SIK2 and SIK3 Differentially Regulate Mouse Granulosa Cell Response to Exogenous Gonadotropins In Vivo.

Salt-inducible kinases (SIKs), a family of serine/threonine kinases, were found to be critical determinants of female fertility. SIK2 silencing results in increased ovulatory response to gonadotropins. In contrast, SIK3 knockout results in infertility, gonadotropin insensitivity, and ovaries devoid of antral and preovulatory follicles. This study hypothesizes that SIK2 and SIK3 differentially regulate follicle growth and fertility via contrasting actions in the granulosa cells (GCs), the somatic cells of the follicle. Therefore, SIK2 or SIK3 GC-specific knockdown (SIK2GCKD and SIK3GCKD, respectively) mice were generated by crossing SIK floxed mice with Cyp19a1pII-Cre mice. Fertility studies revealed that pup accumulation over 6 months and the average litter size of SIK2GCKD mice were similar to controls, although in SIK3GCKD mice were significantly lower compared to controls. Compared to controls, gonadotropin stimulation of prepubertal SIK2GCKD mice resulted in significantly higher serum estradiol levels, whereas SIK3GCKD mice produced significantly less estradiol. Cyp11a1, Cyp19a1, and StAR were significantly increased in the GCs of gonadotropin-stimulated SIK2GCKD mice. However, Cyp11a1 and StAR remained significantly lower than controls in SIK3GCKD mice. Interestingly, Cyp19a1 stimulation in SIK3GCKD was not statistically different compared to controls. Superovulation resulted in SIK2GCKD mice ovulating significantly more oocytes, whereas SIK3GCKD mice ovulated significantly fewer oocytes than controls. Remarkably, SIK3GCKD superovulated ovaries contained significantly more preantral follicles than controls. SIK3GCKD ovaries contained significantly more apoptotic cells and fewer proliferating cells than controls. These data point to the differential regulation of GC function and follicle development by SIK2 and SIK3 and supports the therapeutic potential of targeting these kinases for treating infertility or developing new contraceptives.

Clinical pharmacology in adolescent transgender medicine.

Adolescent transgender medicine is a growing clinical field. Gender-affirming medications for transgender youth may include gonadotropin-releasing hormone (GnRH) agonists, gender-affirming hormones or both. To evaluate the potential effects of GnRH agonists (puberty suppression) on pharmacokinetic processes for transgender youth, we searched PubMed from inception to May 2024 for publications on the effects of GnRH agonists on drug absorption, distribution, metabolism or excretion for transgender adolescents or effects on hormones (including gonadotropins, adrenal androgens, sex steroids) that are associated with changes in drug metabolism during puberty in the general adolescent population. No publications discussed the effects of GnRH agonist treatment on pharmacokinetic processes for adolescent transgender people. Sixteen publications observed marked decreases in gonadotropins and sex steroids for both adolescent transgender men and adolescent transgender women and slight effects on adrenal androgens. During GnRH agonist treatment, changes in body composition and body shape were greater for adolescent transgender people than for cisgender adolescent people. Further research is needed to better understand the effects of GnRH agonists on drug metabolism and other pharmacokinetic processes for transgender adolescents receiving GnRH agonists and other gender-affirming medications.

The epithelial Na+ channel (ENaC) in ovarian granulosa cells modulates Ca2+ mobilization and gonadotrophin signaling for estrogen homeostasis and female fertility.

Ovarian granulosa cells are essential to gonadotrophin-regulated estrogen production, female cycle maintenance and fertility. The epithelial Na+ channel (ENaC) is associated with female fertility; however, whether and how it plays a role in ovarian cell function(s) remained unexplored. Here, we report patch-clamp and Na+ imaging detection of ENaC expression and channel activity in both human and mouse ovarian granulosa cells, which are promoted by pituitary gonadotrophins, follicle stimulating hormone (FSH) or luteinizing hormone (LH). Cre-recombinase- and CRISPR-Cas9-based granulosa-specific knockout of ENaC α subunit (Scnn1a) in mice resulted in failed estrogen elevation at early estrus, reduced number of corpus luteum, abnormally extended estrus phase, reduced litter size and subfertility in adult female mice. Further analysis using technologies including RNA sequencing and Ca2+ imaging revealed that pharmacological inhibition, shRNA-based knockdown or the knockout of ENaC diminished spontaneous or stimulated Ca2+ oscillations, lowered the capacity of intracellular Ca2+ stores and impaired FSH/LH-stimulated transcriptome changes for estrogen production in mouse and/or human granulosa cells. Together, these results have revealed a previously undefined role of ENaC in modulating gonadotrophin signaling in granulosa cells for estrogen homeostasis and thus female fertility.

