Effectiveness and safety of gonadotropins used in female infertility: a population-based study in the Lazio region, Italy.

PURPOSE: Infertility is a topic of growing interest, and female infertility is often treated with gonadotropins. Evidence regarding comparative safety and efficacy of different gonadotropin formulations is available from clinical studies, while real-world data are missing. The present study aims to investigate effectiveness and safety of treatment with different gonadotropin formulations in women undergoing medically assisted procreation treatments in Latium, a region in central Italy, through a real-world data approach. METHODS: A retrospective population-based cohort study in women between the ages of 18 and 45 years who were prescribed with at least one gonadotropin between 2007 and 2019 was conducted. Women were enrolled from the regional drug dispense registry, and data on their clinical history, exposure to therapeutic cycles (based on recombinant "REC" or extractives "EXT" gonadotropin, or combined protocol "CMD" (REC + EXT)), and maternal/infantile outcomes were linked from the regional healthcare administrative databases. Multivariate logistic regression models were applied to estimate the association between exposure and outcomes. RESULTS: Overall, 90,292 therapeutic cycles prescribed to 35,899 women were linked to pregnancies. Overall, 15.8% of cycles successfully led to pregnancy. Compared to extractives, recombinant and combined treatments showed a stronger association with conception rate (RRREC adj = 1.06, 95% CI: 1.01-1.12; RRCBD adj = 1.17, 95% CI: 1.11-1.24). Maternal outcomes occurred in less than 5% of deliveries, and no significant differences between treatments were observed (REC vs EXT, pre-eclampsia: RR adj = 1.24, 95% CI: 0.86-1.79, ovarian hyperstimulation syndrome: RR adj = 1.25, 95% CI: 0.59-2.65, gestational diabetes: RR adj = 1.06, 95% CI: 0.84-1.35). Regarding infantile outcomes, similar results were obtained for different gonadotropin formulations (REC vs EXT: low birth weight: RR adj = 0.98, 95% CI: 0.83-1.26, multiple births: RR adj = 1.06, 95% CI: 0.92-1.23, preterm birth: RR adj = 1.03, 95% CI: 0.92-1.26). CONCLUSIONS: Efficacy and safety profiles of REC proved to be similar to those of EXT. Regarding the efficacy in terms of conception rate and birth rate, protocols using the combined approach performed slightly better. Outcomes related to maternal and infantile safety were generally very rare, and safety features were overlapping between gonadotropin formulations.

Live birth and pregnancy rates after in vitro fertilization/intracytoplasmic sperm injection in women with previous unilateral oophorectomy: a systematic review and meta-analysis.

OBJECTIVE: To quantify the effect of unilateral oophorectomy (UO) on the rates of live birth and pregnancy in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). DESIGN: Systematic review and meta-analysis. SETTING: Search of databases of published articles. PATIENT(S): The final analytical cohort encompassed 1,057 IVF/ICSI cycles in women with previous UO and 45,813 IVF/ICSI cycles in control women. Eighteen studies were identified by database searches of MEDLINE, Embase, Web of Science, and cited references. The review encompassed studies published up to June 1, 2021. INTERVENTION(S): UO prior to IVF/ICSI. MAIN OUTCOME MEASURE(S): The primary outcomes were the rates of live birth and pregnancy following IVF/ICSI. The secondary outcomes included the amount of gonadotropins administered for ovarian stimulation and the number of retrieved oocytes. RESULT(S): The studies were rated from medium to high quality (from 5 to 8) according to the Newcastle-Ottawa Quality Assessment Scale. All studies were observational, with inherent bias, and heterogeneity was high. The primary outcome of live birth had a significantly lower odds ratio (OR) in women with previous UO compared with controls (OR = 0.72, 95% confidence interval [CI] 0.57 to 0.91, z = -2.72). The OR for pregnancy rate per initiated treatment cycle was also significantly lower in women with previous UO compared with controls (OR = 0.70, 95% CI 0.57 to 0.86, z = -3.35). Additionally, the dose of administered gonadotropins was significantly higher and the number of retrieved oocytes was significantly lower in women with UO. CONCLUSION(S): The meta-analysis showed a significant detrimental effect of UO on the rates of live birth and pregnancy. The analysis further supports previous data showing a decreased sensitivity to gonadotropins and a lower number of recovered oocytes in women with previous UO. STUDY REGISTRATION NUMBER: PROSPERO 2020, CRD42020160313.

