Early GnRH-agonist therapy does not negatively impact the endometrial repair process or live birth rate.

Study objective: To investigate whether different timings of GnRH-a downregulation affected assisted reproductive outcomes in infertile women with moderate-to-severe intrauterine adhesions (IUAs) accompanied by adenomyosis. Design: A retrospective case series. Setting: An assisted reproductive technology center. Patients: The study reviewed 123 infertile women with moderate-to-severe IUAs accompanied by adenomyosis undergoing their first frozen-thawed embryo transfer (FET) cycles between January 2019 and December 2021. Measurements and main results: The majority of patients had moderate IUA (n=116, 94.31%). The average Basal uterine volume was 73.58 ± 36.50 cm3. The mean interval from operation to the first downregulation was 21.07 ± 18.02 days (range, 1-79 days). The mean duration of hormone replacement therapy (HRT) was 16.93 ± 6.29 days. The average endometrial thickness on the day before transfer was 10.83 ± 1.75 mm. A total of 70 women achieved clinical pregnancy (56.91%). Perinatal outcomes included live birth (n=47, 67.14%), early miscarriage (n=18, 25.71%), and late miscarriage (n=5, 7.14%). The time interval between uterine operation and the first downregulation was not a significant variable affecting live birth. Maternal age was the only risk factor associated with live birth (OR:0.89; 95% CI: 0.79-0.99, P=0.041). Conclusions: The earlier initiation of GnRH-a to suppress adenomyosis prior to endometrial preparation for frozen embryo transfer did not negatively impact repair of the endometrium after resection.

Raphe glucose-sensing serotonergic neurons stimulate KNDy neurons to enhance LH pulses via 5HT2CR: rat and goat studies.

Dysfunction of central serotonergic neurons is known to cause depressive disorders in humans, who often show reproductive and/or glucose metabolism disorders. This study examined whether dorsal raphe (DR) serotonergic neurons sense high glucose availability to upregulate reproductive function via activating hypothalamic arcuate (ARC) kisspeptin neurons (= KNDy neurons), a dominant stimulator of gonadotropin-releasing hormone (GnRH)/gonadotropin pulses, using female rats and goats. RNA-seq and histological analysis revealed that stimulatory serotonin-2C receptor (5HT2CR) was mainly expressed in the KNDy neurons in female rats. The serotonergic reuptake inhibitor administration into the mediobasal hypothalamus (MBH), including the ARC, significantly blocked glucoprivic suppression of luteinizing hormone (LH) pulses and hyperglycemia induced by intravenous 2-deoxy-D-glucose (2DG) administration in female rats. A local infusion of glucose into the DR significantly increased in vivo serotonin release in the MBH and partly restored LH pulses and hyperglycemia in the 2DG-treated female rats. Furthermore, central administration of serotonin or a 5HT2CR agonist immediately evoked GnRH pulse generator activity, and central 5HT2CR antagonism blocked the serotonin-induced facilitation of GnRH pulse generator activity in ovariectomized goats. These results suggest that DR serotonergic neurons sense high glucose availability to reduce gluconeogenesis and upregulate reproductive function by activating GnRH/LH pulse generator activity in mammals.

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.

Effectiveness of leuprolide acetate administered monthly compared to three-monthly in the treatment of central precocious puberty: evaluation at the end of treatment.

Introduction: Gonadotropin-releasing hormone (GnRH) analogs are the standard treatment for central precocious puberty (CPP). Although there are numerous varieties of GnRH agonists, the effectiveness of 1-monthly compared with 3-monthly Leuprolide acetate is still restricted. The objective of this study was to evaluate the outcomes of CPP treatment with Leuprolide acetate at a 1-monthly dosage of 3.75 mg, in comparison to a dosage of 11.25 mg administered every 3 months. Method: This retrospective cohort study involved 143 girls diagnosed with CPP with 72 of them receiving the monthly treatment regimen and 71 receiving the 3-monthly treatment regimen. Anthropometric measurements were compared at the start and end of the therapy. The rates and level of LH suppression were assessed six months after therapy. Results: The regimen administered every 3 months showed more significant suppression of LH. The 3-monthly group showed lower actual height and degree of bone age advancement at the end of therapy. However, the predicted adult height (PAH) remained comparable in both groups. Conclusion: The 3-monthly treatment showed greater hormonal and growth suppression effects, but there was no significant difference in PAH between the two groups.