Are Women with Polycystic Ovary Syndrome at Increased Risk of Alzheimer Disease? Lessons from Insulin Resistance, Tryptophan and Gonadotropin Disturbances and Their Link with Amyloid-Beta Aggregation.

Alzheimer disease, the leading cause of dementia, and polycystic ovary syndrome, one of the most prevalent female endocrine disorders, appear to be unrelated conditions. However, studies show that both disease entities have common risk factors, and the amount of certain protein marker of neurodegeneration is increased in PCOS. Reports on the pathomechanism of both diseases point to the possibility of common denominators linking them. Dysregulation of the kynurenine pathway, insulin resistance, and impairment of the hypothalamic-pituitary-gonadal axis, which are correlated with amyloid-beta aggregation are these common areas. This article discusses the relationship between Alzheimer disease and polycystic ovary syndrome, with a particular focus on the role of disorders of tryptophan metabolism in both conditions. Based on a review of the available literature, we concluded that systemic changes occurring in PCOS influence the increased risk of neurodegeneration.

Elevated temperature impairs gonadal development by suppressing the expression of the genes for kisspeptin, GnRH1 and GTH subunits in Nile tilapia Oreochromis niloticus.

Temperature is a preeminent factor in the regulation of fish reproduction and hinders gonadal development beyond a specific threshold. To comprehend the molecular mechanism responsible for reproductive suppression at different temperature, expression of the genes encoding kisspeptin (kiss2), gonadotropin-releasing hormone (gnrh1) and their receptors (gpr54, gnrh1r) in the brain, and the gonadotropin (GTH) subunits (fshb and lhb) in the pituitary were studied in juvenile Nile tilapia (Oreochromis niloticus) along with gonadal histology. Fish were acclimatized to three distinct temperatures, including 31 °C, 34 °C and 37 °C for 14 days. The mRNA levels of kiss2, gpr54, gnrh1, and gnrh1r were significantly decreased at 37 °C compared to 31 °C and 34 °C in the both sexes. In parallel, the expression level of fshb in the both sexes and lhb in the female were significantly lower at 37 °C in the pituitary. Histologically, the gonads of both sexes had normal growth of gametes at control temperature (31 °C), whereas the spermatogenesis and oocyte maturation were slowed down and atretic oocytes were found in the ovary at 37 °C acclimation temperature. Taken together, the results imply that elevated temperature beyond the specific threshold may have a negative impact on reproduction by suppressing the gene expressions of kisspeptin/GnRH1/GTH system and eventually restrains normal growth and maturation of gametes in the both sexes of Nile tilapia.

Effects and action mechanism of gonadotropins on ovarian follicular cells: A novel role of Sphingosine-1-Phosphate (S1P). A review.

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) control antral follicular growth by regulating several processes, such as the synthesis of hormones and signaling molecules, proliferation, survival, apoptosis, luteinization, and ovulation. To exert these effects, gonadotropins bind to their respective Gs protein-coupled receptors, activating the protein kinase A (PKA) pathway or recruiting Gq proteins to activate protein kinase C (PKC) signaling. Although the action mechanism of FSH and LH is clear, recently, it has been shown that both gonadotropins promote the synthesis of sphingosine-1-phosphate (S1P) in granulosa and theca cells through the activation of sphingosine kinase 1. Moreover, the inhibition of SPHKs reduces S1P synthesis, cell viability, and the proliferation of follicular cells in response to gonadotropins, and the addition of S1P to the culture medium increases the proliferation of granulosa and theca cells without apparent effects on sexual steroid synthesis. Therefore, we consider that S1P is a crucial signaling molecule that complements the canonical gonadotropin pathway to promote the proliferation and viability of granulosa and theca cells.

The impact of clomiphene citrate on the endometrium in comparison to gonadotropins in intrauterine insemination cycles: is it thinner and does it matter?

