High LH Research Articles

Optimising Luteinising Hormone Levels on Trigger Day for Improved Ovarian Response and Pregnancy Outcomes in Gonadotropin-Releasing Hormone Antagonist Protocols: A Retrospective Cohort Study.

To determine the optimal luteinising hormone (LH) level on the trigger day and its impact on pregnancy outcomes in gonadotropin-releasing hormone (GnRH) antagonist protocols using a data-driven approach. Retrospective cohort study. Third Affiliated Hospital of Guangzhou Medical University. Overall, 6107 invitro fertilisation/intra-cytoplasmic sperm injection fresh embryo transfer cycles with GnRH-antagonist protocols were performed between January 1, 2018 and February 1, 2023. Restricted cubic spline analysis and segmented regression identified the optimal LH threshold. Patients were categorised into low (≤ 1.6 IU/L) and high (> 1.6 IU/L) LH groups. Propensity score matching (PSM) and multivariable logistic regression were applied to adjust for confounding factors. Live birth rate per embryo transfer cycle. The high LH group showed significantly higher live birth rates (42.9% vs. 36.9%, adjusted odds ratio [aOR]: 1.468; 95% CI: 1.220-1.766, p < 0.001), ongoing pregnancy rates (51.4% vs. 43.6%, aOR: 1.498; 95% CI: 1.338-1.678, p < 0.001), clinical pregnancy rates (52.4% vs. 45.6%, aOR: 1.439; 95% CI: 1.285-1.611, p < 0.001) and biochemical pregnancy rates compared with the low LH group, despite retrieving fewer oocytes (median 10 vs. 12, p < 0.001). These results remained consistent after PSM and multivariable logistic regression analysis. Higher LH levels on the trigger day are associated with improved pregnancy outcomes in GnRH-antagonist protocols. Maintaining an optimal LH range is crucial for balancing oocyte yield and assisted reproductive technology success, highlighting the importance of individualised ovarian stimulation protocols.

Japan Society of Obstetrics and Gynecology revised diagnostic criteria for polycystic ovary syndrome: JSOG2024 criteria.

Japanese patients with polycystic ovary syndrome (PCOS) exhibit distinct body type characteristics, such that the rate of overweight/obese women is remarkably low. In addition, hyperandrogenism is relatively rare among Japanese PCOS patients. Therefore, these factors are considered in PCOS diagnostic criteria used in Japan. Diagnostic criteria for PCOS were recently revised by the Japan Society of Obstetrics and Gynecology based on a nationwide survey of PCOS and released on December 5, 2023 (JSOG2024). JSOG2024 criteria diagnosed PCOS according to the following three items: (1) irregular menstrual cycle/chronic anovulation, (2) polycystic ovarian morphology or elevated serum anti-Müllerian hormone (AMH) level, and (3) hyperandrogenism or high luteinizing hormone. The presence of all three items is required to diagnose PCOS, after excluding other diseases with symptoms similar to PCOS. We also established AMH cut-off values by age and a system for evaluating ovarian findings useful for both the JSOG2024 and Rotterdam criteria. We anticipate that the JSOG2024 criteria with cut-off values will enhance the treatment of Japanese patients with PCOS and those of other ethnicities with low obesity and hirsutism.

Effects of cloprostenol and oxytocin on ultrasonographic changes of uterine horns in postpartum primiparous Hu sheep

