Hormonal, functional and genetic biomarkers in controlled ovarian stimulation: tools for matching patients and protocols

Variability in the subfertile patient population excludes the possibility of a single approach to controlled ovarian stimulation (COS) covering all the requirements of a patient. Modern technology has led to the development of new drugs, treatment options and quantitative methods that can identify single patient characteristics. These could potentially be used to match patients with the right treatment options to optimise efficacy, safety and tolerability during COS. Currently, age and follicle-stimulating hormone (FSH) level remain the most commonly used single patient characteristics in clinical practice. These variables only provide a basic prognosis for success and indications for standard COS treatment based on gross patient categorisation. In contrast, the anti-Müllerian hormone level appears to be an accurate predictor of ovarian reserve and response to COS, and could be used successfully to guide COS. The antral follicle count is a functional biomarker that could be useful in determining the dose of FSH necessary during stimulation and the success of treatment. Finally, in the future, genetic screening may allow an individual patient's response to stimulation during COS to be predicted based on genotype. Unfortunately, despite the predictive power of these measures, no single biomarker can stand alone as a guide to determine the best treatment option. In the future, hormonal, functional and genetic biomarkers will be used together to personalise COS

Response: Commentary: Efficacy of Follicle-Stimulating Hormone (FSH) Alone, FSH + luteinizing hormone, human menopausal gonadotropin or FSH + human chorionic gonadotropin on assisted reproductive technology outcomes in the "Personalized" Medicine Era: A meta-analysis

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Efficacy of follicle-stimulating hormone (FSH) alone, FSH + luteinizing hormone, human menopausal gonadotropin or FSH + human chorionic gonadotropin on assisted reproductive technology outcomes in the "personalized" medicine era: A meta-analysis

Setting: Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) act on the same receptor, activating different signal transduction pathways. The role of LH or hCG addition to follicle-stimulating hormone (FSH) as well as menopausal gonadotropins (human menopausal gonadotropin; hMG) in controlled ovarian stimulation (COS) is debated. Objective: To compare FSH + LH, or FSH + hCG or hMG vs. FSH alone on COS outcomes. Design: A meta-analysis according to PRISMA statement and Cochrane Collaboration was performed, including prospective, controlled clinical trials published until July 2016, enrolling women treated with FSH alone or combined with other gonadotropins. Trials enrolling women with polycystic ovarian syndrome were excluded (PROSPERO registration no. CRD42016048404). Results: Considering 70 studies, the administration of FSH alone resulted in higher number of oocytes retrieved than FSH + LH or hMG. The MII oocytes number did not change when FSH alone was compared to FSH + LH, FSH + hCG, or hMG. Embryo number and implantation rate were higher when hMG was used instead of FSH alone. Pregnancy rate was significantly higher in FSH + LH-treated group vs. others. Only 12 studies reported live birth rate, not providing protocol-dependent differences. Patients' stratification by GnRH agonist/antagonist identified patient subgroups benefiting from specific drug combinations. Conclusion: In COS, FSH alone results in higher oocyte number. HMG improves the collection of mature oocytes, embryos, and increases implantation rate. On the other hand, LH addition leads to higher pregnancy rate. This study supports the concept of a different clinical action of gonadotropins in COS, reflecting previous in vitro data

Exploring the Impact of Controlled Ovarian Stimulation and Non-Invasive Oocyte Assessment in ART Treatments.

Invasive and noninvasive features are normally applied to select developmentally competent oocytes and embryos that can increase the take-home baby rates in assisted reproductive technology. The noninvasive approach mainly applied to determine oocyte and embryo competence has been, since the early days of IVF, the morphological evaluation of the mature cumulus-oocyte complex at the time of pickup, first polar body, zona pellucida thickness, perivitelline space and cytoplasm appearance. Morphological evaluation of oocyte quality is one of the options used to predict successful fertilization, early embryo development, uterine implantation and the capacity of an embryo to generate a healthy pregnancy to term. Thus, this paper aims to provide an analytical revision of the current literature relating to the correlation between ovarian stimulation procedures and oocyte/embryo quality. In detail, several aspects of oocyte quality such as morphological features, oocyte competence and its surrounding environment will be discussed. In addition, the main noninvasive features as well as novel approaches to biomechanical parameters of oocytes that might be correlated with the competence of embryos to produce a healthy pregnancy and live birth will be illustrated

