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Characterizing the endometrium in unexplained and tubal factor infertility: A multiparametric investigation
Abstract
To characterize endometrial development in unexplained and tubal factor infertility.
Prospective study of 20 women with unexplained infertility, 22 with tubal factor infertility, and 21 fertile controls in the midproliferative, periovulatory, and midluteal phases of the menstrual cycle.
Reproductive Medicine Department of St. Mary's Hospital, Manchester, United Kingdom.
Women awaiting assisted conception.
Serum hormone assays, transvaginal ultrasound, Doppler, and midluteal endometrial biopsies.
Serum levels of E2, P, and LH, endometrial ultrasound morphometry, uterine and subendometrial artery Doppler, and endometrial histology and biochemistry.
Women with unexplained infertility demonstrated significantly reduced uterine artery flow velocity in all phases, significantly elevated uterine and subendometrial artery impedance in the periovulatory and midluteal phases, and significantly reduced endometrial texture in the midproliferative phase. Women with tubal factor infertility demonstrated significantly reduced uterine artery flow velocity, without a concomitant increase in impedance, and significantly greater expression of endometrial glandular and luminal keratan sulphate.
Unexplained infertility is associated with a profound impairment of endometrial perfusion that might be amenable to treatment by perfusion enhancers. Tubal factor infertility is associated with endometrial developmental defects that might be corrected by salpingectomy. Endometrial ultrasound and Doppler studies are likely to become a vital tool in the investigation of infertility.
... A large spectrum of vascular changes, including hyaline thickening of the vascular wall, small vessel thrombosis, and high vascular density with endothelial proliferation and swelling has been reported in the functional layer of the endometrium of 39% of asymptomatic infertile women [14]. Infertile patients demonstrated significantly reduced uterine artery flow velocity in all menstrual phases, and significantly elevated uterine and subendometrial artery impedance in the periovulatory and midluteal phases [21]. It has been proposed that vascular changes in the endometrium of infertile women might present an evolving stage of vasculopathy that is related to CE. ...
... All women with highly suspected endometriosis who had previously undergone infertility treatment were also excluded from final analysis. Women with tubal, ovulatory, and male infertility factors were excluded from the infertility group, to compare infertile women with only uterine infertility factor (EP) with fertile women, thereby avoiding the confounding effect of other infertility factors [8,9,14,21]. ...
Study objective:
To evaluate the prevalence of chronic endometritis (CE) among fertile and infertile women who underwent hysteroscopic polypectomy.
Design:
A retrospective cohort study.
Setting:
University-affiliated tertiary hospital.
Patients:
A total of 277 women who underwent hysteroscopic polypectomy in the period from 2015 to 2018.
Interventions:
Endometrial polyp samples were obtained after hysteroscopy for histopathologic analysis using hematoxylin-eosin and immunohistochemistry staining with CD138 antibodies for plasma cell detection. All infertile women diagnosed with CE were treated with oral doxycycline 100 mg twice daily for 14 days before infertility treatment.
Measurements and main results:
The prevalence of CE in infertile women (n = 137) was significantly higher than in those with no history of infertility (n = 140) (22.6% vs 8.6%; p = .001). The prevalence of CE between women with primary infertility and those with secondary infertility was similar (25.0% vs 19.3%; p = .43). Clinical pregnancy (32.3% vs 41.5%; p = .35), live birth (29.0% vs 38.7%; p = .33), and miscarriage (10.0% vs 6.8%; p = .73) rates were similar between infertile women with treated CE and those without CE. A multivariate model showed that diagnosis of infertility was significantly associated with the diagnosis of CE (odds ratio, 3.16; 95% confidence interval, 1.53-6.49).
Conclusion:
In women with endometrial polyps, the prevalence of CE in infertile women is higher than that in fertile women. Pregnancy outcome in infertile women with treated CE was similar to those who were infertile and without CE.
... Unexplained infertility (UI) constitutes an important portion of the infertility reasons (up to 30%) [2] and is diagnosed when the causes of male or female infertility remains unknown. Increase in the resistance of uterine, endometrial and subendometrial arteries is detected in patients with UI during peri-implantation period [3][4][5]. On the other hand, increased uterine artery resistance [5] or decreased blood flow [4] in patients with tubal factor infertility (TFI) have been reported. ...
... Increase in the resistance of uterine, endometrial and subendometrial arteries is detected in patients with UI during peri-implantation period [3][4][5]. On the other hand, increased uterine artery resistance [5] or decreased blood flow [4] in patients with tubal factor infertility (TFI) have been reported. ...
We aimed to compare ovarian (O), uterine (U) and spiral (S) artery (A) resistance of patients diagnosed as fertile, unexplained infertility (UI) and tubal factor infertility (TFI) in the peri-implantation period and independent from the impact of the treatment. UI (n = 70), TFI (n = 75) and fertile (n = 72) patients' ovarian, uterine and spiral artery pulsatility index (PI), resistance index (RI) and the endometrial thickness, serum estradiol and progesterone levels were compared. The specificity and sensitivity values were calculated according to determined cutoff values. Both TFI and control groups' UA PI values were significantly lower than the UI group's PI values. The highest UA RI values were found in UI group and the lowest values were in the control group. UI and TFI groups' OA PI/RI values were significantly higher than the control group. Both the control and TFI groups' SA PI/RI values were significantly lower than UI group's PI/RI values. UI patients' uterine and spiral arteries PI values >1.86 and >0.85, RI values >0.80 and >0.53 can be used as a valuable test showing reduced uterine perfusion. Ovarian artery PI values >0.96 and RI values >0.58 can be used as tests showing decreased ovarian perfusion in patients with TFI. In these patients, embryo cryopreservation can be considered.
... In the present study endometrial blood flow was multifocal in 72% women in the study group whereas in the control group, only 38% women had multifocal blood flow (P = 0.001). Edi Osagie et al. 13 in their multiparametric approach concluded that women with unexplained infertility had a consistent impairment of endometrial perfusion in all phases of the cycle. Till date, to the best of our knowledge there has been no controlled randomized study to assess the effect of GnRH antagonist on endometrial blood flow. ...
... On compiling all the scores of individual parameters we computed a total biophysical profile score. It was seen in the present study that 66% women who were administered GnRH antagonist had a favorable score (11)(12)(13)(14)(15) whereas in the control group it was only in 18% cases. Thus, it was concluded that there was a statistically significant difference between the two groups in uterine score (P <0.001). ...
... ET-1 is expressed in the endometrium of humans and is inversely related to the plasma levels of estradiol [47], indicating that they both might work together, regulating blood flow to the endometrium. Metformin may influence uterine perfusion by decreasing androgen levels [48,49], exerting a vasoconstrictive impact on vascular tissues [50]. This study had several limitations. ...
Polycystic ovary syndrome (PCOS) is one of the most prevalent metabolic diseases during female reproductive life, often associated with insulin resistance and hyperprolactinemia. The efficacy of metformin and cabergoline for managing PCOS remains debated in the literature. This three-arm interventional study in Iraq assessed the effects of these drugs on body mass index (BMI), hormonal balance, and uterine artery blood flow in 75 women with PCOS and hyperprolactinemia. Participants were randomized into three groups: metformin (500 mg twice daily), cabergo-line (0.5 mg weekly), and a combination of both, with 25 patients in each group. Baseline and 90-day follow-up characteristics included BMI, serum hormonal levels, and ultrasound features. Metformin resulted in significant weight reduction (p=0.038); however, the addition of cabergoline caused a more significant reduction in body mass index (p=0.001). The combined treatment significantly lowered testosterone levels (p=0.008). In addition, this combination significantly reduced the level of LH (p=0.043) and increased the level of FSH (p=0.047). The results suggest that metformin and cabergoline when used together, act synergistically and safely to reduce BMI, testosterone, and LH levels while increasing FSH levels. Furthermore, this combination improved endometrial blood flow and ovulation in women with PCOS.
... In women investigated for infertility, endometrial biopsy for histological examination is not recommended in the absence of other indications (Coutifaris et al., 2004;Edi-Osagie et al., 2004). ...
Study question:
What is the recommended management for couples presenting with unexplained infertility (UI), based on the best available evidence in the literature?
Summary answer:
The evidence-based guideline on UI makes 52 recommendations on the definition, diagnosis, and treatment of UI.
What is known already:
UI is diagnosed in the absence of any abnormalities of the female and male reproductive systems after 'standard' investigations. However, a consensual standardization of the diagnostic work-up is still lacking. The management of UI is traditionally empirical. The efficacy, safety, costs, and risks of treatment options have not been subjected to robust evaluation.
Study design, size, duration:
The guideline was developed according to the structured methodology for ESHRE guidelines. Following formulation of key questions by a group of experts, literature searches, and assessments were undertaken. Papers written in English and published up to 24 October 2022 were evaluated.
Participants/materials, setting, methods:
Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the guideline development group (GDG). Following stakeholder review of an initial draft, the final version was approved by the GDG and the ESHRE Executive Committee.
Main results and the role of chance:
This guideline aims to help clinicians provide the best care for couples with UI. As UI is a diagnosis of exclusion, the guideline outlined the basic diagnostic procedures that couples should/could undergo during an infertility work-up, and explored the need for additional tests. The first-line treatment for couples with UI was deemed to be IUI in combination with ovarian stimulation. The place of additional and alternative options for treatment of UI was also evaluated. The GDG made 52 recommendations on diagnosis and treatment for couples with UI. The GDG formulated 40 evidence-based recommendations-of which 29 were formulated as strong recommendations and 11 as weak-10 good practice points and two research only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, one by moderate-quality evidence, nine by low-quality evidence, and 31 by very low-quality evidence. To support future research in UI, a list of research recommendations was provided.
Limitations, reasons for caution:
Most additional diagnostic tests and interventions in couples with UI have not been subjected to robust evaluation. For a large proportion of these tests and treatments, evidence was very limited and of very low quality. More evidence is required, and the results of future studies may result in the current recommendations being revised.
Wider implications of the findings:
The guideline provides clinicians with clear advice on best practice in the care of couples with UI, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. The full guideline and a patient leaflet are available in www.eshre.eu/guideline/UI.
Study funding/competing interest(s):
The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline in collaboration with the Monash University led Australian NHMRC Centre of Research Excellence in Women's Health in Reproductive Life (CREWHIRL). The guideline group members did not receive any financial incentives; all work was provided voluntarily. D.R. reports honoraria from IBSA and Novo Nordisk. B.A. reports speakers' fees from Merck, Gedeon Richter, Organon and Intas Pharma; is part of the advisory board for Organon Turkey and president of the Turkish Society of Reproductive Medicine. S.B. reports speakers' fees from Merck, Organon, Ferring, the Ostetric and Gynaecological Society of Singapore and the Taiwanese Society for Reproductive Medicine; editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press; is part of the METAFOR and CAPE trials data monitoring committee. E.B. reports research grants from Roche diagnostics, Gedeon Richter and IBSA; speaker's fees from Merck, Ferring, MSD, Roche Diagnostics, Gedeon Richter, IBSA; E.B. is also a part of an Advisory Board of Ferring Pharmaceuticals, MSD, Roche Diagnostics, IBSA, Merck, Abbott and Gedeon Richter. M.M. reports consulting fees from Mojo Fertility Ltd. R.J.N. reports research grant from Australian National Health and Medical Research Council (NHMRC); consulting fees from Flinders Fertility Adelaide, VinMec Hospital Hanoi Vietnam; speaker's fees from Merck Australia, Cadilla Pharma India, Ferring Australia; chair clinical advisory committee Westmead Fertility and research institute MyDuc Hospital Vietnam. T.P. is a part of the Research Council of Finland and reports research grants from Roche Diagnostics, Novo Nordics and Sigrid Juselius foundation; consulting fees from Roche Diagnostics and organon; speaker's fees from Gedeon Richter, Roche, Exeltis, Organon, Ferring and Korento patient organization; is a part of NFOG, AE-PCOS society and several Finnish associations. S.S.R. reports research grants from Roche Diagnostics, Organon, Theramex; consulting fees from Ferring Pharmaceuticals, MSD and Organon; speaker's fees from Ferring Pharmaceuticals, MSD/Organon, Besins, Theramex, Gedeon Richter; travel support from Gedeon Richter; S.S.R. is part of the Data Safety Monitoring Board of TTRANSPORT and deputy of the ESHRE Special Interest Group on Safety and Quality in ART; stock or stock options from IVI Lisboa, Clínica de Reprodução assistida Lda; equipment/medical writing/gifts from Roche Diagnostics and Ferring Pharmaceuticals. S.K.S. reports speakers' fees from Merck, Ferring, MSD, Pharmasure. HRV reports consulting and travel fees from Ferring Pharmaceuticals. The other authors have nothing to disclose.
Disclaimer:
This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).
... A number of studies showed that poor uterine and ovarian blood flow can be an important -often undiagnosed factor -in infertility, miscarriage and IVF failure; research shows that poor blood flow may be at the root of 'unexplained infertility' too. However, most women with a diagnosis of 'unexplained' would never be offered the diagnostic test for uterine blood flow impairment and would never be offered treatment, instead they would retain their frustrating nonspecific diagnosis of 'unexplained' (2) . ...
... 10 When the endometrium is not appropriately primed for implantation of the blastocyst, pregnancy failure results. Some studies have postulated that abnormal endometrial receptivity secondary to impaired uterine and endometrial vascularity may play a role in the pathogenesis of unexplained infertility, 3,4,[11][12][13][14] whereas others have refuted this, reporting that impaired uterine or endometrial blood flow is not a significant factor in unexplained infertility. 5,15 Following a diagnosis of unexplained infertility, if natural conception is deemed not achievable, such couples are often referred for assisted reproductive techniques (ARTs) with in vitro fertilisation (IVF) being the most commonly offered. ...
Objectives:
To investigate the uterine artery Doppler parameters and endometrial characteristics in women with unexplained infertility.
Methods:
A prospective case-control study of 42 women with unexplained infertility and 42 fertile controls. Their mid-luteal phase transvaginal Doppler parameters of both uterine arteries and endometrial characteristics (endometrial blood flow, thickness and volume) were investigated and analysed. P values < 0.05 was statistically significant.
