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Granulosa cell (GC) differentiation, stimulated by FSH and LH, drives oocyte maturation and follicle development. FSH promotes GC proliferation, and LH triggers ovulation. In clinical practice, hCG is used to mimic LH. Despite various controlled ovarian stimulation (COS) protocols employing exogenous gonadotropins and GnRH analogs to prevent premature ovulation, their effectiveness and safety remain debated. To identify markers predicting a positive treatment response, the secretome of gonadotropin-stimulated GC using the human granulosa-like tumor cell line (KGN) via proteomics was analyzed. Additionally, a novel 2D-FFT quantitative method was employed to assess cytoskeleton fiber aggregation and polymerization, which are critical processes for GC differentiation. Furthermore, the activation of key kinases, focal adhesion kinase (FAK), and Rho-associated coiled-coil-containing protein kinase 1 (ROCK-1), which are implicated in cytoskeleton dynamics and hormone signaling, was evaluated. The proteomic analysis revealed significant modulation of proteins involved in extracellular matrix organization, steroidogenesis, and cytoskeleton remodeling. Notably, the combined FSH/hCG treatment led to a dynamic upregulation of the semaphorin pathway, specifically semaphorin 7A. Finally, a significant reorganization of the cytoskeleton network and signaling was detected. These findings enhance our understanding of folliculogenesis and suggest potential novel molecular markers for predicting patient responses to gonadotropin stimulation.

Gonadotropin-inducible ovarian transcription factor-1 (Giot1) belongs to a family of fast-responsive genes, and gonadotropins rapidly induce its expression in steroidogenic cells of ovaries and testes of rats. Gonadal Giot1 gene expression is regulated by cyclic adenosine monophosphate (cAMP) -dependent protein kinase A pathway, with essential role of orphan nuclear receptor NR4A1 transcription factor (nuclear receptor subfamily 4, group A, member 1). A recent study reports that Giot1 is also expressed in adrenals, however, the mechanism of its regulation in adrenal gland is yet to be identified. Therefore, the aim of this study was to characterise the changes in Giot1 gene expression in male and female rat adrenals using wide range of in vivo and in vitro experimental models. Special emphasis was directed at the Giot1 gene regulation by ACTH and gonadotropin. In our study, we found that ACTH rapidly stimulates Giot1 expression both in vivo and in vitro. However, gonadotropin does not affect the adrenal Giot1 gene expression, presumably due to the low expression of gonadotropin receptor in adrenals. Both testosterone and estradiol administered in vivo had inhibitory effect on Giot1 gene expression in the adrenals of post-gonadectomized adult rats. Further, our studies revealed that the intracellular mechanism of Giot1 gene regulation in rat adrenals is similar to that of gonads. As in the case of gonads, the expression of Giot1 in adrenal gland is regulated by cAMP-dependent signaling pathway with essential role of the NR4A1 transcription factor. The results of our studies suggest that Giot1 may be involved in the regulation of rat adrenocortical steroidogenesis.

This study analyzes the effects of neonatal androgenization on follicular growth and first ovulation in response to gonadotrophins, using a model of exogenous stimulation or the use of subcutaneous ovary grafts in castrated animals to replace the hypothalamus–pituitary signal. Neonatal rats (days 1–5) were treated with testosterone, dihydrotestosterone or vehicle. At juvenile period, rats were stimulated with PMSG, hCG (alone or combined) or used as ovarian donors to be grafted on castrated adult female rats. Ovulation and ovarian histology were analyzed in both groups. Animals treated with vehicle or dihydrotestosterone stimulated with gonadotrophins (pharmacological or by using an ovary graft) ovulated, showing a normal histological morphology whereas rats exposed to testosterone and injected with the same doses of gonadotrophins did not it. In this group, ovulation was reached using a higher dose of hCG. Ovaries in the testosterone group were characterized by the presence of follicles with atretic appearance and a larger size than those observed in control or dihydrotestosterone groups. A similar appearance was observed in testosterone ovary grafts although luteinization and some corpora lutea were also identified. Our findings suggest that neonatal exposure to aromatizable androgens induces a more drastic signalling on the ovarian tissue that those driven by non-aromatizable androgens in response to gonadotrophins.

Gonadotropins are the key regulators of ovarian follicles development. They are applied in therapeutic practice in assisted reproductive technology clinics. In the present review we discuss the basic gonadotropic hormones – recombinant human follicle-stimulating hormone, its derivatives, luteinizing hormone and gonadotropin serum of pregnant mares, their origin, and application in ovarian follicle systems in in vitro culture systems.

