"hCG priming" effect in controlled ovarian stimulation through a long protocol

<p>Abstract</p> <p>Background</p> <p>Recently, it has been demonstrated that, in patients down-regulated by GnRH analogues (GnRHa), a short-term pre-treatment with recombinant LH (rLH), prior to recombinant FSH (rFSH) administration, increases the number of small antral follicle prior to FSH stimulation and the yield of normally fertilized embryos. However, no data exist in the literature regarding the potential beneficial effect of "hCG priming" in controlled ovarian hyperstimulation (COH) through a long GnRH-a protocol, which binds the same receptor (LH/hCGR), though it is a much more potent compared to LH. The primary aims of this study were to assess the effect of short-term pre-rFSH administration of hCG in women entering an ICSI treatment cycle on follicular development, quality of oocytes and early embryo development. The secondary endpoints were to record the effects on endometrial quality and pregnancy rate.</p> <p>Methods</p> <p>Patients with a history of at least one previous unsuccessful ICSI cycle were randomly assigned into two groups to receive treatment with either a long protocol with rFSH (control group) or a long protocol with rFSH and pre-treatment with hCG (hCG group). In particular, in the latter group, a fixed 7 days course of 200 IU/day hCG was administered as soon as pituitary desensitization was confirmed.</p> <p>Results</p> <p>The mean number of oocytes retrieved was not significantly different between the two treatment groups, although the percentage of mature oocytes tended to be higher but not significantly different in hCG-treated patients. The percentage of patients with more than one grade 3 embryos was higher in the pre-treatment group, which also showed a higher pregnancy rate.</p> <p>Conclusion</p> <p>All the above clinical observations, in conjunction with previous data, suggest a point towards a beneficial "hCG priming" effect in controlled ovarian hyperstimulation through a long GnRH-a down-regulation protocol, particularly in patients with previous ART failures.</p

Correlation of the biological and clinical features of Asn/Ser, Asn/Asn, Ser/Ser polymorphisms of the FSH receptor gene and of PvuKK and RsaI polymorphism of the ESR1 and ESR2 genes of oestrogen receptors ERα and ERβ in in vitro fertilization