Results:
The mean uterine artery pulsatility index (PI) and resistivity index (RI) of the cases (women with unexplained infertility) were significantly higher compared to the values in the fertile controls (PI = 2.81±0.61 vs 2.15±0.65; p=0.001) (RI= 0.87±0.08 vs 0.82±0.07; p=0.003). In addition, the end-diastolic volume (EDV) (6.12±4.17 vs 9.37±5.14; p=0.007) and endometrial-subendometrial blood flow (p=0.036) were significantly lower in the cases compared to the controls. Multivariate logistics analysis showed that PI was independently associated with infertile status (p=0.006). There was no significant difference in the mean PSV (48.69±10.9 vs 50.58±11.30; p=0.602), endometrial thickness (10.30+3.13 vs 10.72+3.10; p=0.544), endometrial volume (7.82+1.56 vs 8.23+1.71; p=0.323), mean age (32.28±4.062 vs 31.91±3.58 years; p=0.502), body mass index (26.15±2.71kg/m2 vs 25.24±2.85 kg/m2; p=0.18) menstrual bleeding days (4.07±0.89 days vs 4.02±0.95 days; p=0.481) duration of menstrual cycle (28.02±1.09 days vs 27.64±1.36 days; p= 0.162), smoking history (p=0.909) and alcohol intake (p=0.507) of the infertile women compared with the fertile controls, respectively.
Conclusion:
Women with unexplained infertility have increased uterine artery Doppler PI and RI and reduced endometrial-subendometrial perfusion compared with fertile controls.
... Edi-Osagie et al suggested that a favorable outcome might be expected with enhancing uterine perfusion in unexplained infertility cases. 25 Treatment with sildenafil citrate improved endometrial thickness, increased pregnancy rate as well as opposing the endometrial adverse outcomes associated with clomiphene treatment. 15,26,27 Isosorbide mononitrite significantly improved uterine artery and sub-endometrial perfusion. ...
Background: Impaired sub-endometrial perfusion might reduce endometrial receptivity and possibly contribute to unexplained infertility. A favorable effect on sub-endometrial blood flow has been demonstrated with nitric oxide.Methods: This randomized controlled trial evaluated the effect of nitroglycerine on uterine and sub-endometrial blood flow in women with unexplained infertility. Sixty women were randomized into 2 equal groups. The study group received 5mg nitroglycerine patch daily from day 2 of the cycle till the evaluation day and the control group received no treatment. Independent of the study arms, 30 parous women were included as the fertile group. Six to eight days after detecting luteinizing hormone surge, women were assessed for endometrial thickness, uterine artery blood flow with color Doppler and sub-endometrial blood flow with three-dimensional power Doppler.Results: Compared to fertile women, cases with unexplained infertility (control group) had a significantly thinner endometrium, higher uterine artery Doppler indices and lower sub-endometrial blood flow. Women who received nitroglycerin showed a significant improvement in sub-endometrial blood flow while uterine artery blood flow did not show a significant difference; however, the values were also comparable to fertile women. In addition, no effect on endometrial thickness was found with nitroglycerin treatment. Nitroglycerin treatment side effects were headache, blurring of vision and hypotension. These adverse effects were not significant compared to controls.Conclusions: In women with unexplained infertility, nitroglycerin significantly improved the sub-endometrial blood flow but did not affect the endometrial thickness.
... Defects of the endometrium that contribute to infertility have been linked to a wide array of disorders, including endometriosis, endometrial injury, endometrial fibrosis, and endometrial adhesions, all of which can reduce endometrial receptivity and negatively impact implantation [59][60][61]. Compromised receptivity of the endometrium is a major cause of unexplained infertility, implantation failure, and subclinical pregnancy loss [62][63][64]. As the diseases linked to endometrial defects easily recur and have many sequelae, consequently, searching for a safe and effective treatment which can repair the defect is being necessary in the reproductive field [65]. ...
Infertility is a global reproductive disorder which is caused by a variety of complex diseases. Infertility affects the individual, family, and community through physical, psychological, social and economic consequences. The results from recent preclinical studies regarding stem cell-based therapies are promising. Stem cell-based therapies cast a new hope for infertility treatment as a replacement or regeneration strategy. The main features and application prospects of mesenchymal stem cells in the future of infertility should be understood by clinicians. Mesenchymal stem cells (MSCs) are multipotent stem cells with abundant source, active proliferation, and multidirectional differentiation potential. MSCs play a role through cell homing, secretion of active factors, and participation in immune regulation. Another advantage is that, compared with embryonic stem cells, there are fewer ethical factors involved in the application of MSCs. However, a number of questions remain to be answered prior to safe and effective clinical application. In this review, we summarized the recent status of MSCs in the application of the diseases related to or may cause to infertility and suggest a possible direction for future cytotherapy to infertility.
... Many studies concluded that decreased uterine artery blood flow and endometrial perfusion could be an important factor for diagnosis of unexplained infertility, abortion, and in vitro fertilization (IVF) failure [6]. Many studies concluded that women with unexplained infertility had higher uterine artery impedance than that of the normal fertile women so decreased uterine artery blood flow and uterine perfusion could be a cause of unexplained infertility [7]. ...
Background
The study aimed to compare the values of uterine artery Doppler indices including resistance index (RI), pulsatility index (PI), and systolic/diastolic (S/D) ratios in fertile female and female with unexplained infertility and investigate their association with unexplained infertility. This study included 70 women divided into two groups. Study group included 40 women with unexplained infertility and control group included 30 fertile women.
Results
The mean ages of study and control groups were 26.9 and 28.5 years respectively. In infertile group, the mean values of uterine arteries resistance index (RI), pulsatility index (PI), and systolic/diastolic (S/D) ratios were 0.9, 2.9, and 8.0 respectively. In the fertile control group, mean RI and PI values and S/D ratio were 0.6, 1.5, and 2.7 respectively. There was statistically significant difference as regards RI, PI, and S/D ratios between study and control groups. The best cut off values of RI, PI, and S/D ratios for predicting increased uterine blood flow impedance were more than 0.67, 1.95, and 3 respectively with sensitivity of 100%, 95%, and 100% respectively, specificity of 96.7%, 86.7%, and 96.7% respectively, and diagnostic accuracy of 98.6%, 91.42%, and 98.57% respectively.
Conclusion
Uterine artery Doppler indices mean values were higher in unexplained infertility women than fertile women. Uterine artery Doppler indices have high sensitivity and specificity for diagnosis of high uterine blood flow impedance. High uterine blood flow impedance diagnosed by uterine artery Doppler may contribute in the etiology of unexplained infertility. Uterine artery Doppler should be included in investigation of unexplained infertility.
... Pulsed wave Doppler was used with a sampling gate set at 2 mm to image the entire vessel. The angle of insonation was set at less than 60 as previously described by Edi-Osagie et al. (2004). Three consecutive similar waveforms were obtained. ...
Traditionally, the assessment of endometrial receptivity at transvaginal ultrasound scan has been based on the thickness and the morphological appearance of the endometrium. The objective of this study was to prospectively evaluate endometrial thickness (ET), endometrial morphology and uterine artery Doppler parameters prior to assisted reproduction treatment (ART) in the prediction of pregnancy outcome. This was a prospective cohort study. ET, morphology and uterine artery Doppler (UtAD) pulsatility index (PI) and resistance index (RI) were measured in the mid-luteal stage of the menstrual cycle ultrasonographically, timed with urinary luteinizing hormone testing. A total of 50 women were included in the analysis. The clinical pregnancy rate (CPR) per embryo transfer was 42.0% (n = 21/50). Twenty nine women (58.0%) had an unsuccessful outcome. There were no differences in mean ± SD endometrial thickness (ET) (10.0 ± 1.8 mm vs. 10.5 ± 2.4; p = 0.43), or endometrial morphology (100% (n = 21) vs 100% (n = 29); p = 1.00) between the pregnant and not pregnant groups. Similarly, there were no differences in mean ± SD UtAD PI (2.17 ± 0.83 vs. 2.07 ± 0.81; p = 0.67 or mean ± SD UtAD RI (0.84 ± 0.10 vs. 0.81 ± 0.10; p = 0.30). Ultrasonographic endometrial assessment did not differentiate between those who would have a subsequent clinical pregnancy.
... 2 Various cellular and molecular defects in the endometrium are believed to be the primary cause of unexplained infertility. [3][4][5] Considering the importance of the immune system in the success of pregnancy, it is believed that at least 50% of unexplained infertilities are due to an imbalance in the immune system activation during the pregnancy course. 1 Adaptive immune responses led by T helper cells play a critical role in the pregnancy period. In recent years, several subsets of T CD4 + helper cells regulating the immune responses in a network manner have been introduced. ...
Unexplained infertility (UI) is one of the most common diagnoses in the fertility care. Seminal plasma (SP) plays a crucial role in the regulation of female immune responses and the success of a pregnancy. In vitro fertilization (IVF) is a well-known method for the treatment of UI. In this study, we aimed to investigate the effect of SP on the differentiation of T helper (Th) cell subsets and the relationship between these subsets with the rate of IVF success in a group of women complicated with UI compared to those with normal pregnancy. This study was conducted on 20 UI couples (ten with successful and ten with unsuccessful IVF outcome) and 10 fertile couples as the control group. Four color flow cytometry technique was used to detect Th cell subsets in the peripheral blood mononuclear cells (PBMC) with or without stimulation by SP. Results indicated that the frequencies of IL-17+ and Foxp3+ T cells after incubation with SP was significantly increased in couples with unsuccessful IVF outcome as compared to successful and healthy groups (p<0.05). Additionally, a positive correlation was observed between Th1 and Th2 cells in the unsuccessful IVF group (R=0.6, p=0.03). In summary, the results of the present study demonstrated that exposure to SP might increase Th17 and Treg cell frequencies in infertile women with unsuccessful IVF, and might also balance inflammatory to regulatory responses to finally tune-up the Th1/Th2/Th17/Treg balance and support the success of IVF.
... Inadequate uterine receptivity is responsible for approximately two-thirds of implantation failures (37). A range of cellular and molecular endometrial defects has been associated with unexplained infertility (38). Microarray analysis demonstrated that endometrial gene expression at the time of embryo implantation is considerably different in the unexplained infertile patients compared to the fertile women (39). ...
Background:
Failure in the endometrial receptivity may account for a significant number of infertility cases including unexplained infertility in women. Reduction in the endometrial estrogen receptor-alpha (ER-α) expression during implantation may be a critical event that coincides with the expression of specific genes and the formation of a receptive endometrium. The aim of the present study was to assess the expression of ER-α in the mid-secretory phase in the endometrium of women with unexplained infertility.
Materials and methods:
This case-control study was carried out on randomly selected fertile (n=10) and infertile (n=16) women whose source of infertility remained unexplained. We evaluated the expression of ER-α and glycodelin- A (GdA) through mRNA level measurement with real-time polymerase chain reaction (PCR) in the endometrium of fertile women and patients suffering from unexplained infertility and fertile women. Endometrial biopsies of each subject were collected during a single menstrual cycle 7 days after the peak of luteinizing hormone (LH+7).
Results:
Endometrial expression level of ER-α was significantly (P<0.05) higher in the patients with unexplained infertility compared to the control. Significantly (P<0.05) lower levels of GdA expression were seen in women with unexplained infertility. A statistically non-significant negative correlation was observed between ER-α and GdA mRNA expression.
Conclusion:
Our findings demonstrate that reduction in the endometrial GdA expression is associated with elevated expression of ER-α in mid-luteal phase. Disruption in the endometrial ER-α expression, which leads to defects in uterine receptivity, may contribute to unexplained infertility.
... Thus, the present study could not establish inadequate vascularization of the endometrium as one of the factors involved in unexplained infertility as observed by Sahasrabudhe et al. [4] Deficient blood flow to the endometrium as studied by Edi-Osagie et al. and Steer et al., might be the reason in such cases. [16,17] In atrophic endometrium, mean of average blood vessel concentration was slightly lower as compared to control, but not statistically significant that was also observed by Hickey et al. [18] The endometrial glands were lined by mitotically inactive bland epithelium in a similar spindled inactive stroma. In some cases, the glands were cystically dilated and lined by cuboidal to flattened epithelium. ...
... In 1988, Goswamy et al. [4] reported decreased uterine blood flow and uterine receptivity in patients with UI and other studies found that CC decreases uterine blood flow and causes thin endometrium [5][6][7]. These factors were claimed for the low pregnancy rate and some investigators suggested treatment by using perfusion enhancer drugs [8,9]. Endothelial nitric oxide (eNO) generated in vivo from the essential amino acid Larginine relaxes arterial smooth muscles leading to vasodilatation and increase blood flow [10,11] and has other important roles in the process of reproduction [12][13][14][15]. ...
This study evaluated the effects of nitric oxide donor’s treatment on the pregnancy rate and uterine blood flow in patients with unexplained infertility undergoing clomiphene citrate stimulation and intrauterine insemination. A total of 120 patients were randomly allocated to a control group who received 100 mg clomiphene citrate daily from day 5 to 9 of cycle plus placebo vaginal tablets, and a study group received clomiphene citrate plus isosorbide mononitrate 10 mg vaginal tablets. Vaginal ultrasound was done before treatment and every other day starting from day 12 of cycle to count mature follicles and ovulation was triggered by IM injection of 10 000 IU hCG when one follicle measured 18 ≥ mm followed by intrauterine insemination after 36 h. The endometrial thickness, uterine arteries resistance and pulsation indices, and endometrial vascular flow and vascular flow indices were measured before treatment and at day of hCG injection. Results were analyzed after one cycle treatment using the Mean ± SD, the Student t test and the Fisher Exact test. Significant result was considered at p values <0.05. The study group had significant higher pregnancy rate/cycle, higher endometrial and lower uterine artery blood flow indices (p < 0.05).
... Compromised receptivity of the endometrium is a major cause of unexplained infertility, implantation failure and subclinical pregnancy loss. In women, unexplained infertility has been coupled with a range of cellular and molecular defects in the endometrium [7][8][9]. Several genomics and proteomics approach based studies have revealed large number of differentially regulated genes/proteins by comparing pre-receptive (LH+2) and receptive phase (LH+7) endometrium of fertile women [10][11][12][13]. Although, these studies have provided a large number of molecular candidates that are important during endometrial receptivity and some of them have been established as receptivity markers for fertile endometrium but to date the causes of unexplained infertility are not well explored. ...
Background
Compromised receptivity of the endometrium is a major cause of unexplained infertility, implantation failure and subclinical pregnancy loss. In order to investigate the changes in endometrial protein profile as a cause of unexplained infertility, the current study was undertaken to analyze the differentially expressed proteins of endometrium from early-secretory (LH+2) to mid-secretory phase (LH+7), in women with unexplained infertility.
Methods
2-D gel electrophoresis was performed to analyze the proteomic changes between early- (n = 8) and mid-secretory (n = 8) phase endometrium of women with unexplained infertility. The differentially expressed protein spots were identified by LC-MS analysis and validated by immunoblotting and immuno-histochemical analysis in early- (n = 4) and mid-secretory (n = 4) phase endometrium of infertile women. Validated proteins were also analyzed in early- (n = 4) and mid-secretory (n = 4) phase endometrium of fertile women.