This study aimed to evaluate the effects of exogenous hormones on postpartum ultrasonographic changes of uterine horn in Hu sheep. 90 nulliparous Hu sheep were divided into three groups according to the number of lambs. Each group was further randomly subdivided into three groups (n = 10), a control group (sodium chloride), a PG group (cloprostol), and a PG+OT group (cloprostol + oxytocin). The effects of different treatments on ultrasonographic changes of uterine horn and reproductive performance of ewes were determined after the treatment. Then, 90 nulliparous ewes were divided into a control group, PG group, and PG+OT group according to hormone injections received. Each group (n = 30) consisted of 10 single, 10 twin, and 10 triple ewes. Changes in the levels of hormones P4, LH, FSH, and E2 in the serum of postpartum ewes, the time of the first estrus, and the conception rate were detected. Results showed that the higher the lambing rate, the slower the rate of ultrasonographic changes of uterine horn. The rate of ultrasonographic changes of uterine horn in the PG+OT group was faster than that in respective PG and the control groups. Caruncle diameter was not affected by the number of lambs or hormone treatment. After delivery, the concentrations of P4 and LH increased rapidly and remained at a relatively high level, while the concentration of E2 increased in all ewes. The PG+OT group had lower P4 concentrations compared to the control group, but higher LH, FSH, and E2 levels. The time to first postpartum estrus was significantly shorter in the PG+OT group, but differences in pregnancy rate were not significant. Thus, PG+OT treatment can significantly accelerate postpartum ultrasonographic changes of uterine horn, which can prepare postpartum ewes for the next reproductive cycle.

Effect of Oral Bisphosphonates on Vertebral Fractures in Males Living with HIV: A Seven Year Study.

Background: Osteoporosis and vertebral fractures (VFs) are frequently observed in males living with HIV (MLWH). While bisphosphonates seem effective on bone mineral density (BMD) in MLWH, data on VFs are lacking. In this real-life longitudinal study performed on 118 MLWH (median age 53) who were followed-up for a median of 7 years, we aimed to evaluate the long-term efficacy of oral bisphosphonates on VFs in MLWH. Methods: The inclusion criteria were age >18, stable HIV infection, bisphosphonate-naïve, blood samples from the same laboratory, and three densitometries and morphometries performed with the same densitometer. Results: At baseline, VFs were detected in 29/118 patients (24.6%). Patients with VFs were older (p. 0.042), had longer HIV infection duration (p. 0.046) and antiretroviral exposure (p. 0.025), and demonstrated higher luteinizing hormone levels (LH, p. 0.044). Of the 29 patients with VFs at inclusion, 11 developed new VFs, of which 8 were under oral bisphosphonates (p. 0.018). Among the 89 without basal VFs, 11 developed VFs, of which 2 were under oral bisphosphonates. Patients with a worsened bone condition (regarding BMD and/or new VFs, n. 32) had more frequently high LH levels (>9.4 mIU/mL, p. 0.046) and higher HCV co-infection compared to patients with a stable bone condition (p. 0.045). It should be noted that 38.6% of patients discontinued oral bisphosphonates due to medical indication or personal choice, and 14.0% never started them. Conclusions: In conclusion, we found that oral bisphosphonates were not completely effective in preventing VFs, especially in patients with VFs at baseline; this is probably due to the multifactorial pathogenesis of fragility fractures in this population. A poor adherence to treatment and attention to gonadal function are also important issues in this population.

A New Sperm Concentration Threshold for Y Chromosome Microdeletion Analysis in Infertile Men: Could It Be Azoopermia?

We aimed to assess the frequency of Y-chromosome microdeletions (YCMs) in a non-multiethnic urban population in our region, define predictive factors, and determine a new clinical threshold for YCMs in infertile men. A total of 281 patients with a sperm concentration ≤5 million/mL were retrospectively evaluated. Oligozoospermic and/or azoospermic patients with a sperm concentration of ≤5 million/mL were screened for the YCM analysis. Y-chromosome microdeletion was detected in 9 (3.2%) of the 281 patients. All patients with YCM were azoospermic. The presence of azoospermia, a high folliclestimulating hormone level, and a high luteinizing hormone level were found to be important determinants for the identification of a microdeletion (P = .002, P = .002, and P=.021, respectively). If the presence of azoospermia and a sperm concentration threshold of <1 million/mL had been applied for the YCM test, the number of tests performed would have been reduced by 54.4% (153 tests) and 42.7% (120 tests), respectively, resulting in cost saving of approximately $11 474 and $9000, respectively. We recommend that the threshold for sperm concentration for YCM analysis be set at <1 million in individuals in developed countries and only in patients with azoospermia in developing countries, in order to reduce costs and save labor by excluding unnecessary tests. These proposed thresholds (azoospermia and sperm counts less than <1 million/mL) provide cost-effectiveness by significantly reducing the number of genetic tests ordered without affecting the diagnosis rate.