Higher exogenous gonadotrophin doses increase the risk of small for gestational age singletons after fresh embryo transfers.

RESEARCH QUESTION: A negative relationship has been reported between exogenous gonadotrophin dosage and the live birth rate in IVF. It is unclear whether total gonadotrophin dosage is associated with neonatal outcomes. The effect of exogenous gonadotrophin dosage on neonatal outcomes of singletons after fresh embryo transfer (FET) was investigated. DESIGN: A retrospective cohort study of 2020 live singletons evaluating neonatal outcomes. All patients underwent autologous IVF cycles between 1 August 2016 and 30 April 2020 and delivered a live singleton birth after FET. Patients with polycystic ovary syndrome were excluded. Patients were divided according to total gonadotrophin dose: group 1: ≤1800 IU; group 2: 1801-2500 IU; and group 3: >2500 IU. RESULTS: After adjusting for confounding factors by multiple regression models, the adjusted rate of small for gestational age (SGA) was significantly higher in group 3 (adjusted [a]OR 2.25, 95% CI 1.24 to 4.08). The risk of SGA increased 2.25 times when total gonadotrophin dose exceeded 2500 IU versus gonadotrophin doses below 1800 IU. The hierarchical analysis showed that an increased rate of SGA infants occurred in the GnRH agonist long protocol (aOR 2.09, 95% CI 1.02 to 5.17) and in the antagonist protocol (aOR 2.75, 95% CI 1.05 to 7.22). CONCLUSIONS: For patients without polycystic ovary syndrome, an excessive total gonadotrophin dose during ovarian stimulation, i.e. more than 2500 IU, may negatively affect neonatal outcomes by increasing the SGA rate of singletons after FET. Therefore, total gonadotrophin dose administered during ovarian stimulation should preferably not exceed 2500 IU.

Does the additional use of clomiphene citrate or letrozole for in vitro fertilization deserve more attention?

BACKGROUND: Adding clomiphene citrate (CC) and/or letrozole (LE) to in vitro fertilization (IVF) cycles for mild ovarian stimulation is a general approach. Although lots of researches have demonstrated partial benefits of the strategy, all-around effects of oral medications remained deficient. This paper aims to assess whether an addition of oral medication will result in considerable outcomes on T-Gn (total dose of gonadotropin), Gn days, total retrieved ova, high quality embryos, blastocyst number, ovarian hyperstimulation syndrome (OHSS) rate, clinical pregnancy rate and cumulative pregnancy rate, even if it was not conventional mild/minimal stimulations. RESULTS: Participants were categorized to three diverse populations as high responders, normal responders and poor responders according to basal antral follicle count. T-Gn in patients treated with CC/LE distinctly decreased from 2496.96 IU/d to 1827.68 IU/d, from 2860.28 IU/d to 2119.99 IU/d, and from 3182.15 IU/d to 1802.84 IU/d, respectively. For high ovary responders and normal responders, the OHSS incidence rate also declined from 29.2 to 4.3% (P < 0.001) and from 1.1 to 0.0% (P = 0.090). Other, there was no statistical difference with respect to the T-retrieved ova (total retrieved ova), high quality embryos, cultured blastocyst and blastocyst number in high responders. For normal responders and poor ovary responders, T-Gn, Gn days, T-retrieved ova, high quality embryos, cultured blastocyst and blastocysts number in oral medications group all apparently decreased. Clinical pregnancy rate per fresh cycle of poor responders with prior oral medications was significantly decreased (25.7% vs. 50.8%, P = 0.005), and no significant differences in high responders and normal responders were expressed (52.5% vs. 44.2%, P = 0.310; 51.9% vs. 42.4%, P = 0.163) between two groups of participants. The numbers of cumulative pregnancy rates were lower in the conventional group compared to the add group for high (75.90% versus 81.03%, P = 0.279), normal (62.69% versus 71.36%, P = 0.016) and poor (39.74% versus 68.21%, P < 0.001) responders. CONCLUSIONS: The addition of CC/LE to the ovulation induction during IVF has certain efficacy in terms of low cost, low OHSS incidence. CC/LE deserves more recommendations as a responsible strategy in high responders due to advantageous pregnancy outcomes. For normal responders, the strategy needs to be considered with more comprehensive factors.