Results
Nine proteins were found to be differentially expressed between early- and mid- secretory phases of endometrium of infertile women. The expression of Ras-related protein Rap-1b, Protein disulfide isomerase A3, Apolipoprotein-A1 (Apo-A1), Cofilin-1 and RAN GTP-binding nuclear protein (Ran) were found to be significantly increased, whereas, Tubulin polymerization promoting protein family member 3, Superoxide dismutase [Cu-Zn], Sorcin, and Proteasome subunit alpha type-5 were significantly decreased in mid- secretory phase endometrium of infertile women as compared to early-secretory phase endometrium of infertile women. Validation of 4 proteins viz. Sorcin, Cofilin-1, Apo-A1 and Ran were performed in separate endometrial biopsy samples from infertile women. The up-regulated expression of Sorcin and down-regulated expression of Cofilin-1 and Apolipoprotein-A1, were observed in mid-secretory phase as compared to early-secretory phase in case of fertile women.
Conclusions
De-regulation of the expression of Sorcin, Cofilin-1, Apo-A1 and Ran, during early- to mid-secretory phase may have physiological significance and it may be one of the causes for altered differentiation and/or maturation of endometrium, in women with unexplained infertility.
... Treatments of unexplained infertility are empirical and all are designed, one way or another, to increase gamete density, bringing together more than the usual numbers of eggs and sperm in a timely way as in ovarian stimulation and intrauterine insemination (2). A new approach was suggested that unexplained infertility is associated with a profound impairment of endometrial perfusion that might be amenable to treatment by perfusion enhancer drugs (19). ...
Objective: Altered utero-ovarian blood flow has been claimed to be a subtle cause of unexplained infertility. The aim of this study was to compare between the flow velocity indices in the uterine and ovarian arteries during the luteal phase in fertile and unexplained infertility women.
Study design: Observational, cross section, controlled study done at the departments of Obstetrics and Gynecology, Benha Faculty of Medicine, Egypt, during the period from October 2010 to October 2011.
Patients and methods: Two groups each of 30 cases and aged 20-25 years were studied. A control group of fertile women who got pregnant within one year of marriage, and a study group of women with unexplained infertility were included. Trans-vaginal pulsed color Doppler ultrasound was done at days 21–23 of the cycle to measure uterine and ovarian arteries resistance and pulsation indices.
Outcome measures: Mean uterine and ovarian arteries resistance and pulsation indices in both groups and their values in the diagnosis of altered blood flow in unexplained infertility were measured.
Results: Women with unexplained infertility had significantly higher uterine and ovarian arteries pulsation index (P
... 001HS There were significant differences in the numbers and percentages of the pregnant cases between the studied groups. There were high significant differences in the numbers and percentages between the pregnant and non pregnant cases in group V and significant differences in groups II, IV while no significant differences in group I. 6 001HS There was high significant difference in the mean score between the pregnant and non pregnant cases in group V and significant differences in groups II, IV while no significant differences in group I. Giving a + marks according to the action of the drug groups in the Us & Doppler parameters. All the studied drugs enhanced the endometrial receptivity through enhancement of the different US & Doppler parameters. ...
... Successful embryo implantation depends on interactions between the embryo and the uterus and a favorable endometrium environment is essential for pregnancy success. It has been shown that unexplained infertility was associated with a profound impairment of endometrial perfusion displaying as significantly reduced uterine artery flow velocity in all phases, elevated uterine and subendometrial artery impedance in the periovulatory and midluteal phases, and reduced endometrial texture in the midproliferative phase (Edi-Osagie et al., 2004). The human endometrium undergoes a complex series of organized proliferative and secretory changes in each menstrual cycle, and exhibits only a short period of receptivity , known as the ''window of implantation'' (Strowitzki et al., 2006). ...
It is well known that maternal ageing not only causes increased spontaneous abortion and reduced fertility, but it is also a high genetic disease risk. Although assisted reproductive technologies (ARTs) have been widely used to treat infertility, the overall success is still low. The main reasons for age-related changes include reduced follicle number, compromised oocyte quality especially aneuploidy, altered reproductive endocrinology, and increased reproductive tract defect. Various approaches for improving or treating infertility in aged women including controlled ovarian hyperstimulation with intrauterine insemination (IUI), IVF/ICSI-ET, ovarian reserve testing, preimplantation genetic diagnosis and screening (PGD/PGS), oocyte selection and donation, oocyte and ovary cryopreservation before ageing, miscarriage prevention, and caloric restriction are summarized in this review. Future potential reproductive techniques for infertile older women including oocyte and zygote micromanipulations, derivation of oocytes from germ stem cells, ES cells, and iPS cells, as well as through bone marrow transplantation are discussed.
... Our finding may assist physicians in determining the phase of the menstrual cycle, thus reducing invasive procedures to evaluate the status of the endometrium [13]. To further examine this technique in clinical practice, we are conducting another study of patients with malignant versus benign intrauterine pathology. ...
Sonographic gray-scale histogram is used to assess the endometrial changes in the different phases of the menstrual cycle. The objective was to examine the usefulness of a gray-scale histogram and computer-assisted image analysis software in assessing normal physiologic states of the endometrium with sonography.
Thirty-eight patients, who visited the Taipei Medical University-Wan Fang Hospital and matched the eligibility criteria, were categorized into one of three groups: (1) menstrual phase; (2) follicular phase; and (3) luteal phase of the menstrual cycle. Ultrasonography of the uterus was performed on each patient and the endometrium was analyzed with ImageJ image analysis software.
A statistically significant difference in signal intensity scores of the gray-level histogram, represented as m(j), was found among the three groups.
Sonographic images analyzed by using computer-assisted image analysis software and gray-level histogram are proven to be useful in assessing the physiological state of the endometrium.
... Unexplained infertility appears to be associated with impairment of endometrial perfusion. Women with unexplained infertility demonstrated significantly reduced uterine artery flow velocities in all phases of a spontaneous menstrual cycle and significantly elevated uterine and subendometrial artery impedance in the periovulatory and midluteal phases, when compared with those with tubal infertility (Edi-Osagie et al., 2004). Similarly, Raine-Fenning et al. (2004b) found that endometrial and subendometrial vascularity of women with unexplained infertility were significantly lower during the mid-late follicular phase of a natural cycle than that of normal fertile women. ...
No information exists in the literature regarding the factors affecting the blood flow towards the endometrial and subendometrial regions during IVF treatment.
We examined the effect of women's age, their smoking habits, their type of infertility (i.e. primary or secondary) and parity, causes of infertility and serum estradiol (E2) concentration on endometrial and subendometrial blood flows as measured by a three-dimensional (3D) power Doppler ultrasound during IVF treatment. All patients received a standard long protocol of ovarian stimulation and serum E2 concentration was determined on the day of hCG. 3D ultrasound examination with power Doppler was performed on the day of oocyte collection to determine vascularization index (VI), flow index (FI) and vascularization flow index (VFI) of endometrial and subendometrial regions.
The age of women, their smoking habits, their types of infertility and parity and causes of infertility had no effect on the endometrial and subendometrial 3D power Doppler flow indices. There was a negative correlation between serum E(2) concentration and endometrial FI (r = -0.109; P = 0.006).
Endometrial blood flow in IVF treatment was negatively affected by serum E2 concentration only.
... Compromised receptivity of the endometrium is believed to be a primary cause of unexplained infertility manifesting as implantation failure and subclinical pregnancy loss. In women, unexplained infertility has been associated with a range of cellular and molecular defects in the endometrium (Graham et al., 1990; Lessey et al., 1995; Edi-Osagie et al., 2004). A less well-explored, but important, factor in adequate endometrial accommodation of the implanting embryo is an appropriate maternal immune response to the semi-allogeneic conceptus. ...
A receptive endometrial environment requires adequate immunological tolerance to protect the implanting embryo from maternal immune rejection. Studies in mice implicate CD4+CD25+ T-regulatory (Treg) cells as essential mediators of immune tolerance in pregnancy. The aim of this study was to evaluate the link between Treg cells and fertility in women. Expression of Foxp3, a master regulator of Treg cell differentiation, was quantified in endometrial tissue from women experiencing primary unexplained infertility and normal fertile women. Endometrial biopsies were collected during the mid-secretory phase of the menstrual cycle from women meeting rigorously defined criteria for unexplained infertility after experiencing repeated failed cycles of IVF treatment (infertile, n = 10), or women classified as proven fertile (control, n = 12). Expression of Foxp3 mRNA was reduced approximately two-fold in the tissue of infertile women. In contrast, mRNAs encoding T cell transcription factors T-bet and GATA3, associated with differentiation of Th1 and Th2 CD4+ T cells respectively, were unchanged. Treg cell differentiation is controlled by TGFbeta, but the relative abundance in endometrial tissue of TGFbeta1, TGFbeta2, TGFbeta3 mRNAs was not changed in infertile women. Cytokines influencing Th1 and Th2 cell differentiation, including IFNgamma, IL-2, IL-4, IL-5, IL-10 and IL-12p40, as well as dendritic cell-regulating cytokines IL-1alpha, IL-1beta, IL-6, LIF, GM-CSF and TNFalpha were also expressed similarly regardless of fertility status. The finding of reduced endometrial Foxp3 implicates impaired differentiation of uterine T cells into the Treg phenotype as a key determinant of fertility in women. The factors underpinning this aberration in the immune response remain to be identified.
... Reduced uterine blood flow due to sympathetic hyperactivity may be prevented by the partial inactivation of NE by MAO. The reported association between unexplained infertility and impairment of endometrial perfusion, assessed by Doppler ultrasound, is in keeping with this speculation (Chien et al., 2002;Edi-Osagie et al., 2004). However, MAO-A protein was found mainly in epithelial cells rather Grading of immunofluorescent staining of MAO-A in sections of human endometrium obtained from women who had previously participated as recipients in oocyte donation cycles, who repeatedly failed to have implantation of the transferred embryos (group A) or had succeeded in having implantation as recipients in the same oocyte donation program (group B). ...
Successful implantation depends both on the quality of the embryo and on the endometrial receptivity. The latter depends on progesterone-induced changes in gene expression, a process that has been characterized by microarray analysis. One of the genes whose transcription appears to be enhanced during the receptive period is monoamine oxidase A (MAO-A). Our first objective was to confirm the increased expression of MAO-A in the endometrium during the receptive phase of spontaneous normal cycles using real time PCR and immunofluorescence. The second objective was to examine the endometrial expression of MAO-A during the receptive phase induced by exogenous estradiol (E(2)) and progesterone in patients whose endometrium was shown to have been either receptive or non-receptive to embryo implantation in repeated cycles of oocyte donation. Results showed that MAO-A transcript levels increased between the pre-receptive (LH+3) and receptive phase (LH+7) in all spontaneous cycles examined, with a median increase of 25-fold. Immunofluorescent labelling demonstrated MAO-A localization to the glandular and luminal epithelium with an increasing positive score between LH+3 and LH+7. Conversely, prior failure of embryo implantation was associated with a 29-fold decrease in MAO-A mRNA levels and a substantial reduction in MAO-A protein immunofluorescent label score. These results show a strong association between endometrial receptivity and MAO-A expression in the endometrial epithelium, suggesting an important role for this enzyme in normal implantation.
This study aims to understand differences/similarities in the genetic profile of the endometrium at the start of window of implantation (WOI) in women with unexplained infertility (UI) and unexplained recurrent pregnancy loss (uRPL). Differentially expressed genes (DEGs) from the endometrium were evaluated using gene expression array and pathway enrichment analysis was performed to analyse gene expression pathways involved in both conditions. We found 2,171 genes arranged in 117 pathways and 730 genes arranged in 33 pathways differentially expressed in endometrium of patients in UI and uRPL, respectively. Complement-coagulation cascades, morphine addiction pathway, and PI3K-Akt signalling pathway were predominantly differentially expressed in UI. Cancer pathways, NF-κB signalling pathway, and actin cytoskeleton regulation pathway showed significant changes in uRPL. Forty-eight percent of DEGs and 84% of differentially expressed pathways in uRPL were found in the endometrium of UI patients. Unexpected close association in gene expression pathways between UI and uRPL is observed supporting the hypothesis ‘uRPL is a clinical subset of UI’. Yet 100% DEGs overlap wasn’t found suggesting the endometrium has still some different gene expression patterns at start of WOI in UI and uRPL. Lastly, diagnostic tools may be developed for uRPL because more specific genes-pathways are involved compared with UI, which shows broader genetic expression profile.
Purpose of review:
To succinctly review the basic mechanisms of implantation and luteal phase endometrial differentiation, the etiologies of impaired endometrial function and receptivity, and the current methods that exist to evaluate and treat impaired endometrial receptivity.
Recent findings:
Human embryo implantation requires bidirectional communication between blastocyst and a receptive endometrium. Etiologies of impaired endometrial receptivity are varied. Some of these include delayed endometrial maturation, structural abnormalities, inflammation, and progesterone resistance. Current methods to evaluate endometrial receptivity include ultrasonography, hysteroscopy, and endometrial biopsy. Treatments are limited, but include operative hysteroscopy, treatment of endometriosis, and personalized timing of embryo transfer.
Summary:
Although some mechanisms of impaired endometrial receptivity are well understood, treatment options remain limited. Future efforts should be directed towards developing interventions targeted towards the known mediators of impaired endometrial receptivity.
The vagina is considered a potential route for delivering drugs to the uterus with minimizing side effects and increasing bioavailability. Vardenafil is a type of 5-specific phosphodiesterase inhibitors, with low oral bioavailability about 15%. Thus targeting drug delivery through vagina is considered perfect for drugs such as vardenafil.
The objective of this study is to formulate and evaluate vardenafil vaginal suppositories, to study the effect of different surfactants and additives on the drug release rate. Suppositories containing 20 mg of vardenafil were prepared and characterized for weight variation, content uniformity, hardness, disintegration time. The in vitro dissolution medium was also investigated.
Unexplained infertility (UI) and recurrent implantation failure (RIF) are diagnoses based on failed pregnancy attempts within current infertility treatment models. Both diagnoses are made when fertility is unexplained based on current diagnostic methods and has no clear cause; UI is diagnosed when testing is inconclusive, and RIF is diagnosed after three failed in vitro fertilization cycles. In both cases, interventions are often introduced without an understanding of the cause of the infertility, frequently leading to frustration for patients and caregivers. Here, we review evidence to support an influence of endometrial factor in patients given these poorly defined diagnoses and possible treatments targeting the endometrium to improve outcomes in these patients.