Objective: To determine whether endometrial thickness (EMT) differs between i) clomiphene citrate (CC) and gonadotropin (Gn) utilizing patients as their own controls, and ii) patients who conceived with CC and those who did not. Furthermore, to investigate the association between late-follicular EMT and pregnancy outcomes, in CC and Gn cycles. Methods: Retrospective study. Three sets of analyses were conducted separately for the purpose of this study. In analysis 1, we included all cycles from women who initially underwent CC/IUI (CC1, n=1252), followed by Gn/IUI (Gn1, n=1307), to compare EMT differences between CC/IUI and Gn/IUI, utilizing women as their own controls. In analysis 2, we included all CC/IUI cycles (CC2, n=686) from women who eventually conceived with CC during the same study period, to evaluate EMT differences between patients who conceived with CC (CC2) and those who did not (CC1). In analysis 3, pregnancy outcomes among different EMT quartiles were evaluated in CC/IUI and Gn/IUI cycles, separately, to investigate the potential association between EMT and pregnancy outcomes. Results: In analysis 1, when CC1 was compared to Gn1 cycles, EMT was noted to be significantly thinner [Median (IQR): 6.8 (5.5-8.0) vs. 8.3 (7.0-10.0) mm, p<0.001]. Within-patient, CC1 compared to Gn1 EMT was on average 1.7mm thinner. Generalized linear mixed models, adjusted for confounders, revealed similar results (coefficient: 1.69, 95% CI: 1.52-1.85, CC1 as ref.). In analysis 2, CC1 was compared to CC2 EMT, the former being thinner both before [Median (IQR): 6.8 (5.5-8.0) vs. 7.2 (6.0-8.9) mm, p<0.001] and after adjustment (coefficient: 0.59, 95%CI: 0.34-0.85, CC1 as ref.). In analysis 3, clinical pregnancy rates (CPRs) and ongoing pregnancy rates (OPRs) improved as EMT quartiles increased (Q1 to Q4) among CC cycles (p<0.001, p<0.001, respectively), while no such trend was observed among Gn cycles (p=0.94, p=0.68, respectively). Generalized estimating equations models, adjusted for confounders, suggested that EMT was positively associated with CPR and OPR in CC cycles, but not in Gn cycles. Conclusions: Within-patient, CC generally resulted in thinner EMT compared to Gn. Thinner endometrium was associated with decreased OPR in CC cycles, while no such association was detected in Gn cycles.

Gonadotropin Activity during Early Folliculogenesis and Implications for Polycystic Ovarian Syndrome and Premature Ovarian Insufficiency: A Narrative Review.

Female fertility depends on the ovarian reserve of follicles, which is determined at birth. Primordial follicle development and oocyte maturation are regulated by multiple factors and pathways and classified into gonadotropin-independent and gonadotropin-dependent phases, according to the response to gonadotropins. Folliculogenesis has always been considered to be gonadotropin-dependent only from the antral stage, but evidence from the literature highlights the role of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) during early folliculogenesis with a potential role in the progression of the pool of primordial follicles. Hormonal and molecular pathway alterations during the very earliest stages of folliculogenesis may be the root cause of anovulation in polycystic ovary syndrome (PCOS) and in PCOS-like phenotypes related to antiepileptic treatment. Excessive induction of primordial follicle activation can also lead to premature ovarian insufficiency (POI), a condition characterized by menopause in women before 40 years of age. Future treatments aiming to suppress initial recruitment or prevent the growth of resting follicles could help in prolonging female fertility, especially in women with PCOS or POI. This review will briefly introduce the impact of gonadotropins on early folliculogenesis. We will discuss the influence of LH on ovarian reserve and its potential role in PCOS and POI infertility.

Effect of the gonadotropin surge on steroid receptor regulation in preovulatory follicles and newly formed corpora lutea in the cow.

The objective of the study was to characterize the mRNA expression patterns of specific steroid hormone receptors namely, estrogen receptors (ESRRA-estrogen related receptor alpha and ESRRB-estrogen related receptor beta) and progesterone receptors (PGR) in superovulation-induced bovine follicles during the periovulation and subsequent corpus luteum (CL) formation. The bovine ovaries (n = 5 cow / group), containing preovulatory follicles or early CL, were collected relative to injection of the gonadotropin-releasing hormone (GnRH) at (I) 0 h, (II) 4 h, (III) 10 h, (IV) 20 h, (V) 25 h (preovulatory follicles) and (VI) 60 h (CL, 2-3 days after induced ovulation). In this experiment, we analyzed the steroid receptor mRNA expression and their localization in the follicle and CL tissue. The high mRNA expression of ESRRA, ESRRB, and PGR analyzed in the follicles before ovulation is significantly reduced in the group of follicles during ovulation (25 h after GnRH), rising again significantly after ovulation in newly formed CL, only for ESRRA and PGR (P < 0.05). Immunohistochemically, the nuclei of antral follicles' granulosa cells showed a positive staining for ESRRA, followed by higher activity in the large luteal cells just after ovulation (early CL). In contrast, the lower PGR immunopresence in preovulatory follicles increased in both small and large luteal cell nuclei after follicle ovulation. Our results of steroid receptor mRNA expression in this experimentally induced gonadotropin surge provide insight into the molecular mechanisms of the effects of steroid hormones on follicular-luteal tissue in the period close to the ovulation and subsequent CL formation in the cow.

