken in the outpatients surgical unit. PATIENTS: 149 polypectomies carried out by hysteroscopy in the Outpatient Surgical Unit (O.S.U.) of Dr. Peset University Hospital in Valencia between 2000 and 2002. RESULTS: - The relative frequency of non-atypical hyperplasia on the polyp was 34 %. - The relative frequency of atypical hyperplasia on the polyp was 4 %. - The relative frequency of adenocarcinoma on the polyp was 0.6 %. CONCLUSIONS: Bearing these results in mind and until the time when other prospective, more specific, studies can provide more detailed data, we must continue with our policy of using hysteroscopic surgery under general anaesthetic to remove all those polyps that we cannot eliminate by hysteroscopy in the doctor’s surgery, inasmuch as the potential risk of them becoming malignant exceeds any risk of surgical complications (AU)