Background. Patients with comorbid pathology occupy leading positions in the practice of a doctor of any specialty especially in patients with HIV. Reproductive system is known to be the gateway for viruses. This fact could explain the severity of changes developing in the female reproductive system infected with HIV, in particular in the endometrium. The purpose of this study was to assess morphological changes in the endometrium caused by the combined effects of HIV infection and chronic alcoholism. Materials and methods: The study included sectional material taken from 60 women of reproductive age (20-40 years). They were all divided into two groups. The first group (30 people) consisted of HIV-positive individuals who, according to a survey of relatives and according to an autopsy (the main symptom is the presence of alcoholic cirrhosis of the liver), alcohol abuse was confirmed. The following parameters were determined: the average diameter of the endometrial glands (proliferative type), the minimum diameter of the endometrial glands (proliferative type), the maximum diameter of the endometrial glands (proliferative type), wall thickness (proliferative type), the relative volume of the epithelium (proliferative type), the average diameter of the glands (secretory type), the minimum diameter of the glands (secretory type), the maximum diameter of the glands (secretory type), the relative volume of the epithelium (secretory type), the thickness of the epithelium. Results. the average diameter of the endometrial glands (proliferative type) decreased from 51.71 ± 2.90 x 10-6 m in the comparison group to 39.42 ± 2.35 x 10-6 m in the HIV-infected group, which was 23.77%. The minimum diameter of the endometrial glands (proliferative type) reduced from 32.47 ± 1.83 x10-6 m to 27.13 ± 1.73x10-6 m (16.45%), the maximum diameter from 72.14 ± 2.21 x10-6 m to 63.84 ± 3.29 x10-6 m (11.5%). the relative volume of the epithelium (proliferative type) decreased by 5.41% (from 54.43 ± 1.79% in the study group to 49.02 ± 2.65% in the control group). The thickness of the uterine wall was also significantly reduced from 15.18 ± 1.60 x10-6 m to 14.52 ± 1.19 x10-6 m, which was 4.35%. The maximum volume of glands (secretory type) changed from 127.98 ± 2.10 x10-6 m to 97.18 ± 3.12 x10-6 m (24%). Changes by 3.6% were also observed when examining the wall thickness (from 13.02 ± 1.36 x10-6 m to 12.55 ± 1.68 x10-6 m). Conclusion. The study evaluated features of endometrial restructuring in alcohol-abusing HIV-infected women.
Purpose
To determine how subcategorizing unexplained infertility based on female laparoscopy and total‐motile‐sperm‐count assessment would impact cumulative live‐births after one in‐vitro fertilization (IVF) cycle.
Methods
Seven hundred twenty one IVF cycles from Jan 2014‐April 2019 performed at a single‐center were retrospectively analyzed. Couples with unexplained infertility having normal uterine and endometrial morphology were subcategorized into three cohorts, UI (1): those with no tuboperitoneal pathology on laparoscopy and total‐motile‐sperm‐count (TMSC) ≧20 million: n = 103; UI (2): tuboperitoneal pathology on laparoscopy or TMSC <20 million, n = 86; and UI(3): tuboperitoneal status not known: n = 114. Controls were severe male factor, bilateral tubal block, and grade 3/4 endometriosis: n = 418. Primary Outcome was cumulative‐live‐birth‐per‐initiated‐IVF cycle (CLBR). Odds ratio for live‐births were adjusted for confounding factors.
Results
The CLBR in UI1 cohort was significantly lower than controls (29.1% vs 39; OR = 0.62; 95%CI = 0.39‐0.98; P = .04); but similar in UI2 and UI3 vs. controls. (37.2% vs 39.95%; OR = 0.89, 95%CI = 0.55‐1.44; P = .89) and (38.6% vs 39.95%; OR = 0.98, 95%CI = 0.64‐1.55; P = .98). After adjusting for age, infertility duration, past live‐births, and AMH, the adjusted odds for CLBR in UI1 was 0.48 (95%CI = 0.28‐0.82; P = .007).
Conclusions
Unexplained infertility when defined after a normal laparoscopy and TMSC significantly lowered cumulative‐live‐births‐per‐initiated‐IVF cycle when compared with traditional diagnosis of tubal, endometriosis, or male factor infertility. In UI subcategory with abnormal laparoscopy or TMSC, CLBR remained unaffected. This information could be useful for counseling couples prior to IVF. Large‐scale prospective studies are needed to confirm this observation.
There is a violation of the secretory transformation of the endometrium during the implantation window in patients with the infertility associated with inflammatory diseases of the small pelvic organs, against the background of a high incidence of chronic endometritis and salpingitis. The impact of inflammatory changes in the small pelvic organs leads to disruption of morphological and functional state of the endometrium and also to receptor imbalance.
A receptive endometrial environment requires adequate immunological tolerance to protect the implanting embryo from maternal immune rejection. Studies in mice implicate CD4+CD25+ T-regulatory (Treg) cells as essential mediators of immune tolerance in pregnancy. The aim of this study was to evaluate the link between Treg cells and fertility in women. Expression of Foxp3, a master regulator of Treg cell differentiation, was quantified in endometrial tissue from women experiencing primary unexplained infertility and normal fertile women. Endometrial biopsies were collected during the mid-secretory phase of the menstrual cycle from women meeting rigorously defined criteria for unexplained infertility after experiencing repeated failed cycles of IVF treatment (infertile, n = 10), or women classified as proven fertile (control, n = 12). Expression of Foxp3 mRNA was reduced approximately two-fold in the tissue of infertile women. In contrast, mRNAs encoding T cell transcription factors T-bet and GATA3, associated with differentiation of Th1 and Th2 CD4+ T cells respectively, were unchanged. Treg cell differentiation is controlled by TGF beta, but the relative abundance in endometrial tissue of TGF beta 1, TGF beta 2, TGF beta 3 mRNAs was not changed in infertile women. Cytokines influencing Th1 and Th2 cell differentiation, including IFN gamma, IL-2, IL-4, IL-5, IL-10 and IL-12p40, as well as dendritic cell-regulating cytokines IL-1 alpha, IL-1 beta, IL-6, LIF, GM-CSF and TNF alpha were also expressed similarly regardless of fertility status. The finding of reduced endometrial Foxp3 implicates impaired differentiation of uterine T cells into the Treg phenotype as a key determinant of fertility in women. The factors underpinning this aberration in the immune response remain to be identified.
Embryo implantation failure and recurrent abortion are common indications for endometrial evaluation to determine the implantation window and diagnose endometrial anomalies. There are few research studies comparing the efficacy of different techniques used for endometrial sampling in infertile females during the luteal phase. Likewise, morphometric studies of the endometrium through aspiration biopsy are scant. A cross-sectional study of 30 infertile and 10 fertile females was carried out. The study participants underwent hysteroscopic and aspiration biopsies (pipelle) at the midluteal phase. Computer-assisted morphometric and pathological anatomy analyses were conducted independently by two pathologists blinded to the study. The two endometrial sampling biopsy techniques were compared through morphometric and pathological anatomy analyses using three parameters: a) the amount of material collected for the endometrial studies; b) the scope and origin of sampled materials; and c) the quality of the sample. Both biopsy techniques produced sufficient material for analysis. The directed biopsies yielded higher quality samples from targeted segments of the uterine cavity because samples were homogeneous and had no architectural distortion (p<0.05). Blood was present only in the samples obtained through a Pipelle. Endometritis was detected in 10% of the infertile women. Our findings suggest that hysteroscopic biopsies are superior to blinded aspiration biopsies.
Objective: To study whether the unexpected poor ovarian responders optimization of uterine re- ceptivity with a flexible controlled ovarian hyper stimulation protocol based on the Biophysical Profile of the Uterus, has an impact on their reproductive performance. Design: Observational Prospective study. Setting(s): i) General hospital-IVF and Infertility Centre; ii) University hospital. Patient(s): 44 normogonadotrophic young women (26 - 38 yrs) with previous "unexpected" poor ovarian response underwent IVF/ICSI treatment on a protocol based on the Biophysical Profile of their uterus (Group A). The same patients were used as controls in a preceded IVF cycle on the conventional stimulation protocol. Intervention(s): None. Main outcome measure(s): Pregnancy, miscarriage and home take baby rates, amount and duration of gonadotropins required, number and quality of embryos resulted, Biophysical Profile of the Uterus score. Result(s). Treatment in Group A in comparison to Group B resulted in significantly larger number of eggs retrieved per pa- tient, and improved fertilization rates and higher number of embryos/ET (p = 0.011, 0.010 and 0.034 respectively). Group A also demonstrated a trend for higher rates of clinical pregnancy (29.5% v.s. 15.9%), viable stage pregnancies ≥ 24 weeks (33.3% v.s. 20%) and home take babies (26.6% v.s. 16%). The amount of gonadotropins used per patient (IU) was similar in the two groups (p = * Corresponding author.
Objective: to estimate endometrial receptivity in women with unexplained infertility. Design: prospective clinical trial Setting: Suez canal and Cairo University hospitals Materials and Methods: The study included 63 women with unexplained infertility and a control group = 31 normal fertile women. All women had transvaginal Doppler imaging of the uterine and spiral arteries on the same day of interleukin assay. 39 patients of the study group were monitored during natural cycles, while the remaining 24 patients were monitored through stimulated cycles using clomiphene citrate, gonadotropins, and a combination of both. Outcome measures: The resistance index (RI) and the pulsatility index (PI) were evaluated in uterine and spiral arteries. All women had a serum assay of IL-1b using the ELISA technique on cycle day 21 -24. Results: The PI and the RI of the uterine arteries were significantly higher in the study group (3.8 ± 0.61, 0.96 ± 0.04) compared to the control group (2.82 ± 0.10, 0.83 ± 0.07). The endometrial thickness was significantly higher in stimulated cycles compare to natural cycles. The PI and the RI of spiral arteries were significantly higher in the study group (1.4 ± 0.39, 0.67 ± 0.06) compared to the control group (0.96 ± 0.10, 0.58 ± 0.05). When a cut of value of 15 pg/ml was considered, there was no significant difference between the 2 groups regarding serum IL-1b.Conclusion: Doppler study of endometrial blood flow can be an important tool in evaluation of uterine receptivity in women with unexplained infertility. Serum IL-1b appears of less value in this respect.
Objective: Letrozole appears not to have any of the adverse effects on the endometrium that are frequently associated with clomiphene citrate (CC) during ovulation induction. The aim of the study is to compare the effect of letrozole compared to CC on endometrial thickness and endometrial and subendometrial blood flow. Materials and methods: Infertile women with polycystic ovary syndrome (PCOS) were allocated for ovulation induction; 102 women were treated with Letrozole and 99 women with CC. Thirty-five patients from the CC group showed a resistance to or failure of CC with a thin endometrium, and were re-treated with letrozole. The main outcome measures were ovulation and pregnancy rates/cycle, endometrial thickness, detection rates, and resistance index (RI) and pulsatility index (PI) of subendometrial and endometrial blood flow. Results: In spite of a nonsignificant difference in ovulation rate between letrozole and CC groups (70.6% vs. 64.6%), a clinical pregnancy rate was achieved in 29/102 (28.4%) women with letrozole and 20/99 (20.2%) women with CC treatment (p<0.05) and in 6/35 (17.1%) in women re-treated with letrozole after CC resistance or failure. There were significant differences in endometrial thickness, detection rates, and RI and PI of subendometrial and endometrial blood flow between the two groups and between 35 women re-treated with letrozole after CC resistance or failure when compared with CC treatment alone. Conclusions: Letrozole may increase fertility by improving endometrial receptivity compared with CC alone. (J GYNECOL SURG 28:405)
Monoamine oxidases (MAO), functioning as the metabolism of neuroamines, have been reported to be required for endometrial receptivity recently. The aim of this study was to examine the expression patterns of the two subtypes, MAOA and MAOB, during the peri-implantation period and to investigate whether MAOA or MAOB is a useful marker for receptivity.
A total of 30 uteri were collected from females of gestational day 0, 2, 4, 6, 8, and mRNA and protein expression of MAOA/B were examined by real-time PCR, Western blot analysis and Immunohistochemistry analysis, respectively.
We found that the mRNA of MAOA expressed in the uteri at all stages of peri-implantation and began to rise on day 4 with a continuous increase up to day 8 of pregnancy, consistent with the changes of MAOA protein expression. The summit of MAOB mRNA and protein level was observed on day 4. Immunohistochemistry analysis revealed that both of MAOA and MAOB were mainly localized in the glandular and luminal epithelium cells, as well as their intense staining signals observed in the trophoblast cells on day 6 and 8.
Both MAOA and MAOB were up-regulated in the uteri during the peri-implantation period, which could play a role in mouse embryo implantation and endometrial receptivity; the temporal and spatial marked increase of MAOs may be traced as a useful marker for mouse endometrial receptivity; the expression mode of mouse MAOs should pave a way for further study.
Adrenomedullin (AM) and its receptor subunit, calcitonin receptor-like receptor (CLR) are known to be important for endothelial function. The genotypes and phenotypes of AM and CLR in the endometrium were studied in relation to unexplained infertility. Endometrial biopsies from 12 fertile and 11 infertile women and blood samples from 156 fertile and 106 infertile women were collected. Protein and mRNA expression of AM and CLR was determined using immunohistochemistry and real time PCR. Allele and genotype frequencies in the AM (rs4399321 and rs7944706) and CLR genes (rs696574, rs1528233 and rs3771073) were performed using Taqman genotyping assays. Unexplained infertility was characterised by lower number of vessels stained with CLR in endometrium compared to fertile controls. There was no difference in AM expression. This could not be explained by SNP analysis in the AM or CLR genes. Imbalance in the AM/CLR system might alter endothelial function in women with unexplained infertility.
Female infertility patients with diverse etiologies show increased production of autoantibodies.
Immunoblot analysis of sera from patients with endometriosis and tubal factor infertility (TFI) and mass spectrometry identification of candidate antigens.
The immunoblot results demonstrated the presence of IgA and IgG anti-endometrial antibodies (AEA) to various antigens at molecular weights ranging from 10 to 200 kDa. Differences were detected in certain AEA reactions between the patients' groups and particular AEA were associated with in vitro fertilization (IVF) implantation failure. IgA AEA to a 47-kDa protein were more prevalent in TFI patients and were associated with unsuccessful IVF treatment. This antigen was subsequently identified as alpha-enolase.
Determination of the presence and spectra of AEA in patients with endometriosis and TFI undergoing IVF may be a useful marker to predict their pregnancy outcome.
Käesolev uurimus keskendub endometrioosi ja tubaarse viljatusega patsientide seerumis esinevatele autoantikehadele ja nende omavahelistele seostele ning autoantikehade esinemise seostele IVF ravi tulemustega. Uuringu tulemused kinnitavad, et viljatutel endometrioosi ja tubaarse infertiilsusega patsientidel esineb kõrvalekaldeid immuunsüsteemi regulatsioonis. Detekteeritud erinevat tüüpi autoantikehade esinemine on omavahel positiivselt seotud ning võib lisaks olla seotud neil patsientidel esineva infertiilsuse patogeneesiga.
