Low Gonadotropin Research Articles

Does hCG-trigger in the mild stimulation protocol for endometrial preparation have any effect on pregnancy outcome in frozen-thawed embryo transfer?

BackgroundRecent literature has explored the role of human chorionic gonadotropin (hCG) triggering in frozen embryo transfer (FET) cycles with natural endometrial preparation. Despite this, the impact of hCG triggering on pregnancy outcomes following endometrial preparation with mild stimulation (mST) using Letrozole and Gonadotropins remains inadequately characterized. This study aimed to elucidate the effects of hCG-trigger on pregnancy outcomes in mST-FET cycles.MethodsIn the present retrospective cohort study, the pregnancy outcomes of 409 eligible patients who underwent FET cycles with endometrial preparation using a mild ovarian stimulation protocol by letrozole plus low dose gonadotropins at the Royan Institute between 2020 and 2022, were investigated. The study population were segregated into two distinct groups according to type of ovulation: the spontaneous ovulation group (n = 138) and the hCG-trigger group (n = 271). The pregnancy outcomes including implantation and clinical pregnancy rates (CPR) and live birth rates (LBR) were compared between two groups. The multivariable logistic regression was performed to detect the most significant variables related to the LBR in the mST-FET cycles.ResultsDemographic and baseline characteristics were comparable between groups. No significant difference was found in terms of implantation rate (0.65 ± 0.32 vs. 0.60 ± 0.30, P-value: 0.31), CPR (37% vs. 39.7%, P-value: 0.53), and LBR (35.5% vs. 37.3%, P-value: 0.74) in the spontaneous ovulation and hCG-trigger groups, respectively. The logistic regression analysis revealed that only the stage of the transferred embryo exhibited a significant relationship with LBR (blastocyst vs. cleavage: odds ratio (OR); 2.33, 95% confidence interval (CI):1.41–3.86, P-value = 0.001).ConclusionPregnancy outcomes in the mST-FET cycles, including implantation rate, CPR, and LBR are comparable in cycles with or without hCG triggering. Based on the findings from multivariate regression analysis, the sole significant predictive factor for the LBR was the transfer of blastocyst embryos. It is recommended that these results be examined and discussed in future prospective studies with a larger sample size, considering the lack of comparable research in this field.

Functional hypothalamic amenorrhoea and polycystic ovarian morphology: a narrative review about an intriguing association.

Functional hypothalamic amenorrhoea (FHA) is responsible for 20-35% of all cases of secondary amenorrhoea and, thus, is the second most common cause of secondary amenorrhoea after polycystic ovary syndrome (PCOS). A high number of patients with FHA reveal polycystic ovarian morphology (PCOM) on ultrasound. The combination of amenorrhoea and PCOM can lead to confusion. First, amenorrhoeic women with PCOM fulfil the revised Rotterdam criteria and, thus, can easily be misdiagnosed with PCOS. Moreover, it has been claimed that some women with FHA and concomitant PCOM differ from those without PCOM in terms of endocrine regulation and metabolic traits. The main focus of this article was on studies about FHA, which differentiated between patients with or without PCOM. The aim was to estimate the prevalence of PCOM and to look if it has an impact on pathophysiologic, diagnostic and therapeutic issues as well as on long-term consequences. Peer review original and review articles were selected from PubMed searches for this review. Searches were performed using the search terms 'polycystic AND functional hypothalamic amenorrhoea'. The reference lists of publications found were searched for relevant additional studies. The inclusion criteria for publications were: English language, patients' age ≥ 18 years, year of publication >1980, original studies, validated diagnosis of FHA, and validated diagnosis of PCOM using transvaginal ultrasound. The prevalence of PCOM in women with FHA varied from 41.9% to 46.7%, which is higher than in healthy non-PCOS controls. Hypothetically, the high prevalence might be due to a mixture of silent PCOM, as in the general population, and pre-existing PCOS. Several differences in metabolic and hormonal parameters were found between FHA-PCOM and FHA-non-PCOM patients. While oestrogen deficiency is common to both groups of patients, FHA-PCOM patients have a higher BMI, higher levels of anti-Müllerian hormone (AMH) and testosterone, a higher increase in LH in the course of a GnRH test, and lower sex hormone binding globulin (SHBG) levels than FHA-non-PCOM patients. The differential diagnosis between FHA-PCOM and PCOS, especially PCOS phenotype D (PCOM and oligo-/anovulation without hyperandrogenism), can be challenging. Several parameters have been suggested, which are helpful though not absolutely reliable. They include the typical causes for FHA (excessive exercise, energy deficit, and/or psychological stress), the serum levels of LH, testosterone, and SHBG, as well as the progestin challenge test. Whether FHA-PCOM has a different risk profile for long-term consequences concerning patients' metabolic and cardiovascular situation as well as their bone mass, is unclear. Concerning therapeutic aspects, there are only few data about FHA-PCOM compared to FHA-non-PCOM. To treat anovulation, the use of pulsatile GnRH treatment seems to be equally effective in both groups. Similar to FHA-non-PCOM patients, pulsatile GnRH therapy would be more efficient than exogenous gonadotropins in FHA-PCOM patients. Women with FHA-PCOM present a special sub-population of FHA patients. The diagnostic pitfall of FHA-PCOM should be emphasized in clinical guidelines about FHA and PCOS. The fact that almost half of the women with FHA have an ovarian follicle excess (i.e. PCOM) in face of low gonadotropin serum levels suggests that the intra-ovarian regulation of folliculogenesis is subject to individual variations, for unknown reasons, either genetic or epigenetic. Further studies are needed to investigate this hypothesis. Not applicable.