Pulsatile gonadotropin releasing hormone therapy for spermatogenesis in congenital hypogonadotropic hypogonadism patients who had poor response to combined gonadotropin therapy.

Objective: Both pulsatile gonadotropin-releasing hormone (GnRH) and combined gonadotropin therapy are effective to induce spermatogenesis in men with congenital hypogonadotropic hypogonadism (CHH). This study aimed to evaluate the effect of pulsatile GnRH therapy on spermatogenesis in male patients with CHH who had poor response to combined gonadotropin therapy. Materials and methods: Patients who had poor response to combined gonadotropin therapy ≥ 6 months were recruited and shifted to pulsatile GnRH therapy. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, testosterone, and testicular volume were used for data analysis. Results: A total of 28 CHH patients who had poor response to combined gonadotropin (HCG/HMG) therapy for 12.5 (6.0, 17.75) months were recruited and switched to pulsatile GnRH therapy for 10.0 (7.25, 16.0) months. Sperm was detected in 17/28 patients (60.7%). The mean time for the appearance of sperm in semen was 12.0 (7.5, 17.5) months. Compared to those who could not achieve spermatogenesis during pulsatile GnRH therapy, the successful group had a higher level of LH60min (4.32 vs. 1.10 IU/L, P = 0.043) and FSH60min (4.28 vs. 1.90 IU/L, P = 0.021). Testicular size increased during pulsatile GnRH therapy, compared to previous HCG/ HMG therapy (P < 0.05). Conclusion: For CHH patients with prior poor response to one year of HCG/ HMG therapy, switching to pulsatile GnRH therapy may induce spermatogenesis.

Intracerebroventricular PROK2 infusion could increase the secretion of male reproductive hormones by stimulating the HPG axis.

BACKGROUND: Prokineticin 2 (PROK2), an important neuropeptide that plays a key role in the neuronal migration of gonadotropin-releasing hormone (GnRH) in the hypothalamus, is known to have regulatory effects on the gonads. In the present study, the impact of intracerebroventricular (icv) PROK2 infusion on hypothalamic-pituitary-gonadal axis (HPG) hormones, testicular tissues, and sperm concentration was investigated. METHODS AND RESULTS: Rats were randomly divided into four groups: control, sham, PROK2 1.5 and PROK2 4.5. Rats in the PROK2 1.5 and PROK2 4.5 groups were administered 1.5 nmol and 4.5 nmol PROK2 intracerebroventricularly for 7 days via an osmotic mini pump (1 µl/h), respectively. Rat blood serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone hormone levels were determined with the ELISA method in the blood samples after 7 days of infusion. GnRH mRNA expression was determined with the RT-PCR in hypothalamus tissues. analyze Sperm concentration was determined, and testicular tissue was examined histologically with the hematoxylin-eosin staining method. It was observed that GnRH mRNA expression increased in both PROK2 infusion groups. Serum FSH, LH and testosterone hormone levels also increased in these groups. Although sperm concentration increased in PROK2 infusion groups when compared to the control and sham, the differences were not statistically significant. Testicular tissue seminiferous epithelial thickness was higher in the PROK2 groups when compared to the control and sham groups. CONCLUSION: The present study findings demonstrated that icv PROK2 infusion induced the HPG axis. It could be suggested that PROK2 could be a potential agent in the treatment of male infertility induced by endocrinological defects.

GnRH agonist trigger in poor prognosis patients undergoing a multicycle approach through DuoStim or consecutive stimulations: a SWOT analysis.

PURPOSE OF REVIEW: Identify the most recent and significant evidence regarding the ovulation trigger within the framework of a multicycle approach through DuoStim, providing valuable insights for improving treatment strategies in patients with a poor prognosis. RECENT FINDINGS: The trigger method plays a pivotal role in optimizing in-vitro fertilization (IVF) stimulation, influencing oocyte retrieval and maturation rates, as well as follicle recruitment in consecutive ovarian stimulations such as double stimulation. Decision-making involves multiple factors and, while guidelines exist for conventional stimulation, specific recommendations for the multicycle approach are not well established. SUMMARY: The different methods for inducing oocyte maturation underscore the need for personalization of IVF protocols. The GnRH agonist trigger induces rapid luteolysis and establishes favorable hormonal conditions that do not adversely affect the recruitment of consecutive follicular waves in the context of DuoStim. It serves as a valid alternative to hCG in freeze-all cycles. This strategy might enhance the safety and flexibility of ovarian stimulations with no impact on oocyte competence and IVF efficacy.