Ovarian stimulation in Assisted Reproduction Techniques (ART) poses a question mark, especially during the first stimulation treatment. Several parameters like age, endocrine parameters (basal FSH, AMH, Inhibin B) and ultrasound parameters (antral follicular count) can be used to predict the ovarian reserve, with different sensitivity. Currently, no markers exist to guide clinicians in FSH starting dose selection, in ART protocols. This is based solely in clinician experience. The quantity of FSH used is arbitrary, which may lead either to low-dose and thus non-effective treatment, either to over-dose treatment with great risk for the appearance of ovarian hyperstimulation syndrome (OHSS). In order to be able to use reliable markers for the prediction of the ovarian response to controlled ovarian stimulation (COS), the research turned into the use of genetic markers and Pharmacogenetics. The ultimate goal of the field of Pharmacogenetics, combining the knowledge from pharmacology and genetics, is to optimize the administration of drugs, increase their efficacy and predict or even minimize their undesirable effects. In order to broaden the area of interest and to describe the important role of the whole genome on drug response, the term Pharmacogenomics has been issued. Pharmacogenomics covers the stydy of the genome and its products that are related to drug response (mRNA, proteins). By obtaining this knowledge, it will be possible to lead to the development of diagnostic tests to predict the efficacy and safety of a number of drugs, in order to achieve individualization of drug administration in patients. After 2000, when Perez-Mayorga presented evidence for the association of FSH receptor genotype with ovarian response to FSH in women undergoing controlled ovarian stimulation, the bibliography is rich in attempting to establish whether it exists an interaction between the genetic variability of FSH receptor and the exogenous use of FSH, the basal FSH levels, the ovarian response or the pregnancy rates. Concerning the oestrogen receptors, several studies have claimed that certain oestrogen receptor alpha gene (ESR1) polymorphisms may be involved in COS outcome and infertility. Moreover, there exist investigations on new polymorphisms concerning oestrogen receptor beta gene (ESR2). Heterogeneity of the results observed may be explained by the different ethnic populations involved and the design of the studies. Previous studies in humans concluded that a multigenic model including specific FSHR, ESR1 and ESR2 genotype patterns may partially explain the poor response to FSH. These polymorphisms seem to play a great part in determining the ovarian response in controlled ovarian stimulation during assisted reproduction techniques, considering women with normal ovarian function. These genetic alterations are a fine example when trying to relate genetic changes with the endocrine regulation of reproduction. The aim of our study is to analyse three different polymorphisms, PvuII (T/C) polymorphism in ESR1 gene, RsaI (G/A) polymorphism in ESR2 gene and Ser680Asn polymorphism in FSH receptor gene, in a Greek population and their involvement in ovarian stimulation outcome and pregnancy rates. A total of 109 normally ovulating female patients underwent IVF or ICSI. The genotyping for the three polymorphisms was performed with real-time polymerase chain reaction. Each locus was studied alone, and in combination with the others. The study focused in the associations of gene polymorphisms with COS and pregnancy outcome of IVF/ICSI, and in the associations of gene polymorphisms combinations with COS and pregnancy outcome of IVF/ICSI. Studying each locus alone, no significant results were drawn for ESR1 and ESR2 genes. Concerning the FSHR gene polymorphism, the women carrying the Asn/Asn variant presented higher total amount of gonadotrophins used (P=0.048) and tended to have higher number of stimulation days (P=0.057). Considering the ESR1 and FSHR gene polymorphisms in combination, the TC/SA combination presents the highest number of pregnancies in poor responders group (3/4 patients with pregnancy carried this genotype), in good responders group (4/12 patients with pregnancy carried this genotype) and in the total population (10/26 patients with pregnancy