Background Diminished ovarian reserve (DOR) is one of the obstacles affecting the reproductive outcomes of patients receiving assisted reproductive therapy. The purpose of this study was to investigate whether dual trigger, including gonadotropin‐releasing hormone agonist (GnRHa) and human chorionic gonadotropin (hCG), can improve pregnancy outcomes in patients with DOR undergoing in vitro fertilization (IVF) cycles using mild stimulation protocols. Methods A total of 734 patients with DOR were included in this retrospective study. Patients were divided into a recombinant hCG trigger group and a dual trigger group (hCG combined with GnRHa) according to the different trigger drugs used. The main outcome measures included the number of oocytes retrieved, the fertilization rate, the number of transferable embryos, the implantation rate, the clinical pregnancy rate, the miscarriage rate, the live birth rate (LBR), and the cumulative live birth rate (CLBR). Generalized linear model and logistic regression analyses were performed for confounding factors. Results There were 337 cycles with a single hCG trigger and 397 cycles with dual trigger. The dual trigger group demonstrated significantly higher numbers of retrieved oocytes [3.60 vs. 2.39, adjusted β = 0.538 (0.221–0.855)], fertilized oocytes [2.55 vs. 1.94, adjusted β = 0.277 (0.031–0.523)] and transferable embryos [1.22 vs. 0.95, adjusted β = 0.162 (-0.005–0.329)] than did the hCG trigger group, whereas no significant difference in the fertilization rate was observed between the two groups. Moreover, the embryo transfer cancellation rate (35.5% vs. 43.9%) was obviously lower in the dual trigger group. Among the fresh embryo transfer cycles, the implantation rate, clinical pregnancy rate, miscarriage rate and live birth rate were similar between the two groups. After controlling for potential confounding variables, the trigger method was identified as an independent factor affecting the number of oocytes retrieved but had no significant impact on the CLBR. Conclusions Dual triggering of final oocyte maturation with hCG combined with GnRHa can significantly increase the number of oocytes retrieved in patients with DOR but has no improvement effect on the implantation rate, clinical pregnancy rate or LBR of fresh cycles or on the CLBR.

Superovulation with gonadotropins alters the hormonal milieu during early embryo development and placentation, and may be responsible for fetal and placental changes observed after in vitro fertilization (IVF). We hypothesized that superovulation has differential effects depending on timing of exposure. To test our hypothesis, we isolated the effect of superovulation on pre- and peri-implantation mouse embryos. Blastocysts were obtained from either natural mating or following superovulation and mating, and were transferred into naturally mated or superovulated pseudopregnant recipient mice. Fetal weight was significantly lower after peri-implantation exposure to superovulation, regardless of preimplantation exposure (p = 0.006). Placentas derived from blastocysts exposed to superovulation pre- and peri-implantation were larger than placentas derived from natural blastocysts that are transferred into a natural or superovulated environment (p < 0.05). Fetal-to-placental weight ratio decreased following superovulation during the pre- or peri-implantation period (p = 0.05, 0.01, respectively) and these effects were additive. Peg3 DNA methylation levels were decreased in placentas derived from exposure to superovulation both pre- and peri-implantation compared with unexposed embryos and exposure of the preimplantation embryo only. Through RNA sequencing on placental tissue, changes were identified in genes involved in immune system regulation, specifically interferon signaling, which has been previously implicated in implantation and maintenance of early pregnancy in mice. Overall, we found that the timing of exposure to gonadotropin stimulation can have differential effects on fetal and placental growth. These findings could impact clinical practice and underscores the importance of dissecting the role of procedures utilized during IVF on pregnancy complications. Summary Sentence Preimplantation embryo exposure to superovulation affects placental growth, whereas peri-implantation exposure affects fetal growth. Placental effects occur via changes in immune-related gene expression and epigenetic changes in growth-related genes.