To quantify endometrial and subendometrial blood flow in Caucasian women with polycystic ovarian syndrome (PCOS) and to determine whether these values differ according to the phenotypic expression of PCOS.
Transvaginal pelvic ultrasound was performed on the 3(rd)-5(th) day of the menstrual cycle in 36 women with PCOS and 36 controls to examine the endometrial and subendometrial vascularity. The subendometrial and endometrial blood flow indices (vascularizaton index (VI), flow index (FI) and vascularization flow index (VFI)) were measured using three-dimensional power Doppler angiography. Uterine artery blood flow was assessed through analysis of two-dimensional (2D) pulsed-wave Doppler waveforms. Analysis was performed to compare PCOS with non-PCOS women, and subgroup analysis was performed of the PCOS women categorized according to their phenotypic manifestation.
There were no significant differences in endometrial volume, subendometrial vascularity and uterine artery blood flow between women with PCOS and controls after controlling for body mass index (BMI). On subgroup analysis, compared with anovulatory but clinically normoandrogenic women with polycystic ovaries (PCO) and with controls, women with PCO who were both clinically hyperandrogenic and anovulatory had significantly lower endometrial (VI: 0.57% vs. 1.11% and 0.86%, respectively, both P = 0.01; VFI: 0.14 vs. 0.42 and 0.28, respectively, both P = 0.02) and subendometrial (VI: 1.59% vs. 3.17% and 2.47%, P = 0.01 and 0.02, respectively; VFI: 0.50 vs. 1.67 and 0.96, P = 0.01 and 0.02, respectively) blood flow. Moreover, clinically hyperandrogenic but ovulatory women with PCO also had significantly lower endometrial blood flow (VI: 0.52% vs. 1.11%, P = 0.04) than did anovulatory but clinically normoandrogenic women with PCO. There were no differences in any of the 2D pulsed-wave Doppler measures of blood flow between the subgroups.
Subendometrial and endometrial blood flow is significantly impaired in women with PCOS who have clinical signs of hyperandrogenism.
Five hundred endometrial specimens were studied to document the changes in blood vessels in various phases of menstrual cycle, menstrual disturbances and in unexplained infertility. Sixty-three cases were taken as control and 437 cases as study group which included cases of dysfunctional uterine bleeding (DUB), endometrial polyps, fibroids, adenomyosis, infertility and atrophic endometrium. Using light microscopy, the vascular morphology was studied. The blood vessels were concentrated more in basal layer in the proliferative phase and in functional layer in the secretory phase. Cases of complex hyperplasia and pill endometrium had significantly higher vessel concentration. Congestion and dilatation of blood vessels were significantly higher in cases of DUB. The present study showed a positive correlation between endometrial angiogenesis and menstrual disorders. The alteration in blood vessel morphology has significant role in prognosis and in various anti-angiogenic therapies.
The aim of this study was to determine the correlation between three-dimensional power Doppler sonography (3D-PDS) of the (sub)endometrium and concentrations of angiogenic cytokines in patients attending an IVF programme. A total of 42 patients was included in a prospective, non-randomized clinical study. 3D-PDS of the (sub)endometrium was performed on the day of oocyte aspiration, with and without contrast agent. Quantitative assessment included the following 3D Doppler parameters: vascularization index, flow intensity, and vascularization flow index. On the same day, concentrations of oestradiol (serum only), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF) 1, IGF-binding protein 3 (IGFBP-3) and leptin were determined in the serum and in the follicular fluid. All 3D-PDS indices were significantly higher with contrast enhancement (P < 0.05). Follicular fluid concentrations of VEGF and IGFBP-3, as well as serum concentrations of leptin, showed significant P-values when correlated with (sub)endometrial Doppler indices. A weak linear dependency appeared between flow intensity and VEGF and leptin. Furthermore, weak dependencies were apparent between 3D Doppler parameters and high follicular fluid concentrations of VEGF and IGFBP-3. It is concluded that there is only little evidence for an association between (sub)endometrial Doppler indices as assessed by 3D-PDS and concentrations of angiogenic cytokines.
To compare endometrial dating and ultrasound texture in a natural cycle before IVF and relate these to outcome and to fertile references.
Prospective study with a fertile reference group.
Four university IVF clinics.
Seventy-five IVF patients and 21 fertile women.
Ultrasound, biopsy, blood sampling. In vitro fertilization-ET in the following cycle.
Endometrial evaluation, P, IVF outcome.
At day LH+7, 42% infertile vs. 67% fertile women demonstrated endometria that were in phase (statistically nonsignificant difference). Nine percent had an accelerated endometrium, and 47% (infertile) vs. 24% (fertile) had a delayed endometrium (statistically nonsignificant difference). Statistically significantly fewer women with tubal factor and no hydrosalpinges had an endometrium in phase (20%) than was the case in fertile women (67%). Dating could not predict outcome. Statistically significantly more women in the hydrosalpinx group had a visible midline at day LH+7 compared with the case in other infertile groups. Forty-three percent conceived after IVF-ET. Plasma P was statistically significantly lower in nonpregnant women compared with in women with ongoing pregnancies and with fertile controls. A periovulatory hyperechogenic endometrium resulted in no ongoing pregnancies.
In a natural cycle preceding IVF, a low midluteal P level predicts a low implantation rate. A periovulatory hyperechogenic endometrium or hydrosalpinges visible at ultrasound may have some predictive value. Endometrial dating was of no help.
Sildenafil is an active substance that has already been approved by FDA for human use. It is known to be an active compound for the treatment of sexual dysfunction in men. Some encouraging results have been published concerning the treatment of infertility with sildenafil in women, but there is no pharmaceutical preparation available. Therefore, various formulations were prepared and the most suitable sildenafil release was found to be with the sildenafil-containing suppositories prepared using Eudragit RS100 and Witepsol H15. The vaginal insert with EVAC 210 polymer containing sildenafil has also provided sildenafil release for a longer period.
To study a group of women with unexplained infertility to see whether they have a defect that is intrinsic to the endometrium.
Evaluation of the functional response of the endometrium by examining endometrial biopsy specimens using immunohistochemical methods in a group of women with unexplained infertility and in a control group of women with normal fertility.
27 Women with unexplained infertility (average age 33.2); median duration of infertility five years. A control group of 44 women with normal fertility (average age 33.8) who were requesting sterilisation or reversal of sterilisation.
Infertility clinic, Jessop Hospital for Women, Sheffield.
Secretory phase endometrial biopsy specimens were taken, with informed consent, as an outpatient procedure.
Immunohistochemistry with monoclonal antibody D9B1, was used to assess the production and secretion of an oligosaccharide epitope produced by endometrial gland cells between two and seven days after the luteinising hormone surge. A reflected light measuring system was used to assess the amount of epitope within the gland cells, and in the gland lumen.
In the control group of women, mean reflected light measurements at the cell base and cell apex peaked at three and five days after the luteinising hormone surge respectively, and in the gland lumen the epitope accumulated rapidly from three days, reaching a peak at seven days. In the women with infertility the peaks of epitope at the cell base and cell apex were lower, broader, and delayed in onset, and the build up of epitope in the gland lumen was retarded. The synthesis and secretion of the epitope in the women with infertility was therefore significantly reduced and delayed, even in the presence of normal concentrations of circulating progesterone.
The results suggest that a primary dysfunction of the endometrium might be associated with hitherto unexplained infertility.
The impact of endometriosis and unexplained infertility on follicular function and fertilization of oocytes in cycles totally unperturbed by exogenous gonadotrophins, when compared with controls with tubal damage, were examined.
In natural cycles, without any exogenous gonadotropins, endocrine and ultrasonographic studies of follicular maturation in 18 women with minor endometriosis (41 cycles), 15 women with unexplained infertility (31 cycles), and 34 women with tubal damage (88 cycles) were performed.
The endometriosis group had a significantly longer follicular phase (median: 15, 13, and 13 days). Both endometriosis and unexplained infertility had significantly reduced LH concentrations in follicular fluid compared with tubal damage (median: 12.1, 11.5, and 15.9 IU/L, respectively). Endometriosis was associated with a significantly reduced fertilization rate compared with unexplained infertility or tubal damage (46, 65, and 69%, respectively).
These data show continuing evidence of ovulatory dysfunction leading to reduced fertilization rates in women with minor endometriosis.
This study aims to determine the relative contribution of oocyte and/or sperm dysfunction to the reduction of fertilization rates in vitro in cases of minor endometriosis and prolonged unexplained infertility. The results of in-vitro fertilization (IVF) treatment with ovarian stimulation have been compared between couples with the above conditions and women with tubal infertility (as control for oocyte function) and the use of donor spermatozoa (as control for sperm function). Fertilization and cleavage rates using husband's spermatozoa were significantly reduced in endometriosis couples (56%, n = 194, P < 0.001) and further significantly reduced in couples with unexplained infertility (52%, n = 327, P < 0.001) compared with tubal infertility (60%, n = 509). Using donor spermatozoa the rates were the same as using husband's spermatozoa in tubal infertility (61%, n = 27) or endometriosis (55%, n = 21) but significantly though only partly improved with unexplained infertility (57%, n = 60, P < 0.02). In unexplained infertility, a significantly increased proportion of couples experienced complete failure of fertilization and cleavage in a cycle (5-6% versus 2-3%). However, complete failure was not usually repetitive, and the affected couples did not account for the overall reduction in fertilization and cleavage rates, which remained significantly lower in the rest of the unexplained and endometriosis groups. Implantation and pregnancy rates appeared similar in all groups. The benefit of IVF treatment in cases of minor endometriosis and prolonged unexplained infertility is due to superabundance of oocytes obtained by stimulation. The reduction in natural fertility associated with endometriosis appears to be at least partly due to a reduced fertilizing ability of the oocyte. In unexplained infertility, there is distinct impairment due to otherwise unsuspected sperm dysfunction but probably also oocyte dysfunction.
Hydrosalpinges have been associated with poor in-vitro fertilization (IVF) outcome in some, but not all, studies, perhaps through endometrial effects. To determine whether hydrosalpinges affect IVF outcome via endometrial factors alone, we analysed the results of recipients of donor oocytes with hydrosalpinges, thereby controlling for confounding variables, while isolating the intrauterine environment. We retrospectively analysed 110 patients who underwent 121 donor oocyte cycles in a university-based assisted reproduction programme. Thirteen cycles involving recipients (n = 10) with hydrosalpinges were compared to 108 cycles involving recipients (n = 100) without hydrosalpinges. Pregnancy, implantation, miscarriage, and ectopic pregnancy rates were compared between women with and without hydrosalpinges. There were no significant differences between the hydrosalpinx and no hydrosalpinx groups with respect to donor age, recipient age, or number or grade of embryos transferred. Patients with a hydrosalpinx had significantly lower embryo implantation rates (7.1 versus 19.3%, P < 0.05) and significantly higher miscarriage (75.0 versus 14.9%, P < 0.05) and ectopic pregnancy rates (33.3 versus 0.0%, P < 0.05) than normal controls. We conclude that the presence of a hydrosalpinx adversely affects early pregnancy events by altering the intrauterine environment.
The objective of the present study was prospectively and randomly to evaluate the role of L-arginine in improving uterine
and follicular Doppler flow and in improving ovarian response to gonadotrophin in poor responder women. A total of 34 patients
undergoing assisted reproduction was divided in two groups according to different ovarian stimulation protocols: (i) flare-up
gonadotrophin-releasing hormone analogue (GnRHa) plus elevated pure follicle stimulating hormone (pFSH) (n = 17); and (ii) flare-up GnRHa plus elevated pFSH plus oral L-arginine (n = 17). During the ovarian stimulation regimen, the patients were submitted to hormonal (oestradiol and growth hormone), ultrasonographic
(follicular number and diameter, endometrial thickness) and Doppler (uterine and perifollicular arteries) evaluations. Furthermore,
the plasma and follicular fluid concentrations of arginine, citrulline, nitrite/nitrate (NO2–/NO3–), and insulin-like growth factor-1 (IGF-1) were assayed. All 34 patients completed the study. In the L-arginine treated group
a lower cancellation rate, an increased number of oocytes collected, and embryos transferred were observed. In the same group,
increased plasma and follicular fluid concentrations of arginine, citrulline, NO2–/NO3–, and IGF-1 was observed. Significant Doppler flow improvement was obtained in the L-arginine supplemented group. Three pregnancies
were registered in these patients. No pregnancies were observed in the other group. It was concluded that oral L-arginine
supplementation in poor responder patients may improve ovarian response, endometrial receptivity and pregnancy rate.
The purpose of this study was to investigate the relationship between mid-luteal phase echo patterns and IVF–embryo transfer
outcome in women who have demonstrated adequate endometrial development by the late proliferative phase. A prospective study
was carried out of 86 patients undergoing IVF–embryo transfer and 86 patients undergoing frozen embryo transfer who all underwent
sonographic monitoring of the endometrium 3 days after embryo transfer. The cycles were classified into two groups: those
with the homogeneous hyperechogenic (HH) pattern and those without it. The women who had an HH pattern had higher clinical
pregnancy (32.8 versus 10.7%, P < 0.05) and implantation rates in stimulated cycles (14.3 versus 4.1%, P < 0.05 respectively) than those that did not. There was no significant difference in the clinical pregnancy or implantation
rates by echo pattern (18.2 and 8.1% for non-HH and 18.7 and 8.0% for HH respectively) in frozen embryo transfer cycles. These
data demonstrate that in embryo transfer cycles where ovarian stimulation was used, there were decreased pregnancy and implantation
rates in cycles where the HH pattern was not observed 3 days after transfer. The failure of the endometrium to display this
pattern may indicate some endometrial abnormality resulting in implantation defects.
Objectives To study endometrial differentiation in the peri-implantation phase of women with recurrent miscarriage and to compare the results with endometrium of normal fertile women. Design A prospective study of endometrial specimens precisely timed from the LH surge, using traditional histologic dating (Noyes’ criteria), quantitative histologic measurement (morphometric analysis), and immunohistochemical techniques. Results Fifteen of 25 (60%) subjects in the recurrent miscarriage group had retarded endometrial development in the peri-implantation period as monitored by morphometry. The recurrent miscarriage group showed reduced levels of four mucin-related secretory epitopes, and greater reductions were associated with morphological retardation. Normal differentiation was observed in all of the 14 subjects in the control group. Conclusions Women with idiopathic recurrent pregnancy loss may be divided into two distinct subgroups on the basis of their endometrial response in the peri-implantation period. Precisely timed endometrial biopsy should be incorporated in the investigation of recurrent miscarriage.