carried this genotype). All other genotype combinations presented incidence of pregnancy, except the CC/AA combination. The CC/AA genotype presents the worst profile of ovulation induction, confirming a poor responder profile: the total amount of gonadotrophins used was highest in CC/AA group (P<0.05). The peak E2, the number of follicles and of retrieved oocytes and the pregnancy rate were significantly lower (P<0.05). This genotype combination seems to be over-presented in the poor responders group in a statistically significant way (P=0.038). Women with CC/AA combination have 1.5- 2.4 times more risk to be poor responders in comparison with women that do not carry that combination. This study supports the hypothesis that an oligogenic model including the well studied ESR1 and FSHR genes is involved in the controlled ovarian stimulation outcome indicating that the CC/AA genotype presents the worst ovulation induction profile, while the TC/SA genotype presents the higher number of pregnancies in this population. This observation opens a new avenue for investigation of the genetic profile of patients that present many failures in previous IVF/ICSI attempts and support the choice of appropriate regimes for ovarian stimulation before enrolled in an IVF/ICSI procedure, depending on genetic markers The selection and combination of the appropriate genetic markers will lead in a better prediction of the ovarian response to stimulation and of pregnancy.Η διέγερση των ωοθηκών κατά την Υποβοηθούμενη Αναπαραγωγή (ΥΑ) θέτει ορισμένα ερωτήματα, ιδιαίτερα σε ότι αφορά την πρώτη θεραπευτική προσπάθεια ωοθηκικής διέγερσης. Αρκετές παράμετροι όπως η ηλικία, ενδοκρινικές παράμετροι (βασική τιμή FSH, AMH, Ινχιμπίνη Β) και υπερηχογραφικές παράμετροι (μέτρηση ωοθυλακίων με άντρο-antral follicular count) μπορούν να χρησιμοποιηθούν για την πρόβλεψη της ωοθηκικής εφεδρείας, με διαφορετική ευαισθησία. Προς το παρόν, δεν υπάρχουν δείκτες οι οποίοι να μπορούν να καθοδηγήσουν τους κλινικούς ιατρούς στην επιλογή της δόσης έναρξης της χορηγούμενης FSH, στα θεραπευτικά πρωτόκολλα υποβοηθούμενης αναπαραγωγής. Ο καθορισμός της δόσης βασίζεται μόνο την κλινική εμπειρία. Η ποσότητα της χορηγούμενης FSH είναι αυθαίρετη, γεγονός που μπορεί να οδηγήσει είτε σε χαμηλή δόση και επομένως μη αποτελεσματική θεραπεία, είτε σε υπερβολική δόση με κίνδυνο εμφάνισης του συνδρόμου ωοθηκικής υπερδιέγερσης (ovarian hyperstimulation syndrome-OHSS). Αποσκοπώντας στη χρήση αξιόπιστων δεικτών για την πρόβλεψη της ωοθηκικής απάντησης στην ελεγχόμενη ωοθηκική διέγερση (controlled ovarian stimulationCOS), η έρευνα στράφηκε στη χρήση των γενετικών δεικτών και της Φαρμακογενετικής. Ο απώτερος στόχος του πεδίου της Φαρμακογενετικής, συνδυάζοντας τη γνώση από τη φαρμακολογία και τη γενετική, είναι να βελτιστοποιήσει την χορήγηση των φαρμάκων, να αυξήσει την αποτελεσματικότητά τους και να προβλέψει ή ακόμα να περιορίσει τις ανεπιθύμητες ενέργειές τους. Προκειμένου να διευρυνθεί το πεδίο του ενδιαφέροντος και να περιγραφεί ο σπουδαίος ρόλος του συνόλου του γονιδιώματος στην απάντηση στη φαρμακοθεραπεία, εισήχθει ο όρος Φαρμακογενωμική. Η Φαρμακογενωμική περιλαμβάνει τη μελέτη του γονιδιώματος και των παραγώγων του (mRNA, πρωτείνες) σε σχέση με την ανταπόκριση του ατόμου σε φαρμακευτικές ουσίες. Διαθέτοντας αυτή τη γνώση, θα είναι δυνατό να αναπτυχθούν διαγνωστικές δοκιμασίες για την πρόβλεψη της αποτελεσματικότητας και της ασφάλειας φαρμάκων με σκοπό την εξατομίκευση της φαρμακευτικής αγωγής σε ασθενείς. Μετά το 2000, όταν ο Perez-Mayorga παρουσίασε στοιχεία για τον συσχετισμό του γονότυπου του υποδοχέα της FSH (FSHR) με την ωοθηκική απάντηση στη διέγερση με FSH των γυναικών που υποβάλλονται σε ελεγχόμενη ωοθηκική διέγερση, η βιβλιογραφία είναι πλούσια σε προσπάθεια να αποδείξει εάν υπάρχει αλληλεπίδραση μεταξύ της γενετικής ποικιλότητας στον υποδοχέα της FSH και στην εξωγενή χορήγηση FSH, στη βασική τιμή FSH, στην απάντηση των ωοθηκών ή στα ποσοστά κύησης. Σε ότι αφορά στους οιστρογονικούς υποδοχείς, πολλές μελέτες ισχυρίστηκαν ότι ορισμένοι πολυμορφισμοί στο γονίδιο του οιστρογονικού υποδοχέα άλφα-ΕRα (ESR1) μπορεί να εμπλέκονται στη έκβαση της ελεγχόμενης ωοθηκικής διέγερσης και στην υπογονιμότητα. Επιπλέον, υπάρχουν έρευνες για νέους πολυμορφισμούς που αφορούν στο γονίδιο του οιστρογονικού υποδοχέα