12500 Objective Evaluation Of Clustering Methods For Resolving The Heterogeneity Of PCOS

Abstract Disclosure: K. Brewer: None. R. Sisk: None. M. Dapas: None. C. Li: None. A. Dunaif: Consulting Fee; Self; AcaciaBio, Inc, Neurocine Biosciences, Inc. Speaker; Self; Quest Diagnostics. Other; Self; Co-Editor Endocrine Today, Healio, Slack Inc. Clustering methods have been used to resolve heterogeneity within complex diseases to elucidate underlying biologic mechanisms. We (Dapas et al. PLoS Med, 2020) and others have applied these methods to PCOS and identified discrete subtypes, including those that capture distinct reproductive or metabolic features. We objectively compared two widely used methods, hierarchical clustering (HC), which recursively merges subjects based on their similarity, and k-means (Km), which iteratively groups individuals to minimize their distance to cluster centroids. The number of clusters (k) was predefined in both approaches. We compared HC vs Km in 874 European ancestry PCOS cases diagnosed by NIH criteria using 8 traits (BMI, testosterone, SHBG, DHEAS, LH, FSH, fasting insulin, fasting glucose) and 9 traits with the addition of AMH. The ConsensusClusterPlus R package was used to evaluate cluster stability of both approaches with k=2, 3, or 4, using 8 or 9 traits. Genomewide association study (GWAS) meta-analysis was performed as reported with a discovery cohort (620 cases, 2951 controls) and a replication cohort (371 cases, 926 controls), except that genotypes were imputed to the newer TOPMED (r2) panel. Clustering using 8 traits and k=3 resulted in the best cluster stability for both HC and Km (pairwise consensus proportion: HC 0.98, Km 0.93) compared to k=2 with 8 traits (HC 0.88, Km 0.88) or 9 traits (HC 0.95, Km 0.92). No stability was observed for k=4 with 8 or 9 traits using either method (range: 0.35-0.66). Km showed slightly better cluster separation than HC (average silhouette width: Km 0.12 vs HC 0.09) with k=3 and 8 traits. The biologic relevance of the three PCOS subtypes, which we have designated as reproductive (cases with higher LH, FSH, SHBG), metabolic (higher BMI, insulin, glucose), and background, was assessed by GWAS, an orthogonal (i.e., uncorrelated) approach for subtype confirmation. The subtypes identified with HC had genomewide significant associations (metabolic subtype, c9orf3/FANCC, rs10761370, minor allele frequency [MAF] 0.47, p=1.21 x 10-8; background subtype, FSHB/ARL14EP, rs10835649, MAF 0.17, p=8.49 x 10-[1]0). There were no genomewide significant signals when the subtypes were identified with Km despite having a better cluster separation. In summary, only HC clusters appeared to capture biologically meaningful differences since two of the three subtypes thus identified were associated with genomewide significant loci. Neither the addition of AMH nor increasing the number of groups improved clustering metrics. Our results emphasize the importance of independent validation of clustering approaches using an orthogonal confirmation strategy such as GWAS. We conclude that HC clustering using 8 traits is superior to Km for resolving the genetic heterogeneity of PCOS. Presentation: 6/2/2024

