Assessment of Anti-Mullerian Hormone and Anti-Mullerian Hormone Type II Receptor Variants in Women with Repeated Implantation Failures.

Repeated implantation failure (RIF) is a common endocrine disease that causes female infertility and the etiology is unknown. The abnormal expression of key proteins and hormones at the maternal-fetal interface affected the maternal-fetal communication and leads to adverse pregnancy outcomes. The expression of anti-Mullerian hormone (AMH) and AMH receptor II (AMHRII) was observed in the endometrium. This study aimed to investigate the expression of AMH and AMHRII at the human endometrium, decidual tissue, and blastocyst. Furthermore, the expression of AMH and AMHRII were examined in the RIF patients using immunohistochemistry and quantitative real-time PCR to test the AMHRII expression. The results demonstrated that AMH and AMHRII were present in healthy endometrium and AMHRII was highly expressed in mid-luteal phase. In addition, AMHRII expression was detected throughout the pregnancy and AMHRII's highest expression was in the second trimester. AMHRII was expressed in the blastocysts; however, AMH was not observed. The positive expression rate for AMHRII was significantly higher in the endometrium from RIF. Estrogen receptor (ER), insulin-like growth factor binding protein 1(IGFBP1), and prolactin (PRL) were significantly less expressed in RIF with high expression of AMHRII. The apoptosis was significantly higher in patients with high expression of AMHRII than in patients with normal expression of AMHRII. Our data suggests that AMHRII had an effect on RIF via the AMH and AMHRII signaling pathway. It participated in the development of RIF by interfering with endometrial decidualization and apoptosis.

Assessment of endometrial receptivity during implantation window in women with unexplained infertility.

This study aimed to assess the endometrial receptivity during implantation window in women with unexplained infertility. A prospective study recruited 168 women with unexplained infertility and 169 fertile women. Ultrasonic parameters and biomarkers in the uterine fluid were detected. The endometrial vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were significantly higher in fertile women as compared with unexplained infertile women, and the integrin αvß3, vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), and leukemia inhibitory factor (LIF) levels in uterine fluid were significantly higher in fertile women. The biochemical pregnancy rate, clinical pregnancy rate, and ongoing pregnancy rate in fertile women were 20.12%, 18.34%, and 17.75%, respectively, which were significantly higher compared with unexplained infertile women (7.14%, 5.36%, and 4.17%, respectively). Endometrial thickness (ET), endometrial volume (EV), VI, FI, and VFI measured by ultrasound, and the integrin αvß3, VEGF, TNF-α, and LIF levels in uterine fluid were all significantly higher in pregnant women as compared with nonpregnant women. The best parameters of ultrasonic indicators for predicting endometrial receptivity in women with unexplained infertility were FI(AUC = 0.894, sensitivity 93.8%, and specificity 83.1%). Integrin αvß3 had the best predictive value for endometrial receptivity among biomarkers in the uterine fluid (AUC = 0.921, sensitivity 96.7%, and specificity 89.5%). Women with unexplained infertility present declined endometrial receptivity. Endometrial ultrasonic parameters detected by three-dimensional power Doppler and biomarkers in the uterine fluid may be effective indicators to predict endometrial receptivity.

Long-term medical management of endometriosis with dienogest and with a gonadotropin-releasing hormone agonist and add-back hormone therapy.

Endometriosis can recur after either surgical or medical therapy. Long-term medical therapy is implemented to treat symptoms or prevent recurrence. Dienogest and gonadotropin-releasing hormone (GnRH) analogues with hormone add-back therapy seem to be equally effective for long-term treatment of pain symptoms associated with endometriosis. There is insufficient evidence to support the superiority of one therapy over the other. However, add-back hormone therapy (HT) is recommended for patients using GnRH agonists. The treatment selection depends on therapeutic effectiveness, tolerability, drug cost, the physician's experience, and expected patient compliance.

Comparison of Uterine Receptivity between Fertile and Unexplained Infertile Women by Assessment of Endometrial and Subendometrial Perfusion Using Contrast-Enhanced Ultrasound: Which Index is Better--Peak Intensity or Area under the Curve?