Total gonadotropin dose did not affect euploid blastocyst rates: an analysis of more than 19,000 oocytes.

BACKGROUND: To evaluate whether increasing total gonadotropin (Gn) dose is associated with changes in euploid blastocyst rate in preimplantation genetic testing (PGT) oocytes. METHODS: This retrospective cohort study was conducted between 2017 and 2022, and 19,246 oocytes were grouped and analyzed based on tri-sectional quantiles of total Gn doses. SETTING: Single reproductive medical center. SUBJECTS: All the patients who underwent PGT cycles, including PGT for aneuploidy, monogenic disorders, and structural rearrangements, were included. EXPOSURE: Next-generation sequencing platforms for chromosomal analysis. MAIN OUTCOME MEASURES: Blastocyst formation and euploid blastocyst rates. RESULTS: In total, 19,246 oocytes and 5375 PGT blastocysts were analyzed. There were significant differences in blastocyst formation and euploid blastocyst rates among the groups classified according to tri-sectional quantiles of total Gn doses. Significant differences in age, body mass index (BMI), proportion of primary infertility, anti-Müllerian hormone (AMH) levels, number of oocytes retrieved, controlled ovarian stimulation (COS) regimen, type of Gn, and PGT category were observed among the three groups. After stratifying the analysis by age, BMI, infertility diagnosis, AMH levels, number of oocytes retrieved, PGT category, type of Gn, and COS regimen, significant differences were only seen in a small number of specific subgroups. Furthermore, the results of the multiple logistic regression analysis showed that the blastocyst formation and euploid blastocyst rates did not significantly increase or decrease with the total Gn dose, whether treated as a continuous variable or divided into three Gn groups as categorical variables. Notably, advancing age was a risk factor for blastocyst formation and euploid blastocyst rates. PGT for structural rearrangements was a risk factor for blastocyst formation and euploid blastocyst rates as compared with PGT for aneuploidy. CONCLUSION: In the total PGT cycles, advancing age, and preimplantation genetic testing for structural rearrangements negatively affected blastocyst formation and euploid blastocyst rates; however, the total Gn dose did not affect blastocyst formation and euploid blastocyst rates.

Two livebirths achieved in cases of hypergonadotropic hypogonadism nonobstructive azoospermia, treated with GnRH agonist and gonadotrophins: a case series and review of the literature.

Non-obstructive azoospermia (NOA) is the most severe form of male factor infertility. It results form from either primary or secondary testicular failure. Here, we report cases of two patients with NOA due to maturation arrest and increased serum FSH, treated with GnRH agonist and gonadotrophins. The two NOA patients underwent a pharmacological treatment consisting of pituitary desensibilization using a GnRH agonist and testicular stimulation using menotropin. Testicular stimulation started one month after the beginning of GnRH agonist treatment. The female partner underwent controlled ovarian stimulation (COS) followed by intracytoplasmic sperm injection (ICSI). On the third day of the cycle, menotropin daily doses was administered. When at least one follicle ≥14 mm was visualized, pituitary blockage was performed using GnRH antagonist ganirelix. When three or more follicles attained a mean diameter of ≥17 mm, triptorelin acetate was administered to trigger final follicular maturation. Oocyte retrieval was performed 35 hours later. After treatment, male partner blood levels of the FSH, LH, decreased and total testosterone were increased. Spermatozoa was observed after semen collection in both cases. After COS, oocytes were retrieved and ICSI was performed. Embryos were biopsied for preimplantation genetic testing (PGT) and those considered euploidy were transferred resulting in positive implantation, ongoing pregnancy, and livebirth on both cases. In this report we present a successful strategy for hypergonadotropic hypogonadism AOA men, as an alternative approach to the surgical testicular sperm recovery. Nevertheless, prospective randomized trials are needed to confirm our findings.

