Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and ...maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition—something addressed in an earlier portion of this Views and Reviews.
Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment.
In mouse female preimplantation embryos, the paternal X chromosome (Xp) is silenced by imprinted X chromosome inactivation (iXCI). This requires production of the noncoding Xist RNA in cis, from the ...Xp. The Xist locus on the maternally inherited X chromosome (Xm) is refractory to activation due to the presence of an imprint. Paternal inheritance of an Xist deletion (XpΔXist) is embryonic lethal to female embryos, due to iXCI abolishment. Here, we circumvented the histone-to-protamine and protamine-to-histone transitions of the paternal genome, by fertilization of oocytes via injection of round spermatids (ROSI). This did not affect initiation of XCI in wild type female embryos. Surprisingly, ROSI using ΔXist round spermatids allowed survival of female embryos. This was accompanied by activation of the intact maternal Xist gene, initiated with delayed kinetics, around the morula stage, resulting in Xm silencing. Maternal Xist gene activation was not observed in ROSI-derived males. In addition, no Xist expression was detected in male and female morulas that developed from oocytes fertilized with mature ΔXist sperm. Finally, the expression of the X-encoded XCI-activator RNF12 was enhanced in both male (wild type) and female (wild type as well as XpΔXist) ROSI derived embryos, compared to in vivo fertilized embryos. Thus, high RNF12 levels may contribute to the specific activation of maternal Xist in XpΔXist female ROSI embryos, but upregulation of additional Xp derived factors and/or the specific epigenetic constitution of the round spermatid-derived Xp are expected to be more critical. These results illustrate the profound impact of a dysregulated paternal epigenome on embryo development, and we propose that mouse ROSI can be used as a model to study the effects of intergenerational inheritance of epigenetic marks.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Context
Different phenotypical features of women with hypothalamic hypogonadism (HH), also known as World Health Organization-1 anovulation, including ovarian morphology, have been scarcely ...described in large cohorts. Some studies have reported increased levels of anti-Müllerian hormone (AMH) in women with HH.
Objective
To assess whether women with HH, compared with healthy controls, have increased serum levels of AMH and what proportion of these women erroneously meet the Rotterdam Criteria for Polycystic Ovarian Syndrome (PCOS).
Design, Setting and Participants
Retrospective cohort study in a Dutch academic medical center including 83 women with neither anovulation nor menstrual cycle disorders (healthy controls), 159 women with HH and 3640 women with PCOS. Age matching was used between the HH and PCOS group (1:2 ratio) to create a second group consisting of 318 age-matched women with PCOS.
Intervention
None.
Main outcome measures
AMH levels and ovarian morphology.
Results
Median AMH serum levels for the HH group were 3.8 (<0.1–19.8), compared with 7.5 (<0.1–81.0) in the PCOS group and 1.9 (<0.1–21.5) in the control group (P < 0.001). In the HH group, 58 (36%) erroneously met the Rotterdam Criteria for PCOS (meeting 2 of 3 criteria).
Conclusions
AMH levels are increased in women with HH. We hypothesize that this increase, although there was no increase in follicle count, may be explained by the presence of a relatively large pool of antral follicles smaller than 2 mm in diameter, that are undetectable by transvaginal ultrasound. This study highlights the importance of measuring gonadotropins and estradiol before diagnosing a patient with PCOS.
Context:
The concept of cardiovascular health was recently introduced. Sex steroids and sex hormone-binding globulin (SHBG) influence different health domains, but no studies assessed their role in ...cardiovascular health.
Objective:
To assess the association between estradiol (E2), testosterone (T), SHBG, and free androgen index (FAI) with cardiovascular health.
Design, setting, and participants:
Analyses included 1647 men (68.6 y) and 1564 naturally postmenopausal women (69.6 y) with available data on sex steroids and cardiovascular health from the population-based Rotterdam Study.
Exposures:
E2, T, SHBG, and FAI.
Outcome:
To define cardiovascular health, 7 metrics including 3 health factors (total cholesterol, fasting glucose, and blood pressure) and 4 health behaviors (physical activity, smoking, body mass index, and diet) were adopted. Three category levels of each metric were added up to a total score ranged 0–14. Logistic regression was performed to explore the association between E2, T, SHBG, and FAI and optimal cardiovascular health (OCH) (score of 11–14).