βήτα-ΕRβ (ESR2). Η ετερογένεια στα παρατηρούμενα αποτελέσματα μπορεί να εξηγηθεί λαμβάνοντας υπόψη τη μελέτη πληθυσμών διαφορετικών εθνικοτήτων και το διαφορετικό σχεδιασμό των εκάστοτε μελετών. Προηγούμενες μελέτες στο ανθρώπινο είδος κατέληξαν ότι ένα πολυγονιδιακό μοντέλο που περιλαμβάνει συγκεκριμένους γονοτύπους των γονιδίων FSHR, ESR1 και ESR2 μπορεί να εξηγήσει μερικώς την πτωχή απάντηση στην FSH. Οι πολυμορφισμοί σε αυτά τα γονίδια φαίνεται να διαδραματίζουν ρόλο στον καθορισμό της απάντησης των ωοθηκών στην ελεγχόμενη ωοθηκική διέγερση κατά την υποβοηθούμενη αναπαραγωγή, σε γυναίκες με φυσιολογική λειτουργία των ωοθηκών. Αυτές οι γενετικές διαφοροποιήσεις αποτελούν εξαιρετικό παράδειγμα στην προσπάθεια συσχετισμού των μεταβολών σε γενετικό επίπεδο με την ενδοκρινική ρύθμιση της αναπαραγωγής. Ο σκοπός αυτής της μελέτης είναι να αναλύσει τρεις διαφορετικούς γονιδιακούς πολυμορφισμούς- τους πολυμορφισμούς PvuII (T/C) του γονιδίου ESR1, RsaI (G/A) του γονιδίου ESR2 και Ser680Asn του γονιδίου FSHR- σε ελληνικό πληθυσμό και τη συμμετοχή τους στην έκβαση της διέγερσης των ωοθηκών και στα ποσοστά των κυήσεων. Συνολικά, 109 γυναίκες με φυσιολογική ωορρηξία υποβλήθηκαν σε IVF ή ICSI. Η γονοτύπηση για τους τρεις πολυμορφισμούς πραγματοποιήθηκε με αλυσιδωτή αντίδραση πολυμεράσης πραγματικού χρόνου. Κάθε γονιδιακός τόπος μελετήθηκε ξεχωριστά, και σε συνδυασμό με τους υπόλοιπους. Η μελέτη επικεντρώθηκε στους συσχετισμούς των γονιδιακών πολυμορφισμών με την έκβαση της ελεγχόμενης διέγερσης των ωοθηκών (COS outcome) και τα ποσοστά των κυήσεων σε IVF/ICSI, και στους συσχετισμούς των συνδυασμένων γονιδιακών πολυμορφισμών με την έκβαση της ελεγχόμενης διέγερσης των ωοθηκών (COS outcome) και τα ποσοστά των κυήσεων σε IVF/ICSI. Μελετώντας κάθε γονιδιακό τόπο ξεχωριστά, δεν εξάγονται στατιστικώς σημαντικά αποτελέσματα για τα γονίδια ESR1 και ESR2. Σε ότι αφορά τον πολυμορφισμό στο γονίδιο FSHR, οι ασθενείς που φέρουν τον γονότυπο Asn/Asn παρουσίασαν αυξημένο συνολικό αριθμό μονάδων γοναδοτροπινών που χρησιμοποιήθηκαν για διέγερση (Ρ=0.048) και έτειναν να έχουν υψηλότερο αριθμό ημερών διέγερσης (Ρ=0.057). Μελετώντας τον συνδυασμένο γονότυπο για τους πολυμορφισμούς των γονιδίων ESR1 και FSHR, ο γονοτυπικός συνδυασμός TC/SA παρουσιάζει τον υψηλότερο αριθμό σε κυήσεις στην ομάδα των πτωχών απαντητριών (3/4 ασθενείς με κύηση φέρουν αυτόν τον γονοτυπικό συνδυασμό), στην ομάδα των καλών απαντητριών (4/12 ασθενείς με κύηση φέρουν αυτόν τον γονοτυπικό συνδυασμό) και στο σύνολο του πληθυσμού μελέτης (10/26 ασθενείς με κύηση φέρουν αυτόν τον γονοτυπικό συνδυασμό). Όλοι οι γονοτυπικοί συνδυασμοί παρουσίασαν επίπτωση θετικής κλινικής κύησης στο σύνολο του πληθυσμού μελέτης, εκτός από τον γονοτυπικό συνδυασμό CC/AA. Ο γονότυπος CC/AA παρουσιάζει το χειρότερο προφίλ πρόκλησης ωοθυλακιορρηξίας, επιβεβαιώνοντας ένα προφίλ «πτωχής απάντησης»: ο συνολικός αριθμός μονάδων γοναδοτροπινών που χρησιμοποιήθηκαν για διέγερση ήταν υψηλότερος στην ομάδα CC/AA (Ρ<0.05). Η τιμή της οιστραδιόλης την ημέρα χορηγήσεως της hCG, ο αριθμός των ωοθυλακίων και των ωαρίων που ελήφθησαν καθώς και τα ποσοστά κύησης ήταν σημαντικά χαμηλότερα (Ρ<0.05). Αυτός ο γονοτυπικός συνδυασμός φαίνεται πως υπερεκφράζεται στην ομάδα των πτωχών απαντητριών με τρόπο στατιστικά σημαντικό (Ρ<0.38). Οι γυναίκες που φέρουν το γονοτυπικό συνδυασμό CC/AA έχουν 1.5-2.4 φορές περισσότερο κίνδυνο να είναι πτωχές απαντήτριες σε σχέση με τις γυναίκες που δε φέρουν αυτό το συνδυασμό. Αυτή η μελέτη υποστηρίζει την υπόθεση ότι ένα ολιγογονιδιακό μοντέλο που περιλαμβάνει τα εκτενώς μελετημένα γονίδια ESR1 και FSHR εμπλέκεται στην έκβαση της ελεγχόμενης διέγερσης των ωοθηκών, υποδεικνύοντας τον γονοτυπικό συνδυασμό CC/AA ως τον συνδυασμό με το χειρότερο προφίλ πρόκλησης ωοθυλακιορρηξίας, ενώ ο γονοτυπικός συνδυασμός TC/SA παρουσιάζει τον υψηλότερο αριθμό κυήσεων στον μελετώμενο πληθυσμό. Αυτή η παρατήρηση ανοίγει νέες οδούς στην έρευνα του γονιδιακού προφίλ των ασθενών που παρουσιάζουν πολλαπλές αποτυχίες σε προηγούμενες προσπάθειες IVF/ICSI και υποστηρίζει την επιλογή των κατάλληλων πρωτοκόλλων διέγερσης ωοθηκών πριν την διαδικασία IVF/ICSI, ανάλογα με τους γενετικούς δείκτες. Η επιλογή και ο συνδυασμός των κατάλληλων γενετικών δεικτών θα οδηγήσει σε καλύτερη πρόβλεψη της ωοθηκικής απάντησης στη διέγερση και της κύησης