Differential impact of controlled ovarian hyperstimulation on live birth rate in fresh versus frozen embryo transfer cycles: a Society for Assisted Reproductive Technology Clinic Outcome System study.

OBJECTIVE: To study the impact of both controlled ovarian hyperstimulation (COH) length and total gonadotropin (GN) dose individually and in concert on live birth rates (LBR) in both fresh and freeze-all in vitro fertilization embryo transfer (IVF-ET) cycles. DESIGN: Historical cohort study. SETTING: Not applicable. PATIENT(S): The U.S. national database from the Society of Assisted Reproductive Technology Clinic Outcome Reporting System from 2014 to 2015 was used to identify patients undergoing autologous GN stimulation IVF cycles with the use of GnRH antagonist-based suppression protocols where a single embryo transfer was performed as part of a fresh IVF-ET cycle (fresh, n = 14,866) or the first frozen embryo transfer after a freeze-all cycle (frozen, n = 2,964), and not including preimplantation genetic testing cycles. The patients' demographic and cycle characteristics, duration of COH, total GN dose, and pregnancy outcomes were extracted. Binomial regression models estimated trend and relative risk of live birth with respect to days of stimulation and total GN dose singularly, and after adjustment for a priori confounders including age, parity, body mass index, diagnosis, and maximum follicle-stimulating hormone in both fresh and frozen embryo transfer cycles. Both days of stimulation and total GN dose were then added to the multivariate model to show whether they were independently associated with LBR. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Live birth rate. RESULTS: In both fresh and frozen cycles, length of COH was significantly associated with total GN dose. On univariate analysis, LBR decreased significantly with increasing length of stimulation and increasing total GN dose in both fresh and frozen cycles. On multivariable analysis including both days of stimulation and total GN dose, days of stimulation was no longer significantly correlated with LBR, whereas total GN dose remained significantly correlated with LBR in fresh cycles only. When total GN doses ranging from <2,000 IU through 5,000 IU to >5,000 IU were compared, a significant improvement in live birth rate was noted with lower total GN doses. Specifically, GN doses <2,000 IU had a 27% higher rate of live birth compared with GN dose >5,000 IU. For GN dose groups up to 4,000 IU, the estimated effect on LBR was similar. There was a marginal improvement (13%) in LBR with GN doses of 4,000 IU to 5,000 IU compared with >5,000 IU. When the multivariate model was applied to the frozen cycles, neither total GN dose nor days of stimulation was significantly associated with LBR. CONCLUSIONS: High total GN dose but not prolonged COH is associated with decreasing LBRs in fresh cycles, whereas neither factor significantly affects LBR in frozen cycles. Consideration should be given to minimizing the total GN dose when possible in fresh autologous cycles, either by decreasing the daily dose or by limiting the length of stimulation to improve LBRs. In freeze-all cycles, the use of higher GN doses does not seem to adversely affect the LBR of the first frozen embryo transfer. High total GN dose likely exerts a negative impact on the endometrium and/or oocyte/embryo unrelated to the length of stimulation. The differential effect of total GN dose on LBR in fresh and frozen cycles may imply a greater impact exerted on the endometrium rather than the oocyte.

Pregnancy registry: three-year follow-up of children conceived from letrozole, clomiphene, or gonadotropins.

OBJECTIVE: To study the development of children conceived from non-IVF infertility treatments consisting of gonadotropins, clomiphene, or letrozole. DESIGN: Prospective cohort study. SETTING: U.S. academic health centers. PATIENT(S): Children of women with polycystic ovary syndrome who conceived with letrozole (LTZ) or clomiphene (CC) in the PPCOS II study or women with unexplained infertility (AMIGOS study) who conceived with LTZ, CC, or gonadotropin (GN). INTERVENTION(S): Longitudinal annual follow-up from birth to age 3. MAIN OUTCOME MEASURE(S): Scores from Ages and Stages Developmental Questionnaire (ASQ), MacArthur-Bates Communicative Development Inventory (MCDI), and annual growth. RESULT(S): One hundred eighty-five children from 160 families participated in at least one follow-up evaluation from the two infertility trials. Most multiple gestations in the follow-up study resulted from GN treatment (n = 14) followed by CC (n = 6) and LTZ (n = 3). There were no significant differences among the three groups at any time point with respect to abnormal scores on the ASQ. On the MCDI Words and Gestures, the LTZ group scored significantly higher than the GN group for most items (phrases, early gestures, later gestures, and total gestures). Children in the CC group scored significantly higher than the GN group for the later gestures and total gestures items. CONCLUSION(S): Differences in growth and cognitive developmental rates among children conceived with first-line infertility therapies, including LTZ, are relatively minor and likely due to differences in multiple pregnancy rates.