The cumulative live birth rate and cost-effectiveness of the clomiphene and gonadotropin cotreatment protocol versus the mid-luteal GnRH agonist protocol in women over 35 years old.

The decrease in assisted reproductive technology success among older women, attributed to decreased oocyte quantity and quality, poses a significant challenge. Currently, no consensus on the optimal ovarian stimulation protocol for older women undergoing IVF exists. This retrospectively registered cohort study aimed to compare the cumulative live birth rate (CLBR), time to live birth (TTLB), and cost-effectiveness among women older than 35 years who were receiving either the gonadotropin-releasing hormone agonist (GnRHa) or clomiphene citrate and gonadotropin cotreatment with ovarian stimulation (CC cotreatment) protocol. To compare treatment outcomes, we performed propensity score matching (PSM) on 2871 IVF cycles in women older than 35 years who received either the GnRHa or CC cotreatment protocol, resulting in 375 cycles in each group. Additionally, a decision tree model was utilized to assess the cost-effectiveness of the two protocols. Following PSM, both groups had similar baseline characteristics. The CC cotreatment protocol resulted in a greater rate of cycle cancellation (13.07% vs. 8.00%, p = 0.032), but the groups maintained comparable fertilization rates and embryo quality. Although the TTLB was longer in the CC cotreatment group, the CLBR per initial cycle (41.07% vs. 45.33%, p = 0.269) and delivery outcomes were similar between the two groups at the 24 months follow-up. Additionally, the average cost per live birth in the CC cotreatment group was 21.27% lower than in the GnRHa group (¥32,301.42 vs. ¥39,174.22). In conclusion, for women older than 35 years undergoing IVF, the CC cotreatment protocol offered a comparable CLBR to the GnRHa protocol but with reduced costs, indicating its potential as a viable and cost-effective ovarian stimulation option.Clinical trial registration: https://www.chictr.org.cn/ , identifier [ChiCTR2300076537].

Determining the optimal daily gonadotropin dose to maximize the oocyte yield in elective egg freezing cycles.

OBJECTIVE: Ovarian stimulation (OS) with high daily gonadotropin doses are commonly offered to patients attempting social/elective egg freezing. However, the optimal daily gonadotropin dose that would allow a higher oocyte yield in the successive IVF cycle attempt was not settled and should be determined. PATIENTS AND METHODS: Data from all women admitted to our IVF unit for social/EEF, who underwent two consecutive IVF cycle attempts, with only those who used in the first attempt a starting daily gonadotropin dose of 300IU were analyzed. Patients characteristics and OS variables were used in an attempt to build a logistic model, helping in determining the daily gonadotropin dose that should be offered to patient during their second EEF attempt, aiming to further increase their oocyte yield. RESULTS: Three hundred and thirteen consecutive women undergoing two successive IVF cycle attempts were evaluated. Using logistic regression model, two equations were developed using individual patient-level data that determine the daily gonadotropin dose needed aiming to increase the oocyte yield in the successive cycle. (a): X=-0.514 + 2.87*A1 + 1.733*A2-0.194* (E2/1000) and (b): P = EXP(X) / [1 + EXP(X)]. CONCLUSIONS: Using the aforementioned equations succeeded in determining the daily gonadotropin dose that might result in increasing oocyte yield, with an AUC of 0.85. Any additional oocyte retrieved to these EEF patients might get them closer to fulfil their desire to parenthood.

Quality evaluation of highly purified human menopausal gonadotropin preparations by means of gel electrophoresis and mass spectrometry.

Human gonadotropins are glycoprotein hormones with a highly complex structure, which demands the application of sophisticated analytical methodologies to assess their quality. The principal objective of this study was a comparative evaluation of gel electrophoretic techniques and mass spectrometry-based methods for the quality study of the two urinary-derived, highly purified, human menopausal gonadotropin preparations, Menopur 75/75 I. U. and Meriofert 75 I. U. Molecular mass (Mr), isoelectric point (pI), and isoform pattern of studied compounds were estimated via SDS-PAGE and 2D gel electrophoresis, whereas matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used for the downstream characterization of peptides obtained after in-gel tryptic digestion of selected protein spots. Additionally, for the estimation of the glycosylation pattern of these biologics, the enzymatic release of oligosaccharides was performed, and the isoform pattern was studied. Gel electrophoresis showed a typical electrophoretic behaviour for protein biotherapeutics medicines consisting of extremely complex spot patterns migrating at different masses and pIs. MS analysis proved to be a powerful tool for the identification and detailed characterization of the gonadotropins and the relevant peptides were identified with high sequence coverages. The results of this study are not only useful for the quality assessment of this class of complex biopharmaceuticals but may also serve as a supporting platform for further development of biopharmaceuticals based on modulation of the glycosylation pattern to enhance efficacy or reduce side effects.