The Impact of Genetics Profile (Gene Polymorphisms) in Obese Non-PCOS Women Entering an IVF/ICSI Program

Data concerning the effects of increased body mass index (BMI) on ovarian and pregnancy outcome are rich, but the results are rather controversial. Regarding pharmacogenetics, gene polymorphisms of hormonal receptor genes, such as Estrogen Receptor alpha (ESR1), Estrogen Receptor beta (ESR2) and FSH receptor (FSHR) genes, are associated with ovarian stimulation and pregnancy outcome and may constitute a useful tool for ART experts for the prediction of this outcome. The aim of this study is to track differences in the distribution of gene polymorphisms among obese non-PCOS and non-obese patients concerning three distinct genes which are involved in the ovarian stimulation mechanism: PvuII polymorphism of ESR1 gene, RsaI polymorphism of ESR2 gene and Ser680Asn variation of FSHR gene, using restriction fragment length polymorphism analysis and real-time polymerase chain reaction. A total of 151 normally ovulating female patients underwent IVF or ICSI. Interestingly, the pregnancy rate in the BMI &gt;= 30 kg/m(2) group was higher in a statistically significant way (40.9% versus 17.8%, p=0.023). The obese patients of this study were in need of increased total FSH dose in order to achieve a satisfactory oocyte number (p&lt;0.001) and needed more days of stimulation (p=0.002), but also presented lower basal FSH levels (p=0.032), which may explain, to an extend, the better pregnancy outcome. Concerning the polymorphisms of ESR1, ESR2 and FSHR genes, we did not observe differences in the genotype distribution when we compared the obese non-PCOS population with the non-obese population. Thus, obesity does not constitute an additional indication to perform a genetic analysis before entering an IVF/ICSI program