Results:
OCH was reached by 153 men (9.3%) and 162 women (10.4%). The prevalence of OCH was higher in the lowest tertile of E2 (38.9%), and of T (43.8%), and the highest tertile of SHBG (48.1%) in women, and the highest tertile of T (43.1%) and SHBG (47.1%) in men. After adjustment for confounders, OCH was associated with lower T (odds ratio and 95% confidence interval, 0.69 0.48–1.00) and lower FAI (0.43 0.32–0.57) and higher levels of SHBG (4.55 2.99–6.94) among women and with higher levels of SHBG (2.56 1.45–4.49) in men.
Conclusions:
OCH was associated with sex steroids and with SHBG in both men and women. The complexity and temporality of the interrelation between sex steroids, SHBG, and cardiovascular health requires further investigation.
Lower levels of testosterone were associated with cardiovascular health in women, and higher levels of sex hormone-binding globulin were associated with cardiovascular health in both men and women.
Abstract
BACKGROUND
Worldwide, the prevalence of obesity in women of reproductive age is increasing. Bariatric surgery is currently viewed as the most effective, long-term solution for this problem. ...Preconception bariatric surgery can reduce the prevalence of obesity-related subfertility and adverse maternal, pregnancy and birth outcomes. Maternal health during the periconception period is crucial for optimal gametogenesis and for embryonic and fetal development which also affects health in the later lives of both mother and offspring. Although preconception bariatric surgery improves several pregnancy outcomes, it can also increase the prevalence of pregnancy complications due to excessive and rapid weight loss. This can lead to iatrogenic malnutrition with vitamin deficiencies and derangements in metabolic and endocrine homeostasis. Thus, bariatric surgery can greatly influence periconception maternal health with consequences for reproduction, pregnancy and health in later life. However, its influence on periconception maternal health itself has never been reviewed systematically.
OBJECTIVE AND RATIONALE
The aim of this review was to investigate associations between bariatric surgery and determinants of periconception maternal health such as endocrine changes, fertility, vitamin status, irregular menstrual cycles, miscarriages and congenital malformations.
SEARCH METHODS
Medline, Embase, PubMed, Web of Science, Google Scholar and the Cochrane databases were used for the literature search until 1 November 2020. The search strategy terms included, among others, bariatric surgery, hormones, fertility, malformations, miscarriages and vitamin status. We searched for human studies that were written in English. Abstracts, reviews, meta-analyses and conference papers were excluded. The ErasmusAGE score was used to assess the quality of the included studies.
OUTCOMES
A total of 51 articles were analysed. The mean quality score was 5 (range 2–8). After bariatric surgery, hormonal axes normalized and menstrual cycle regularity was restored, resulting in increased fertility. Overall, there were no short-term risks for reproductive outcomes such as the increased risk of miscarriages or congenital malformations. However, the risk of vitamin deficiencies was generally increased after bariatric surgery. A meta-analysis of 20 studies showed a significant decrease in infertility (risk difference (RD) −0.24, 95% confidence interval (CI) −0.42, −0.05) and menstrual cycle irregularities (RD −0.24, 95% CI −0.34, −0.15) with no difference in rates of miscarriage (RD 0.00, 95% CI −0.09, 0.10) and congenital malformations (RD 0.01, 95% CI −0.02, 0.03).
WIDER IMPLICATIONS
The current systematic review and meta-analysis show associations between bariatric surgery and periconception maternal health and underlines the need for providing and personalizing preconception care for women after bariatric surgery. We recommend preconception care including the recommendation of postponing pregnancy until weight loss has stabilized, irrespective of the surgery-to-pregnancy interval, and until vitamin status is normalized. Therefore, regular monitoring of vitamin status and vitamin supplementation to restore deficiencies is recommended. Furthermore, this systematic review emphasizes the need for a long-term follow-up research of these women from the periconception period onwards as well as their pregnancies and offspring, to further improve care and outcomes of these mothers and children.
Purpose
To investigate the association between oocyte area and fertilization rate, embryo usage, and preimplantation embryo development in order to establish if oocyte area can be a marker for ...optimal early embryo development.
