Reproduction & Fertility最新文献

Abstract: Studies evaluating pregnancy outcomes after assisted reproductive treatment (ART) in women with high-normal (2.5-4.5 mIU/L) thyroid-stimulating hormone (TSH) levels are conflicting, possibly due to different patient charactistics and subfertility indications. The aim of this study was to examine the hypothesis that high-normal compared to low-normal TSH levels are associated with adverse implications for pregnancy outcomes in conventional in vitro fertilization (IVF)-treated women. Therefore, we analyzed retrospectively the characteristics and pregnancy outcomes of 949 subfertile women with TSH 0.3-4.5 mIU/L, treated with conventional IVF between January 2008 and March 2012. Demographic and baseline characteristics were compared between groups of patients based on TSH quartiles, using one-way Anova, Kruskal-Wallis ANOVA and chi-square test. Women with high-normal quartile TSH were significantly more likely to be primary subfertile (P = 0.01), with a higher prevalence of unexplained subfertility and with 15% fewer live births after IVF compared to lower TSH quartiles (P = 0.02). In secondary subfertile women with high-normal TSH, male factor subfertility prevailed (P = 0.01), with more live births (P = 0.01). When analyzing primary and secondary subfertile women as one group, these differences failed to be observed, showing no differences in cumulative pregnancy outcomes of IVF between TSH quartiles (I: 0.3-1.21 mIU/L; II: 1.22-1.68 mIU/L; III: 1.69-2.31 mIU/L; IV: 2.32-4.5 mIU/L). In conclusion, primary subfertile women predominate in the high-normal TSH quartile, associated with significantly fewer live births in a subgroup of primary unexplained subfertile women (9%; n  = 87/949), while in secondary subfertile women, dominated by male factor subfertility, high-normal TSH is associated with more live births.

Lay summary: Thyroid hormones are required for all cell processes in the body. An underactive thyroid gland, in which insufficient thyroid hormones are produced and thyroid-stimulating hormone (TSH) rises, is associated with a lower chance of pregnancy. It is not yet clear above which TSH level, 4.5 or also 2.5 mIU/L, this lower probability occurs. Therefore, in 949 couples treated with conventional IVF, we examined whether high-normal TSH levels (TSH: 2.5-4.5 mIU/L) compared to low normal TSH levels (0.3-2.5 mIU/L) affect the live birth rate. We found that women who were trying to become pregnant for the first time, especially without any other cause, that is unexplained subfertility, were more likely to have higher TSH levels. These women had a much lower chance of having a baby compared to women with low-normal TSH levels.

There is a worldwide trend for women to have their first pregnancy later in life. However, as oocyte quality declines with maternal aging, this trend leads to an increase in subfertility. The cellular mechanisms underlying this decline in oocyte competence are poorly understood. Oocyte mitochondria are the subcellular organelles that supply the energy that drives early embryogenesis, and thus their quality is critical for successful conception. Mitochondria contain their own DNA (mtDNA) and mutations in mtDNA cause mitochondrial diseases with severe symptoms, such as neurodegeneration and heart disease. Since mitochondrial function declines in tissues as humans age accompanied by an accumulation of mtDNA mutations, mtDNA is implicated as a cause of declining oocyte quality in older mothers. While this mutation load could be caused by declining accuracy of the mitochondrial replisome, age-related decline in mitochondrial quality control likely contributes, however knowledge is lacking. Mitophagy, a cellular process which specifically targets and recycles damaged mitochondria may be involved, but studies are scarce. And although assisted reproductive technologies can help older mothers, how these techniques affect the mechanisms that regulate mitochondrial and oocyte quality have not been studied. With the long-term goal of understanding the molecular mechanisms that control mitochondrial quality in the oocyte, model systems including Drosophila and mouse as well as human oocytes have been used. In this review, we explore the contribution of mitophagy to oocyte quality and the need for further systematic investigation in oocytes during maternal aging using different systems.