The role of steroid hormones in ART

Steroid hormones hold a major role in female fertility and their proper utilisation and monitoring in modern assisted reproduction protocols is important. Oocyte maturation and endometrial receptivity are the two major factors that appear to be related to a successful outcome in Assisted Reproductive Technology (ART). Many reports suggest that oocyte immaturity accounts for a considerable loss of efficiency in ART, mainly due to the poor quality of the obtained embryos and their inability to develop normally. Oestrogen appears to exert its effects on the cytoplasmic maturation of the oocyte, while progesterone has been shown to accelerate meiotic resumption. Moreover, ovarian stimulation appears to affect the normal luteal function and shifts in the window of implantation as a response to hormonal supplementation have also been observed. The ethical limitations in conducting in vivo studies of human implantation, have led to an indirect hormonal- and morphologic-oriented assessment of endometrial receptivity. The two main protocols of luteal support involve either progesterone supplementation or hCG administration, whereas the combined supplementation with oestradiol remains controversial. This brief review aims to summarize the current knowledge on steroidal actions during the above processes and to address their potential use in the improvement of current ART protocols. (C) 2008 Elsevier Ltd. All rights reserved

Combined study on the single nucleotide polymorphisms in the follicle-stimulating hormone receptor (Ser680Asn) and anti-Mullerian hormone receptor type II (-482A&gt;G) as genetic markers in assisted reproduction

Background: Infertile women may have underlying genetic abnormalities. There is, at present, a significant number of studies on the relation between the follicle stimulating hormone receptor (FSHR) or anti-Mullerian hormone type II receptor (AMHRII) polymorphisms and response to in-vitro fertilisation (IVF) treatment. However, it is not yet clear which genotype or combination of genotypes is favourable towards a better ovarian stimulation and pregnancy outcome. Materials and methods: In this study we assessed the distribution of the genotypes of FSHR Ser680Asn and of AMHRII -482A&gt;G gene polymorphisms in a group of 126 infertile women and a control group of 100 fertile women by using real-time polymerase chain reaction (RT-PCR). Results: Statistical analysis showed that the frequency of the genotypes is similar in both control and IVF/ intracytoplasmic sperm injection (ICSI) groups. Further investigation of the frequency of the nine possible combinations of these polymorphisms in the groups revealed no correlation between infertility and combination of the polymorphisms. Women with one polymorphism have on average 5.5 units higher levels of AMH compared to women carrying no polymorphism. In women with no polymorphisms, for each unit of FSH increase, the average concentration of blood AMH is expected to be 72% lower. Conclusion: The distribution of the FSHR Ser680Asn and of the AMHRII -482A&gt;G gene polymorphisms, in the Greek population is similar in fertile and infertile women. The study showed that FSH and AMH correlated levels in certain cases could be used to estimate a patient’s ovarian reserve

The Role of FSHR SNPs and AMH in Follicular Fluid and Serum in Ovarian Response during COS: A Pilot Study.