Impact of presynchronization and Ovsynch on early postpartum ovarian activity and fertility of dairy cows in Libya.

Background: Reproductive efficiency affects dairy cow profitability. Ovarian function in postpartum (P.P.) has been better understood using ultrasound and hormonal assays. Optimizing ovulation synchronization and carefully timing artificial insemination (TAI) can greatly enhance reproductive rates in dairy cows. Aim: This experiment was designed to investigate the reproductive performance and ovarian activity in early postpartum lactating dairy cows using the Presynch-PGF2α, Ovsynch protocol, and TAI. Methods: Randomly the cows were assigned to a control group and a treatment group, based on the chronological order of their calving date. On day 14 P.P., both groups received two cloprostenol treatments, 14 days apart. Ultrasonographic inspections were conducted on day 14 to check ovarian activity and uterine contents. On day 11, after presynchronization, cows in the treatment group were given 100 µg IM. of cystorelin, followed by a luteolytic dose of 500 µg IM., cloprostenol on day 7, and a second dose of cystorelin on day 8 (36 hours later). After the second cystorelin injection by 16-20 hours, cows were inseminated, while the control group had all cows displaying spontaneous estrus between day 0 and day 28 were artificially inseminated. Results: Ovarian activity began to improve at 82.61% on day 19 P.P., with complete recovery between days 24 and 27 P.P. The second cloprostenol injection approached, causing follicular size to reach 8.41 ± 1.04 mm. After the second injection, ovarian activity switched from follicular to luteal, with corpus luteum rates of 23.91% and 26.1%. The presynchronized PGF2α regimen significantly enhanced ovarian activity from days 19-35 P.P. Ovulation and pregnancy rates in the Ovsynch group were 54.2% and 41.7% at the first timed artificial insemination (TAI), compared to 54.5% and 31.8% in the control group. There was no significant impact between them; it was just high in the presynchronized Ovsynch group. However, the P.P. period was minimized to 47-49 days till the first AI reached a 41.7% pregnancy rate and 20.8% at the second AI, for an overall 62.5%. Conclusion: The current study concludes that presynchronization during preservice in clinically normal P.P. dairy cows reduces P.P. duration, increases ovarian activity performance, and reduces ovarian dysfunctions from day 19 to day 35 P.P., as well as improves the pregnancy rate.

The corrective role of superparamagnetic iron oxide nanoparticles for the genes controlling hypothalamus-pituitary-testis-axis in male obesity-associated secondary hypogonadism.

Background: Obesity is one of the most prevalent and perilous health affairs. Male obesity-associated secondary hypogonadism (MOSH) is one of many of its complexities, which is mounting in parallel with the aggravation of obesity. Magnetic nanoparticles seem to be an advanced favorable trend in multiple biomedical fields. Aim: In this study, we explore the therapeutic effects of superparamagnetic iron oxide nanoparticles (SPIONs) coated with carboxymethyl cellulose (CMC) on an obese male rat model with MOSH syndrome, comparing their impacts with a well-known anti-obesity medication (Orlistat). Methods: 42 male albino rats split into 7 equal groups: 1-negative control: nonobese, untreated; 35 rats fed the high fat-high fructose (HFHF) diet for a period of 12 weeks. Obese rats splitted into 6 equal groups; 2-positive control: obese untreated; 3-obese given Orlistat (30 mg/kg); 4-obese given CMC-SPIONs (25 mgFe/kg); 5-obese given CMC-SPIONs (50 mgFe/kg); 6-obese given CMC-SPIONs(25 mgFe/kg) + Orlistat (30 mg/kg), 7-obese given CMC-SPIONs (50 mgFe/kg) + Orlistat (30 mg/kg); all treatments given orally for 4 weeks. During sacrifice, blood serum and sectioned hypothalamic, pituitary, testicular, and adipose tissues were collected for biochemical and biomolecular assessments. Results: The HFHF diet for 12 weeks resulted in a significant upsurge in body weight, body mass index, serum fasting glucose, insulin resistance, TAG, total cholesterol, and LDL-c; HDL-c was dropped. Serum FSH, LH, and testosterone values declined. A significant disorder in expression levels of genes regulating the hypothalamic-pituitary-testicular-axis pathway. Hypothalamic GnRH, Kisspeptin-1, Kisspeptin-r1, and Adipo-R1 values declined. GnIH and Leptin-R1 values raised up. Pituitary GnRH-R values declined. Testicular tissue STAR, HSD17B3, and CYP19A1 values declined. Adipose tissue adiponectin declined, while leptin raised up. CMC-SPIONs 25-50 mg could modulate the deranged biochemical parameters and correct the deranged expression levels of all previous genes. Co-treatments revealed highly synergistic effects on all parameters. Overall, CMC-SPIONs have significant efficiency whether alone or with Orlisat in limiting obesity and consequence subfertility. Conclusion: CMC-SPIONs act as an incoming promising contender for obesity and MOSH disorders management, and need more studies on their mechanisms.