Combined gonadotropin therapy to replace mini-puberty in male infants with congenital hypogonadotropic hypogonadism.

Infants born with severe central disorders of the hypothalamic-pituitary-gonadal axis leading to gonadotropin deficiency not only lack pubertal development in adolescence, but also lack infantile mini-puberty. This period of mini-puberty, where infants have gonadotropin and sex steroid concentrations up into the adult range, is vital for future reproductive capacity, particularly in boys. At present, there is no consensus on the diagnosis or management of infants with gonadotropin deficiency due to congenital hypogonadotropic hypogonadism or multiple pituitary hormone deficiency. Case series suggest that gonadotropin treatment in male infants with absent mini-puberty is effective in promoting both testicular descent in those with undescended testes and also facilitating increased penile size. Moreover, replacement with follicle-stimulating hormone increases the testicular Sertoli cell population, measurable as an increase in testicular volume and inhibin B, thus hypothetically increasing the capacity for spermatogenesis in adult life for these patients. However, long-term follow-up data is limited for both outcomes pertaining to fertility and nonreproductive sequelae, including neurodevelopment and psychological well-being. The use of international registries for patients with gonadotropin deficiency is a key element in the collection of high-quality, geographically widespread data to inform best-practice management from birth to adulthood.

Effect of hormonal treatment on artificial propagation, spawning performance and embryonic development of striped snakehead Channa striata (Bloch, 1793).

Present study describes the spawning induction of striped Snakehead, Channa striata using carp pituitary extract (CPE) and LH-RH agonist i.e. Buserelin (Glp-His-Trp-Ser-Tyr-Ser-tBu-Leu-Arg-Pro-NHEt). Total four treatments were designed under both hormones trail and treated as control group, T1, T2, and T3 with three replications of each treatment. While breeders under all hormone treatments showed spawning performances, no spawning performance was observed in control group. Latency time after hormonal treatment was lowest (20-24 hrs) in case of CPE than Buserelin (25-30 hrs). Regarding to CPE, spawning, fertilization and hatching rate were higher with the increasing doses of CPE in different treatments. The highest mean ± Standard deviation spawning, fertilization and hatching rate were 85.60±8.58 %, 79.38±4.89 % and 64.33±6.60 % respectively in T3 where dose of CPE was 80 mg kg-1. Similarly, in case of Buserelin hormone highest spawning rate was found in T3 (80.61±5.59) where dose of Buserelin was 0.80 µg kg-1 body weight. Fertilization rate was on the level 48.57±5.99, 70.62±5.33 and 90.32±4.79 respectively for T1, T2, and T3.Whilst, hatching rate was found 20.81±4.91, 37.11±4.50 and 61.33±6.61 in T1, T2, and T3 treatments respectively. However, T3 exhibited best performance regarding spawning, fertilization and hatching rate which were significantly higher than other two treatments.The current study revealed that spawning induction using carp pituitary extract and Buserelin is effective and might be useful for artificial breeding of Channa striata. Regarding to dose application i.e. 80 mg kg-1 of CPE and 0.80 µg kg-1 of Buserelin may be successfully applied to ovulation stimulation of Channa striata.

Comparison of stimulation protocols for dose determination of gonadotropins: A systematic review and Bayesian network meta-analysis based on randomized controlled trials.