BACKGROUND: Several studies have investigated on the polymorphism Ser680Asn of FSHR and its use as a predictive indicator of response to an IVF/ICSI protocol. Furthermore, measurement of AMH in serum and follicular fluid is a useful prognostic indicator for the outcome of an assisted reproduction attempt. The purpose of this study is to examine the FSH receptor Ser680Asn polymorphism in combination with AMH levels in both serum and follicular fluid, on the day of oocyte collection. MATERIALS AND METHODS: A total of 32 women who underwent IVF/ICSI were included. Women were grouped into 2 groups: those who received rFSH (n = 11) and those who received hMG (n = 21). Serum AMH was measured on day 3 of the cycle, and AMH in the follicular fluid on the day of oocyte retrieval; the same day peripheral blood was collected for the genotyping of Ser680Asn. RESULTS: No statistical significant difference was found between serum AMH and follicular fluid AMH regarding the FSH receptor genotype for the Ser680Asn polymorphism. Regarding the sAMH/ffAMH ratio in the 3 genotypes, the value was lower in Asn/Asn women than Ser/Ser and Ser/Asn, but no statistical difference was obtained. Women who carry the Ser allele have a higher number of follicles, retrieved oocytes, and mature oocytes than women who do not contain the Ser allele. Women with AMH {\textless} 2.22 ng/ml presented lower AMH follicular fluid levels and lower serum AMH/follicular fluid AMH ratio in a statistically significant manner. Concerning the genotype for the polymorphism Ser680Asn of FSHR in relation to AMH levels, no statistically significant differences were found. CONCLUSIONS: The identification of polymorphisms, such as Ser680Asn of FSHR, along with the determination of endocrine markers in the follicular fluid, such as AMH, could lead at some point, to the personalized therapy setting per woman

The Role of FSHR SNPs and AMH in Follicular Fluid and Serum in Ovarian Response during COS: A Pilot Study

Background. Several studies have investigated on the polymorphism Ser680Asn of FSHR and its use as a predictive indicator of response to an IVF/ICSI protocol. Furthermore, measurement of AMH in serum and follicular fluid is a useful prognostic indicator for the outcome of an assisted reproduction attempt. The purpose of this study is to examine the FSH receptor Ser680Asn polymorphism in combination with AMH levels in both serum and follicular fluid, on the day of oocyte collection. Materials and Methods. A total of 32 women who underwent IVF/ICSI were included. Women were grouped into 2 groups: those who received rFSH (n=11) and those who received hMG (n=21). Serum AMH was measured on day 3 of the cycle, and AMH in the follicular fluid on the day of oocyte retrieval; the same day peripheral blood was collected for the genotyping of Ser680Asn. Results. No statistical significant difference was found between serum AMH and follicular fluid AMH regarding the FSH receptor genotype for the Ser680Asn polymorphism. Regarding the sAMH/ffAMH ratio in the 3 genotypes, the value was lower in Asn/Asn women than Ser/Ser and Ser/Asn, but no statistical difference was obtained. Women who carry the Ser allele have a higher number of follicles, retrieved oocytes, and mature oocytes than women who do not contain the Ser allele. Women with AMH<2.22 ng/ml presented lower AMH follicular fluid levels and lower serum AMH/follicular fluid AMH ratio in a statistically significant manner. Concerning the genotype for the polymorphism Ser680Asn of FSHR in relation to AMH levels, no statistically significant differences were found. Conclusions. The identification of polymorphisms, such as Ser680Asn of FSHR, along with the determination of endocrine markers in the follicular fluid, such as AMH, could lead at some point, to the personalized therapy setting per woman

Past, Present, and Future of Gonadotropin Use in Controlled Ovarian Stimulation During Assisted Reproductive Techniques

A variety of protocols have evaluated the use of several forms of gonadotropins in controlled ovarian stimulation (COS). We aim to review the evolving trends on the use of gonadotropins human chorionic gonadotropin (hCG), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) over time and their combinations in COS for patients who undergo assisted reproductive techniques (ART) protocols. A meticulous search of three electronic databases was performed for articles published in the field up to September 2020. The administration of hCG seems a promising alternative to conventional modalities for COS related to the enhancement of LH activity. The use of gonadotropins was associated with significantly elevated pregnancy rates that ranged from 20.8% to 46.2%. However, the currently available outcomes with regards to oocytes retrieved, number of embryos are still conflicting. A potential beneficial effect was observed by the majority of the studies in terms of the number of embryos and implantation rates, which is, however, highly affected by the type of protocol used (gonadotropin-releasing hormone [GnRH] agonist or antagonist). Further studies are warranted to elucidate the exact pathways of action of gonadotropins in controlled ovarian stimulation to attain the optimal effect