Methods
From 2017 to 2020, 378 couples with an indication for IVF (
n
= 124) or ICSI (
n
= 254) were included preconceptionally in the Rotterdam Periconception Cohort. Resulting oocytes (
n
= 2810) were fertilized and submitted to time-lapse embryo culture. Oocyte area was measured at the moment of fertilization (t0), pronuclear appearance (tPNa), and fading (tPNf). Fertilization rate, embryo usage and quality, and embryo morphokinetics from 2-cell stage to expanded blastocyst stage (t2-tEB) were used as outcome measures in association with oocyte area. Oocytes were termed “used” if they were fertilized and embryo development resulted in transfer or cryopreservation, and otherwise termed “discarded”. Analyses were adjusted for relevant confounders.
Results
Oocyte area decreased from t0 to tPNf after IVF and ICSI, and oocytes with larger area shrank faster (β − 12.6 µm
2
/h, 95%CI − 14.6; − 10.5,
p
< 0.001). Oocytes that resulted in a used embryo were larger at all time-points and reached tPNf faster than oocytes that fertilized but were discarded (oocyte area at tPNf in used 9864 ± 595 µm
2
versus discarded 9679 ± 673 µm
2
,
p
< 0.001, tPNf in used 23.6 ± 3.2 h versus discarded 25.6 ± 5.9 h,
p
< 0.001). Larger oocytes had higher odds of being used (oocyte area at tPNf OR
used
1.669, 95%CI 1.336; 2.085,
p
< 0.001), were associated with faster embryo development up to the morula stage (e.g., t9 β − 0.131 min, 95%CI − 0.237; − 0.025,
p
= 0.016) and higher ICM quality.
Conclusion
Oocyte area is an informative marker for the preimplantation development of the embryo, as a larger oocyte area is associated with higher quality, faster developing embryos, and higher chance of being used. Identifying determinants associated with oocyte and embryo viability and quality could contribute to improved preconception care and subsequently healthy pregnancies.
To evaluate the association between estrogen (E) exposure and deficiency and cardiovascular disease (CVD) risk among women with primary ovarian insufficiency (POI).
Cross-sectional study conducted ...between 1996 and 2016.
Tertiary referral centers.
A total of 385 women with POI, defined by amenorrhea and FSH levels ≥40 IU/L before 40 years of age, were recruited.
None.
Women underwent a standardized intake questionnaire including data on menstrual cyclicity. Lifetime E exposure and E-free period were assessed. Serum was analyzed for endocrine and CVD profiles. The Framingham 30-year risk of CVD was calculated.
Lifetime E exposure (mean ± SD) was 19.3 ± 7.0 years, E-free period was 3.1 ± 4.1 years, and age at screening was 34.8 ± 7.4 years. In multivariate models E-free interval associated positively with estimated risk of hard and general CVD events (β 0.18 95% confidence interval 0.08, 0.29; 0.20 0.05, 0.35, respectively), and lifetime E exposure associated negatively with estimated risk of hard and general CVD events (−0.15 −0.24, −0.05; −0.16 −0.29, −0.03, respectively), as well as low density lipoprotein cholesterol (−0.03 −0.06, 0.00) and non–high density lipoprotein cholesterol (−0.04 −0.07, 0.00).
Prolonged E deprivation is associated with an increased estimated risk of CVD, whereas prolonged E exposure is associated with a reduced estimated risk. These results support the policy of early and continued use of E replacement therapy in women with POI.
NCT0230904.
Abstract
STUDY QUESTION
What are the best practices for undertaking epidemiologic and phenotypic studies in polycystic ovary syndrome (PCOS)?
SUMMARY ANSWER
Best practices for the undertaking of ...epidemiologic and phenotypic studies in PCOS are outlined.
WHAT IS KNOWN ALREADY
Currently methodologies used for studies of PCOS epidemiology and phenotypes vary widely, and the comparability of studies is low, reducing the ability to harmonize studies.
STUDY DESIGN, SIZE, DURATION
The Androgen Excess and PCOS (AE-PCOS) Society established a Task Force to draft a research resource for epidemiologic and phenotypic studies in PCOS, with the aim of providing guidelines on study design and execution, insights into the limitations and alternatives and protocols to be used, taking into consideration a global perspective.
PARTICIPANTS/MATERIALS, SETTING, METHODS
A targeted review of the literature was carried out as necessary.