The goal of this study was to compare uterine receptivity between women with normal fertility and those with unexplained infertility during natural cycles by assessment of endometrial and subendometrial perfusion using contrast-enhanced ultrasound (CEUS). We wanted to determine the better index: peak intensity (PI) or area under the curve (AUC). Thirty women with unexplained infertility were recruited into the study group, and 30 women with normal fertility were recruited into the control group. All women underwent CEUS during the late proliferative phase, ovulation phase, and implantation window of a menstrual cycle. Endometrial PI, endometrial AUC, subendometrial PI and subendometrial AUC were analyzed. In the late proliferative phase, the control group had a significantly higher endometrial PI (p < 0.001) as well as subendometrial PI (p < 0.001) and AUC (p = 0.004) than the study group. In the ovulation phase, the control group had a significantly higher endometrial PI (p < 0.001) and AUC (p = 0.021), as well as subendometrial PI (p < 0.001) and AUC (p = 0.003). During the implantation window, there were no significant differences between the two groups. Only subendometrial PI underwent a significant periodic change during the menstrual cycle in both groups. This finding was further confirmed by evaluation of the microvessel density of endometria. In conclusion, CEUS can be used to assess endometrial and subendometrial perfusion to evaluate uterine receptivity. Subendometrial PI was the most sensitive index compared with endometrial PI, endometrial AUC and subendometrial AUC.

Cost-effectiveness of diagnostic strategies for the management of abnormal uterine bleeding (heavy menstrual bleeding and post-menopausal bleeding): a decision analysis.

BACKGROUND: Heavy menstrual bleeding (HMB) and post-menopausal bleeding (PMB) together constitute the commonest gynaecological presentation in secondary care and impose substantial demands on health service resources. Accurate diagnosis is of key importance to realising effective treatment, reducing morbidity and, in the case of PMB, reducing mortality. There are many tests available, including transvaginal scan (TVS), endometrial biopsy (EBx), saline infusion sonography and outpatient hysteroscopy (OPH); however, optimal diagnostic work-up is unclear. OBJECTIVES: To determine the most cost-effective diagnostic testing strategy for the diagnosis and treatment of (i) HMB and (ii) PMB. DATA SOURCES: Parameter inputs were derived from systematic quantitative reviews, individual patient data (IPD) from existing data sets and focused searches for specific data. In the absence of data estimates, the consensus view of an expert clinical panel was obtained. METHODS: Two clinically informed decision-analytic models were constructed to reflect current service provision for the diagnostic work-up of women presenting with HMB and PMB. The model-based economic evaluation took the form of a cost-effectiveness analysis from the perspective of the NHS in a contemporary, 'one-stop' secondary care clinical setting, where all indicated testing modalities would be available during a single visit. RESULTS: Two potentially cost-effective testing strategies for the initial investigation of women with HMB were identified: OPH alone or in combination with EBx. Although a combination testing strategy of OPH + EBx was marginally more effective, the incremental cost-effectiveness ratio (ICER) was approximately £21,000 to gain one more satisfied patient, whereas for OPH it was just £360 when compared with treatment with the levonorgestrel intrauterine system (LNG-IUS) without investigation. Initial testing with OPH was the most cost-effective testing approach for women wishing to preserve fertility and for women with symptoms refractory to empirical treatment with a LNG-IUS. For the investigation of PMB, selective use of TVS based on historical risk prediction for the diagnostic work-up of women presenting with PMB generated an ICER compared with our reference strategy of 'no initial work-up' of £129,000 per extra woman surviving 5 years. The ICERs for the two other non-dominated testing strategies, combining history and TVS or combining OPH and TVS, were over £2M each. LIMITATIONS: In the absence of IPD, estimates of accuracy for test combinations presented some uncertainty where test results were modelled as being discordant. CONCLUSIONS: For initial investigation of women presenting to secondary care with HMB who do not require preservation of their fertility, our research suggests a choice between OPH alone or a combination of OPH and EBx. From our investigation, OPH appears to be the optimal first-line diagnostic test used for the investigation of women presenting to secondary care with HMB wishing to preserve their fertility or refractory to previous medical treatment with the LNG-IUS. We would suggest that the current recommendation of basing the initial investigation of women with PMB on the universal TVS measurement of endometrial thickness at a 5-mm threshold may need to be replaced by a strategy of restricting TVS to women with risk factors (e.g. increasing age-raised body mass index, diabetes or nulliparity), obtained from the preceding clinical assessment. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Avaliação endometrial em pacientes usuárias de tamoxifeno / Endometrial assessment in patients taking tamoxifen

