Reproduction & Fertility最新文献

The objective of this study was to examine the pregnancy outcomes from frozen embryo transfer (FET) cycles using different endometrial preparation regimens, compared to ovulation induction with letrozole (letrozole OI). A retrospective cohort study was conducted at a fertility centre in Sydney, Australia, on 6060 FET cycles. The cycles were stratified into one of four ways to achieve endometrial preparation. These were either a natural, letrozole OI, OI with follicle-stimulating hormone (FSH OI) or a programmed cycle. The primary outcome was live birth rate (LBR) per embryo transfer. Secondary outcomes included clinical pregnancy and biochemical pregnancy rates, adverse events including miscarriage, ectopic pregnancy, stillbirth, neonatal death and multiple births. Ovarian stimulation parameters were also analysed including the time taken to reach the luteal phase and the number of blood or urine tests required for monitoring the cycle. The results of the study showed that the LBR following letrozole OI cycles was higher when compared to natural cycles (odds ratio (OR): 1.27 (1.07-1.49)) and programmed cycles (OR: 2.36 (1.67-3.34)). There was no significant difference between letrozole OI and FSH OI LBR (OR: 0.99 (0.76-1.28)). An improved LBR with letrozole OI compared to natural cycles was maintained when only women with a normal length cycle were considered (OR: 1.44 (1.10-1.89)). There was a significant reduction in miscarriage rates when letrozole OI was compared to programmed cycles (OR: 0.46 (0.26-0.83)). It was therefore concluded that the use of letrozole OI for endometrial preparation in an FET cycle may be associated with higher LBR and lower miscarriage rate, compared to using a programmed cycle.

Lay summary: Couples suffering from infertility frequently try to conceive following the transfer of an embryo which has been frozen during an in vitro fertilisation cycle. Embryos will only lead to a pregnancy if the woman's womb lining has particular characteristics that allow it to accept the embryo. Despite the thousands of frozen embryo transfer cycles carried out across the world, it is not known how best to prepare a woman's lining so it has these particular characteristics. This study looked at the pregnancy outcomes of 6060 cycles to compare four different ways to prepare a woman's womb lining. These included relying on a woman's natural menstrual cycle, or using an oral medication called letrozole, or injectable medicine called follicle-stimulating hormone, or oestrogen and progesterone hormonal medications. The comparison found that using letrozole before transfer of a frozen embryo may be associated with higher rates of a live birth for some women.

In previous studies, we had shown the synergistic effect of 10^-5 M forskolin (FSK) on the detection threshold of the cyclic AMP response to luteinizing hormones (LH) and chorionic gonadotropins (CG) from various species in the mouse Leydig tumor cell (mLTC) cell line. Independently, we started to study the effect of 10^-12-10^-6 M oxytocin (OXT) also on the cyclic AMP response to LH and CG preparations on these same cells and found an amplifying effect on the luminescence response caused by gonadotropins. The aim was then to explore the effects of 10^-12-10^-6 M OXT on the gonadotropin-induced cAMP response, in the presence or absence of 10 µM FSK to optimize the assay down to a sensitivity compatible with the detection of the circulating concentrations of these hormones in various species. Finally, the optimization relies on three independent phenomena: (1) the inhibition of nucleotide phosphodiesterase by IBMX (3-isobutyl-1-methylxanthine) to avoid cAMP degradation; (2) the strong synergy of 10 µM forskolin with low concentrations of LH or CG during the 1-h luminescence measurement; (3) the stimulatory effect of 10^-8M OXT on the amplitude of transfected cAMP-sensitive luciferase response. By doing this, the detectable concentrations are at the 1-10 pg/well (pM range) for the LHs and CGs from various species. The bioactivities of circulating LHs and CGs in blood or urine are therefore expected to be measurable in 10 µL-plasma samples from mammalian species and maybe others. Indeed, a preliminary study with equine and donkey plasma samples shows that the measured bioactivity was fully inhibited by a specific MAB against the receptor-binding region of equine LH (eLH) and equine CG (eCG), thus eliminating a possible response due to interfering substances other than eLH or eCG. From these data, it is expected that the bioactivity profiles of these hormones will be measurable in the blood of human, equine, and ovine species and very likely in rodents, ruminants, and hopefully in most other mammalian species.

Lay summary: Luteinizing hormone (LH) plays a central role in controlling ovary and testicle functions in many animals, including humans. The highly sensitive method, known as an assay, described in this paper, measures the biological activity of LH in the blood of mammals. The assay is performed in culture of cells derived from mouse testicles in the presence of factors that diminish the detection threshold for LH. The knowledge of the bioactive LH concentration dynamics in the blood is very informative about the reproductive status of male and female mammals. This new in vitro bioassay provides a powerful tool to get this information.

Previous reports indicate that red pandas (Ailurus fulgens styani) may experience fetal loss during gestation; however, neither the rate nor timing of pregnancy failure has been described in this species. The objective of this study was to utilize ultrasound video and images collected between 2010 and 2020 at the Cincinnati Zoo and Botanical Garden to better characterize pregnancy loss and fetal development. Trans-abdominal ultrasound examinations were performed on six female red pandas over a 10-year period, resulting in 12 profiles. Pregnancy was diagnosed via ultrasound in 10 of 12 profiles, and 40.0% of pregnancies showed evidence of fetal loss prior to parturition. Pregnancy loss was classified into lost (2 of 10; 20.0%), in which no cubs were produced, or partial loss (2 of 10; 20.0%), in which two concepti were visualized via ultrasound, but only one cub was born. Fetal loss occurred between days 51 and 23 pre-partum. Fetal growth characteristics were documented, including skeletal ossification (occurring between days 32 and 27 pre-partum), crown-rump length, head length, cranial length, and fetal heart rate (173-206 b.p.m.). These findings provide novel insights into pregnancy loss, may serve as a reference for milestones of fetal development, and may be useful in diagnosing pregnancy and assessing pregnancy loss in red pandas.

Lay summary: For many wildlife species, there is no non-invasive method of determining pregnancy; therefore, the rate of pregnancy loss oftentimes is unknown. Many red pandas in human care that are paired for breeding are observed exhibiting normal mating behaviors; however, only a relatively low proportion of females produce cubs. We utilized animals conditioned for ultrasound examination to diagnose pregnancy and characterize the incidence and timing of pregnancy loss. In total, 12 potential pregnancies were monitored, beginning after breeding season and ending ~2 weeks prior to anticipated cubbing. Of these, ten were (83.3%) were diagnosed as pregnant, with 40% undergoing either full or partial pregnancy loss. Fetal growth characteristics, such as body length and head size, are described which may be useful for monitoring pregnancies and estimating fetal age. Results of this study provide novel data on pregnancy loss in red pandas. Insights into the rate and timing of reproductive failure may illuminate causes and contributing factors, ultimately allowing for improvements in husbandry which may result in greater reproductive success of individuals recommended for breeding.

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.

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.

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