The role of QRFP43 in the secretory activity of the gonadotrophic axis in female sheep.

In mammals reproduction is regulated by many factors, among others by the peptides belonging to the RFamide peptide family. However, the knowledge concerning on the impact of recently identified member of this family (QRFP43) on the modulation of the gonadotrophic axis activity is still not fully understood and current research results are ambiguous. In the present study we tested the in vivo effect of QRFP43 on the secretory activity of the gonadotrophic axis at the hypothalamic-pituitary level in Polish Merino sheep. The animals (n = 48) were randomly divided into three experimental groups: controls receiving an icv infusion of Ringer-Locke solution, group receiving icv infusion of QRFP43 at 10 µg per day and 50 µg per day. All sheep received four 50 min icv infusions at 30 min intervals, on each of three consecutive days. Hypothalamic and pituitaries were collected and secured for further immunohistochemical and molecular biological analysis. In addition, during the experiment a blood samples have been collected for subsequent RIA determinations. QRFP43 was found to downregulate Kiss mRNA expression in the MBH and reduce the level of IR material in ME. This resulted in a reduction of GnRH IR material in the ME. QRFP43 increased plasma FSH levels while decreasing LH levels. Our findings indicate that QRFP43 inhibits the activity of the gonadotropic axis in the ovine at the level of the hypothalamus and may represent another neuromodulator of reproductive processes in animals.

Cytotoxic activity and cell specificity of a novel LHRH peptide drug conjugate, D-Cys6-LHRH vedotin, against ovarian cancer cell lines.

Ovarian cancer is the most deadly female gynaecological malignancy in developed countries and new treatments are urgently needed. The luteinising hormone releasing hormone (LHRH) peptide drug conjugate Zoptarelin doxorubicin is one such potential new drug modality that entered clinical trials for treating LHRH receptor-positive gynaecological cancers. However, development stopped after disappointing Phase 3 results in 2017. We believe the lack of efficacy was due to linker instability and payload potency. In this work, we replaced its linker-toxin with vedotin (MC-VC-PABC-MMAE), yielding the novel peptide drug conjugate D-Cys6-LHRH vedotin. A GI50 and cell specificity comparison against cancerous and non-cancerous ovarian cell lines showed significantly superior bioactivity and selectivity over Zoptarelin doxorubicin (GI50 4 vs. 453 nM) and other chemotherapeutic drugs used for treating ovarian cancers. Our results suggest D-Cys6-LHRH vedotin can potentially be used as a treatment for ovarian cancer.

Reproductive outcomes of dual trigger therapy with GnRH agonist and hCG versus hCG trigger in women with diminished ovarian reserve: a retrospective study.

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 ß = 0.538 (0.221-0.855)], fertilized oocytes [2.55 vs. 1.94, adjusted ß = 0.277 (0.031-0.523)] and transferable embryos [1.22 vs. 0.95, adjusted ß = 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.

[Recent advances in the genetic etiology of central precocious puberty]. / é—ä¼ ç¼ºé™·è‡´ä¸­æž¢æ€§æ€§æ—©ç†Ÿç— å› å­¦çš„ç ”ç©¶æ–°è¿›å±•.