Lay summary: Mitochondria are small parts of cells called organelles that generate the chemical energy needed for life. Hundreds of thousands of mitochondria in the developing eggs of the mother support the initial growth and development of the fertilized egg. However, due to increasingly diminished function over time, mitochondria generate less energy as we age, posing real problems for older women considering pregnancy. It is possible that this declining energy could be responsible for declining fertility as women age. Energy may decline because mitochondria fail and the cell's way of keeping them healthy become less efficient as we age. This review summarizes what is known about mitochondrial quality control in developing eggs as they age. In the future, understanding how the best mitochondria are selected and maintained in the egg, and hence the future baby, may enable older women with or without mitochondrial problems, to have healthy children.

ProAKAP4 is synthetized as a precursor polypeptide that must be converted into mature AKAP4 in living spermatozoa and is considered as a functional marker of spermatozoa. The gene is well-conserved in mammals although uncharacterized in Camelidae. In the present study, we investigate the expression metabolism of proAKAP4 and AKAP4 proteins and evaluate their seasonal dynamics relative to semen quality in dromedary camels. Semen parameters including volume and viscosity and characteristics of sperm including concentration, total production, total and progressive motility, vitality, acrosome integrity and morphological abnormalities were assessed in semen samples collected weekly from six camels during the rutting season, from November to April. Only total sperm production varied, peaking in January. Both the precursor proAKAP4 and AKAP4 proteins were investigated and shown to express biochemical properties similar to those described in other mammals. ProAKAP4 concentrations expressed in ng/10 million spermatozoa as assayed using a specific ELISA showed a strong positive correlation with ejaculate volume (P = 0.045), viscosity (P < 0.001) and sperm total motility (P = 0.049). Furthermore, their concentrations exhibited clear seasonal variations in camel semen. In conclusion, the assessment of proAKAP4 concentrations in camel sperm provides a novel parameter to assess sperm quality. Further studies should be performed to investigate proAKAP4 concentrations relative to fertility in Camelidae that may help to define the right time for mating and semen collection and increase the success of breeding programs.

Lay summary: Breeding related to the seasons/time of year in the camel has been reported in several studies. A better knowledge of semen quality during the breeding season would assist in determining the best period for mating in camels. However, conventional sperm parameters are held to be unsatisfactory because they cannot predict breeding potential. ProAKAP4 a sperm-specific protein has been described as a functional marker of sperm and a key fertility marker in several species but has not been described in camels. Motility or membrane integrity parameters of semen collected throughout the breeding season and also the presence of proAKAP4 protein were investigated. ProAKAP4 was identified for the first time in camels and their concentrations exhibited clear seasonal variations in camel semen showing strong correlations with ejaculate volume and total motility and viscosity. Further studies should be performed to investigate proAKAP4 concentrations relative to fertility in camels to define the right time for mating and increase the success of breeding programs.

The current approach to treating endometriosis is often inadequate or intolerable for many patients. Until more effective therapies are available, we should aim to maximize the effectiveness of our current options. Optimization may be possible by reducing nocebo effects, which are the negative therapeutic effects not directly caused by a treatment. Awareness of these effects, how they arise, and the factors influencing them, is invaluable if we aim to limit their magnitude. The unique nature of endometriosis diagnosis and management is especially prone to nocebo effects due to multiple factors, including diagnostic delays, feelings of invalidation, social transmission of expectations, and persistent symptoms despite numerous treatments. This commentary discusses the origins of these effects in people with endometriosis, methods of limiting nocebo effects, and future research directions.

Lay summary: The term 'nocebo' describes the undesirable effects of a medication or treatment that patients may experience which are not directly caused by the treatment (e.g. tiredness from a sugar pill). These arise from pre-existing expectations toward a treatment and are influenced by multiple external factors, including past experiences, online media, personal beliefs, and personality factors. Endometriosis is a disease characterized by cells like those from the inside of the uterus growing outside of the uterus. The complex nature of endometriosis diagnosis and management creates an environment where nocebo effects may affect treatment outcomes. We may be able to limit nocebo effects through awareness and simple actions that strengthen patient-doctor relationships. Effective therapeutic relationships with doctors are crucial in limiting negative expectations and are established through empathy, honesty, and support. Therapeutic relationships built on trust may allow healthcare providers to address negative expectations, nocebo effects, and the misinformation affecting endometriosis management.