BACKGROUND: To date, evidence regarding the effectiveness and safety of individualized controlled ovarian stimulation (COS) compared with standard dose COS has been inadequate. OBJECTIVES: To evaluate the updated evidence from published randomized controlled trials (RCTs) about the efficacy and safety of individualized COS with different ovarian reserve test biomarkers or clinical experience versus standard dose COS. SEARCH STRATEGY: Terms and descriptors related to COS, individualized or standard, and RCT were combined to search, and only English language studies were included. Conference abstracts and comments were excluded. SELECTION CRITERIA: RCTs with comparison between different individualized COS strategies and standard starting dose strategy were included. DATA COLLECTION AND ANALYSIS: Two reviews independently assessed the eligibility of retrieved citations in a predefined standardized manner. Relative risk (RRs) and the weighted mean difference (WMD) with 95% confidence intervals (CIs) were pooled using a random-effects model on R software version 4.2.2. MAIN RESULTS: Compared with the standard dose COS strategy in pairwise meta-analysis, the individualized COS strategy was associated with a notable lower risk of ovarian hyperstimulation syndrome (OHSS; 174/2384 [7.30%] vs 114/2412 [4.73%], RR 0.66, 95% CI: 0.47-0.93, I2 = 46%), a significantly lower risk of hyperresponse to stimulation (hyperresponse; 476/2402 [19.82%] vs 331/2437 [13.58%], RR 0.71, 95% CI: 0.57-0.90, I2 = 61%), and a slightly longer ovarian stimulation days (duration of stimulation; WMD 0.20, 95% CI: 0.01-0.40, I2 = 66%). Bayesian network meta-analysis also found that biomarker-tailored strategy had a significantly lower risk of OHSS than standard dose strategy (OHSS; RR 0.63, 95% CI: 0.41-0.97, I2 = 47.5%). CONCLUSION: Compared with standard dose COS strategy, individualized COS strategy could significantly reduce the risks of OHSS and hyperresponse to stimulation, but the duration of stimulation was slightly longer. TRIAL REGISTRATION: PROSPERO: CRD42023358439.

Oocyte retrieval in social fertility preservation: challenging traditional beliefs on gonadotropin dosing and follicular size.

OBJECTIVES: To investigate treatment approaches for fertility preservation patients, with a focus on timing of oocyte retrieval, and to determine whether their characteristics differ from those of other IVF patients. Additionally, to evaluate the significance of follicle size on triggering day in the context of fertility preservation. METHODS: This retrospective cohort study was conducted in a tertiary, university-affiliated medical center. It compared 140 matched patients undergoing social fertility preservation to 140 patients undergoing IVF treatment due to male factor infertility. RESULTS: Patients undergoing fertility preservation received a higher initial gonadotropin dose and had more oocytes retrieved than the control group. Within the fertility preservation cohort, a negative correlation was observed between the rate of large follicles and the number of retrieved oocytes. While there was no significant association between rate of large follicles and oocyte maturation rate in the entire group, age-stratified analysis revealed a negative relationship. Analysis revealed that although traditional treatment determinants such as follicular size and gonadotropin dosing were considered, peak estradiol levels were consistently identified as significant predictors of treatment outcomes. CONCLUSIONS: Physicians may modify treatments for fertility preservation, emphasizing a higher gonadotropin dosage to maximize oocyte retrieval. Elevated estradiol levels can serve as a real-time predictive marker for the number of mature oocytes. While treatment strategies can influence outcomes, intrinsic patient factors, particularly baseline ovarian function, remain crucial. These results challenge beliefs regarding the importance of larger follicles and suggest the need for a tailored approach, considering patient age and specific fertility preservation objectives.

GnRH-driven FTO-mediated RNA m6A modification promotes gonadotropin synthesis and secretion.

BACKGROUND: Gonadotropin precisely controls mammalian reproductive activities. Systematic analysis of the mechanisms by which epigenetic modifications regulate the synthesis and secretion of gonadotropin can be useful for more precise regulation of the animal reproductive process. Previous studies have identified many differential m6A modifications in the GnRH-treated adenohypophysis. However, the molecular mechanism by which m6A modification regulates gonadotropin synthesis and secretion remains unclear. RESULTS: Herein, it was found that GnRH can promote gonadotropin synthesis and secretion by promoting the expression of FTO. Highly expressed FTO binds to Foxp2 mRNA in the nucleus, exerting a demethylation function and reducing m6A modification. After Foxp2 mRNA exits the nucleus, the lack of m6A modification prevents YTHDF3 from binding to it, resulting in increased stability and upregulation of Foxp2 mRNA expression, which activates the cAMP/PKA signaling pathway to promote gonadotropin synthesis and secretion. CONCLUSIONS: Overall, the study reveals the molecular mechanism of GnRH regulating the gonadotropin synthesis and secretion through FTO-mediated m6A modification. The results of this study allow systematic interpretation of the regulatory mechanism of gonadotropin synthesis and secretion in the pituitary at the epigenetic level and provide a theoretical basis for the application of reproductive hormones in the regulation of animal artificial reproduction.