7945 Modelling the Factors Associated With Sexual and Mood Symptoms Within the First Year of Anabolic-Androgenic Steroid Cessation in Men

Abstract Disclosure: B. Grant: None. J. Kean: None. N.L. de Silva: None. O. Quinton: None. P. Bassett: None. J. McVeigh: None. A. Lingford-Hughes: None. S. Minhas: None. S. Bhasin: None. W.S. Dhillo: None. C.N. Jayasena: None. Context: Anabolic-androgenic steroids (AAS) are misused by millions of men worldwide to boost muscle size and physical performance. Recent studies have quantified the recovery of cardiovascular markers and testicular function following AAS cessation. Qualitative studies demonstrate that low mood, anxiety, suicidal ideation, and sexual dysfunction are also common following AAS cessation. However, no previous study has focused on quantifying symptoms within the first year of AAS cessation, nor investigated independently associated factors for these symptoms. Methods: Cross-sectional, observational study of 165 men in 3 groups; non-AAS (n=43); current-AAS (n=76); past-AAS ≤1 year (n=46). All participants completed questions on substance misuse, Beck Depression Inventory-II (BDI-II), International Index Erectile Function-15 (IIEF-15), General Anxiety Disorder (GAD-7), Quality-of-life (SF-36), and underwent fasting, morning blood sampling with urine toxicology. Results: As expected, current-AAS had lower gonadotropins and elevated serum total testosterone compared with past-AAS and non-AAS. Sexual function measured using IIEF-15 was impaired in men stopping AAS <1year (past-AAS) compared with current AAS users: (1) total: 69.0 [95% CI 64.0, 71.0], current-AAS; 61.0 [95% CI 56.0, 66.0], past-AAS; p=0.077; (2) erectile function: 30.0 [95% CI 29.0, 30.0], current-AAS; 28 [95% CI 21.0, 29.0], past-AAS; p=0.015; (3) sexual desire: 9.0 [95% CI 8.0, 10.0], current-AAS; 6.0 [95% CI 5.0, 8.0], past-AAS; p<0.0001; (4) overall satisfaction: 10.0 [95% CI 8.0, 10.0], current-AAS; 7.0 [95% CI 7.0, 8.0], past-AAS; p=0.002. Multivariable analysis suggested that psychiatric comorbidity (coefficient -6.5 [95% CI -13.0, -1.3] p=0.03) and AAS cessation (coefficient -10.8 [95% CI -5.6, -17.2]; p<0.001) were associated with lower total IIEF-15 scores.Depression scoring was worse in the past-AAS group compared with non-AAS: BDI-II 4.0 [95% CI 2.0, 7.0], non-AAS; 7.0 [95% CI 4.0, 16.0], past-AAS; p=0.0448. Multivariable analysis suggested that psychiatric comorbidity (OR 2.39 [95% CI 1.60, 3.57]; p<0.001) and lower serum total testosterone (OR 0.85 [95% CI 0.88, 0.94]; p=0.002) were associated with higher BDI-II scores.Energy and fatigue measured using SF-36 was lower in the past-AAS group compared with non-AAS: 70 [95% CI 65, 75], non-AAS; 60 [95% CI 50, 65], past-AAS; p=0.0498. No significant differences in anxiety scoring were detected. Discussion: We report the first, detailed quantification and modelling of symptoms in men currently misusing and stopped AAS within the previous year. These data reveal potentially treatable factors to improve symptoms of AAS cessation if proven within interventional studies. Presentation: 6/2/2024

7945 Modelling the Factors Associated With Sexual and Mood Symptoms Within the First Year of Anabolic-Androgenic Steroid Cessation in Men

Abstract Disclosure: B. Grant: None. J. Kean: None. N.L. de Silva: None. O. Quinton: None. P. Bassett: None. J. McVeigh: None. A. Lingford-Hughes: None. S. Minhas: None. S. Bhasin: None. W.S. Dhillo: None. C.N. Jayasena: None. Context: Anabolic-androgenic steroids (AAS) are misused by millions of men worldwide to boost muscle size and physical performance. Recent studies have quantified the recovery of cardiovascular markers and testicular function following AAS cessation. Qualitative studies demonstrate that low mood, anxiety, suicidal ideation, and sexual dysfunction are also common following AAS cessation. However, no previous study has focused on quantifying symptoms within the first year of AAS cessation, nor investigated independently associated factors for these symptoms. Methods: Cross-sectional, observational study of 165 men in 3 groups; non-AAS (n=43); current-AAS (n=76); past-AAS ≤1 year (n=46). All participants completed questions on substance misuse, Beck Depression Inventory-II (BDI-II), International Index Erectile Function-15 (IIEF-15), General Anxiety Disorder (GAD-7), Quality-of-life (SF-36), and underwent fasting, morning blood sampling with urine toxicology. Results: As expected, current-AAS had lower gonadotropins and elevated serum total testosterone compared with past-AAS and non-AAS. Sexual function measured using IIEF-15 was impaired in men stopping AAS <1year (past-AAS) compared with current AAS users: (1) total: 69.0 [95% CI 64.0, 71.0], current-AAS; 61.0 [95% CI 56.0, 66.0], past-AAS; p=0.077; (2) erectile function: 30.0 [95% CI 29.0, 30.0], current-AAS; 28 [95% CI 21.0, 29.0], past-AAS; p=0.015; (3) sexual desire: 9.0 [95% CI 8.0, 10.0], current-AAS; 6.0 [95% CI 5.0, 8.0], past-AAS; p<0.0001; (4) overall satisfaction: 10.0 [95% CI 8.0, 10.0], current-AAS; 7.0 [95% CI 7.0, 8.0], past-AAS; p=0.002. Multivariable analysis suggested that psychiatric comorbidity (coefficient -6.5 [95% CI -13.0, -1.3] p=0.03) and AAS cessation (coefficient -10.8 [95% CI -5.6, -17.2]; p<0.001) were associated with lower total IIEF-15 scores.Depression scoring was worse in the past-AAS group compared with non-AAS: BDI-II 4.0 [95% CI 2.0, 7.0], non-AAS; 7.0 [95% CI 4.0, 16.0], past-AAS; p=0.0448. Multivariable analysis suggested that psychiatric comorbidity (OR 2.39 [95% CI 1.60, 3.57]; p<0.001) and lower serum total testosterone (OR 0.85 [95% CI 0.88, 0.94]; p=0.002) were associated with higher BDI-II scores. Energy and fatigue measured using SF-36 was lower in the past-AAS group compared with non-AAS: 70 [95% CI 65, 75], non-AAS; 60 [95% CI 50, 65], past-AAS; p=0.0498. No significant differences in anxiety scoring were detected. Discussion: We report the first, detailed quantification and modelling of symptoms in men currently misusing and stopped AAS within the previous year. These data reveal potentially treatable factors to improve symptoms of AAS cessation if proven within interventional studies. Presentation: 6/2/2024

Puberty progression in girls with Turner syndrome after ovarian tissue cryopreservation.