Future perspectives of PoseidOn stratification for clinical practice and research

A total of 50% of patients undergoing IVF treatment has previously been estimated to fulfill the POSEIDON classification criteria; importantly, although the reproductive prognosis differs between patients, POSEIDON patients share the same characteristic of a low ovarian response to exogenous gonadotropin stimulation\u2014independent of age. POSEIDON patients require focused attention as regards ovarian stimulation in order to increase the chances of having at least one euploid blastocyst for transfer\u2014the success criterion for stimulation set forth by the POSEIDON Group. The key to success seems to be individualization in all steps of treatment. In this perspective article we discuss the future impact of the POSEIDON stratification for daily clinical practice as well as for research

The ATLAS muon micromegas R&D project: towards large-size chambers for the s-LHC

Detectors based on the bulk-Micromegas technology exhibit position resolution better than 100 m m at counting rates of up to several tens of kHz/cm(2), along with trigger capabilities. These characteristics, combined with the detector's mechanical robustness and the possibility for cost-effective industrial production, makes them a promising candidate for the ATLAS Muon Spectrometer upgrade in a future luminosity enhancement of the LHC. The R&D project status will be presented together with the obtained results in the effort to define the baseline system specifications

Luteal Phase Support Using Subcutaneous Progesterone: A Systematic Review

Luteal phase support (LPS) is crucial in assisted reproductive technology (ART) cycles when the luteal phase has been found to be defective. Such deficiency is most likely related to the supraphysiological steroid levels that usually occurr in stimulated cycles which, in turn, could severely affect luteinizing hormone (LH) secretion and function, thereby negatively influencing the luteal phase. A number of different medications and routes have been successfully used for LPS in ART. Although an optimal protocol has not yet been identified, the existing plethora of medications offer the opportunity to personalize LPS according to individual needs. Subcutaneous administration progesterone has been proposed for LPS and could represent an alternative to a vaginal and intramuscular route. The aim of the present systematic review is to summarize the evidence found in the literature concerning the application of subcutaneous progesterone in ARTs, highlighting the benefits and limits of this novel strategy. With this aim in mind, we carried out systematic research in the Medline, ISI Web of Knowledge, and Embase databases from their inception through to November 2020. Randomized controlled trials (RCTs) were preferred by the authors in the elaboration of this article, although case-control and cohort studies have also been considered. According to our findings, evidence exists which supports that, in women with a good prognosis undergoing a fresh in vitro fertilization (IVF) cycle, subcutaneous Pg is not inferior to vaginal products. In the Frozen-thawed embryo transfer (FET) cycle, data concerning efficacy is mixed with an increased miscarriage rate in women undergoing a subcutaneous route in oocyte donor recipients. Data concerning the acceptance of the subcutaneous route versus the vaginal route are encouraging despite the different scales and questionnaires which were used. In addition, a cost-effective analysis has not yet been conducted

Immunobiology of pregnancy: from basic science to translational medicine

: Embryo implantation failure and spontaneous abortions represent the main causes of infertility in developed countries. Unfortunately, incomplete knowledge of the multiple factors involved in implantation and fetal development keeps the success rate of medically assisted procreation techniques relatively low. According to recent literature, cellular and molecular mechanisms of 'immunogenic tolerance' towards the embryo are crucial to establish an 'anti-inflammatory' state permissive of a healthy pregnancy. In this review we dissect the role played by the immune system in the endometrial-embryo crosstalk, with a particular emphasis towards the fork-head-box-p3 (Foxp3+) CD4+CD25+ regulatory T (Treg) cells and discuss the most recent therapeutic advances in the context of early immune-mediated pregnancy loss

Hyperhomocysteinemia in women with unexplained sterility or recurrent early pregnancy loss from Southern Italy: a preliminary report