Prolactin and placental lactogens increase during pregnancy and are involved with many aspects of maternal metabolic adaptation to pregnancy, likely to impact on fetal growth. The aim of this study was to determine whether maternal plasma prolactin or placental lactogen concentrations at 20 weeks of gestation were associated with later birth of small-for-gestational-age babies (SGA). In a nested case-control study, prolactin and placental lactogen in plasma samples obtained at 20 weeks of gestation were compared between 40 women who gave birth to SGA babies and 40 women with uncomplicated pregnancies and size appropriate-for-gestation-age (AGA) babies. Samples were collected as part of the 'screening of pregnancy endpoints' (SCOPE) prospective cohort study. SGA was defined as birthweight <10th customized birthweight centile (adjusted for maternal weight, height, ethnicity, parity, infant sex, and gestation age) in mothers who remained normotensive. No significant differences were observed in concentrations of prolactin or placental lactogen from women who gave birth to SGA babies compared with women with uncomplicated pregnancies. However, a sex-specific association was observed in SGA pregnancies, whereby lower maternal prolactin concentration at 20 weeks of gestation was observed in SGA pregnancies that were carrying a male fetus (132.0 ± 46.7 ng/mL vs 103.5 ± 38.3 ng/mL, mean ± s.d., P = 0.036 Student's t-test) compared to control pregnancies carrying a male fetus. Despite the implications of these lactogenic hormones in maternal metabolism, single measurements of either prolactin or placental lactogen at 20 weeks of gestation are unlikely to be useful biomarkers for SGA pregnancies.

Lay summary: Early identification during pregnancy of small for gestational age (SGA) babies would enable interventions to lower risk of complications around birth (perinatal), but current detection rates of these at risk babies is low. Pregnancy hormones, prolactin and placental lactogen, are involved in metabolic changes that are required for the mother to support optimal growth and development of her offspring during pregnancy. The levels of these hormones may provide a measurable indicator (biomarker) to help identify these at risk pregnancies. Levels of these hormones were measured in samples from week 20 of gestation from women who went on to have SGA babies and control pregnancies where babies were born at a size appropriate for gestation age. Despite the implications of prolactin and placental lactogen in maternal metabolism, no significant differences were detected suggesting that single measures of either prolactin or placental lactogen at 20 weeks gestation are unlikely to be useful biomarker to help detect SGA pregnancies.

Even partway through an IVF cycle, at the point when a woman's eggs have been collected, it is hard to provide reliable answers to the common question of 'Am I likely to have a good embryo to transfer?' Sometimes, it only takes one good egg to be successful. However, doctors and patients are acutely aware that low egg numbers, older age and having conditions such as endometriosis can stack the odds against success. We have developed a model to try and answer this question for those patients who wish for more information to help guide their expectations after egg collection. A new tool is presented to predict whether a woman having IVF treatment will have a good enough embryo either to transfer on day 5 or freeze. It was built using information from all 2015 to 2016 UK cycles and predicts using age, number of eggs collected and cause of subfertility.

Objectives: Pouch of Douglas (POD) obliteration is a severe consequence of inflammation in the pelvis, often seen in patients with endometriosis. The sliding sign is a dynamic transvaginal ultrasound (TVS) test that can diagnose POD obliteration. We aimed to develop a deep learning (DL) model to automatically classify the state of the POD using recorded videos depicting the sliding sign test.

Methods: Two expert sonologists performed, interpreted, and recorded videos of consecutive patients from September 2018 to April 2020. The sliding sign was classified as positive (i.e. normal) or negative (i.e. abnormal; POD obliteration). A DL model based on a temporal residual network was prospectively trained with a dataset of TVS videos. The model was tested on an independent test set and its diagnostic accuracy including area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and positive and negative predictive value (PPV/NPV) was compared to the reference standard sonologist classification (positive or negative sliding sign).

Results: In a dataset consisting of 749 videos, a positive sliding sign was depicted in 646 (86.2%) videos, whereas 103 (13.8%) videos depicted a negative sliding sign. The dataset was split into training (414 videos), validation (139), and testing (196) maintaining similar positive/negative proportions. When applied to the test dataset using a threshold of 0.9, the model achieved: AUC 96.5% (95% CI: 90.8-100.0%), an accuracy of 88.8% (95% CI: 83.5-92.8%), sensitivity of 88.6% (95% CI: 83.0-92.9%), specificity of 90.0% (95% CI: 68.3-98.8%), a PPV of 98.7% (95% CI: 95.4-99.7%), and an NPV of 47.7% (95% CI: 36.8-58.2%).