To study the impact of unilateral ovariectomy for ovarian tissue cryopreservation (OTC) on the function of the remaining ovary in girls with Turner syndrome. A prospective cohort study as follow up of OTC in a research setting (The TurnerFertility trial, NCT03381300). University hospital in Nijmegen, the Netherlands. A total of 28 girls with Turner syndrome with follicles in their cryopreserved ovarian cortex tissue, aged 5-19 years. Of the 28 girls, 21 girls had a 45,X/46,XX mosaic karyotype, five had structural aberrations of the X-chromosome, one girl had a 45,X monosomy, and one girl had a 45,X/47,XXX karyotype. Girls were monitored annually after OTC for pubertal development and levels of anti-Müllerian hormone (AMH), Follicle Stimulating Hormone, Luteinizing Hormone, Estradiol, and Inhibin B. Thelarche, menarche and onset of premature ovarian insufficiency. The girls were monitored for a median duration of 3.4 years (maximum 6.6 years). The pubertal development of five prepubertal girls is still unknown, all were under the age of 10 and had low gonadotropins and estradiol levels at the end of the follow-up. Seven of the eight girls around pubertal age (10-12 years) experienced spontaneous thelarche, while one received medication to induce puberty. Eleven of the fourteen girls between the age of 14-17 years experienced spontaneous menarche, three other girls with thelarche still had ongoing puberty at the end of follow-up with normal gonadotropins and AMH levels above the detection limit. Around six to twelve months after OTC, a decline in AMH concentration was observed in 57% of girls (16/28 girls), followed by an increase in AMH concentration in the following years. Six of the total 28 girls started hormone replacement therapy due to symptoms of premature ovarian insufficiency, and all had AMH levels below 0.50 μg/L before OTC. Pubertal development progressed after unilateral ovariectomy for OTC in most girls with Turner syndrome. Hormone replacement therapy was required within a few years for girls with unfavorable parameters before OTC, such as AMH below 0.50 μg/L. Decisions regarding OTC should be personalized, considering the girl's preferences and specific characteristics.

Correlation of Recombinant FSH Doses with Follicular and Serum Level Resolvin E1 in Polycystic Ovarian Syndrome Women Undergoing ICSI

Background: Reproduction is a intricately structured process achieved by interaction of the higher centers in the brain, the gonads, and different body parts; Whereas infertility is a multifactorial pathological condition affecting approximately 10–15% of couples, especially in industrialized region.RESOLVIN E1 is a member of specialized pro resolving mediator family of bio active lipids. It has anti-inflammatory effects in various inflammatory diseases. A promising researches in their way to prove its positive role in reproduction through direct effect on folliculogenesis. It has a fundamental role in regulating follicular growth and maturation at central and peripheral levels highlighting its possible role in diagnosing and treating infertility problems. High level of RESOLVIN E1 which might play critical role in poly cystic ovarian syndrome due to its anti-inflammatory effects. Objectives: To investigate the correlation of serum and follicular RESOLVIN E1 to gonadotropin (recombinant FSH doses) in PCOS patient undergoing ICSI. Subject, Patients, Materials, and Method: A prospective cross-sectional study conducted in the high institute for infertility diagnosis and assisted reproductive technology /Al Nahrain University /Baghdad /Iraq, from November 2023 till March 2024. Twenty-nine infertile PCOS women who were undergoing intracytoplasmic sperm injection were enrolled in the study. Serum and follicular RESOLVIN E1 at day of oocyte pickup were measured using ELISA technique. Results: The current study shows significantly lower gonadotropins stimulation dose needed for PCOS females (p <0.001). It also revealed no significant correlations between total gonadotropins dose with both serum and follicular fluids resolvin E1, while there were insignificant negative correlations between serum and follicular fluids resolvin E1 with patients’ ages and body mass indices among PCOS females. Conclusions: There is no correlation between the serum and follicular RvE1 levels in PCOS infertile females.

Luteinizing hormone supplementation with human menopausal gonadotropin versus low dose human chorionic gonadotropin during ovarian stimulation does not affect live birth rates after fresh and frozen embryo transfer.

Luteinizing hormone (LH) plays an important role in ovarian follicle maturation. Human menopausal gonadotropin (hMG) or low dose human chorionic gonadotropin (hCG) can provide LH supplementation during in vitro fertilization (IVF) ovarian stimulation, though studies directly comparing their impact on IVF outcomes are limited. The aim of the study was to determine whether LH supplementation with hMG versus low dose hCG during IVF stimulation affects live birth rate. Fresh and frozen embryo transfers (ET) from 2017 to 2021 after standard long or antagonist protocols supplemented with hMG (75-250 IU) or low dose hCG (50-100 IU) during stimulation cycles in our academic center were included. Statistical analysis was performed with T-tests, Mann-Whitney U tests, Chi-square, and multiple linear and logistic regression. Four hundred and sixty eight unique stimulation cycles resulting in 213 fresh and 412 frozen embryo transfers were analyzed. There was a lower mature oocyte yield (10.9 vs. 11.8, p = 0.044) but similar high-quality blastocyst yield (3.6 vs. 3.9, p = 0.11) for hMG vs low dose hCG. Live birth rates per transfer were comparable for fresh (42% vs. 49%, p = 0.24) and frozen (46% vs. 53%, p = 0.45) embryo transfers. Multiple logistic regressions showed no association between supplemental gonadotropin and live birth for both fresh and frozen embryo transfers. Fresh and frozen IVF-ET pregnancy outcomes were comparable after hMG versus low dose hCG supplementation, suggesting flexibility in supplemental LH dosing regimens that may address patient or physician preference or cost concerns.

Effects of Zishen Yutai pills combined with metformin on women with polycystic ovary syndrome undergoing in vitro fertilization.