[Effect of exogenous gonadotropin dosage on embryo aneuploidy rate and pregnancy outcome in patients of preimplantation genetic test].

Objective: To investigate the effect of gonadotropin (Gn) on embryo aneuploidy rate and pregnancy outcome during preimplanptation genetic testing for aneuploidy (PGT-A) cycles. Methods: The clinical data of patients undergoing PGT-A cycle at the First Medical Center of the PLA General Hospital from January 1, 2013 to May 31, 2019 were retrospectively analyzed. Patients were divided into younger patient group (<35 years old) and elder patient group (≥35 years old) by maternal age, then divided into two groups in line with Gn dosage (≤2 250 U, >2 250 U), and into four groups by number of oocytes retrieved (1-5, 6-10, 11-15 and ≥16 oocytes). The embryo aneuploidy rate and pregnancy outcome between the groups were compared. Logistic regression was used to analyze the relationship between the cumulative amount of Gn, embryo aneuploidy rate and live-birth rate. Results: A total of 402 cycles (338 patients) and 1 883 embryos were included in the study. (1) In the younger patients, the aneuploidy rate was 52.5% (304/579) in the group of Gn≤2 250 U and 48.6% (188/387) in the group of Gn>2 250 U, with no significant difference between them (P=0.232). In the elderly patients, the difference in embryo aneuploidy rate between the two Gn group [57.9% (208/359) versus 60.6% (319/526)] was not statistically significant (P=0.420). (2) The embryonic aneuploidy rate in different protocol of ovary stimulation was analyzed,in the younger group, the embryonic aneuploidy rate in patients using antagonist long protocol was 50.3% (158/314), it was 50.0% (121/242) in agonist long protocol, 52.1% (207/397) in agonist short protocol and 6/13 in luteal phase protocol, no statistical difference was found in above groups (P=0.923); in the elder group, embryonic aneuploidy rate was 60.8% (191/314) in antagonist protocol, 58.4% (132/226) in agonist long protocol, 59.2%(199/336) in agonist short protocol, 5/9 in luteal phase protocol, respectively,no significant difference was found (P=0.938). (3) In the younger patients, the aneuploidy rate in 1-5 oocytes group, 6-10 oocytes group, 11-15 oocytes group and ≥16 oocytes group was 37.9% (11/29), 54.0% (94/174), 52.5% (104/198) and 50.1% (283/565) respectively, no significant difference was found between the groups (P=0.652); while in the elder patients, the difference between aneuploidy rate in each retrieved oocytes group [73.6% (89/121), 57.5% (119/207), 56.3% (108/192), 57.8% (211/365)] was statistically significant (P=0.046). (4) Logistic regression analysis of age, cumulative dosage of Gn, number of oocytes obtained, and embryo aneuploidy rate showed that there was no association between the amount of Gn and embryo aneuploidy rate (P>0.05); the increase in maternal age would increase the risk of aneuploidy rate of embryos, which was statistically significant (OR=1.031, 95%CI: 1.010-1.054, P=0.004); the increase in oocytes retrived would significantly decrease the risk of aneuploidy (OR=0.981, 95%CI: 0.971-0.991, P<0.01). (5) There was no significant difference in biochemical pregnancy rate [55.6% (80/144) versus 52.1% (63/121)], clinical pregnancy rate [50.0% (72/144) versus 47.9% (58/121)] and live-birth rate [46.5% (67/144) versus 40.5% (49/121)] between different Gn dosage groups (P=0.613, P=0.738, P=0.324). The logistic regression analysis showed that the maternal age, the cumulative dosage of Gn, the number of oocytes obtained, and the ovarian stimulation protocol had no effect on the live-birth rate (all P>0.05). Conclusions: In PGT-A cycle, the dosage of Gn has no association with the embryo aneuploidy rate and pregnancy outcome. In the patients ≥35 years old, the increase in number of oocytes obtained may decrease the risk of aneuploidy. Age is an important factor affecting the embryo aneuploidy in PGT-A cycle.