Familial MTC with RET exon 8 Gly533Cys mutation: origin and prevalence of second malignancy

Introduction: High prevalence of RET p.Gly533Cys (c.1597G > T) has been found in familial MTC in Greece (exon 8 fMTC). We studied their origin and compared clinical characteristics with non-exon 8 fMTC. Methods: 102 fMTC (FMTC and MEN2A) patients (31.4% males) were followed for 2.9–37 years (median 6 years). Fifty-one carried the RET exon 8 mutation; the remaining were non-exon 8 fMTC (exons 10, 11, 13, 14). Pre-, post-operative calcitonin, disease extent at diagnosis and follow-up and families’ place of origin were recorded. Results: Exon 8 fMTC were older (42.3 ± 13.3 vs 30.8 ± 17.8 years, P < 0.001), including index cases (P = 0.016). In index cases, the stage at diagnosis was more favorable in exon 8 fMTC compared to non-exon 8 fMTC (stage I and II: 65% vs 23.8%, stage III: 25% vs 57.1%, stage IV: 10% vs 19%, P = 0.025). More favorable outcome was noted in exon 8 fMTCs (remission: 72.5% vs 45.8%, stable disease: 27.5% vs 41.7%, progression: 0.0% vs 12.5%, P = 0.001). Exon 8 fMTC patients carried more frequently a second malignancy (25.5% vs 6.3%, P = 0.009); 69% of these were PTCs. Exon 8 fMTC patients were significantly older at diagnosis compared to non-exon 8 moderate-risk RET carriers and presented more favorable clinical outcome (remission: 72.5% vs 50%, stable disease: 27.5% vs 41.7%, progression: 0.0% vs 8.3%, P = 0.021). This difference remained when only index cases were analyzed. ‘Hot spots’ in the origin of exon 8 fMTCs families were recognized. No phenotype or outcome differences were found between the exon 8 families from the various regions. Conclusions: In exon 8 fMTCs’ older age, favorable disease stage at diagnosis and favorable outcome suggest slow disease progression compared to non-exon 8 fMTC. Compared with moderate-risk RET mutation carriers, exon 8 fMTC patients have a more favorable clinical outcome. The higher prevalence of second malignancies, especially PTC, not previously reported, merits further investigation. Increased awareness for inherited disease is required for patients with apparently sporadic MTC originating from recognized ‘hot spots’, as the age at presentation is usually delayed

Do estrogen receptor alpha polymorphisms have any impact on the outcome in an ART program?

To investigate two of the most studied estrogen receptor alpha polymorphisms (PvuII and XbaI) in combination, in order to evaluate their impact on an ART program outcome. 203 normally ovulating women who underwent IVF or ICSI treatment were genotyped for PvuII and XbaI polymorphisms in ESR1 intron 1 using Real-Time PCR. The relationship between the presence of polymorphic alleles and the ovulation induction parameters and outcome was examined. Women were grouped according to the number of polymorphic alleles they carried in two groups (0-2 versus 3-4 polymorphic alleles). The presence of 3 or more polymorphic alleles was associated with significantly lower E2 levels on the day of hCG administration and a significantly lower rate of good quality embryos. There is an association between ESR1 polymorphisms and some ART parameters such as the level of E2 on the day of hCG administration and the quality of the embryos. These results underline the importance of ESR1 as a candidate gene for the prediction of ovarian response to IVF/ICSI protocols. Future research work concerning several more genes is necessary for a better evaluation of patients before entering an IVF/ICSI program