MAIN RESULTS AND THE ROLE OF CHANCE
High level recommendations include the following:
(i) Before initiating the study, a number of critical factors should be addressed including selecting the population and diagnostic criteria (which should ideally align with the recommendations of the International Guidelines), the type of observational study to be undertaken and the primary and secondary endpoint(s) of the study.(ii) To assess the ‘natural’ or true phenotype and epidemiology of PCOS, the least medically biased, broadest and most generalizable population, and the broadest definition of PCOS, should be used.(iii) Four PCOS phenotypes (Phenotypes A through D), based on the presence or absence of three general features (oligo-anovulation, hyperandrogenism and polycystic ovarian morphology), should be ascertained.(iv) In epidemiologic and phenotypic studies, the detection of PCOS rests on the accuracy and sensitivity of the methods used for assessing the individual features of the disorder, and how ‘normal’ is defined.(v) Although an assessment algorithm that minimizes the use of certain measures (e.g. androgen levels and/or ovarian ultrasonography) can be devised, when possible it is preferable to uniformly assess all subjects for all parameters of interest.
(vi) The inclusion of subjects in epidemiologic studies who do not appear to have PCOS (i.e. ‘non-PCOS’) will provide the necessary cohort to establish population-specific normative ranges for the various features of PCOS.
(vii) Epidemiologic studies of PCOS in unselected populations will yield relatively limited numbers of PCOS subjects available for genetic study; alternatively, large population-based epidemiologic studies of PCOS will potentially generate large numbers of unaffected individuals that may serve as genetic controls.
(viii) Epidemiologic studies of PCOS will benefit from a clear governance structure and should begin by informing, educating and engaging both the formal and informal leaders of the populations targeted for study.
(ix) In designing their study investigators should, in advance, establish statistical power and recognize, manage and account for inherent biases.
(x) Subjects suspected of having PCOS but who do not/cannot complete their evaluation (i.e. have ‘possible PCOS’) can be included by imputation, assigning them a ‘diagnostic weight’ based on those subjects of similar clinical phenotype that have completed the study.
(xi) In obtaining, storing and retrieving subject data, subjects should be assessed consecutively using a uniform data collection form; providing as complete and in depth data as possible.
(xii) Maintenance of both paper and electronic medical records should focus on ensuring data quality, accuracy and institutional ethical compliance, and familiarity with country-dependent laws, including biobanking-specific laws, tissue laws and research laws.
(xiii) In obtaining and biobanking study samples, these should be ideally collected at the time of the first assessment.
(xiv) Access to stored data sets should ideally be granted to other bona fide researchers conducting research in the public interest.
(xv) SOPs detailing the exact method of each of the activities for handling the data and the samples are necessary to ensure that all methods are performed uniformly.
(xvi) Epidemiologic studies of PCOS must be resourced adequately.
LIMITATIONS, REASONS FOR CAUTION
As with all reports involving expert interpretation of experiential and published data, inherent individual biases are possible. This risk is minimized in the present study by including experts from varying fields of study, aligning with recent international evidence-based guidelines and obtaining consensus approval of the recommendations from the Task Force and the board of the AE-PCOS.
WIDER IMPLICATIONS OF THE FINDINGS
These guidelines should encourage investigators worldwide to undertake much needed epidemiologic studies of PCOS, increasing the validity, integrity and comparability of the data.
STUDY FUNDING/COMPETING INTEREST(S)
The study received no funding. R.A. serves as consultant for Medtronic, Spruce Biosciences and Ansh Labs; has received research funding from Ferring Pharmaceuticals; and is on the advisory board of Martin Imaging; R.L. has received research funding from MSD Pharmaceuticals; J.L. has received fees and/or grant support from the Dutch Heart Association, The Netherlands Organisation for Health Research and Development (ZonMw), Ferring Pharmaceuticals, Danone, Euroscreen/Ogeda and Titus Health Care; H.T. receives grant funding from the National Health and Medical Research Council; K.K., L.M.-P., S.S.M. and B.O.Y. have no potential conflicts of interest.
TRIAL REGISTRATION NUMBER
N/A
Context:
A young age at menopause has been associated with increased cardiovascular disease (CVD) risk.
Objective:
To compare the cardiovascular risk profile between women with premature ovarian ...insufficiency (POI) and premenopausal controls of comparable age.
Design:
Cross-sectional case control study.
Setting:
Two university medical centers.