<p>Abstract</p> <p>Background</p> <p>Hyperhomocysteinemia has been described as a risk factor for unexplained recurrent pregnancy loss. Increased levels of homocysteine may be due to inadequate dietary intake of folate and vitamin B12 and inherited defects within the methionine-homocysteine pathway such as MTHFR C677T gene polymorphism. However, the association between hyperhomocysteinemia and sterility problems have been underlined only for recurrent pregnancy loss while a relationship between hyperhomocysteinemia and female sterility is still matter of discussion.</p> <p>Aim</p> <p>This study sought to find out a possible relationship between sterility (primary sterility or secondary sterility due to recurrent pregnancy loss) and homocysteine metabolism.</p> <p>Patients and Methods</p> <p>We selected 20 patients with recurrent pregnancy loss, 20 patients with unexplained female sterility and 20 healthy women as control group. Several whole blood samples were collected by venipuncture. Firstly homocysteinemia and other related variables were tested (i.e. folate and vitamin B12 levels); thereafter DNA was extracted by a further whole blood sample collected in EDTA in order to screen MTHFR C677T gene polymorphism. Statistical analysis was performed by chi square test; differences were considered to be significant if p < 0.05.</p> <p>Results</p> <p>The median fasting total plasma homocysteine concentration was 19.2 ± 6.14 μM for patients with recurrent pregnancy loss, while was 21.05 ± 8.78 μM for patients with unexplained sterility, vs 7.85 ± 3.31 μM of control group (p < 0.05). Fifteen patients with unexplained female sterility showed MTHFR C677T homozigosity vs 17 with recurrent pregnancy loss and 3 in the control group (p < 0.05). On the other hand no significant differences were found in the levels of vitamin B 12 in the three groups, while reduced folate concentrations were found in women with unexplained female sterility and recurrent pregnancy loss (p < 0.05 vs control group.</p> <p>Discussion</p> <p>MTHFR C677T gene polymorphism is frequent in the studied populations. These data raise questions on the role of the homocysteine metabolism in sterility problems. Even though increased homocysteine (i.e. > 15 μM) and MTHFR C677T homozigosity have already been described as risk factors for recurrent pregnancy loss, few studies evaluated their role in women with unexplained sterility. Further studies on larger series are needed to better understand the role of homocysteine metabolism, including folate metabolism, in this clinical setting.</p

A prospective, randomised, controlled clinical study on the assessment of tolerability and of clinical efficacy of Merional (hMG-IBSA) administered subcutaneously versus Merional administered intramuscularly in women undergoing multifollicular ovarian stimulation in an ART programme (IVF)

<p>Abstract</p> <p>Background</p> <p>Multifollicular ovarian stimulation (MOS) is widely used in IVF and the compliance to treatment is deeply influenced by the tolerability of the medication(s) used and by the ease of self-administration. This prospective, controlled, randomised, parallel group open label, multicenter, phase III, equivalence study has been aimed to compare the clinical effectiveness (in terms of oocytes obtained) and tolerability of subcutaneous (s.c.) self-administered versus classical intramuscular (i.m.) injections of Merional, a new highly-purified hMG preparation.</p> <p>Methods</p> <p>A total of 168 normogonadotropic women undergoing IVF were enrolled. Among them, 160 achieved pituitary suppression with a GnRH-agonist long protocol and were randomised to MOS treatment with Merional s.c. or i.m. They started MOS with a standard hMG dose between 150–300 IU, depending upon patient's age, and underwent a standard IVF procedure.</p> <p>Results</p> <p>No statistically significant difference in the mean number of collected oocytes (primary endpoint) was observed between the two study subgroups (7.46, SD 4.24 vs. 7.86, SD 4.28 in the s.c. and i.m. subgroups, respectively). As concerns the secondary outcomes, both the pregnancy and the clinical pregnancy rates were comparable between subgroups. The incidence of adverse events was similar in the two groups (2.4% vs. 3.7%, respectively). Pain at injection site was reported only the i.m. group (13.9% of patients).</p> <p>Conclusion</p> <p>Merional may be used by s.c. injections in IVF with an effectiveness in terms of retrieved oocytes that is equivalent to the one obtained with i.m administration and with a better local tolerability. With the limitations due to the sample size af this study, s.c. and i.m. administration routes seem to have the same overall safety.</p