EVALUATION OF THE RISK FACTORS OF CERVICAL INSUFFICIENCY IN WOMEN WITH INFERTILITY ASSOCIATED WITH ANOVULATION.

Cervical insufficiency is a common problem in obstetrical care. There are not enough studies about its development in women with infertility. The aim of the article was to determine the risk factors of the development of cervical insufficiency in women with infertility associated with anovulation. The object of the study were 308 pregnant women (110 pregnant women with cervical insufficiency and without infertility, 92 pregnant women with infertility associated with anovulation and with cervical insufficiency, 76 pregnant women with infertility associated with anovulation and without cervical insufficiency, 30 pregnant women without cervical insufficiency and infertility (controls)). We analyzed the data of obstetrical anamnesis, gynecological diseases, extragenital pathology. In fertile women with cervical insufficiency the traumatic factor of the cervix (previous labors, gynecological procedures connected with cervical dilatation) was the main in the development of this pathology. While in the women with infertility associated with anovulation the forming of cervical insufficiency was associated with hormonal reasons (hyperandrogenism (OR=3.04, 95 % CI=1.15-8.05, p=0.03), diminished ovarian reserve (OR=6.00, 95 % CI=1.97-18.24, p=0.002), controlled ovarian stimulation with gonadotropin and clomiphene citrate use (OR=3.69, 95% CI=1.93-7.04, p<0.001), use of additional reproductive technology (OR=1.95, 95 % CI=1.05-3.63, p=0.03).

Gonadotropins versus oral ovarian stimulation agents for unexplained infertility: a systematic review and meta-analysis.

OBJECTIVE: To compare live birth and multiple gestation in patients diagnosed with unexplained infertility undergoing intrauterine insemination after ovarian stimulation (OS-IUI) with oral medications versus gonadotropins. DESIGN: Systemic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Patients undergoing OS-IUI for treatment of unexplained infertility. INTERVENTION(S): Clomiphene, letrozole, or gonadotropins for OS-IUI. MAIN OUTCOME MEASURE(S): Live birth and multiple gestation. RESULT(S): Eight total trials were identified that met the inclusion criteria and comprised 2,989 patients undergoing 6,590 cycles. One study reported a significant increase in both live births and multiple gestations with the use of gonadotropins, two studies found an increased likelihood of live birth with the use of gonadotropins, and two studies found an increased risk of twins with gonadotropins. The relative risk of live birth in subjects receiving gonadotropins was 1.09. The relative risk of multiple gestation in subjects receiving gonadotropins was 1.06. Clinical pregnancy was higher in protocols with lax cancellation policies or higher gonadotropin doses, with subsequent increased relative risks of multiple gestations of 1.20 and 1.15, respectively. Singleton births per subject were similar between the two groups. The results did not change in per-protocol, per cycle, or fixed-effect model sensitivity analyses. CONCLUSION(S): For every birth gained with the use of gonadotropins, a similar increased risk of multiple gestation occurs. The randomized data do not support the use of gonadotropin for OS-IUI in women with unexplained infertility. CLINICAL TRIAL REGISTRATION NUMBER: Prospero CRD4201911998.

Differential impacts of gonadotrophins, IVF and embryo culture on mouse blastocyst development.

RESEARCH QUESTION: Conception via assisted reproductive technology (ART) increases the risk of type 2 diabetes and cardiovascular disease in adulthood. Underlying differences between ART-conceived and in-vivo-conceived embryos that contribute to this increased risk are, however, not known. DESIGN: This study examined the developmental characteristics of mouse blastocysts derived from ART- compared with in-vivo-conceived embryos. To determine the effect of ovarian stimulation versus IVF versus in-vitro embryo culture on phenotype, six distinct groups of blastocysts were generated. Female mice were naturally cycling or treated with high or mild doses of gonadotrophin, followed by natural mating or IVF under clinical conditions. Embryo morphokinetics were assessed by continuous time-lapse monitoring. Cell lineage allocation to the inner cell mass (Oct4+) or trophectoderm (Cdx2+) was determined by immunohistochemistry, and mitochondrial DNA (mtDNA) copy number was measured by quantitative PCR. RESULTS: Ovarian stimulation increased embryo number but reduced the percentage of blastocysts. Morphokinetic analysis showed that gonadotrophin treatment led to advanced development (P < 0.05) due to earlier post-pronuclear breakdown. The blastocyst rate was reduced in IVF embryos compared with those fertilized in vivo before culture (P < 0.001). Morphokinetics showed that embryo development was slower in all the IVF groups (P < <0.05), due to a delay from the 3-cell stage. A reduced total and trophectoderm cell number was observed in all groups of cultured blastocysts compared with naturally conceived blastocysts (P < 0.01). Gonadotrophin treatment did not affect the blastocyst mtDNA copy number; however, IVF embryos exhibited reduced mtDNA copy number compared with naturally conceived embryos. CONCLUSION: Ovarian stimulation, IVF and in-vitro culture differentially impair blastocyst developmental kinetics, differentiation and mtDNA copy number.