12500 Objective Evaluation Of Clustering Methods For Resolving The Heterogeneity Of PCOS

Abstract Disclosure: K. Brewer: None. R. Sisk: None. M. Dapas: None. C. Li: None. A. Dunaif: Consulting Fee; Self; AcaciaBio, Inc, Neurocine Biosciences, Inc. Speaker; Self; Quest Diagnostics. Other; Self; Co-Editor Endocrine Today, Healio, Slack Inc. Clustering methods have been used to resolve heterogeneity within complex diseases to elucidate underlying biologic mechanisms. We (Dapas et al. PLoS Med, 2020) and others have applied these methods to PCOS and identified discrete subtypes, including those that capture distinct reproductive or metabolic features. We objectively compared two widely used methods, hierarchical clustering (HC), which recursively merges subjects based on their similarity, and k-means (Km), which iteratively groups individuals to minimize their distance to cluster centroids. The number of clusters (k) was predefined in both approaches. We compared HC vs Km in 874 European ancestry PCOS cases diagnosed by NIH criteria using 8 traits (BMI, testosterone, SHBG, DHEAS, LH, FSH, fasting insulin, fasting glucose) and 9 traits with the addition of AMH. The ConsensusClusterPlus R package was used to evaluate cluster stability of both approaches with k=2, 3, or 4, using 8 or 9 traits. Genomewide association study (GWAS) meta-analysis was performed as reported with a discovery cohort (620 cases, 2951 controls) and a replication cohort (371 cases, 926 controls), except that genotypes were imputed to the newer TOPMED (r2) panel. Clustering using 8 traits and k=3 resulted in the best cluster stability for both HC and Km (pairwise consensus proportion: HC 0.98, Km 0.93) compared to k=2 with 8 traits (HC 0.88, Km 0.88) or 9 traits (HC 0.95, Km 0.92). No stability was observed for k=4 with 8 or 9 traits using either method (range: 0.35-0.66). Km showed slightly better cluster separation than HC (average silhouette width: Km 0.12 vs HC 0.09) with k=3 and 8 traits. The biologic relevance of the three PCOS subtypes, which we have designated as reproductive (cases with higher LH, FSH, SHBG), metabolic (higher BMI, insulin, glucose), and background, was assessed by GWAS, an orthogonal (i.e., uncorrelated) approach for subtype confirmation. The subtypes identified with HC had genomewide significant associations (metabolic subtype, c9orf3/FANCC, rs10761370, minor allele frequency [MAF] 0.47, p=1.21 x 10-8; background subtype, FSHB/ARL14EP, rs10835649, MAF 0.17, p=8.49 x 10-[1]0). There were no genomewide significant signals when the subtypes were identified with Km despite having a better cluster separation. In summary, only HC clusters appeared to capture biologically meaningful differences since two of the three subtypes thus identified were associated with genomewide significant loci. Neither the addition of AMH nor increasing the number of groups improved clustering metrics. Our results emphasize the importance of independent validation of clustering approaches using an orthogonal confirmation strategy such as GWAS. We conclude that HC clustering using 8 traits is superior to Km for resolving the genetic heterogeneity of PCOS. Presentation: 6/2/2024

Investigation of the Effect of Nano-melatonin on Oxidative Stress in Sera of Patients with Polycystic Syndrome

Background: The association between polycystic ovary syndrome (PCOS) and oxidative stress in women, the possible causes of PCOS, insulin resistance (IR), obesity, and oxidative stress. Oxidants are chemical elements that tend to gain electrons, losing positive charge. The Oxidative Stress (OS) is defined as an imbalance between the formation and synthesis of free radicals and the antioxidant defense system, which results in oxidative damage. Objective: The purpose of this research is to investigate the effect of nano-melatonin on oxidative stress in the sera of patients with polycystic syndrome. Methods: The study includes 120 Iraqi women, divided into two groups: 60 PCOS patients and 60 healthy control patients. Sample Analysis Biochemistry analyses the hormonal profile and determines the hormonal levels (LH, FSH, Testosterone, and Prolactin) that were identified for all controls and patients. Hormones analysis was performed using the enzyme-linked fluorescent assay (ELFA) technique. Synthesized ML nanoparticles by ultrasonic sonication. Results: The results indicate that the mean of serum LH significantly increased (P&lt;0.02) in PCOS BMI ≥ 25 patients G1 (6.19±3.13) mIU/mL compared with controls C1 (4.504±1.591) mIU/mL, while a nonsignificant difference (P&gt;0.05) when compared the BMI&lt;25 kg/m2 for G2 (5.55±1.93) with control group C2 (6.31±2.58) of luteinizing hormone in G1 and G2. Conclusions: An increased ratio of LH to FSH was shown to be characteristic of PCOS. For PCOS, high LH values are crucial. For the purpose of diagnosing PCOS, high LH values are crucial release of gonadotropin hormones (LH, FSH) from the pituitary. To higher the production of androgen in ovarian theca cells, The LH receptor is activated by the luteinizing hormone (LH). The nano Mel was higher in the inhibition of Oxidative stress two causes nano-melatonin high surface area and small size.