Central precocious puberty (CPP) is a developmental disorder caused by early activation of the hypothalamic-pituitary-gonadal axis. The incidence of CPP is rapidly increasing, but the underlying mechanisms are not fully understood. Previous studies have shown that gain-of-function mutations in the KISS1R and KISS1 genes and loss-of-function mutations in the MKRN3, LIN28, and DLK1 genes may lead to early initiation of pubertal development. Recent research has also revealed the significant role of epigenetic factors such as DNA methylation and microRNAs in the regulation of gonadotropin-releasing hormone neurons, as well as the modulating effect of gene networks involving multiple variant genes on pubertal initiation. This review summarizes the genetic etiology and pathogenic mechanisms underlying CPP.

α-Klotho levels in girls with central precocious puberty: potential as a diagnostic and monitoring marker.

Background: Recent studies suggest a link between the Klotho protein, sex hormones, and insulin-like growth factor-1 (IGF-1), indicating that α-Klotho levels may rise during puberty, including in central precocious puberty (CPP) cases. This study aimed to explore α-Klotho levels in girls with CPP to assess its potential as a diagnostic and monitoring tool for this condition. Methods: In total, 139 girls, comprising 82 patients diagnosed with CPP and 57 healthy prepubertal controls, were enrolled in this study. From March 2020 to May 2023, we assessed both α-Klotho levels and clinical parameters. α-Klotho concentrations were measured using an α-Klotho ELISA kit. For the girls with CPP, we additionally analyzed samples taken 6 months after GnRH agonist treatment. Results: α-Klotho levels were higher in the CPP group compared with the control (CPP group: 2529 ± 999 ng/mL; control group: 1802 ± 675 pg/mL) (P < 0.001), and its level modest decreased after 6 months of GnRH agonist treatment (2147± 789 pg/mL) (P < 0.001). The association between α-Klotho and IGF-1 SDS, follicular stimulating hormone and baseline luteinizing hormone was assessed by partial correlation after adjusting for age, BMI SDS (r= 0.416, p= <0.001; r= 0.261, p= 0.005; r= 0.278, p= 0.002), respectively. Receiver operating characteristic curve analysis identified an α-Klotho cut-off differentiating CPP from controls, with a cut-off of 1914 pg/mL distinguishing girls with CPP from controls with a sensitivity of 69.5% and specificity of 70.2%; the area under the curve was 0.723. Conclusion: The findings of our study are the first step towards deciphering the role of α-Klotho in puberty induction. With additional data and further research, α-Klotho could potentially be utilized as a significant diagnostic and monitoring tool for CPP.

The Involvement of the microRNAs miR-466c and miR-340 in the Palmitate-Mediated Dysregulation of Gonadotropin-Releasing Hormone Gene Expression.

Diets high in saturated fatty acids are associated with obesity and infertility. Palmitate, the most prevalent circulating saturated fatty acid, is sensed by hypothalamic neurons, contributing to homeostatic dysregulation. Notably, palmitate elevates the mRNA levels of gonadotropin-releasing hormone (Gnrh) mRNA and its activating transcription factor, GATA binding protein 4 (Gata4). GATA4 is essential for basal Gnrh expression by binding to its enhancer region, with Oct-1 (Oct1) and CEBP-ß (Cebpb) playing regulatory roles. The pre- and post-transcriptional control of Gnrh by palmitate have not been investigated. Given the ability of palmitate to alter microRNAs (miRNAs), we hypothesized that palmitate-mediated dysregulation of Gnrh mRNA involves specific miRNAs. In the mHypoA-GnRH/GFP neurons, palmitate significantly downregulated six miRNAs (miR-125a, miR-181b, miR-340, miR-351, miR-466c and miR-503), and the repression was attenuated by co-treatment with 100 µM of oleate. Subsequent mimic transfections revealed that miR-466c significantly downregulates Gnrh, Gata4, and Chop mRNA and increases Per2, whereas miR-340 upregulates Gnrh, Gata4, Oct1, Cebpb, and Per2 mRNA. Our findings suggest that palmitate may indirectly regulate Gnrh at both the pre- and post-transcriptional levels by altering miR-466c and miR-340, which in turn regulate transcription factor expression levels. In summary, palmitate-mediated dysregulation of Gnrh and, consequently, reproductive function involves parallel transcriptional mechanisms.