Objective To compare the midluteal uterine artery impedance to blood flow as measured by the pulsatility index in women with different causes of infertility with that of women with normal fertility and to correlate this with endometrial thickness. Design A prospective study of normal women undergoing insemination with donor semen and subfertile women with tubal damage, endometriosis, premature ovarian failure, anovulation, or unexplained infertility. Setting A tertiary infertility center. Patients One-hundred sixty-one women (25 to 40 years of age) who were attending the clinic for subfertility treatment and 23 normal women who were having artificial insemination with donor sperm because their partners were azoospermic. Interventions All women were examined by transvaginal ultrasonography, with color flow imaging and blood flow analysis, on day 21 of an unstimulated ovarian cycle. Main Outcome Measures The mean pulsatility index of the left and right uterine arteries and the endometrial thickness. Results The patients were grouped according to the causes of infertility and compared with normal women. There were 23 women in the normal group (median pulsatility index, 1.91; range, 0.84 to 2.95), 35 with unexplained infertility (median pulsatility index, 2.45; range, 1.0 to 7.0), 91 with tubal damage (median pulsatility index, 2.65; range, 1.25 to 8.0), 8 with endometriosis (median pulsatility index, 2.32; range, 2.05 to 5.7), and 22 with anovulatory infertility (median pulsatility index, 3.03; range, 1.6 to 7.0). All the infertile groups had significantly different median pulsatility indexes when compared with the normal group, and the pulsatility indexes correlated with endometrial thickness. Conclusions The impedance to uterine artery blood flow is significantly different in women with different causes of infertility as compared with women of normal fertility. Increased resistance to uterine blood flow in the midluteal phase may be an important contributing factor to some causes of infertility and the cause of some previously “unexplained” infertility.
It is asserted that examination of the endometrium during the secretory phase yields more information about the time of ovulation degree of progestational change and normality of the endometrium than any other test used in sterility studies. Attention to qualitative changes in 8 morphological factors is most useful in dating the endometrial biopsy. During the 1st week of luteal activity attention should be focused on changes occurring in gland epithelium: gland mitosis pseudostratification of nuclei basal vacuolation and secretion. During the 2nd week stromal changes (including edema) predecidual reaction stromal mitosis and leukocytic infiltration are the key criteria. Tissue from the fundus of the uterus gives the most reliable information. These critera were used in 300 sterility biopsies taken from normally menstruating women over a 3-year period. Absence of organic endometrial disease and availability of accurate menstrual history were the only selection criteria. 12 observers dated the biopsies. 42 of the 300 patients (14%) menstruated on the day predicted 36 (12%) menstruated later and 222 (74%) menstruated earlier. When a +or- 1 day error was allowed 112 patients (38%) were found to menstruate at the time predicted. When these same slides were reviewed by a single observer and the date for the most advanced area of the biopsy was used 179 patients (60%) menstruated within 1 day of prediction. To test the validity of the dating criteria change in basal body temperature was used to correlate endometrial dating with ovulation rather than onset of menstruation. Of the 40 patients who had adequate temperature records 31 (78%) ovulated as predicted allowing a +or- 1 day error indicating that dating is a better gauge of duration of progesterone effect than predictor of onset of menses. To determine whether biopsy caused early menstruation the secretory phases of the 25 patients who had recorded temperatures in at least 2 cycles in addition to that in which the biopsy was taken were examined. The secretory phase was definitely shorter in the biopsied than control cycle suggesting that biopsy does accelerate the onset of flow. However further analysis showed that biopsy does not interfere with length of flow or succeeding menstrual rhythm.
Artificial programming of the menstrual cycle in rhesus monkeys is a remarkable advance in primate uterine biology (Hodgen, 1983). Ovariectomized mature monkeys receive subcutaneous silastic implants of estradiol and progesterone that mimic the serum steroidal hormonal profile of a natural 28-day menstrual cycle. Transfer of surrogate preimplantation embryos into the ampulla of the fallopian tube during artificial cycles has resulted in successful pregnancies and birth of normal offspring. This achievement was followed by production of fertile cycles in women who had been ovariectomized or had primary ovarian failure (Lutjen et al., 1984; Navot et al., 1986). These fundamental demonstrations established that primate uterine cyclic growth depends primarily on an appropriate pattern of systemic estradiol and progesterone secretion.
Hydrosalpinges have been associated with poor in-vitro fertilization (IVF) outcome in some, but not all, studies, perhaps
through endometrial effects. To determine whether hydrosalpinges affect IVF outcome via endometrial factors alone, we analysed
the results of recipients of donor oocytes with hydrosalpinges, thereby controlling for confounding variables, while isolating
the intrauterine environment. We retrospectively analysed 110 patients who underwent 121 donor oocyte cycles in a university-based
assisted reproduction programme. Thirteen cycles involving recipients (n = 10) with hydrosalpinges were compared to 108 cycles involving recipients (n = 100) without hydrosalpinges. Pregnancy, implantation, miscarriage, and ectopic pregnancy rates were compared between women
with and without hydrosalpinges. There were no significant differences between the hydrosalpinx and no hydrosalpinx groups
with respect to donor age, recipient age, or number or grade of embryos transferred. Patients with a hydrosalpinx had significantly
lower embryo implantation rates (7.1 versus 19.3%, P < 0.05) and significantly higher miscarriage (75.0 versus 14.9%, P < 0.05) and ectopic pregnancy rates (33.3 versus 0.0%, P < 0.05) than normal controls. We conclude that the presence of a hydrosalpinx adversely affects early pregnancy events by
altering the intrauterine environment.
The relationship between endometrial histology and ultra sonographic texture in the follicular phase was investigated. The
endometrial sonographic texture of 32 infertile women with normal menstrual cycles was dassified into three patterns (L, H
and I) and histological and morphometrical analyses were performed. Endometrial specimens from pattern L, which showed multi-layered
endometriwn characterized by three hyperechogenic lines with inner hypo echogemc regions, had smaller, similar-sized endometrial
glands and few stromal cells. Those from pattern H which showed entirely homogeneous hyperechogenic endo metrium, had larger,
various-sized glands and more stromal cells. Those from pattern I which showed heterogeneous hyperechogenic and partially
hypo-echogenic endo metrium, had the largest, most variable-sized glands and many stromal cells. The differences in sonographic
texture may he related to the histological and morphometrical findings.
The understanding and control of embryo implantation represents the major challenge for assisted reproductive technologies. Along with developments in basic research and efforts to optimize embryo quality, the improvement of noninvasive and reliable methods to assess uterine receptivity constitutes an important step toward meeting such a challenge. Today, ultrasound-based approaches to evaluate endometrial echogenicity and uterine perfusion and contractility are available for practical use. Increasing evidence indicates that echogenic patterns of the endometrium reflect histologic processes that are involved in the establishment of receptivity. This constitutes a possible explanation for the reported association between premature hyperechogenic patterns of the endometrium and poor implantation rates. Nevertheless, additional studies aiming at correlating further morpho-biochemical events in the endometrium with its echogenicity patterns are needed. Further, developments in vascular assessment by Doppler, Doppler-related, and vascular detection technologies will also be instrumental in monitoring and improving vascular changes that lead to uterine receptivity. Finally, data supporting the hypothesis that uterine contractility, as visualized by ultrasound, influences in vitro fertilization-embryo transfer (IVF-ET) pregnancy rates encourage further investigation on both the regulation and control of uterine contractions. This article discusses some of the advantages and limitations of ultrasonographic assessments of uterine receptivity in the perspective of the new millennium.
Background. In articles and textbooks the prevalence of uterine leiomyomas is said to be 20–25% in women over the age of 30. The aim of this study was to investigate the rate of uterine leiomyoma, the thickness and the texture of the endometrium, and the size of the uterus in a random sample of asymptomatic women 25–40 years old.
Methods. A random sample of women 25–40 years old was offered a transvaginal ultrasonographic examination and 335 (72%) accepted the invitation.
Results. In 18 women uterine leiomyomas were detected, i.e. 5.4% (95% CI 3.0–7.8%). The prevalence of leiomyomas increased with age, being 3.3% (95% CI 0.7–6.0%) in the 25–32 years age group and 7.8% (95% CI 3.6–12.0%) in the 33–40 age group. The size of the uterus correlated to parity, age and height. In women on combined oral contraceptives the size of the uterus was smaller than in women with natural cycles. The size of the uterus did not correlate to body mass index, cycle day or smoking habits. The endometrium increased in thickness and had in most cases a triple line appearance during the proliferative phase until day 15, whereafter it was unchanged in thickness throughout the secretory phase and hyperechogenic in appearance.
Conclusions. This study confirms earlier studies on the endometrium based on selected populations. The size of the uterus increased with parity, age and height, and was smaller in combined oral contraceptive users. The prevalence figures for uterine leiomyomas in textbooks are not confirmed.
A simple procedure is described for eliminating non-specific staining with avidin—peroxidase conjugates. Murine ovaries were embedded in either paraffin wax or epoxy resin and, after blocking endogenous peroxidase activity, were treated with 10 g/ml biotinylatedPisum sativum agglutinin. Avidin—peroxidase conjugates (5 g/ml), diluted in standard 0.05m tris-buffered saline, pH 7.6, containing 0.139m NaCl, produced considerable background coloration and intense mast cell staining in controls without the lectin. This background diminished as the ionic strength of the buffer was raised. At 0.125m Tris-buffered saline (containing 0.347m NaCl) the background was completely unstained, with elimination of all binding to mast cells and only minimal loss of specific lectin binding.
Purpose: The objective was to evaluate the effect of aspirinon infertile women with thin endometrium.
Methods: Patients who had thin endometrium ( 8 mm)and intrauterine insemination were divided into the aspirinand nonaspirin groups. Endometrial pattern (trilaminar andnontrilaminar) and thickness, the pulsatility index (PI) andresistance index (RI) of the uterine artery, spiral artery, andovarian dominant follicles, and pregnancy rates of bothgroups were measured.
Results: A total of 114 and 122 women were included inthe aspirin and nonaspirin groups, respectively. There weresignificantly higher percentages of trilaminar endometrium(46.5% vs. 26.2%) and pregnancy rate (18.4% vs. 9.0%)after aspirin therapy. There was nonsignificant differencein the endometrial thickness, and PI/RI values of the uterineartery, spiral artery, and ovarian dominant follicle betweenboth groups.
Conclusions: Higher pregnancy rate and better endometrialpattern were achieved in patients with thin endometriumafter aspirin administration. Aspirin therapy could notsignificantly increase the endometrial thickness and theresistance of uterine and ovarian flow.
This review describes the current use of Doppler ultrasound to examine blood flow in the uterus and ovaries in infertile patients and during early pregnancy. The basics of Doppler ultrasound and the different methods of measuring blood flow are discussed from the viewpoint of the clinician who may be unfamiliar with Doppler physics and terminology. Normal values in the menstrual cycle and the relationship of uterine and ovarian blood flow to infertility and to implantation following in-vitro fertilization are presented. Normal values for uterine blood flow in the first 16 weeks of pregnancy and the effect of sex steroids and ovulation induction on their values are described. The possible relationship of defective uterine blood flow to recurrent abortion is examined. New areas of investigation, such as the effect of standing on blood flow, and the effect of drugs are explored. The findings of this review indicate that Doppler blood flow studies may provide significant information about possible causes of some disorders of infertility and early pregnancy and methods of treatment for the same.
The development of tubal obstruction and subsequent infertility is a major sequelum of upper genital tract infection with Chlamydia trachomatis; however, little is known about the pathogenesis of the infection. In this investigation, the authors present a detailed study of the progression of ascending chlamydial infection in female guinea pigs resulting from intravaginal inoculation of the Chlamydia psittaci agent of guinea pig inclusion conjunctivitis (GPIC). Isolation of chlamydiae from different tissues of the genital tract revealed definitive evidence for ascending infection that was not dose-related. By 7 days after infection, GPIC was isolated from the endometrium and oviducts of 78% of the animals. Pathologic changes analogous to those seen in human chlamydial disease, including polymorphonuclear, mononuclear, and plasma cell infiltration, were seen in the endometrium and oviducts, although not all isolation positive animals developed overt tubal disease. Long-term fibrosis, often in combination with hydrosalpinx, was noted in the mesosalpingeal tissue in 20% of the animals. Thus, the guinea pig:GPIC system represents a model for ascending chlamydial infection resulting from vaginal inoculation of normal guinea pigs that closely approximates the disease as seen in humans and can be used to study the pathogenesis of chlamydial genital infection.
The distribution of N-linked glycans in rat testis has been probed using a panel of lectins derived from Galanthus nivalis (snowdrop, GNA), Canavalia ensiformis (jack bean, Con A), Lens culinaris (lentil, LCA), Pisum sativum (garden pea, PSA) and Phaseolus vulgaris, erythro- and leucoagglutinins (kidney bean, ePHA and lPHA). Several classes of N-linked glycan were identified in the spermatogenic series, and during differentiation into spermatozoa they altered in both their pattern of distribution and relative abundance. A population of tetra-antennary, non-bisected, complex glycans, detected by lPHA, was lost during the transition from spermatogonia to spermatocytes, while high-mannose structures were acquired; these were most abundant in spermatocytes, as were bi- and tri-antennary complex, non-bisected glycans, the latter becoming increasingly abundant on acrosomes and spermatozoa. Their bisected counterparts were more generally expressed throughout spermatogenic cells, although marked localization onto acrosomes and nuclear caps was again seen. Transition from spermatocytes to spermatids involved mainly changes of the acrosomal granule and nuclear cap, which were carried through to the final stages of differentiation. Sertoli cell surfaces and cytoplasmic granules showed a high level of N-glycan expression.
To investigate whether peri-implantation phase endometrium in women with unexplained infertility differs from the endometrium of normal fertile women.
Assessment of the function of the endometrium by using endometrial biopsy specimens and lectin histochemistry.
Infertility Clinic, Jessop Hospital for Women, Sheffield, United Kingdom.
Eighteen normal fertile women (group I) and 18 women with unexplained infertility (group II).
Endometrial biopsies were obtained from both groups at 5, 7, and 9 days after the luteinizing hormone (LH) surge.
Five biotinylated lectins, concanavalin A (ConA), wheat germ agglutinin (WGA), soybean agglutinin, Peanut, and Ulex europaeus I were used as analytical probes to study endometrial glycoconjugates. Histochemical staining was performed using the avidin-biotin peroxidase method. The lectin binding by endometrial glands, surface epithelium, stromal cells, and vessels was assessed.
In group I, ConA stained the subnuclear glandular cytoplasm, glandular lumen, stroma cells, and surface epithelium. In group II, ConA binding to glandular or surface epithelium was none or equivocal. In group I, WGA bound to glandular cytoplasm and stroma cells on days LH + 5 and LH + 7. In group II, WGA binding was absent in glands but present in stroma.