Experiments were designed to investigate the effect of different doses and timing of an eCG treatment given during GnRH-based synchronization protocols on follicular dynamics and fertility in cattle. In Exp. 1, Angus heifers (n = 50) received a 7-d Ovsynch + progesterone protocol (on d 0, GnRH and progesterone insert were administered; on d 7, progesterone insert was removed and PGF2α was injected; and on d 9.5, GnRH was injected 56 h after progesterone removal) with eCG (0, 300, 500, 700, or 1,000 IU) administered on d 7. In Exp. 2, Angus cows (n = 27) received the same protocol as Exp. 1 and were assigned randomly to receive 0 or 400 IU eCG i.m. on d 2 or 7. In Exp. 3, Angus cows (n = 18) received a 6-d Ovsynch + progesterone protocol and were randomly assigned to receive 0 or 800 IU eCG on d 3 of the protocol (Exp. 3a). A pilot field trial was also performed using the same treatments in suckled Angus-cross cows (n = 72; Exp. 3b). In Exp. 4, beef heifers (n = 200) were assigned randomly to the same treatments as in Exp. 3, but the second GnRH was not given, with Holstein bulls introduced on d 6. In Exp. 5, Angus cows (n = 12) received the same treatment as in Exp. 3, but were not inseminated. Progesterone concentrations were assessed in plasma collected during the estrous cycle following synchronization. Ultrasonography was used to monitor ovarian dynamics and to diagnose pregnancy. In Exp. 1, the mean number of ovulations was affected (P < 0.02) by the dose of eCG and the stage of follicular development when administered. Treatment with eCG on d 2 tended (P < 0.08) to extend the interval from PGF2α to ovulation, but was not successful in inducing double ovulations. In contrast, eCG on d 3 increased (P < 0.01) the number of cows with double ovulation when administered i.m. and increased (P < 0.04) pregnancy rate in single ovulating heifers after bull breeding (68.0 vs. 53.1%). This treatment also elevated progesterone concentrations during the estrous cycle following synchronization. Thus, the mechanism by which administration of eCG on d 3 of the synchronization increased pregnancy rates may be through supporting development of a healthy follicle and subsequent corpus luteum capable of secreting increased concentrations of progesterone during early pregnancy. In conclusion, strategic administration of eCG during a synchronization protocol can be used to improve reproductive performance through increased pregnancy rates in single ovulating animals as well as the induction of twin ovulations for twinning.

Abstract The Javaen barb Systomus rubripinnis is an endemic fish not domesticated in Indonesia. This study aims to evaluate the effectiveness of gonadotropin and melatonin hormones in inducing ovulation of female Javaen barb. A total of 12 female fish (BW: 142.12 ± 18.08 g; egg diameter 1.0-1.2 mm) were selected to be injected with a combination of different hormones. The treatments were ovaprimTM at a dose of 0.6 mL/kg without melatonin (L0.6M0), ovaprimTM at 0.3 mL/kg with 0.25 mg/kg melatonin (L0.3M0.25), 500 IU/kg of human chorionic gonadotropin with 0.25 mg/kg melatonin (H500M0.25), and 0.25 mg/kg melatonin (M0.25). The L0.6M0 and L0.3M0.25 treatments were injected twice. The first injection was 40% of the total dose, while the rest (60%) was injected 6 hours after the first injection. Melatonin injection was carried out at the same time as the first injection. In the H500M0.25 treatment, melatonin injection was carried out 24 hours after HCG injection. Fish injected with ovaprimTM with and without melatonin had the fastest latency period, and ovulation occurred in all fish. The H500M0.25 treatment had an ovulation rate of 66.7%, while those injected with only melatonin (M0.25) did not ovulate. The number of ovulated eggs, fertilization and hatching rate from ovaprimTM injected broodstock were higher than those of HCG. In contrast, the larvae’s survival rate, body weight, and length were similar. In conclusion, ovaprimTM is practical in inducing ovulation of Javaen barb, and melatonin has a complementary effect on Javaen barb ovulation. Resumo O barbo de Java Systomus rubripinnis é um peixe endêmico não domesticado na Indonésia. Este estudo teve como objetivo avaliar a eficácia dos hormônios gonadotrofina e melatonina na indução da ovulação de fêmeas de barbo de Java. Um total de 12 fêmeas (PC: 142,12 ± 18,08 g; diâmetro do ovo 1,0-1,2 mm) foi selecionado para receber uma combinação de diferentes hormônios. Os tratamentos foram ovaprimTM na dose de 0,6 mL/kg sem melatonina (L0,6M0), ovaprimTM a 0,3 mL/kg com 0,25 mg/kg de melatonina (L0,3M0,25), 500 UI/kg de gonadotrofina coriônica humana com 0,25 mg/kg de melatonina (H500M0,25) e 0,25 mg/kg de melatonina (M0,25). Os tratamentos L0,6M0 e L0,3M0,25 foram injetados duas vezes. A primeira injeção foi de 40% da dose total, enquanto o restante (60%) foi injetado 6 horas após a primeira injeção. A injeção de melatonina foi realizada ao mesmo tempo que a primeira injeção. No tratamento H500M0,25, a injeção de melatonina foi realizada 24 horas após a injeção de HCG. Peixes injetados com ovaprimTM com e sem melatonina apresentaram o período de latência mais rápido, e a ovulação ocorreu em todos os peixes. O tratamento H500M0,25 apresentou uma taxa de ovulação de 66,7%, enquanto aqueles injetados apenas com melatonina (M0,25) não ovularam. O número de ovos ovulados, a fertilização e a taxa de eclosão dos reprodutores injetados com ovaprimTM foram maiores do que os do HCG. Em contraste, a taxa de sobrevivência, o peso corporal e o comprimento das larvas foram semelhantes. Em conclusão, o ovaprimTM é prático na indução da ovulação do barbo de Java e a melatonina tem um efeito complementar na ovulação do barbo de Java.