Early onset of cabergoline therapy for prophylaxis from ovarian hyperstimulation syndrome (OHSS): A potentially safer and more effective protocol.

Vascular endothelial growth factor (VEGF) is the most important angiogenic mediator in ovarian hyperstimulation syndrome OHSS. Studies proved that cabergoline administration blocks the increase in vascular permeability via dephosphorylation of VEGF receptors and hence can be used as prophylactic agent against OHSS. This study aimed at evaluating the effectiveness of early administration of cabergoline in the prevention of OHSS in high risk cases prepared for ICSI. This case series study was conducted on 126 high risk patients prepared for ICSI using the fixed antagonist protocol. High risk patients were defined as having more than 20 follicles >12 mm in diameter, and/or E2 more than 3000 pg/ml when the size of the leading follicle is more than 15 mm. When the size of the leading follicle reached 15 mm, cabergoline was administered (0.5 mg/day) for 8 days. Patients were followed up clinically, ultrasonographically and hematologically. The final E2 was 6099.5 ±â€¯2730 and the mean number of retrieved oocytes was 19.7 ±â€¯7.8. The clinical pregnancy rate was 62/126 (49.2%). There were no significant changes (p > 0.05) comparing hematological parameters, renal function tests and liver function tests between the day of HCG and the day of blastocyst transfer. The incidence of severe OHSS in this group was 1/126 (0.9%), while moderate OHSS was 12 (9.5%) and there were no cases of critical OHSS. We concluded that early administration of cabergoline is a safe and potentially more effective approach for prophylaxis against OHSS in high risk cases.

HORMONAL SUPPLEMENTATION TRIGGERING CHOROIDAL NEOVASCULARIZATION IN HEALTHY YOUNG FEMALES.

PURPOSE: To report three cases of choroidal neovascularization after hormonal treatment for ovarian stimulation during a fertility therapy. METHODS: A comprehensive ophthalmic examination was performed in all cases including best-corrected visual acuity, color fundus examination, fluorescein angiography, and optical coherence tomography. RESULTS: Three females in their thirties developed unilateral acuity vision loss and metamorphopsia. They all were undergoing hormonal supplementation for ovarian stimulation with gonadotropins at the moment of presentation. Intravitreal therapy with ranibizumab was used; all cases showed a significant functional and anatomical improvement. DISCUSSION: Hormonal supplementation for fertility therapy is a common procedure that may be associated with the development of choroidal neovascularization in healthy young females. Further studies should be performed to evaluate this association, but both ophthalmologist and gynecologist should be aware of this potential complication.

Low Gonadotropin Dosage Reduces Aneuploidy in Human Preimplantation Embryos: First Clinical Study in a UAE Population.

TYPE OF STUDY: Retrospective analysis of embryo aneuploidy in patients undergoing in vitro fertilization (IVF) cycles. AIM: To evaluate factors that might affect the incidence of embryo aneuploidy during IVF cycles. METHODS: Three hundred twelve IVF cases were included in the present study. Preimplantation genetic testing for aneuploidy (PGT-A) was performed for all the subjects involved. Subject stratification was done based on maternal age, gonadotropin drug dosage, and IVF outcomes data. Maternal age <35 years were placed in the "Young" age group and age ≥35 years were placed in the "Advanced Maternal Age" group. Similarly, IVF drug administered <200 International units (IU) was considered "low dosage," group and ≥200 IU were considered "high dosage" group. Patients were stratified into four groups-group 1: age <35 years and administered <200 IU; group 2: age <35 years and administered ≥200 IU; group 3: age ≥35 years and administered at <200 IU; and group 4: age ≥35 years and administered ≥200 IU. PGT-A results were attained using a next-generation sequencing-based protocol. Embryo transfer was guided by transabdominal ultrasound. Statistical significance was calculated with the use of chi-square test. RESULTS: One thousand fifty blastocyst trophectoderm biopsies from 312 IVF cases were retrieved. The IVF outcome of a total of 105 normal cases resulted in 65.71% pregnancies. Stratifying for maternal age and IVF drug stimulation with PGT-A analyses we found the euploid embryo percentages equal to 37.59% in Group 1; 16.18% in Group 2; 22.44% in Group 3; and 2.59% in Group 4. Similarly the aneuploid embryo (percentage)s were 62.40% for Group 1; 83.81% for Group 2; 77.55% for Group 3; and 87.40% for Group 4. CONCLUSION: This is the first clinical study reporting that gonadotropin dosage may act as a contributing factor in increasing aneuploidy incidences for the patients undergoing IVF cycles in the UAE population. This study shows that in all patient age groups, lower drug stimulation leads to an increasing trend in embryo euploidy.