O câncer de mama é a neoplasia maligna mais frequente em mulheres tanto no Brasil quanto no mundo. A doença é mais comum acima dos 50 anos, coincidindo com a faixa etária de risco para o câncer de endométrio. O tamoxifeno é um modulador seletivo de receptor de estrogênio (SERMs), usadona terapêutica das mulheres portadoras de câncer de mama. Assim como os outros SERMs (raloxifeno,toremifeno,arzoxifeno e lasoxifeno), o tamoxifeno pode atuar como antagonista ou agonista, dependendo do tecido-alvo.Nestas pacientes, o uso destes agonistas seletivos embora apresente maior benefício do que risco para o tratamento do câncer de mama, pode causar efeitos secundários no endométrio, com aumento do risco para doenças malignas. Consensos atuais, porém, não demonstram benefício de nenhum método de rastreio para câncer endometrial de rotina. O que se recomenda, nas pacientes na pré e pós-menopausa com câncer de mama, é o exame ginecológico com intervalo anual e o prosseguimento com propedêutica, através de biópsia do endométrio nas pacientes pós-menopausa que apresentam sangramento vaginal.(AU)

Breast cancer is the most common malignancy in women both in Brazil and in the world. The disease is more common over 50 years, coinciding with the age of risk for endometrial cancer. Tamoxifen is a selective modulator of estrogen receptor (SERMs) used in the treatment of women with breast cancer. Like other SERMs (raloxifene, toremifene, arzoxifeno and lasoxifeno), tamoxifen may act as antagonist or agonist depending on the target tissue. In these patients, although showing greater benefit of what risk for the treatment of the breast cancer, can cause side effects on the endometrium, with increased risk for malignant diseases. Current consensus, however, do not demonstrate any benefit from routine screening method for endometrial cancer. Women with breast cancer should undergo annual gynecologic examinations for premenopausal and postmenopausal patients and further workup by means of biopsy in patients with postmenopausal vaginal bleeding.(AU)

Receptivity assessment of an ultrasonographic homogeneous endometrium in the late follicular phase of infertile women with natural cycles.

OBJECTIVE: The purpose of this study was to assess the receptivity of the homogeneous endometrium in the late follicular phase in infertile women with natural cycles. STUDY DESIGN: Twenty-eight infertile women with ultrasonographically homogeneous (group 1) or trilaminar (group 2) endometria in the late follicular phase underwent endometrial biopsies. Some molecular markers and development of pinopodes were evaluated. RESULTS: In the late follicular phase, the mean level of vascular endothelial growth factor was significantly lower in group 1 than in group 2 (0.96 ± 0.37 marks vs 1.39 ± 0.46 marks; P = .010). In the mid luteal phase, a decreased leukemia inhibitory factor and integrin alpha v beta 3 levels were found in group 1 (1.58 ± 0.99 marks vs 2.59 ± 0.61 marks; 1.85 ± 0.72 marks vs 2.60 ± 0.73 marks; 1.92 ± 0.91 marks vs 2.83 ± 0.57 marks; P = .003; P = .011; P = .004). The rate of fully developed pinopodes in the mid luteal phase was significantly decreased in group 1 (P = .018). CONCLUSION: An ultrasonographically homogeneous endometrium in the late follicular phase was associated with poor receptivity in infertile women with natural cycles.

Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin ZK 137 316: morphometric assessment of the uterus and oviduct.

The long-term effects of the antiprogestin ZK 137 316 on reproductive tract morphology in rhesus macaques were investigated. The monkeys were injected daily (i.m.) for five menstrual cycles with vehicle or 0.01, 0.03 or 0.1 mg ZK 137 316/kg body weight. Reproductive tracts (n = 3/ group) were collected during the mid-luteal phase (day 8) of the fifth cycle in the control, 0.01 and 0.03 mg/kg groups, or 6-7 days after the oestradiol peak in the 0.1 mg/kg group. ZK 137 316 treatment resulted in a dose-dependent atrophy of the endometrium, marked by reduced mitotic activity in the glands, compaction of the stroma, degradation of spiral arteries and dilation of veins. There was no effect of ZK 137 316 on myometrial or oviductal weight. Treatment with 0.1 and 0.03 mg/kg, but not 0.01 mg/kg resulted in fully ciliated and secretory oviducts, indicating a dose-dependent blockade of progesterone antagonism of oestrogen-dependent oviductal differentiation. In the endometrium, the suppressive action of progesterone on oestrogen and progestin receptors was also blocked by ZK 137 316 in a dose-dependent manner. However, endometrial atrophy appeared due to inhibition of progesterone action together with a blockade of oestrogen-dependent proliferation. The profoundly suppressed endometrium produced by chronic low-dose ZK 137 316 treatment is unlikely to support implantation. Such treatment may therefore provide a novel contraceptive modality.

