Progesterone concentrations and dosage with frozen embryo transfers - What's best?

BACKGROUND: There is a lack of consensus on the optimal dose and form of progesterone supplementation during frozen-thawed embryo transfer with hormone replacement therapy. AIMS: We aim to identify the serum progesterone concentration on day 16 most likely to result in positive pregnancy outcomes. MATERIALS AND METHODS: We undertook a retrospective study of 4582 women who underwent frozen embryo transfer with hormone replacement therapy, or natural frozen embryo transfer, over 14 years at a multi-site private in vitro fertilisation clinic. Embryos were 3-5 days of age at time of transfer. We extracted data on serum progesterone concentrations and outcomes, as well as dose and form of progesterone supplementation, from patient and pharmacy records. RESULTS: Increased live birth rates for frozen embryo transfer with hormone replacement therapy were seen with day 16 serum progesterone concentrations >50 nmol/L (26.4% vs 11.3% for <50 nmol/L; adjusted odds ratio (OR) 3.14 (95% CI 2.21-4.48)). Similarly, a decreased pregnancy loss rate was seen in this group (14.3% vs 32.6% for ≤50 nmol/L; adjusted OR 0.26 (95% CI 0.12-0.58)). There was a positive correlation between live births and the number of progesterone doses per day (r = 0.119, P = 0.026) and day 16 progesterone concentrations (r = 0.128, P = 0.011). CONCLUSION: Improved pregnancy outcomes are seen with day 16 serum progesterone concentrations >50 nmol/L. There is a statistically significant correlation between live births, number of progesterone doses per day and day 16 serum progesterone concentrations in this study.

Human Blastocyst Secreted microRNA Regulate Endometrial Epithelial Cell Adhesion.

Successful embryo implantation requires synchronous development and communication between the blastocyst and the endometrium, however the mechanisms of communication in humans are virtually unknown. Recent studies have revealed that microRNAs (miRs) are present in bodily fluids and secreted by cells in culture. We have identified that human blastocysts differentially secrete miRs in a pattern associated with their implantation outcome. miR-661 was the most highly expressed miR in blastocyst culture media (BCM) from blastocysts that failed to implant (non-implanted) compared to blastocysts that implanted (implanted). Our results indicate a possible role for Argonaute 1 in the transport of miR-661 in non-implanted BCM and taken up by primary human endometrial epithelial cells (HEECs). miR-661 uptake by HEEC reduced trophoblast cell line spheroid attachment to HEEC via PVRL1. Our results suggest that human blastocysts alter the endometrial epithelial adhesion, the initiating event of implantation, via the secretion of miR, abnormalities in which result in implantation failure.

Cryopreserved oocytes: update on clinical applications and success rates.

IMPORTANCE: Over the past 3 decades, oocyte cryopreservation procedures have improved rapidly. However, there is limited research reviewing the efficacy of different cooling protocols and inadequate data comparing in vitro fertilization (IVF) outcomes from fresh oocytes with cryopreserved oocytes. OBJECTIVE: The present review was performed to investigate advances in oocyte cryopreservation technologies and identify areas for further research, to determine whether results from IVF using cryopreserved oocytes are comparable to IVF using fresh oocytes, and to identify the patient populations requiring access to oocyte cryopreservation. EVIDENCE ACQUISITION: A literature review was conducted. OVID (MEDLINE) and PubMed databases were queried using phrases such as "oocyte or egg" and "cryopreservation," "vitrification," or "slow cooling or slow freezing." A total of 180 studies were selected for review. RESULTS: Current literature suggests that vitrified oocytes produce superior IVF results to slow-frozen oocytes and may yield comparable outcomes to IVF with fresh oocytes in certain patient populations. Patients at risk of infertility due to disease or age-related decline or oocyte donation programs, couples who fail to produce semen when required for IVF, and patients with legal or ethical reasons against embryo cryopreservation may access cryopreserved oocytes. CONCLUSIONS: We suggest that women who comprise the previously mentioned patient populations should be offered oocyte vitrification technology. Further research is required to confirm IVF success across all patient populations and determine the best cryopreservation protocols. RELEVANCE: This review will be relevant to clinicians interested in fertility treatments using cryopreserved oocytes, fertility preservation, oncology and fertility, and immunology and fertility.

Localisation of the Notch family in the human endometrium of fertile and infertile women.

To investigate the spatial and temporal immunolocalisation and staining intensity of the Notch signalling family in endometrium of fertile and infertile women, endometrial biopsies were collected by curettage from 25 fertile women across the menstrual cycle and 10 infertile women in the mid secretory phase of menstrual cycle. Immunohisotchemistry was completed for NOTCH1, -2, -3, -4, cleaved Notch, DLL1, -3, -4, JAGGED1, -2, HES and NUMB and immunostaining intensity measured in both the endometrial glandular and luminal epithelium. NOTCH1 and the ligands DLL1 and JAGGED1 were key proteins displaying increased staining intensity during the receptive phase of the menstrual cycle and dysregulated in infertile endometrium. Conversely, NUMB a negative regulator of Notch signalling was decreased in the mid secretory phase of the menstrual cycle in fertile women and increased with infertility.

Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence.

BACKGROUND: Improvements in vitrification now make frozen embryo transfers (FETs) a viable alternative to fresh embryo transfer, with reports from observational studies and randomized controlled trials suggesting that: (i) the endometrium in stimulated cycles is not optimally prepared for implantation; (ii) pregnancy rates are increased following FET and (iii) perinatal outcomes are less affected after FET. METHODS: This review integrates and discusses the available clinical and scientific evidence supporting embryo transfer in a natural cycle. RESULTS: Laboratory-based studies demonstrate morphological and molecular changes to the endometrium and reduced responsiveness of the endometrium to hCG, resulting from controlled ovarian stimulation. The literature demonstrates reduced endometrial receptivity in controlled ovarian stimulation cycles and supports the clinical observations that FET reduces the risk of ovarian hyperstimulation syndrome and improves outcomes for both the mother and baby. CONCLUSIONS: This review provides the basis for an evidence-based approach towards changes in routine IVF, which may ultimately result in higher delivery rates of healthier term babies.

Fetal-maternal communication: the role of Notch signalling in embryo implantation.

The establishment of a successful pregnancy requires the implantation of a competent blastocyst into a 'receptive' endometrium, facilitating the formation of a functional placenta. Inadequate or inappropriate implantation and placentation is a major reason for infertility and is thought to lead to first-trimester miscarriage, placental insufficiency and other obstetric complications. Blastocyst-endometrial interactions are critical for implantation and placental formation. The Notch signalling family is a receptor-ligand family that regulates cellular processes as diverse as proliferation, apoptosis, differentiation, invasion and adhesion. Notch signalling is achieved via cell-cell interaction; thus, via Notch, cells can have direct effects on the fate of their neighbours. Recently, a number of studies have identified Notch receptors and ligands in the endometrium, blastocyst and placenta. This review collates current knowledge of this large receptor-ligand family and explores the role of Notch signalling during implantation and placentation, drawing on information from both human and animal studies. Overall, the evidence suggests that Notch signalling is a critical component of fetal-maternal communication during implantation and placentation and that abnormal Notch expression is associated with impaired placentation and pre-eclampsia.

Normal live birth after testicular sperm extraction and intracytoplasmic sperm injection in variant primary ciliary dyskinesia with completely immotile sperm and structurally abnormal sperm tails.

OBJECTIVE: To report on the investigation and fertility management of variant primary ciliary dyskinesia (PCD). DESIGN: Case report. SETTING: University-affiliated assisted reproductive technologies practice. PATIENT(S): A 40 year-old man presenting with 12 months' primary infertility, complete sperm immotility, severe morphologic defects, and moderate sinopulmonary disease. INTERVENTION(S): Electron microscopy (EM) of sperm, nasal cilial function studies, open testis biopsy, and sperm extraction for intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S): Outcome of ICSI treatment using immotile testicular sperm. RESULT(S): EM revealed abnormal connecting pieces, shortened midpieces with attenuated mitochondrial sheaths, poorly developed annulus, abnormal outer dense fibers, and axonemes missing the two central mircotubules. Nasal ciliary beat frequency was subnormal and dyssynchronous. Immotile testicular sperm were selected for ICSI based on physical characteristics and fertilized 12 of 18 eggs. A single day-5 blastocyst achieved a normal pregnancy and delivery of a healthy 3,840-g girl at 38 weeks' gestation. CONCLUSION(S): Nonclassic PCD may present with structurally abnormal completely immotile sperm, with seemingly little prospect of fertility, and moderate respiratory dysfunction supporting the presence of an underlying ciliopathy. Despite testicular sperm also being immotile and showing profound structural defects that would seem to preclude fertilization, more morphologically normal sperm are capable of establishing a normal pregnancy.

Human embryo culture and assessment for the derivation of embryonic stem cells (ESC).

The culture and critical assessment of early human embryos during the first week of human development are reviewed for the derivation of ESC. Both normal and abnormal features are assessed by phase contrast microscopy of whole embryos and in serial sections of fixed material by light and electron microscopy (TEM). Normal embryos follow a time table of development and have equal blastomeres with minimal fragmentation and nuclear defects. Abnormal embryos show more fragmentation and nuclear aberrations such as micronucleation and multinucleation, reflected by aneuploidy, polyploidy, and mosaicism. The selection of normal embryos and the hardiest of embryos that survive to blastocysts is recommended for the derivation and culture of ESC.