Background The goal of this study was to assess the association between endometrial thickness on the chorionic gonadotropin (hCG) day and in vitro fertilization and embryo transfer (IVF-ET) outcome in normal responders after GnRH antagonist administration. Methods A retrospective cohort study was performed in normal responders with GnRH antagonist administration from January 2011–December 2013. Patients were divided into four groups according to endometrial thickness, as follows: <7 mm (group 1), > = 7- < 8 mm (group 2), > = 8- < 14 mm (group 3), and > =14 mm (group 4). Results A total of 2106 embryo transfer cycles were analyzed. The pregnancy rate (PR) was 44.87%.The clinical pregnancy rate, ongoing pregnancy rate and the implantation rate (17.28%, 13.79%, 10.17%, respectively) were significantly lower in group 1 compared to the other three groups (p < 0.05). The miscarriage rate was higher in patients with endometrial thickness less than 7 mm. The clinical pregnancy rate, ongoing pregnancy rate and implantation rate were highest in patients with endometrial thickness higher than 14 mm, but showed no difference in patients with those of endometrial thickness between 8-14 mm. Conclusions There is a correlation between endometrial thickness measured on hCG day and clinical outcome in normal responders with GnRH antagonist administration. The pregnancy rate was lower in patients with endometrial thickness less than 7 mm compared with patients with endometrial thickness more than 7 mm.

Abstract Context Gonadotropin-releasing hormone agonist (GnRH-a) serves as an alternative to human chorionic gonadotropin (hCG) to trigger final oocyte maturation, while it significantly reduces the risk of ovarian hyperstimulation syndrome (OHSS), probably by attenuating vascular/endothelial activation. Objectives The objectives of this work are to compare the effect of different modes of final follicular maturation (hCG vs GnRH-a) following ovarian stimulation (OS) for in vitro fertilization (IVF) on endothelial function. Design and Setting A prospective cohort study was conducted at a tertiary medical center. Participants Patients age 37 years or younger, undergoing OS for IVF, were allocated into 2 groups according to the type of final follicle maturation: the hCG group (n = 7) or the GnRH-a group (n = 8). Intervention Endothelial function was assessed by measurement of the peripheral arterial tonometry in reaction to temporary ischemia at 3 study points: day 3 of menstrual cycle (day 0), day of hCG/GnRH-a administration (day trigger) and day of oocyte pick-up (day OPU). The ratio of arterial tonometry readings before and after ischemia is called the reactive hyperemia index (RHI). Decreased RHI (< 1.67) indicates endothelial dysfunction. Main Outcome Measures The main outcomes measures of this study included endothelial function at 3 study points during OS with different modes of triggering final follicular maturation. Results The mean RHI values at day 0 were within the normal range for all patients and comparable between both groups (hCG: 1.7 ± 0.3 vs GnRH-a: 1.79 ± 0.4, P = .6). All patients presented a decrease in RHI values on day trigger, which did not differ between the 2 groups (1.62 ± 0.3 vs 1.4 ± 0.2, respectively, P = .2). However, the hCG group demonstrated a further decrease in RHI on day OPU, whereas patients who received GnRH-a had restored normal endothelial function reflected by increased RHI values (1.4 ± 0.2 vs 1.75 ± 0.2, respectively, P = .03). Conclusions Triggering final follicular maturation with GnRH-a restored normal endothelial function, whereas hCG trigger resulted in a decrease in endothelial function.