In this study, we analyzed the clinical efficacy of Zishen Yutai pills (ZSYTP) combined with metformin hydrochloride on infertile women diagnosed with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization and embryo transfer (IVF-ET). Patients were assigned into 3 groups: the ZSYTP group (n = 50), the metformin group (n = 50), and the combination group (ZSYTP combined with metformin hydrochloride, n = 50), based on their respective and the indicated treatments before undergoing IVF-ET. Then, their glucose metabolism indices, sex hormone indices, traditional Chinese medicine (TCM) syndrome scores, and outcomes of IVF-ET were compared. Baseline characteristics were not significantly different between the 2 groups. After treatment, various parameters such as body mass index (BMI), fasting plasma glucose (FPG), fasting insulin (FIN), homeostatic model assessment of insulin resistance (HOMA-IR), luteinizing hormone (LH), estradiol (E2), follicle-stimulating hormone (FSH), testosterone (T) levels, and TCM syndrome scores were found to be reduced compared to pretreatment levels in both groups. Moreover, the improvement observed in the treatment group exceeded that of the control group. Specifically, the observation group displayed significantly lower gonadotropin (Gn) dosage and duration, as well as a reduced abortion rate compared to the control group. Furthermore, the observation group had higher numbers of obtained eggs, high-quality embryos, eggs obtained through IVF-ET, average transferred embryos, clinical pregnancy rate, and embryo implantation rate compared to the control group. Pretreatment with ZSYTP combined with metformin before IVF-ET in PCOS patients improves the outcome of IVF-ET.

Effect of Adding Luteinizing Hormone (lh) activity during Controlled Ovarian Hyperstim ulation (coh) by adding Human Chorionic Gonadotropin vs. Low Dosage Human Chorionic Gonadotropin on Subsequent Pregnancy Rates Following Frozen Embryo Transfer

Effect of Adding Luteinizing Hormone (lh) activity during Controlled Ovarian Hyperstim ulation (coh) by adding Human Chorionic Gonadotropin vs. Low Dosage Human Chorionic Gonadotropin on Subsequent Pregnancy Rates Following Frozen Embryo Transfer

IGF-1 Acts through Kiss1-expressing Cells to Influence Metabolism and Reproduction.

Kisspeptin, encoded by the Kiss1 gene, ties puberty and fertility to energy status; however, the metabolic factors that control Kiss1-expressing cells need to be clarified. To evaluate the impact of IGF-1 on the metabolic and reproductive functions of kisspeptin producing cells, we created mice with IGF-1 receptor deletion driven by the Kiss1 promoter (IGF1RKiss1 mice). Previous studies have shown IGF-1 and insulin can bind to each other's receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we also generated mice with simultaneous deletion of the IGF1R and insulin receptor (IR) in Kiss1-expressing cells (IGF1R/IRKiss1 mice). Loss of IGF1R in Kiss1 cells caused stunted body length. In addition, female IGF1RKiss1 mice displayed lower body weight and food intake plus higher energy expenditure and physical activity. This phenotype was linked to higher proopiomelanocortin (POMC) expression and heightened brown adipose tissue (BAT) thermogenesis. Male IGF1RKiss1 mice had mild changes in metabolic functions. Moreover, IGF1RKiss1 mice of both sexes experienced delayed puberty. Notably, male IGF1RKiss1 mice had impaired adulthood fertility accompanied by lower gonadotropin and testosterone levels. Thus, IGF1R in Kiss1-expressing cells impacts metabolism and reproduction in a sex-specific manner. IGF1R/IRKiss1 mice had higher fat mass and glucose intolerance, suggesting IGF1R and IR in Kiss1-expressing cells together regulate body composition and glucose homeostasis. Overall, our study shows that IGF1R and IR in Kiss1 have cooperative roles in body length, metabolism, and reproduction.

P-656 Comparative clinical outcome following individualized follitropin delta dosing in Japanese women undergoing progestin-primed ovarian stimulation for in vitro fertilization /intracytoplasmic sperm injection

Abstract Study question Is ovarian stimulation with follitropin delta (FD) in its individualized regimen as efficacious as follitropin alfa and human menopausal gonadotropin (FAHMG)? Summary answer Ovarian stimulation with individualized FD dosing resulted in a significantly higher fertilization rate and number of blastocysts with good quality compared to conventional FAHMG dosing. What is known already Previous randomized controlled trials conducted in Japan, China, Europe, and both North and South America have demonstrated that ovarian stimulation using the individualized FD dosing regimen, which is based on serum anti-Müllerian hormone (AMH) levels and body weight, effectively modulated the ovarian response without compromising pregnancy and live birth rates. Study design, size, duration A retrospective study was conducted by reviewing the medical records of 1,720 IVF/ICSI cycles in 1,272 Japanese patients. The primary endpoint of the study was the ongoing pregnancy rate, assessed at 8 weeks of gestation, in the frozen-thawed embryo transfer. Participants/materials, setting, methods The FD treatment consisted of a fixed daily dose individualized according to each patient’s initial AMH level and body weight (AMH <2.04 ng/ml: 12 μg; AMH ≥2.04 ng/ml: 0.19 to 0.10 μg/kg; min-max 6–12 μg). The FAHMG dose was determined by the antral follicle count (AFC), with the following protocol: for AFC <25, 300 IU/day; for 40> AFC ≥25, 225 IU/day; and for AFC ≥40: 150 IU/day). A progestin-primed ovarian stimulation (PPOS) protocol was applied. Main results and the role of chance Multiple regression analyses (MRA) showed that the use of FD was negatively correlated with the number of oocytes retrieved (NOR) (P = 0.001), and positively correlated with the fertilization rate (FR) (P = 0.02). NOR was comparable between FD and FAHMG (10.9 ± 6.4 versus 11.8 ± 7.8) when the Mann-Whitney test (MW) was applied (P = 0.111), but significantly higher in FAHMG when the patient is younger than 40 years old with AMH ≥2 ng/ml (P < 0.01). The total gonadotropin use was significantly (P < 0.001) reduced from an average of 167.1 ± 46.9 μg (2789.9 ± 782.9 IU) FAHMG to 102.6 ± 31.6 μg FD. FR was significantly higher in FD compared with FAHMG (78.7% versus 74.1%, P < 0.05) on MW. Additionally, MW indicated a significantly higher number of good-quality blastocysts in FD (2.9±2.6) versus with FAHMG (2.4±2.5) (P < 0.05). The blastocysts obtained from FD also showed a significantly higher implantation rate (50.1% versus 39.7%, P < 0.01) and a comparable ongoing pregnancy rate (28.7% versus 25.7%, P = 0.292) compared to those from FAHMG as determined by chi-square test. The higher implantation rate in FD may be attributed to the greater number of good-quality blastocysts obtained compared with FAHMG. Limitations, reasons for caution This study only covered the clinical outcome of women undergoing PPOS protocol with frozen-thawed blastocyst transfers. Wider implications of the findings The present study shows that FD in its individualized fixed-dose regimen has the potential to improve the success rate in frozen-thawed embryo transfer across all ages and with a lower gonadotropin consumption compared to conventional FAHMG dosing. Trial registration number not applicable