Reproductive failure of women with unexplained infertility may be associated with defective biosynthesis and distribution of glycoconjugates that subsequently results in an unfavorable endometrial environment during the peri-implantation phase.
To determine possible etiologies of unsuccessful fluoroscopically guided tubal canalization, we studied the histology of tubal segments in cases of failed canalization for proximal tubal obstruction. Factors contributing to cases of unsuccessful fluoroscopically guided tubal canalization remain unclear.
Prospective.
Reproductive Endocrinology Clinic.
Twenty-seven cornual and/or isthmic tubal segments from 15 patients who underwent proximal tubal surgery after fluoroscopically guided tubal canalization were studied. Specimens were prepared with hemotoxylin-eosin and Masson trichrome stains.
Histologic examination of excised cornual and isthmic tubal segments revealed abnormalities in 93% of specimens. Obliterative fibrosis (61%), chronic salpingitis (57%), and salpingitis isthmica nodosa (42%) were the most commonly found histologic tubal abnormalities. One case of complete tubal occlusion and tubal schistosomiasis was also detected.
These data suggest that cases of failed fluoroscopically guided tubal canalization may be secondary to severe intrinsic tubal disease and tubal occlusion and not to the technique. Fluoroscopically guided tubal canalization may provide a means of differentiating a functional obstruction amenable to conservative management from true occlusion requiring management by microsurgical techniques or in vitro fertilization.
This is a study using light microscopy and electronic microscopy of Fallopian tube subjected to sterilization; and compare it with a control group. A total of 60 samples from patients with different surgical procedures, whose age was from 20 to 40 years; they were amenorrheic, without antecedents of pelvic inflammatory disease nor endometriosis. Among the control group, there were lesions as isthsmical nodular salpingitis in 30.7%. There was chronic salpingitis in 15.3%; follicular salpingitis in 23%, and polyps in 15%. In the group with OTB antecedents, endosalpingiosis was found in 20%; follicular salpingitis in 30% and chronic salpingitis in the remaining 50%. By means of electronic, ultrastructural microscopy, were seen lesions at myosalpinx level, that is, alterations in myofilaments, formation, much fibrosis and descilliation in the adjacent to OTB. It may be concluded that these findings, never seen before, may condition an alteration of tubal motility in patients subjected to rechannelization procedures, that condition an alteration in gametes transportation, avoiding fecundation or a greater incidence ectopic pregnancy incidence.
The postovulatory period in the primate endometrium of the menstrual cycle is characterized by rapid growth of the coiled arterioles. A great variety of developing microvascular components occurs among a well‐differentiated microvasculature of coiled arterioles, capillaries, and venules. Endometrial biopsies were obtained by hysterotomy during progesterone dominance at 5, 6, 7, 10, 12, and 14 days following the peak of the estrogen surge as determined by serum radioimmunoassay. Arteriolar ultrastructural differentiation is remarkably similar on each of these days.
Ultrastructural evidence of elastogenesis in the extracellular matrix adjacent to certain endothelial tubes provides the initial sign of coiled arteriolar formation. The cellular primordia of the tunica intima and media are identified by spatial location and glycogen storage in smooth muscle cells. Endothelial projections span the incipient internal elastic membrane to make contact with the surfaces of the innermost vascular smooth muscle cells.
Subsequent arteriolar differentiation centers on formation of a muscular media composed of 1 or 2 muscle layers separated by a spiraling lamellar elastic matrix that appears initially between the endothelial tube and the first muscle layer. Vascular smooth muscle cells are highly branched and linked across the elastic matrix by surface contacts. Definitive coiled arterioles consist of interlinked endothelial and smooth muscle cells within a thick, spiraling elastic matrix that provides flexibility for rapid changes in shape. Progressive differentiation of coiled arterioles continues up to the premenstrual stage. This abundant angiogenesis may reflect preparation and maintenance of a suitable uterine environment for the possibility of implantation and pregnancy during each menstrual cycle.
In 45 women from an in vitro fertilization (IVF) program, the uterine and ovarian blood flows were investigated by vaginal Doppler sonography. The resistance index was used to evaluate the blood pattern. When comparing the patients who became pregnant after embryo transfer (ET [group I, n = 12]) with those who did not conceive (group II, n = 33), it is evident that in group I the vascular resistance of the uterine arteries is significantly lower on the day of follicular aspiration. No differences could be detected in the ovarian vessels. The data obtained so far suggest that the receptivity of the endometrium is a crucial factor for successful implantation. In the final analysis, this can be appraised not only on the basis of morphological but also of hemodynamic parameters.
There have been several causes of infertility attributed to gamete quality, congenital anatomical abnormalities and surgical complications. Published research into the reasons for failure of implantation of embryos has been confined to histochemical and histological studies of the endometrium. This paper presents preliminary data from an ongoing study to test the hypothesis that poor uterine perfusion is a cause of failure of implantation of embryos. It would follow that poor uterine perfusion is a cause of infertility. One-hundred-and-fifty-three patients who had been unsuccessful in conceiving despite three previous in-vitro fertilization attempts have been studied. Doppler ultrasound studies of the ascending branch of the uterine artery, during spontaneous ovarian cycles, revealed a poor mid-secretory uterine response in 48% of patients studied. Patients with poor mid-secretory uterine response were treated with orally administered hormone therapy to improve the mid-secretory uterine response prior to subsequent embryo replacement. The results of subsequent in-vitro fertilization therapy in patients with good uterine response and in women with improved uterine response after hormone therapy are presented. The numbers of patients in each group are insufficient for statistical analyses, but the trends observed support the hypothesis that poor uterine blood flow is a cause of infertility. Further evaluation is warranted.
Doppler studies of the uterine artery using an off-set Doppler transducer with a mechanical sector imaging transducer indicate clear changes in uterine perfusion during the ovarian cycle. In this study, 16 volunteers had Doppler studies performed at least twice weekly during spontaneous ovarian cycles. Endocrine assays were performed on each occasion to measure plasma oestradiol, progesterone and luteinizing hormone levels. Conventional criteria to assess uterine impedance using systolic/end diastolic ratio and Resistance Index were modified to obtain meaningful results and a new flow velocity wave form classification is presented. The results indicate increasing uterine perfusion with rising levels of plasma oestradiol and progesterone and a direct correlation with falling oestrogen levels in the follicular phase. We conclude that off-set mechanical sector duplex systems can be used effectively to monitor uterine responses to the hormone environment.
Endometrial biopsies from 90 women with regular menstrual cycles and a hormonal profile compatible with normal luteal function were morphometrically assessed using 11 different indices and the results were plotted in 48-hour periods around the day of the luteinizing hormone (LH) surge (LH +/- 0). The endometrial dating reached its highest significance from days LH -3/-2 to days LH +7/+8, when the changes occurred with a high degree of regularity regardless of the length of the preovulatory and postovulatory phases. It is proposed therefore that the dating of the endometrium should be related to the LH surge rather than to the "ideal" 28-day cycle. The results also seem to suggest the existence of a regulatory mechanism for the synchronization of follicular maturation and midcycle endometrial development. Further study of the factors involved in this mechanism may result in a better understanding of certain forms of unexplained infertility.
Excised tubal segments from 42 women with uterotubal junction obstruction were studied histologically to evaluate the pathologic spectrum of disease and correlate this with clinical data. The most frequent lesion encountered was obliterative fibrosis (38.1%), confirmed by connective tissue stains, which was not associated with cornual nodularity. Other pathologic entities included salpingitis isthmica nodosa (23.8%), intramucosal endometriosis (14.3%), and chronic tubal inflammation (21.4%). Intramucosal endometriosis was distinguishable from salpingitis isthmica nodosa by virtue of its unique stroma confirmed by connective tissue staining. Women with previous pregnancies were included in all the groups. In all instances, the obstruction was present in the transmural portion of the tube and extended a variable distance into the isthmic segment. These observations on uterotubal junction obstruction demonstrate that: 1) There are multiple distinct histologic patterns, 2) Intraabdominal findings do not predict the histology of the uterotubal junction pathology, 3) Any histologic pattern can be associated with a previous intrauterine or ectopic pregnancy, and 4) The obstruction begins within the transmural portion of the oviduct, extends a variable distance into the isthmic segment, but does not obstruct the ampullary segment. These data suggest that the initiating process originates within the uterus and that fibrosis may represent a nonspecific response to chronic injury of the transmural and isthmic segments of the oviduct.
Ninety-four infertility patients were studied by Doppler ultrasound during spontaneous ovulatory menstrual cycles. The pulsatility index (PI) in uterine and ovarian arteries was measured in the follicular and midluteal phase of the cycle. Associations between high PI values and hormones (estradiol, progesterone, prolactin, testosterone, follicle stimulating hormone) measured during the investigated cycle and age were evaluated. A high PI in uterine arteries in the follicular phase was associated with low estradiol (E2) and progesterone (P) levels in the studied cycle. In the luteal phase PI values of uterine arteries have no obvious association with E and P levels, and other vasoactive compounds influence the perfusion of uterus during this period. The other hormones analysed and age did not correlate with vascular resistance in spontaneous ovulatory cycles.
A total of 46 couples with male immunological infertility entered the trial at the infertility clinic of the Family Federation
of Finland. The men all showed a positive mixed antiglobulin reaction to immunoglobulin G in their semen; 31 men were also
tested for sperm-bound IgA immunoglobulins by flow cytometry. Serum antisperm antibodies were checked in a tray agglutination
test. The women showed normal reproductive endocrinology and at least one patent Fallopian tube. The couples were randomized
to undergo either up to three intra-uterine inseminations (IUI), or timed intercourse with cyclic, low-dose (20 mg) prednisolone
therapy of the men. Cross-over was carried out if no pregnancy occurred in the first stage. Timing of ovulation was based
on urinary luteinizing hormone assay and transvaginal ultrasonographic measurements. In all, 40 couples either completed the
study or the female partner conceived. IUI was significantly better (P = 0.04) with nine pregnancies than timed intercourse with prednisolone (one pregnancy). There were no significant associations
between antibody levels, sperm count or motility versus the incidence of pregnancy. In male immunological infertility, well-timed
IUI is an effective treatment method: results are obtained rapidly and steroidal side-effects can be avoided.
To assess uterine receptivity in women with unexplained infertility using integrin cell adhesion molecules as markers.
Prospective, controlled study design.
Eighty-seven nulliparous women with unexplained infertility and 32 fertile and infertile parous controls.
Immunohistochemical staining for alpha 1, alpha 4, and beta 3 integrin subunits in endometrial biopsies obtained during the window of implantation (days 20 to 24), using the semiquantitative HSCORE by two observers in a blinded fashion.
All endometrial biopsies from parous controls contained positive immunostaining for the alpha 1, and beta 3 integrin subunits in glandular epithelium. Some samples from parous controls were missing the alpha 4 subunit. In contrast, compared with parous controls, biopsies from women with unexplained infertility had reduced significantly beta 3 expression, with similar expression of alpha 1 and alpha 4. Two distinct defects in integrin expression were identified: "out-of-phase" samples that lacked beta 3 because of histologic lag (type I defects) and "in-phase" endometrium that still failed to express this integrin (type II defects). These subclassifications accounted for 26% and 39% of the total unexplained infertility group, respectively.
Abnormal endometrial integrin expression was a frequent finding in women with unexplained infertility. These data suggest that defective uterine receptivity may be an unrecognized cause of infertility in this population of women.
To study endometrial differentiation in the peri-implantation phase of women with recurrent miscarriage and to compare the results with endometrium of normal fertile women.
A prospective study of endometrial specimens precisely timed from the LH surge, using traditional histologic dating (Noyes' criteria), quantitative histologic measurement (morphometric analysis), and immunohistochemical techniques.
Fifteen of 25 (60%) subjects in the recurrent miscarriage group had retarded endometrial development in the peri-implantation period as monitored by morphometry. The recurrent miscarriage group showed reduced levels of four mucin-related secretory epitopes, and greater reductions were associated with morphological retardation. Normal differentiation was observed in all of the 14 subjects in the control group.
Women with idiopathic recurrent pregnancy loss may be divided into two distinct subgroups on the basis of their endometrial response in the peri-implantation period. Precisely timed endometrial biopsy should be incorporated in the investigation of recurrent miscarriage.
To compare the midluteal uterine artery impedance to blood flow as measured by the pulsatility index in women with different causes of infertility with that of women with normal fertility and to correlate this with endometrial thickness.
A prospective study of normal women undergoing insemination with donor semen and subfertile women with tubal damage, endometriosis, premature ovarian failure, anovulation, or unexplained infertility.
A tertiary infertility center.
One-hundred sixty-one women (25 to 40 years of age) who were attending the clinic for subfertility treatment and 23 normal women who were having artificial insemination with donor sperm because their partners were azoospermic.
All women were examined by transvaginal ultrasonography, with color flow imaging and blood flow analysis, on day 21 of an unstimulated ovarian cycle.
The mean pulsatility index of the left and right uterine arteries and the endometrial thickness.
The patients were grouped according to the causes of infertility and compared with normal women. There were 23 women in the normal group (median pulsatility index, 1.91; range, 0.84 to 2.95), 35 with unexplained infertility (median pulsatility index, 2.45; range, 1.0 to 7.0), 91 with tubal damage (median pulsatility index, 2.65; range, 1.25 to 8.0), 8 with endometriosis (median pulsatility index, 2.32; range, 2.05 to 5.7), and 22 with anovulatory infertility (median pulsatility index, 3.03; range, 1.6 to 7.0). All the infertile groups had significantly different median pulsatility indexes when compared with the normal group, and the pulsatility indexes correlated with endometrial thickness.
The impedance to uterine artery blood flow is significantly different in women with different causes of infertility as compared with women of normal fertility. Increased resistance to uterine blood flow in the midluteal phase may be an important contributing factor to some causes of infertility and the cause of some previously "unexplained" infertility.
To measure the flow velocity of the uterine, radial, spiral, and ovarian arteries during the periovulatory period in spontaneous and induced ovarian cycles with confirmed ovulation.
Daily measurements during the periovulatory period in 78 patients attending an infertility clinic because of the male factor in infertility.
Uterine flow velocity in spontaneous cycles has a pulsatility index (PI) of 3.16 2 days before ovulation and starts to decrease the day before ovulation (PI = 2.22). In stimulated cycles these changes do not occur, and mean PI of 3.06 remains at that level during the periovulatory period. Clear flow velocity waveforms are obtained from the endometrium and myometrium around the time of ovulation. Data obtained from the radial arteries suggest better myometrial perfusion in patients with natural cycles. Spiral artery flow velocity in spontaneous cycles has a PI of 1.13 the day before ovulation and a nadir of 0.72 is reached the day after ovulation. On the contrary, the mean PI of the spiral artery blood flow in the group with ovulation induction rises during the day before ovulation (PI = 2.32) and reaches a nadir of 1.09 the day after ovulation.