Participants:
Women above 45 years of age who were previously diagnosed with POI (n = 83) and premenopausal population controls of comparable age (n = 266).
Main Outcome Measures:
Blood pressure, body mass index, waist circumference, electrocardiogram, bilateral carotid intima media thickness, estradiol, T, androstenedione, dehydroepiandrosterone sulfate, SHBG, insulin, glucose, lipids, TSH, free T4, N-terminal pro-B-type natriuretic peptide, C-reactive protein, uric acid, creatinine, and homocysteine were measured. Potential associations between POI status and subclinical atherosclerosis were assessed.
Results:
Women with POI exhibited an increased waist circumference (β = 5.7; 95% confidence interval CI, 1.6, 9.9), C-reactive protein (β = 0.75; 95% CI, 0.43, 1.08), free T4 levels (β = 1.5; 95% CI, 0.6, 2.4), and lower N-terminal pro-B-type natriuretic peptide (β = −0.35; 95% CI, −0.62, −0.08), estradiol (β = −1.98; 95% CI, −2.48, −1.48), T (β = −0.21; 95% CI, −0.37, −0.06), and androstenedione (β = −0.54; 95% CI, −0.71, −0.38) concentrations compared to controls, after adjusting for confounders. After adjustment, a trend toward increased hypertension (odds ratio = 2.1; 95% CI, 0.99; 4.56) and decreased kidney function was observed in women with POI (creatinine β = 3.5; 95% CI, −0.05, 7.1; glomerular filtration rate β = −3.5; 95% CI, −7.5, 0.46). Women with POI exhibited a lower mean carotid intima media thickness (β = −0.17; 95% CI, −0.21, −0.13) and decreased odds of plaque presence compared to controls (odds ratio = 0.08; 95% CI, 0.03; 0.26).
Conclusions:
Women with POI exhibited an unfavorable cardiovascular risk profile, including higher abdominal fat, elevated chronic inflammatory factors, and a trend toward increased hypertension and impaired kidney function compared to controls. However, we observed no signs of increased subclinical atherosclerosis in women with POI. Additional studies are required to identify specific determinants of long-term CVD risk in women with POI.
Women with POI exhibited several increased cardiovascular risk factors, however no increased subclinical atherosclerosis compared to controls at middle age.
Many women with Polycystic Ovary Syndrome (PCOS) report high depression rates. The relationship between PCOS and these high depression rates is unclear. Two-component lifestyle interventions have ...revealed short-term effects on depression scores in this group of women. In general, 3-component interventions including diet, exercise, and cognitive behavioral therapy (CBT) are more effective in the long-term to improve emotional well-being. This has not yet been studied in women with PCOS. This study examined the effect of 20 CBT lifestyle (LS) sessions combined with a healthy diet and physical therapy with or without 9 months additional feedback through Short Message Service (SMS) via mobile phone, compared to care as usual (CAU, involving advice to lose weight). In this secondary analysis, 155 women with PCOS and a BMI above 25 kg/m2 were eligible. Depression scores decreased significantly in the LS programme compared to CAU (P = 0.045). In both the LS programme without SMS (P = 0.036) and the LS programme with SMS (P = 0.011) depression scores decreased while no change was observed in CAU (P = 0.875). Self-esteem scores improved significantly in the LS programme compared to CAU (P = 0.027). No differences in body image scores were observed in LS participants compared to CAU (P = 0.087), although body image improved significantly in both the LS without SMS (P = 0.001) and with SMS (P = 0.008) study arms. We found no significant mediating role by androgens in the relationship between LS participants and emotional well-being. Only weight-loss mediated the relationship between LS and self-esteem. To conclude, a three-component lifestyle intervention programme with or without additional SMS resulted in significant improvements in depression and self-esteem compared to CAU, in women with PCOS, obesity, and a wish to achieve a pregnancy. Testosterone, androstenedione, DHEA, insulin, HOMA-IR, and cortisol did not mediate this effect. Weight loss mediated the effects on self-esteem but not on depression and body-image. This suggests that lifestyle treatment independent of weight loss can reduce depression and body-image, but both lifestyle treatment and weight loss can improve self-esteem. Thus, a three-component lifestyle intervention based on CBT could prove successful in improving mood in women with PCOS who are overweight or obese and attempting to become pregnant.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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