Endometrial biopsy in DUB.

OBJECTIVE: To determine the incidence of abnormal endometrial histology in women with dysfunctional uterine bleeding and to evaluate the predictive value of risk factors for endometrial cancer in women with dysfunctional uterine bleeding (DUB). STUDY DESIGN: We conducted a retrospective review of 310 women with DUB who underwent endometrial biopsy. The risk factors for abnormal endometrial histology included menstrual cycle irregularity, diabetes, nulliparity, hypertension, weight > or = 100 kg and age > or = 40 years. The incidence of endometrial abnormalities was determined, and the predictive value of combinations of risk factors was assessed using stepwise logistic regression. RESULTS: Twenty-one patients (6.7%) had abnormal endometrial biopsies. Menstrual cycle irregularity (P = .0001), age > or = 40 years (p = .022) and hypertension (P = .058) were independently significant risk factors for abnormal endometrial histology. The probability of abnormal endometrial histology in a premenopausal woman with DUB whose cycle was regular was < 1%. The presence of menstrual cycle irregularity increased the probability of abnormal endometrial histology to 14.3%. CONCLUSION: The patient who presents with DUB and a history of menstrual cycle irregularity warrants an endometrial biopsy, regardless of age. The current clinical emphasis on age (especially > or = 40 years) as justification for endometrial biopsy is unwarranted in patients with DUB. More careful selection of patients for endometrial biopsy will mean that fewer women are unnecessarily exposed to the discomfort and risk of complications associated with endometrial biopsy.

Vaginal color Doppler assessment of uterine artery impedance correlates with immunohistochemical markers of endometrial receptivity required for the implantation of an embryo.

OBJECTIVE: To investigate the correlation between uterine artery impedance with immunohistochemical histologic, and ultrasonographic markers of uterine receptivity. DESIGN: A prospective study of subfertile women undergoing a frozen embryo replacement cycle. SETTING: A tertiary infertility clinic. PATIENTS: The study was based on 86 patients who had failed to become pregnant during a standard IVF treatment cycle and who had at least two good quality embryos cryopreserved. INTERVENTIONS: All patients had pituitary desensitization with the GnRH analogue buserelin acetate, followed by E2 and P replacement therapy. Vaginal color Doppler images of both uterine arteries were obtained on days 7, 14, and 21 of the first (trial) cycle. On day 21, an endometrial biopsy was taken for dating a 24-kd protein, placental protein 14, and E2 receptor assessment. After a menstrual bleed had been induced, administration of estrogen and P was reinstituted and embryos transferred to the uterus on the 3rd or 4th day of P administration. MAIN OUTCOME MEASURES: The mean pulsatility index of the left and right uterine arteries, a semiquantitative score of endometrial 24-kd protein, PP14, and E2 receptor assessment, endometrial histologic dating, and pregnancy outcome. RESULTS: Nineteen of 76 patients who had a successful ET became pregnant. The pulsatility index on day 14 of both the trial and ET cycles was significantly lower in those who achieved pregnancy as compared with those who did not conceive: 2.65 (range 1.3 to 3.4) versus 3.85 (1.8 to 6.8) and 2.85 (1.4 to 3.6) versus 4.15 (2.1 to 6.8), respectively. There were significant correlations between pulsatility index and 24-kd protein, E2 receptor, and endometrial histology but not with PP14 and endometrial thickness. CONCLUSIONS: Uterine artery impedance has a significant correlation with biochemical markers of uterine receptivity and accurately predicts the probability of pregnancy in frozen embryo replacement cycles. It is a useful method for assessing uterine receptivity in assisted conception programs.