These data suggest the presence of better uterine receptivity during the periovulatory phase of natural cycles compared with induced ovarian cycles. Endometrial perfusion presents accurate noninvasive assay of uterine receptivity that may be used to predict implantation success rate, to reveal unexplained infertility problems, and to select patients for correction of endometrial perfusion abnormalities by an appropriate treatment.
This study examines circulating and follicular hormone concentrations and fertilization of oocytes in cycles totally unperturbed by exogenous gonadotrophins in 10 women (25 cycles) with untreated minimal-mild endometriosis and nine women (23 cycles) with prolonged unexplained infertility compared with 16 women (50 cycles) with tubal damage as functional controls. Endometriosis was associated with a significantly longer follicular phase (median 15, 12, 13 days respectively) and reduced oestrogen secretion (median index area under the curve 3063, 3842, 3805 units respectively) compared with controls. Both endometriosis and unexplained infertility had significantly reduced serum luteinizing hormone (LH) surges [median peak serum (LH) 43, 39, 55 IU/l respectively and median area under the curve 661, 687, 823 units respectively] and reduced LH concentrations in follicular fluid (median 19.6, 10.6, 9.2 IU/l respectively). These findings suggest that infertility associated with minor endometriosis and of apparently unexplained aetiology share a common pathophysiology in impaired LH surge secretion. Whether that represents a primary pituitary disorder or is secondary to a defective ovarian signal is discussed.
To evaluate embryonic and endometrial factors for their value in predicting pregnancy outcome in in-vitro fertilization (IVF) and embryo transfer, a retrospective data collection and prospective uterine artery colour Doppler imaging study was performed in a university-based IVF-embryo transfer programme setting. A total of 210 patients were included and grouped as follows: (I) IVF with controlled ovarian stimulation (214 cycles); (II) frozen-thaw cycle of autologous embryos (30 cycles); (III) oocyte donation, no cryopreservation (12 cycles); (IV) frozen-thaw cycle with embryos from donated oocytes (10 cycles). Embryo quality was significantly better in pregnant than non-pregnant cycles (group I, P = 0.0104; groups II-IV, P = 0.0418). The endometrial echo was significantly thicker in pregnant versus non-pregnant patients in group I (P = 0.0059), but not in groups II-IV (P = 0.741). Past uterine surgery or abnormalities had no effect on pregnancy outcome. There were no significant differences in mean uterine artery resistance index or peak systolic velocity in pregnant versus non-pregnant patients in groups II-IV. Thus, embryo quality is the most reliable predictor of pregnancy outcome. Endometrial measurements were significantly thicker in subsequently pregnant patients only in group I, where the endometrium reflects the hormonal environment. Doppler parameters were not useful in predicting pregnancy outcome.
To evaluate the luteal phase in women with rigorously defined unexplained infertility.
Prospective study.
National Center for Infertility Research at Michigan.
Evaluation of 1,885 women with infertility identified 12 women who met the rigorously defined criteria for unexplained infertility: [1] infertility of > or = 24 months duration, with no male factor, anatomic-functional disorders of the reproductive tract, or immunologic infertility; [2] normal body mass index (BMI); [3] ovulatory cycles ranging from 26 to 32 days; [4] normal luteal phase determined by endometrial biopsy; and [5] normal baseline hormonal profile. Controls (n = 12) were healthy, parous women with normal ovulatory cycles, normal hormonal screen, and were matched for age and BMI to patients.
Pattern of follicular growth rate and luteal phase hormonal profile.
Women with unexplained infertility did not differ in menstrual cycle characteristics, follicular growth rate or mean preovulatory follicle diameter, or endometrial biopsy dating. The mean levels of P tended to be lower in the unexplained infertility group throughout the luteal phase, but only the midluteal interval reached statistical significance. Luteal phase mean integrated P or urinary PDG levels of unexplained infertility women did not differ from those of fertile controls. The ratio of integrated E2:P also was significantly greater in women with unexplained infertility than in fertile controls.
Women with rigorously defined unexplained infertility have subtle hormonal anomalies during the luteal phase when compared with fertile controls.
The aim of this prospective study was to investigate the relationship between the ultrasonographic appearance of the endometrium, histological dating by biopsy, hormonal profile and impedance within the segmental uterine and ovarian circulation for assessment of luteal phase function. A total of 61 infertile patients undergoing endometrial biopsy were studied by transvaginal B‐mode and color and pulsed Doppler ultrasound. Uterine, radial, spiral, ovarian and intraovarian artery impedance throughout the natural ovarian cycle were related to histological and hormonal markers of uterine receptivity. Plasma levels of follicle stimulating hormone, luteinizing hormone (LH) and estradiol were measured on cycle days 5 and 10 and measurements were continued daily until the detection of the LH surge. Endometrial biopsy was performed 7 days after ultrasonically and hormonally detected ovulation. Progesterone levels were evaluated on the day of endometrial biopsy and 3 days later. After all the data were collected, the patients were divided into two groups, according to the histopathology: 15 patients with normal endometrial dating and 43 patients with a delayed endometrial pattern (i.e. luteal phase defect). One patient with an asynchronous endometrium and two anovulatory subjects were excluded from further evaluation.
A significant difference between patients with a luteal phase defect and the control group was obtained for impedance in the uterine ( p < 0.05), radial ( p < 0.05), spiral ( p < 0.00l), ovarian ( p < 0.05) and intraovarian arteries ( p < 0.001) during the luteal phase. The endometrium showed secretory transformation when serum levels of progesterone were higher than 15 ng/ml.
Segmental uterine and ovarian artery perfusion demonstrates a significant correlation with histological and hormonal markers of uterine receptivity. Therefore, blood flow impedance in the corpus luteum and spiral arteries may aid in assessing luteal phase adequacy. Copyright © 1997 International Society of Ultrasound in Obstetrics and Gynecology
A prospective clinical study at the Infertility Clinic of National Cheng Kung University Hospital investigated the effect of aspirin on infertile women with impaired uterine perfusion. A total of 127 women with unexplained infertility or repeated failure with various assisted-conception techniques were enrolled. Uterine perfusion was assessed by Doppler ultrasound and classified as normal or impaired (pulsatility index < 3.0 or > or = 3.0, respectively). One-third (43/127) of the women were found to have impaired uterine perfusion during their menstrual cycles. Those with impaired uterine blood flow were given aspirin (100 mg/day) starting on day 3 of the next ovulatory cycle. Only 36 women completed both the screening and the aspirin-treated cycles. The pulsatility index was measured in the natural and aspirin-treated cycles in the same group of women and compared using repeated measures analyses of variance. A significant improvement in the uterine blood perfusion (p < 0.05) was detected on the day leutinizing hormone peaked and in the midluteal phase (peri-implantation period) of aspirin-treated cycles. Thus, the use of low-dose aspirin may improve uterine perfusion in women with unexplained infertility and impaired uterine blood flow.
To determine hormone levels across the menstrual cycle in women with rigorously defined unexplained infertility.
Prospective study.
National Center for Infertility Research at Michigan.
Evaluation of 1,885 women with infertility identified 12 women who met the following rigorously defined criteria for unexplained infertility: [1] infertility of > or = 24 months' duration, with no male factor, anatomic or functional disorders of the reproductive tract, or immunologic infertility; [2] normal body mass index (BMI); (3) ovulatory cycles ranging from 26 to 32 days; [4] normal luteal phase determined by endometrial biopsy; and [5] normal baseline hormonal profile. Controls (n = 12) were healthy, parous women with normal ovulatory cycles and normal hormonal screens, and were matched for age and BMI with patients.
Daily gonadotropin and steroid hormone levels across the menstrual cycle.
Basal FSH and LH levels in the early, middle and late follicular phases were increased significantly in the group with unexplained fertility compared with the normal controls. The mean (+/-SD) early follicular FSH levels were 7.0 +/- 0.57 mIU/mL in the unexplained-infertility group and 4.7 +/- 0.37 mIU/mL (conversion factor to SI units, 1.00) in the normal controls, respectively. There was no difference between groups over the periovulatory or luteal phase. Midluteal mean (+/-SD) P levels were lower in the unexplained-infertility group than in the normal controls (13.7 +/- 1.6 versus 24.0 +/- 3.2 ng/mL [conversion factor to SI units, 3.180]). Mean E2 concentrations were elevated in the group with unexplained infertility versus normal controls in the early through the late follicular phase but reached significance only in the midfollicular phase. Mean prolactin levels were elevated consistently across the menstrual cycle in the unexplained-infertility group compared with those in normal controls but reached significance only in the early and late follicular and midluteal phases of the cycle. Cortisol concentrations were similar between the two groups.
These data indicate that there are subtle alterations in various hormones measured across the menstrual cycle in women with unexplained infertility compared with those in normal controls, suggesting a diminished ovarian reserve.
To evaluate the effect of low-dose aspirin use in oocyte donation recipients with an endometrial thickness of < 8 mm.
A prospective, randomized study.
An oocyte donation program in a private infertility practice.
Twenty-eight recipients undergoing oocyte donation who failed to develop an endometrial thickness of at least 8 mm in a previous evaluation cycle.
Fifteen recipients received low-dose aspirin (81 mg/d) in addition to standard hormone replacement for an oocyte donation cycle. The remaining 13 recipients did not receive aspirin.
Clinical pregnancy rates, delivery rates, implantation rates, and change in endometrial thickness were compared in the aspirin and nonaspirin groups.
There was no demonstrable increase in endometrial thickness in the aspirin-treated group. However, there was a statistically significant increase in implantation rates in the aspirin-treated group (24% versus 9%) and in implantation rates and clinical pregnancy rates in the aspirin-treated group when the final endometrial thickness was < 8 mm.
Low-dose aspirin therapy improves implantation rates in oocyte donation recipients with a thin endometrium.
To evaluate the clinical usefulness of high-resolution transvaginal ultrasonography in pre- and perimenopausal women suspected to have endometrial pathology.
196 women, aged between 32 and 57 years, were referred to the outpatient clinic for a dilatation and curettage (D&C). In 81% the clinical indication was irregular vaginal bleedings. Before the D&C an examination with transvaginal ultrasonography was performed, and the endometrial thickness and texture were determined. The ultrasonographic results were later compared with the histological diagnosis obtained from the D&C specimen.
Ultrasonographically both normal and pathological endometrial changes could be detected, and 82% of the women had an endometrium characterized as normal. The endometrial phase determination correlated with the histological findings in approximately 50% of the women. Histologically 83% of the women had a normal endometrium. Endometrial hyperplasia was found in 12% and endometrial polyps in 4%. There were no malignancies found in this study. The hormone users (33% of the women) had no higher incidence of hyperplasias than non-users.
Our data indicate that transvaginal ultrasonography is as effective as the D&C for depicting the endometrium in pre- and perimenopausal women with irregular bleedings.
Endometrial growth is thought to depend on uterine artery blood flow and the importance of endometrial development on in-vitro fertilization (IVF) outcome has been previously reported. Nitric oxide (NO) relaxes vascular smooth muscle through a cGMP-mediated pathway and NO synthase isoforms have been identified in the uterus. Sildenafil citrate (Viagra), a type 5-specific phosphodiesterase inhibitor, augments the vasodilatory effects of NO by preventing the degradation of cGMP. In this preliminary report we describe the use of vaginal sildenafil to improve uterine artery blood flow and sonographic endometrial appearance in four patients with prior failed assisted reproductive cycles due to poor endometrial response. The uterine artery pulsatility index (PI) was measured in a mock cycle after pituitary down-regulation with Lupron. The PI was decreased after 7 days of sildenafil (indicating increased blood flow) and returned to baseline following treatment with placebo. The combination of sildenafil and oestradiol valerate improved blood flow and endometrial thickness in all patients. These findings were reproduced in an ensuing gonadotrophin-stimulated cycle. Three of the four patients conceived. Although greater numbers of patients and randomized evaluation are needed to validate this treatment, vaginal sildenafil may be effective for improving uterine artery blood flow and endometrial development in IVF patients with prior poor endometrial response.
The human endometrium is an extremely sensitive target for steroid hormones. During the menstrual cycle, this tissue undergoes dynamic changes that are reflected on the surface morphology of the epithelium and that can be followed by scanning electron microscopy. The morphologic changes peak at the midsecretory phase, with the formation of the so-called pinopodes. Increasing evidence suggests that these pinopodes are accurate markers for endometrial receptivity, and their detection may be of high clinical utility in the preparation of endometrium before embryo transfer. This article recapitulates published figures of endometrial ultrastructure and presents some unpublished data from ongoing studies.
To determine whether endometrial echogenicity, assessed objectively by a computer-assisted system on the day of hCG administration, predicts endometrial receptivity in controlled ovarian hyperstimulation (COH) cycles for IVF-ET.
Prospective analysis.
Assisted reproduction unit, Clamart, France.
Two hundred twenty-one women (aged <38 years with a normal uterus and >/=2 grade A or B embryos transferred) undergoing 228 GnRH agonist and FSH/hCG cycles for IVF-ET.
On the day of hCG administration, uterine ultrasound scans were digitized with an image analysis system. Endometrial echogenicity was assessed as the ratio of the extent of the hyperechogenic transformation over the whole endometrial thickness. According to this, cycles were sorted arbitrarily into six groups: <30% (n = 34), 31%-40% (n = 37), 41%-50% (n = 37), 51%-60% (n = 55), 61%-70% (n = 37), and >70% (n = 28).
Pregnancy and implantation rates.
The groups were similar in regard to population characteristics, ovarian response to COH, and embryology data. Pregnancy rates (59%, 57%, 35%, 20%, 16%, and 11%, respectively) and implantation rates (35%, 23%, 17%, 6%, 7%, and 3%, respectively) fell progressively and significantly from the low-echogenicity group to the high-echogenicity group.
The present results confirm and extend previous observations that advanced hyperechogenic transformation of the endometrium is associated with poor IVF-ET outcome.
The plasma membrane of uterine epithelial cells is very sensitive to ovarian hormones and protrusions of the apical portion
of this membrane have been used as indicators of endocrine status and preparation for implantation in the human uterus in
particular. Protrusions of the apical plasma membrane were first identified in rats and mice where their established pinocytotic
function gave rise to the name `pinopod'. In humans and many other animals however, little evidence of the functional nature
of such protrusions is available but what is available suggests that human `pinopods' (useful though they are as indicators
of endocrine status) might be more similar morphologically to other, larger, membrane protrusions, or apical domes, which
have been shown not to be pinocytotic. Hence, I propose that these latter protrusions, including those in the human uterus,
should be referred to by a term which does not imply a particular function and have settled on the name `uterodome'.