Optimizing nicardipine dosage for effective control of pituitrin-induced hypertension in laparoscopic myomectomy undergoing total intravenous anesthesia.

BACKGROUND: This study aimed to determine the median effective dose (ED50) and 95% effective dose (ED95) of nicardipine for treating pituitrin-induced hypertension during laparoscopic myomectomy, providing guidance for the management of intraoperative blood pressure in such patients. METHODS: Among the initial 40 participants assessed, 24 underwent elective laparoscopic myomectomy. A sequential up-and-down method was employed to ascertain the ED50 of nicardipine based on its antihypertensive efficacy. Nicardipine was initially administered at 6 µg/kg following the diagnosis of pituitrin-induced hypertension in the first patient. Dosing adjustments were made to achieve the desired antihypertensive effect, restoring systolic blood pressure and heart rate to within ± 20% of baseline within 120 s. The dosing increment or reduction was set at 0.5 µg/kg for effective or ineffective responses, respectively. The ED50 and ED95 of nicardipine were calculated using Probit regression by Maximum Likelihood Estimation (MLE) to establish dose-response curves and confidence intervals. RESULTS: 24 patients were included for analysis finally. The ED50 and ED95 of nicardipine for blood pressure control after pituitrin injection were determined. The study found that the ED50 of nicardipine for treating pituitrin-induced hypertension was 4.839 µg/kg (95% CI: 4.569-5.099 µg/kg), and the ED95 was estimated at 5.308 µg/kg (95% CI: 5.065-6.496 µg/kg). Nicardipine effectively mitigated the hypertensive response caused by pituitrin without inducing significant tachycardia or hypotension. CONCLUSIONS: Nicardipine effectively controlled blood pressure after pituitrin injection during laparoscopic myomectomy, with ED50 and ED95 values established. This research highlights the potential utility of nicardipine in addressing hypertensive responses induced by pituitrin, particularly in clinical settings where pituitrin is routinely administered.

Mechanism of elevated LH/FSH ratio in lean PCOS revisited: a path analysis.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5-20% of reproductive-age women. However, the treatment of PCOS is mainly based on symptoms and not on its pathophysiology. Neuroendocrine disturbance, as shown by an elevated LH/FSH ratio in PCOS patients, was thought to be the central mechanism of the syndrome, especially in lean PCOS. LH and FSH secretion are influenced by GnRH pulsatility of GnRH neurons in the hypothalamus. Kisspeptin is the main regulator of GnRH secretion, whereas neurokinin B (NKB) and dynorphin regulate kisspeptin secretion in KNDy neurons. This study aims to deepen the understanding of the neuroendocrine disorder in lean PCOS patients and its potential pathophysiology-based therapy. A cross-sectional study was performed at Dr. Cipto Mangunkusumo Kencana Hospital and the IMERI UI HRIFP cluster with 110 lean PCOS patients as subjects. LH, FSH, LH/FSH ratio, kisspeptin, NKB, dynorphin, leptin, adiponectin, AMH, fasting blood glucose, fasting insulin, HOMA-IR, testosterone, and SHBG were measured. Bivariate and path analyses were performed to determine the relationship between variables. There was a negative association between dynorphin and kisspeptin, while NKB levels were not associated with kisspeptin. There was no direct association between kisspeptin and the LH/FSH ratio; interestingly, dynorphin was positively associated with the LH/FSH ratio in both bivariate and pathway analyses. AMH was positively correlated with the LH/FSH ratio in both analyses. Path analysis showed an association between dynorphin and kisspeptin levels in lean PCOS, while NKB was not correlated with kisspeptin. Furthermore, there was a correlation between AMH and the LH/FSH ratio, but kisspeptin levels did not show a direct significant relationship with the LH/FSH ratio. HOMA-IR was negatively associated with adiponectin levels and positively associated with leptin and FAI levels. In conclusion, AMH positively correlates with FAI levels and is directly associated with the LH/FSH ratio, showing its important role in neuroendocrinology in lean PCOS. From the path analysis, AMH was also an intermediary variable between HOMA-IR and FAI with the LH/FSH ratio. Interestingly, this study found a direct positive correlation between dynorphin and the LH/FSH ratio, while no association between kisspeptin and the LH/FSH ratio was found. Further research is needed to investigate AMH and dynorphin as potential therapeutic targets in the management of lean PCOS patients.