P-670 The impact of fixed day-one versus day-six progestin initiation on ovarian response following progestin primed ovarian stimulation

Abstract Study question Does ovarian response differ between a fixed stimulation day (SD) 1 and SD 6 progestin start in a progestin primed ovarian stimulation (PPOS) protocol? Summary answer Fixed SD 1 and SD 6 PPOS protocols showed no significant differences in terms of ovarian response to stimulation. What is known already Ovulation prior to oocyte retrieval is a potential concern during ovarian stimulation (OS). Progestins, when compared to GnRH analogues, also effectively prevent premature ovulation with the added convenience in terms of its oral administration and lower costs. For this purpose, progestins may be started immediately with OS (SD 1) or later in the cycle, usually around SD 6, when the risk for ovulation increases. While the latter approach may be associated with a lower follicle growth suppression, evidence regarding the impact of the two protocols on ovarian response is still lacking. Study design, size, duration We conducted a single center retrospective cohort study in a private fertility clinic, including 923 patients (584 in the SD1 group and 339 in the SD6 group) who underwent 1064 OS cycles (652 in the SD1 group and 412 in the SD6 group) using a PPOS protocol between January 2016 and May 2023. Among these, 394 (37.03%) were oocyte donation cycles, 341 (32.05%) were autologous IVF/ICSI cycles and 329 (30.92%) were autologous vitrification cycles. Participants/materials, setting, methods We included women under the age of 44 who performed an OS cycle following a PPOS protocol. LH peak suppression was performed with daily desogestrel 75µg started either on SD 1 or on SD 6. The number of oocytes retrieved, number of mature (MII) oocytes, follicle-to-oocyte index (FOI) and follicular output rate (FORT) were compared between the groups. Comparisons are presented as adjusted regression coefficients (β) and 95% confidence intervals (95%CI) following multivariable linear regression. Main results and the role of chance The majority of patients in the SD1 group were donors (59.66%), while in the SD6 group most patients were doing assisted reproductive techniques (ART) with autologous oocytes (98,78%). In the SD1 group, patients were older (38.93±3.81 vs. 37.93±4.00, p < 0.001), had a higher antral follicle count (AFC) (20.79±8.66 vs. 14.12±9.96, p < 0.001), underwent OS with a lower gonadotropin dose (2036.25±766.20IU vs. 2715.20±976.40IU, p < 0.001) and triggered mostly with GnRHa (86.44% vs. 57.50%, p < 0.001). Both groups presented a similar body mass index (BMI) (22.80±2.96 vs. 21.71±3.25kg/m2, p = 0.175). Bivariate analysis revealed a higher number of oocytes retrieved (19.40±12.02 vs. 10.10±8.19, p < 0.001), number of MII oocytes (12.05±5.97 vs. 7.42±5.91, p < 0.001), FORT (81.53±20.59% vs. 73.72±23.80%, p < 0.001) and FOI (95.49±48.78% vs. 76.31±47.60%, p < 0.001) in the SD1 group. No difference was found in the cancellation rates among the two groups (1.99% for SD1 vs. 3.16% for SD6, p = 0.322). Following adjustment for age, BMI, AFC, ART treatment, type of trigger and total gonadotropin dose, no difference was found regarding the number of oocytes retrieved (β=-0.62; 95%CI -2.53 to 1.30), number of MII oocytes (β=-1.66; 95%CI -3.43 to 0.10), oocyte maturation rate (β = 2.30; 95%CI -4.60 to 9.20), FOI (β=-3.29; 95%CI -13.15 to 6.57) or FORT (β=-1.78; 95%CI -5.66 to 2.10). Limitations, reasons for caution Despite attempting to mitigate confounding effects through multivariable linear regression analysis, the retrospective nature of the study and limited sample size may still be insufficient to eliminate bias. Moreover, reproductive and perinatal outcomes were not reported. Wider implications of the findings Our study suggests that both the SD1 and SD6 PPOS protocols can be employed based on patients’ and clinicians’ preference, regardless of the type of ART treatment or patient’s ovarian reserve, without impact on ovarian response to stimulation. Trial registration number not applicable

Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment.

Impaired testosterone secretion is a frequent sequela following hematopoietic stem cell transplantation (HSCT) in pediatrics, but long-term longitudinal trendlines of clinical and biochemical findings are still scanty. Monocentric, retrospective analysis. Male patients transplanted <18 years between 1992 and 2021, surviving ≥2 years after HSCT and showing, upon enrollment, clinical and biochemical signs consistent with pubertal onset and progression were included. Clinical and biochemical data collected every 6-12 months were recorded. Of 130 patients enrolled, 56% were prepubertal, while 44% were peri-/postpubertal upon HSCT. Overall, 44% showed spontaneous progression into puberty and normal gonadal profile, while the remaining experienced pubertal arrest (1%), isolated increase of FSH (19%), compensated (23%) or overt (13%) hypergonadotropic hypogonadism. Post-pubertal testicular volume (TV) was statistically smaller among patients still pre-pubertal upon HSCT (p 0.049), whereas no differences were recorded in adult testosterone levels. LH and testosterone levels showed a specular trend between 20 and 30 years, as a progressive decrease in sexual steroids was associated with a compensatory increase of the luteinizing hormone. A variable degree of gonadal dysfunction was reported in 85%, 51%, 32% and 0% of patients following total body irradiation- (TBI), busulfan-, cyclophosphamide- and treosulfan-based regimens, respectively. TBI and busulfan cohorts were associated with the lowest probability of gonadal event-free course (p<0.0001), while it achieved 100% following treosulfan. A statistically greater gonadotoxicity was detected after busulfan than treosulfan (p 0.024). Chemo-only regimens were associated with statistically larger TV (p <0.001), higher testosterone (p 0.008) and lower gonadotropin levels (p <0.001) than TBI. Accordingly, the latter was associated with a 2-fold increase in the risk of gonadal failure compared to busulfan (OR 2.34, CI 1.08-8.40), whereas being pre-pubertal upon HSCT was associated with a reduced risk (OR 0.15, CI 0.08-0.30). a) patients pre-pubertal upon HSCT showed a reduced risk of testicular endocrine dysfunction, despite smaller adult TV; b) patients showed downwards trend in testosterone levels after full pubertal attainment, despite a compensatory increase in LH; c) treosulfan was associated to a statistically lower occurrence of hypogonadism than busulfan, with a trend towards larger TV, higher testosterone levels and lower gonadotropins.