Fertility Drugs Associated with Thyroid Cancer Risk: A Systematic Review and Meta-Analysis.

Associations have been demonstrated between fertility drugs and a variety of hormone-sensitive carcinomas. The purpose of this study was to determine the relationship between fertility drugs used in the treatment of female infertility and the risk of thyroid cancer. To investigate the clinical significance of fertility drugs used for the treatment of female infertility and the risk associated with thyroid cancer, we performed a literature search using PubMed, MEDLINE, the Cochrane Library, the Web of Science, and EBSCOHOST for comparative studies published any time prior to July 21, 2017. The studies included women who were treated for infertility with fertility drugs, such as clomiphene citrate, gonadotropins, or other unspecified fertility agents, which reported the incidence of thyroid cancer as the main outcome. Eight studies were included in the meta-analyses. Among women with infertility, there was a significant positive association between thyroid cancer risk and the use of fertility drugs (relative risk [RR] = 1.35; 95% confidence interval [CI] 1.12-1.64; P = 0.002). Additionally, among women with infertility, the use of clomiphene citrate was associated with an increased risk of thyroid cancer compared to women who did not use fertility drugs (RR = 1.45; 95% CI 1.12-1.88; P = 0.005). After pooling results, we found that the parity status of infertile women using fertility drugs was not associated with thyroid cancer risk (RR = 0.99; 95% CI 0.61-1.58, P = 0.95). In summary, clomiphene citrate (the most commonly used fertility drug) and other fertility drugs are associated with an increased risk of thyroid cancer.

Comparison of antagonist mild and long agonist protocols in terms of follicular fluid total antioxidant capacity.

OBJECTIVE: A high dose of prolonged gonadotropins can yield higher numbers of oocytes and embryos. The high dose or prolonged regimens can be associated with ovarian hyperstimulation syndrome (OHSS), multiple gestations, emotional stress, economical burden and treatment dropout. In mild stimulation lower doses and shorter duration times of gonadotropin are used in contrast to the conventional long stimulation protocol in IVF. It has been proposed that supraphysiologic levels of hormones may adversely affect endometrium and oocyte/embryo. Also it has been proposed that oxidative stress (OS) may alter ovarian hormone dynamics and could be further affected by additional exogenous hormonal stimulation. Therefore our aim was to compare follicular fluid total antioxidant capacity (TAC) in antagonist mild and long agonist stimulations. MATERIALS AND METHODS: Forty patients received antagonist mild stimulation, starting on the 5th day of their cycle and forty patients received long agonist treatment. Seventy-five patients undergoing their first IVF cycle were included in the final analysis. Follicular fluid (FF) samples were analyzed for estradiol (E2), antimullerian hormone (AMH) and TAC. RESULTS: FF-Total antioxidant capacity (TAC) levels were higher in the long agonist group as opposed to the antagonist group [1.07 ± 0.04 mmol Trolox equivalent/L vs 1 ± 0.13 mmol Trolox equivalent/L] (Fig. 1). Pregnancy rates were not significantly different between the two treatments. The FF-TAC levels were not different among infertility etiologies (Fig. 3). FF-TAC levels did not have a direct correlation with pregnancy but a positive correlation with the total gonadotropin dose was observed. CONCLUSION: Patients with good ovarian reserves and under the age of 35 effectively responded to mild stimulation treatment. Using lower amounts of gonadotropin, yielded less FF-TAC levels in patients who underwent antagonist mild protocol. In patients under the age of 35, antagonist mild stimulation is a patient friendly and effective procedure when undergoing their first IVF cycle.