How to pause fertility.

Prolactin suppresses the ovarian cycles of lactating mice by directly repressing the activity of a cell population known as kisspeptin neurons.

Systematic review and meta-analysis on the effect of adjuvant gonadotropin-releasing hormone agonist (GnRH-a) on pregnancy outcomes in women with endometriosis following conservative surgery.

BACKGROUND: Endometriosis frequently results in pain and infertility. While conservative surgery offers some relief, it often falls short of ensuring satisfactory pregnancy outcomes. Adjuvant GnRH-a is administered post-surgery to mitigate recurrence; however, its impact on pregnancy outcomes remains debated. This study endeavors to assess the efficacy of adjuvant GnRH-a in enhancing pregnancy outcomes post-conservative surgery in endometriosis patients. METHODS: Databases including PubMed, Embase, the Cochrane Library, Medline (Ovid), Web of Science, and Scopus were rigorously searched up to 02 August 2023, without linguistic constraints. Identified articles were screened using strict inclusion and exclusion criteria. Evaluated outcomes encompassed pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, multiple pregnancy rate, mean postoperative pregnancy interval, recurrence rate, and adverse reaction rate. The Cochrane risk of bias tool and the Jadad score evaluated the included studies' quality. Subgroup and sensitivity analysis were implemented to analyze the pooled results. A meta-analysis model expressed results as standardized mean difference (SMD) and Risk ratio (RR). RESULTS: A total of 17 studies about 2485 patients were assimilated. Meta-analysis revealed that post-surgery, the GnRH-a cohort experienced a marginally elevated pregnancy rate (RR = 1.20, 95% CI = 1.02-1.41; P = 0.03) and a reduced mean time to conceive (RR = -1.17, 95% CI = -1.70- -0.64; P < 0.0001). Contrarily, other evaluated outcomes did not exhibit notable statistical differences. CONCLUSIONS: Incorporating adjuvant GnRH-a following conservative surgery may be deemed beneficial for women with endometriosis, especially before Assisted Reproductive Technology (ART). Nonetheless, owing to pronounced heterogeneity, subsequent research is warranted to substantiate these potential advantages conclusively. REGISTRATION NUMBER: CRD42023448280.

Micronized natural progesterone (Seidigestan®) vs GnRH antagonists for preventing the LH surge during controlled ovarian stimulation (PRO_NAT study): study protocol of a randomized clinical trial.

Introduction: Progesterone-primed cycles effectively suppress the pituitary LH surge during ovarian stimulation in oocyte donors and in the infertile population. Particularly in oocyte donors, the use of synthetic progesterone (progestins) has been explored in prospective clinical trials, showing mixed results. This trial was designed to determine whether the use of micronized natural progesterone is as effective as the GnRH-antagonist protocol in terms of the number of mature oocytes (MII) retrieved in oocyte donation cycles as a primary outcome, and it also aims to explore the corresponding results in recipients as a secondary outcome. Methods: We propose a prospective, open-label, non-inferiority clinical trial to compare a novel approach for oocyte donors with a control group, which follows the standard ovarian stimulation protocol used in our institution. A total of 150 donors (75 in each group) will be recruited and randomized using a computer algorithm. After obtaining informed consent, participants will be randomly assigned to one of two ovarian stimulation protocols: either the standard GnRH antagonist or the oral micronized natural progesterone protocol. Both groups will receive recombinant gonadotropins tailored to their antral follicle count and prior donation experiences, if any. The primary outcome is the number of mature metaphase II (MII) oocytes. Secondary measures include treatment duration, pregnancy outcomes in recipients, as well as the economic cost per MII oocyte obtained in each treatment regimen. Analyses for the primary outcome will be conducted in both the intention-to-treat (ITT) and per-protocol (PP) populations. Each donor can participate only once during the recruitment period. The estimated duration of the study is six months for the primary outcome and 15 months for the secondary outcomes. Discussion: The outcomes of this trial have the potential to inform evidence-based adjustments in the management of ovarian stimulation protocols for oocyte donors. Clinical trial registration: ClinicalTrials.gov, identifier, NCT05954962.