#100 : Can the Dual Trigger be Effective in Improving Oocyte Maturation and Embryo Quality Compared to the HCG Trigger or the GnRH-a Trigger?

Background and Aims: HCG was the standard trigger of final oocyte maturation in IVF cycles. An alternative trigger with gonadotropin releasing hormone agonist (GnRH-a) was effective in reducing OHSS. But GnRH-a trigger induced increased luteal insufficiency and cycle cancellation. A dual trigger (HCG with GnRH-a) was introduced to reduce OHSS, luteal insufficiency and cycle cancellation. This study was designed to compare the effect of dual trigger on final oocyte maturation n embryo quality with conventional HCG trigger and GnRH-a trigger. Method: We conducted this retrospective cohort study of patients who underwent IVF antagonist cycles from Jan. 2020 to Dec. 2022. Patients undergoing their oocyte retrieval 36 hours after trigger with only HCG 10,000 units, or only leuprolide acetate 40 units, or a dual trigger of HCG 5000 units with leuprolide acetate 40 units. Male factor infertility and oocyte donor cycle were excluded. The main outcomes were retrieved mature oocyte rate and fertilization rate. Secondary outcomes include implantation rate and pregnancy rate. Results: Total 3266 patients were included. Dual trigger was in 2279, GnRH-a in 282 and HCG in 705 cycles. Patients using GnRH-a were younger (33.7± 4.0 years) compared to those receiving dual trigger (37.8±2.3 years) and HCG only (37.2±3.2 years) (p&lt;0.01). Because GnRH-a groups were younger, despite low total gonadotropin dose, the larger number of oocytes were retrieved. Dual trigger resulted in no difference in mature oocyte ratio, compared to HCG trigger and GnRH-a trigger (63.0%, 58.3%, 62.8% p: 0.074). Analysis did not show any statistical differences in fertilization rate between the types of triggering methods. Cycel cancellation due to no oocyte recovered from multiple follicles aspirated was shown only in GnRH-a cycle (6 cases. 2.1%). Conclusion: Compared to HCG trigger and GnRH-a trigger, the dual trigger showed no difference in mature oocyte rate and fertilization rate. To reduce OHSS and cycle cancellations, dual trigger could be considered the standard care in IVF without decreasing oocyte quality.

#120 : Effect of Aromatase Inhibitor, Letrozole on Semen Parameters in Eugonadotropic Hypoandrogenic Men with Oligozoospermia

Background and Aims: Some men with severely defective sperm production commonly have excess aromatase activity, reflected by low serum testosterone and relatively elevated estradiol level. Elevated levels of estrogen lead to feedback inhibition of the hypothalamic-pituitary-gonadal axis, and the end result is a decrease in LH necessary for the production of testosterone and FSH to optimize sperm production. The aim of the study was to evaluate the effect of aromatase inhibitor, letrozole on the semen parameters of infertile male having oligozoospermia, low serum testosterone level and testosterone to estradiol ratio &lt; 10. Method: This prospective study was conducted in the Department of Reproductive Endocrinology and Infertility at Bangabandhu Sheikh Mujib medical University, Dhaka, Bangladesh during the period from May 2019 to April 2020. The sample size was 30 sub fertile men with oligozoospermia (&lt;-10 million/ml), low serum testosterone level (&lt;300 ng/dl), and low testosterone to estradiol ratio (&lt;10). All patients were treated with letrozole 2.5 mg daily for 4 months. At the end of the 4 months semen analysis was performed. Statistical analysis was carried out by using IBM Statistical Package for Social Sciences version 25 for windows. Results: The sperm concentration, sperm motility and total motile sperm count significantly increased after letrozole treatment. The side effects were mild and well tolerated. Conclusion: This study suggests that some men with oligozoospermia low serum testosterone levels and normal gonadotropin concentration may have a treatable endocrinopathy. Letrozole may be used to improve sperm parameters in infertile men with low serum testosterone to estradiol ratio.

Longitudinal Assessment of Pubertal Attainment and Testicular Function Following Pediatric Hematopoietic Stem Cell Transplantation: The Role of the Conditioning Regimen