Low estradiol responses in oocyte donors undergoing gonadotropin stimulation do not influence clinical outcomes.

PURPOSE: To examine the effect of low and very low estradiol responses in oocyte donors receiving gonadotropins on clinical outcomes of donor in vitro fertilization (IVF) cycles and to identify possible mechanisms responsible for low estradiol response. METHODS: This is a retrospective cohort study of oocyte donors undergoing antagonist IVF cycles with progression to oocyte retrieval between January 2010 and December 2016 at a single urban academic fertility center. Oocyte yield, fertilization rate, blastocyst rate, percentage of normal embryos on preimplantation genetic screening (PGS), pregnancy outcomes, and follicular fluid steroid profiles were compared between donors with normal estradiol response and those with low estradiol response. RESULTS: Three hundred sixty-six antagonist oocyte donor IVF cycles were identified: 42 cycles had a normal estradiol response (NE2), defined as peak serum estradiol (E2) of over 200 pg/mL per retrieved oocyte; 140 cycles had an intermediate estradiol response (iE2), defined as peak serum E2 between 100 and 200 pg/mL per retrieved oocyte; 110 cycles had a low estradiol response (LE2), defined as peak serum E2 between 50 and 100 pg/mL per retrieved oocyte; and 74 cycles had a very low estradiol response (vLE2), defined as peak serum E2 less than 50 pg/mL per retrieved oocyte. LE2 cycles resulted in a greater number of mature oocytes (22.4 vs. 13.6, p < 0.017), and fertilizations versus NE2 donors (18.5 vs. 10.7, p < 0.017), although the number of transferred or cryopreserved blastocysts were similar between groups (8.6, 6.9 vs. 4.8, p = 0.095, p = 1). The percentage of chromosomally normal embryos after PGS was similar between LE2, vLE2, and NE2 cycles (66.4, 71.8 vs. 63.1%, p = 0.99, p = 1). Pregnancy outcomes were similar between LE2, vLE2, and NE2 cycles. Serum AMH obtained on the day of peak E2 was similar to baseline serum AMH and did not differ between LE2 versus NE2 cycles. Follicular fluid E2 levels paralleled serum E2 levels and were lower in LE2 cycles versus NE2 cycles. CONCLUSION: The prevalence of very low E2 responses in donors appears to be high (20.2%). In contrast to autologous IVF cycles, LE2 does not portend poor outcomes in oocyte donors.

Severe multiple sclerosis reactivation after gonadotropin treatment.

Several reports indicate increased disease activity in patients with multiple sclerosis (MS) undergoing assisted reproductive techniques (ART), in the form of gonadtopin releasing hormone (GnRH) agonists. Other forms of ART treatments, like gonadotropin-treatment, have therefore been considered a safer option for MS-patients. We present a patient who despite being completely clinically and radiologically stable for eight years during disease modifying therapy experienced a nearly fulminant disease course almost immediately after starting gonadotropin-treatment, indicating that this form of follicle stimulating treatment could also be a major risk factor for MS disease activity.

The safety of available treatments of male hypogonadism in organic and functional hypogonadism.

INTRODUCTION: In the case of primary male hypogonadism (HG), only testosterone (T) replacement therapy (TRT) is possible whereas when the problem is secondary to a pituitary or hypothalamus alteration both T production and fertility can be, theoretically, restored. We here systematically reviewed and discussed the advantages and limits of medications formally approved for the treatment of HG. AREAS COVERED: Data derived from available meta-analyses of placebo controlled randomized trials (RCTs) were considered and analyzed. Gonadotropins are well-toleratedand their use is mainly limited by higher costs and a more cumbersome treatment schedule than TRT. Available RCTs on TRT suggest that cardiovascular (CV) and venous thromboembolism risk is not a major issue and that prostate safety is guaranteed. The risk of increased hematocrit is mainly limited to the use of short terminjectable preparations. EXPERT OPINION: In the last few years the concept of 'organic' irreversible HG and 'functional' or age- and comorbidity-related HG has been introduced. This definition is not evidence-based. The majority of RCTs enrolled patients with 'functional' HG. Considering the significant improvement in body composition, glucose metabolism and sexual activity, TRT should not be limited to 'organic' HG, but also offered for 'functional'.