Conclusions: We have developed an accurate DL model for the prediction of the TVS-based sliding sign classification.

Lay summary: Endometriosis is a disease that affects females. It can cause very severe scarring inside the body, especially in the pelvis - called the pouch of Douglas (POD). An ultrasound test called the 'sliding sign' can diagnose POD scarring. In our study, we provided input to a computer on how to interpret the sliding sign and determine whether there was POD scarring or not. This is a type of artificial intelligence called deep learning (DL). For this purpose, two expert ultrasound specialists recorded 749 videos of the sliding sign. Most of them (646) were normal and 103 showed POD scarring. In order for the computer to interpret, both normal and abnormal videos were required. After providing the necessary inputs to the computer, the DL model was very accurate (almost nine out of every ten videos was correctly determined by the DL model). In conclusion, we have developed an artificial intelligence that can interpret ultrasound videos of the sliding sign that show POD scarring that is almost as accurate as the ultrasound specialists. We believe

The success of IVF has remained stagnant for a decade. The focus of a great deal of research is to improve on the current ~30% success rate of IVF. Artificial intelligence (AI), or machines that mimic human intelligence, has been gaining traction for its potential to improve outcomes in medicine, such as cancer diagnosis from medical images. In this commentary, we discuss whether AI has the potential to improve fertility outcomes in the IVF clinic. Based on existing research, we examine the potential of adopting AI within multiple facets of an IVF cycle, including egg/sperm and embryo selection, as well as formulation of an IVF treatment regimen. We discuss both the potential benefits and concerns of the patient and clinician in adopting AI in the clinic. We outline hurdles that need to be overcome prior to implementation. We conclude that AI has an important future in improving IVF success.

Purpose: To evaluate the association between a rise in serum luteinizing hormone (LH) levels during artificial frozen-thawed embryo transfer (FET) cycles and clinical pregnancy rate.

Methods: A retrospective cohort study of women undergoing artificial FET cycles. We compared cycles in which LH double itself from the early follicular phase and further (group A) to cycles without a rise in LH (group B). Endometrium preparation was achieved by administration of 2 mg three times per day estradiol valerate tablets. Embryo transfer (ET) was conducted after achieving endometrial thickness > 7 mm and vaginal progesterone was added according to the embryo's age. A beta-hCG was measured 13-14 days after ET. Clinical pregnancy was diagnosed on transvaginal ultrasound.

Results: Data from 984-FET cycles were retrieved. LH, exogenous estradiol (E2), progesterone values, endometrial thickness, and pregnancy outcomes were available in all patients. From 984-FET cycles, 629 (63.9%) had a doubling, and 355 (36.07%) had no rise in LH. Patients mean age was 30 years, similar in both groups. A multivariable logistic regression analysis was calculated to assess the effect of LH rise and pregnancy outcomes, after adjusting for confounders including a rise in E2 level and endometrial thickness. In this model, there was no association between doubling LH values and pregnancy rates (adjusted odds ratio: 1.06, 95% CI: 0.75-1.5, P = 0.74).

Conclusion: LH rise during artificial FET cycles does not alter pregnancy rates. Apparently, hormonal monitoring of LH levels may not yield useful information in the artificial FET cycle and may be omitted.

Lay summary: Supplementation of estradiol, a hormone produced by the ovaries, starting at the beginning of the menstrual cycle of an artificially frozen embryo transfer (FET) can lead to a rise in luteinizing hormone (LH), the hormone that induces ovulation. Such a rise in LH may interfere with embryo implantation, the process where the embryo attaches to the inner lining of the uterus and, therefore, could affect the chances of pregnancy. The current study is the first to assess the effect of a dynamic rise in LH levels during FET cycles on pregnancy rates. This study found no difference in pregnancy rates between FET cycles where the LH doubled compared to cycles without such a rise in LH. Larger, prospective studies should be conducted to assess the impact of LH elevation on pregnancy outcomes.