Introduction. Endocrine disorders and impaired gonadal function are the most frequent sequelae after transplantation. Methods. Male patients &amp;lt;18 years transplanted in the period 1992-2021 in the Pediatric Transplant Unit in Monza, surviving more than 2 years after HSCT, who either experienced spontaneous puberty (Tanner stage ≥2, testicular volume (TV) ≥4 mL or serum testosterone ≥0.2 ng/mL) or received pharmacological pubertal induction were included in this study. Longitudinal endocrine evaluations were performed every 6-12-months, including Tanner stage and TV assessment and LH, FSH, total testosterone, among laboratory data. Results. Of 130 patients (median age 9 years at HSCT, 21 years at last follow-up) fulfilling inclusion criteria, 65% were transplanted for acute leukemia, 9% for other malignancies and 26% for non malignant diseases after a TBI (45%), busulfan (27%), 14% treosulfan-based or 15% a different chemo-only conditioning. Upon HSCT 56% were prepubertal (PreP) and 44% where either peri- or postpubertal (PostP). The pubertal status upon the last endocrine evaluation was consistent with Tanner stage 3, 4 and 5 in 15%, 23% and 62% of the patients, respectively. Overall, 44% had spontaneously progressed into puberty and had a normal gonadal profile (NOR) and 56% had experienced either pubertal arrest (1%), isolated increase of FSH (IIF 19%), compensated hypergonadotropic hypogonadism (cHH, 23%) or overt hypergonadotropic hypogonadism (oHH, 13%). Gonadal outcome was not affected by pubertal status upon HSCT (p 0.298), even though, out of 81 patients who had achieved Tanner stage 5, TV was statistically greater in the PostP (12.2±5.1 ml) than in the PreP cohort (10.3±4.1 ml, p 0.049), whereas there were no significant differences in the last testosterone level recorded in the two cohorts, as well as in the hypogonadal versus the event-free patients (p 0.53), with events defined as any gonadal issue (IIF, cHH, oHH). TV was significantly lower in patients who developed any endocrine disfunction versus those who didn't. LH and testosterone levels showed a specular trend between 20 and 30 years, when a progressive decrease in sexual steroids was associated with a compensatory increase of the luteinizing hormone. Overall, adult LH (p 0.728) as well as FSH levels (p 0.318) were superimposable in the PreP and PostP cohorts. In terms of the impact of the conditioning regimen on gonadal outcomes, a certain degree of gonadal dysfunction (ranging from isolated increase of FSH to hypogonadism or pubertal arrest) was recorded in 37% of the patients overall, and in 85% of the patients after TBI, 51% after busulfan and 32% after cyclophoshamide/fludarabine, whereas no abnormal findings were found among the 18 patients exposed to treosulfan. The likelihood of a gonadal event-free course was lowest for the TBI and busulfan cohorts, both overall (p&amp;lt;0.0001) and for PreP patients (p&amp;lt;0.0001), whereas it was 100% among the 18 patients conditioned with treosulfan-based schedules. A remarkably greater gonadotoxicity was detected in the busulfan compared with the treosulfan cohort (p 0.024), with a similar trend in the PreP and PostP subcohorts. Busulfan/cyclophosphamide-based conditioning regimens were associated with statistically larger median TV (p &amp;lt;0.001), higher testosterone levels (p 0.008) and lower LH/FSH levels (p &amp;lt;0.001) than those exposed to TBI. Conditioning regimen (p 0.047) and pubertal status upon HSCT (p &amp;lt;0.0001) were the only variables significantly associated with testicular outcomes in the Cox model, with exposure to TBI being associated with a 2-fold increase in the risk of gonadal failure compared to busulfan (OR 1.93, CI 1.08-3.70), whereas being pre-pubertal upon HSCT was protective, as it was associated with a halved risk of developing any degree of testicular damage (OR 0.50, CI 0.26-0.70). Conclusions. We demonstrated a i. halved risk of developing post-HSCT hypogonadism in prepubertal patients at HSCT, despite overall smaller final testicular volume; ii. downwards trend in testosterone levels after the achievement of full spontaneous puberty compensated by an inverse upwards trend in LH levels; iii gonadal-sparing profile of treosulfan compared to busulfan-based regimens, with a statistically lower occurrence of hypogonadism and a trend towards larger testicular volume, higher testosterone levels and lower gonadotropins.

Postnatal Development and Maintenance of Functional Pituitary Gonadotrophs Is Dependent on PI4-Kinase A.

Postnatal development of functional pituitary gonadotrophs is necessary for maturation of the hypothalamic-pituitary-gonadal axis, puberty, and reproduction. Here we examined the role of PI4-kinase A, which catalyzes the biosynthesis of PI4P in mouse reproduction by knocking out this enzyme in cells expressing the gonadotropin-releasing hormone (GnRH) receptor. Knockout (KO) mice were infertile, reflecting underdeveloped gonads and reproductive tracts and lack of puberty. The number and distribution of hypothalamic GnRH neurons and Gnrh1 expression in postnatal KOs were not affected, whereas Kiss1/kisspeptin expression was increased. KO of PI4-kinase A also did not alter embryonic establishment and neonatal development and function of the gonadotroph population. However, during the postnatal period, there was a progressive loss of expression of gonadotroph-specific genes, including Fshb, Lhb, and Gnrhr, accompanied by low gonadotropin synthesis. The postnatal gonadotroph population also progressively declined, reaching approximately one-third of that observed in controls at 3 months of age. In these residual gonadotrophs, GnRH-dependent calcium signaling and calcium-dependent membrane potential changes were lost, but intracellular administration of inositol-14,5-trisphosphate rescued this signaling. These results indicate a key role for PI4-kinase A in the postnatal development and maintenance of a functional gonadotroph population.

THU227 Isosexual Peudo-precocious Puberty Due To Leydig Cell Tumor In A Prepubertal Child

Abstract Disclosure: M. Baby: None. A. Xu: None. N. Shacham: None. E. Shapiro: None. B.C. Shah: None. Background: Testicular tumors account for 2-4% of all childhood cancers. Leydig cell tumors are the most common form of sex cord stromal tumors and represent 1-3% of all testicular tumors. In the pediatric population, testicular Leydig cell tumors present with signs of precocious puberty. Workup reveals low gonadotropins with elevated testosterone and testicular mass on ultrasound. Treatment involves surgical enucleation (partial orchiectomy) in most cases. Clinical case: We present the case of a 4 year 10 month old male who presented to endocrine clinic for precocious puberty. He developed pubic hair three months prior with body odor. He did not have any CNS symptoms including headaches or visual changes. There was no use of exogenous androgens at home. He was born full term, small for gestational age with an uncomplicated postnatal course. There was no family history of precocious puberty. Height was at the 99th percentile (z-score 2.7), weight 98th percentile (z-score 2.07), and BMI 86th percentile (z-score 1.09). On exam, he was lean and appeared muscular. His testes were asymmetrical with the right testicle measuring 3 ml and the left testicle 2 ml. Scrotal hair was curly and sparse, Tanner III. Stretched penile length was 7 cm (90th percentile), width was 3.2 cm. Results: Bone age was advanced to 10 year 0 months with height age of 7 year 3 months. Serum gonadotropins were low, testosterone was pubertal at 115 ng/dl (Electrochemiluminescence Immunoassay). Serum 17-hydroxyprogesterone (221 ng/dl, ref range 0-90 ng/dl) androstenedione (163 ng/dl, ref range = &amp;lt; 51 ng/dl), and IGF-1 (368 ng/ml, ref range 108 – 293 ng/ml) were elevated. ACTH, cortisol, thyroid profile, and prolactin were normal. Beta-HCG and AFP were negative. ACTH stimulation test showed normal response. Testicular ultrasound with doppler was performed; right testicle measured 1.82 x 1.06 x 1.36 cm, volume of 1.4 ml, while left measured 1.27 x 0.72 x 0.87 cm, 0.4 ml. Within the right testicle, there was a mass that was hypoechoic, vascular (with a testicular artery feeding branch in the periphery), multinodular and measured 1.2 x 0.8 x 1.10 cm (0.53 ml). He was referred to urology and underwent enucleation of the right testicular mass through an inguinal approach. Grossly, the mass appeared tan and lobulated and surgical pathology confirmed a benign Leydig cell tumor. The patient recovered well and post-operative serum testosterone level at 2 weeks was &amp;lt;2.5 ng/dl. Conclusion: We present a case of a testicular Leydig cell tumor that presented as peripheral precocious puberty marked by low gonadotropins and elevated testosterone with ultrasound findings of a vascular mass with testicular artery feeding branch in the periphery. Early detection of a Leydig cell tumor is crucial as it can be treated by enucleation thus salvaging the testes. Presentation: Thursday, June 15, 2023

FRI193 Early Presentation Of Pediatric Oncocytic Adrenal Tumor Associated With Germline TP53 Pathogenic Variant—Report Of Three Cases

Abstract Disclosure: R.R. Oppenheimer: None. L.P. Lins: None. C.P. Oliveira: None. I.P. Magalhaes: None. A. Latronico: None. B.B. Mendonca: None. M.Q. Almeida: None. A.W. Kuhn: None. H. Charchar: None. M.C. Fragoso: None. Oncocytic adrenal tumors (OAT) are uncommon and usually nonfunctional. In the pediatric age group, OAT are extremely rare and less than 20 cases have been reported. Herein we report the clinical presentation and follow up of 3 non-related children with Li-Fraumeni syndrome with a germline TP53 pathogenic variant (PV) (p.R337H) who developed secreting OAT. Case 1. A 19 month old male presented with moon face, weight gain, irritability and pubic hair (Tanner stage P3) for over 4 months. He had no family history of neoplasms and his parents were unrelated to each other. Hormonal data revealed serum cortisol 33 mcg/dL with a suppressed ACTH. Testosterone was elevated (242 ng/dL - RR &amp;lt;12 ng/dL) with low plasma gonadotropins. Androstenedione 3,08 (RR&amp;lt;0,5ng/mL). Abdominal CT revealed a left adrenal tumor (5.0 x 4.4 x 4.0cm). He underwent a left laparoscopic adrenalectomy and histopathologic analysis confirmed OAT Wieneke score 2/9. Immunohistochemistry was positive for inhibin, p53 and Ki67 (10-15%). The postoperative clinical course was uneventful. The TP53 p.R337H PV was inherited from his father. He is now prepubertal and there is no evidence of relapse in 14 months of monitoring. Case 2. An 18 month old female presented with acne, clitoromegaly, pubic hair (Tanner stage 2), axillary odor, axillary hair and weight gain. Hormonal study showed elevated total testosterone of 624.7 ng/dL, androstenedione, DHEA-S and prepubertal gonadotropins. 17OHP and cortisol were normal. Abdominal CT confirmed a heterogeneous solid nodule of 5.5 x 4.5 x 3.7 cm in the right adrenal topography. The patient underwent a right adrenalectomy and OAT was identified by histopathology (Wieneke score 3/9). Immunohistochemistry was positive for p53, inhibin and Ki67 (30%). The TP53 p.R337H PV was inherited from her mother. She had remission of secondary sexual characteristics and he is now prepubertal. Case 3. A 2 years and 8 months old girl was referred with precocious pubarche and clitoromegaly (2,6cm). She had a right flank palpable mass and tanner 1 breasts. Hormonal studies showed elevated testosterone (70ng/dL), androstenedione (3.81ng/mL) and DHEA-S (13490ng/mL), with LH 0.3IU/L and FSH 3.4IU/L. The cortisol after DST was 5.8mcg/dL and ACTH was suppressed. Abdominal MRI revealed a 5 cm tumor at the right adrenal gland. She underwent laparoscopic adrenalectomy. The histopathologic analysis revealed an OAT Wieneke score 1/9. Immunohistochemistry was positive for p53 and Ki67 (13%). The TP53 p.R337H PV was inherited from her father. Conclusion: Although rare, functional OATs have been reported in children. Herein we describe the first patients with the TP53 p.R337H PV to present with OATs. These are the youngest cases of OAT published so far. The clinical presentation, hormonal data and follow-up were not different from those of other pediatric adrenal tumors. So far there is no evidence of disease relapse during follow-up. Presentation: Friday, June 16, 2023

FRI288 Single-Cell Transcriptomics Identifies Pituitary Gland Cell Type Population Changes In Diet Induced Obesity

Abstract Disclosure: R.E. Ruggiero-Ruff: None. B. Le: None. N. Lainez: None. D. Coss: None. Obesity is a worldwide growing public health concern, with a current prevalence of 43% in the United States and projected future increase. Obesity is associated with type 2 diabetes, cardiovascular disease, stroke, and endocrine abnormalities. The pituitary gland is the master gland that responds to metabolic perturbations and regulates homeostasis via hormone secretion. Thyrotrophic, gonadotropic, somatotropic, lactotropic and corticotropic dysfunctions may occur as a consequence of obesity and perpetuate pathophysiologic conditions since pituitary hormones regulate metabolic function in return. Previous work from our lab determined that mice fed high fat diet have reduced levels of gonadotropin hormones, indicating that diet-induced obesity may play a role in pituitary hormone production. We postulate that diet-induced obesity alters the pituitary transcriptome and/or select population changes. To determine the effect of diet-induced obesity on pituitary gland population plasticity, we performed single-cell RNA-sequencing (scRNA-seq) of pituitary glands from control and high-fat diet-fed mice and characterized population changes and gene expression changes in each population. While gonadotrope population changes levels of gene expression that results in the lower gonadotropin levels, somatotrope and lactotrope populations, on the other hand, change at the population level with alterations in the cell numbers that result in altered levels of growth hormone and prolactin in the circulation. In summary, we defined diet-induced changes in pituitary hormone production and population shifts that may play a role in altered hormone production in obese patients and consequently dysregulation of homeostasis. Presentation: Friday, June 16, 2023