Metabolic and hormonal profiling in polycystic ovarian syndrome: insights into INSR gene variations.

Polycystic Ovary Syndrome (PCOS) is a hormonal disorder characterized by irregular periods, excess androgen levels, and polycystic ovaries, affecting many women of reproductive age. This study employed statistical and molecular analyses to compare hormone and metabolic markers between PCOS patients and controls. Sanger sequencing identified two INSR gene variants linked to high insulin and pre-diabetic conditions. Statistically, no significant age differences were detected (p = 0.492) between the overall PCOS patient pool and controls. However, a substantial variation in Vitamin D levels was observed within PCOS patients compared to controls (p = 0.0006), suggesting an association with PCOS. Correlations between Vitamin D and insulin, as well as HbA1c levels (R2 = 0.141 and 0.143, respectively), suggest Vitamin D's potential impact on glycemic control. Significant differences were found in HbA1c (p < 0.0001), insulin (p < 0.0001), and LDL (p = 0.0004) levels between PCOS patients and controls, highlighting marked disparities in these metabolic markers. LH levels also showed a significant contrast (p < 0.0001), while progesterone levels displayed a notable difference (p = 0.007) between the two groups. Correlation analyses within PCOS patients demonstrated associations among LDL, HbA1c, and insulin, with no such correlations observed in control cases. Additionally, Sanger sequencing identified two INSR gene variants, c.3614C > T (p.Pro1205Leu) and c.3355C > T (p.Arg1119Trp), associated with high insulin, LH, and pre-diabetic conditions. These amino acid changes may trigger metabolic imbalances and hormonal irregularities, potentially contributing to the development of PCOS. The findings highlight the multifaceted nature of PCOS, revealing significant metabolic, hormonal, and genetic differences compared to controls. These insights may inform tailored interventions and management strategies for the complex associations characteristic of PCOS.

Luteinizing Hormone Variability in Polycystic Ovary Syndrome: A Comparative Analysis

An endocrine with metabolic condition known as Polycystic Ovarian Syndrome (PCOS) affects women who are of reproductive age, women with PCOS are a condition often associated with dysregulation of the hypothalamic-pituitary axis. A Cross-sectional study, the study included 88 patients who visited the outpatient clinic in total. These individuals were split up into two groups. All females are assessed the status of obesity by the body mass index (BMI), [BMI= weight (kg) / height (m)²], LH, FSH, Estradiol and Testosterone levels measured by ELISA technique. There was no discernible variation in BMI between groups A and B. (P ≥ 0.456), The patients' mean FSH and LH values were 5.06 mIU/ml and 5.47 mIU/ml, compared with group B mean that equal to 6.05 mlU/ml, 18.91mlU/ml respectively. Serum testosterone was slightly elevated in group B that was (41.19 ± 5.16 ng/dL), and (39.53 ± 4.98 ng/dL) in group A. Moreover, the level of estradiol (E2) in group A was 79.45ng/dL while in group B the level was 72.65 ng/dL there are no significant difference between two groups. The study found conflicting evidence regarding the impact of high LH levels on oocyte quality, fertilization, and pregnancy outcomes in PCOS patients. According to the research, ovarian theca cells from PCOS patients may be more effective than normal theca cells at converting androgenic precursors to testosterone. While ovulatory dysfunction in PCOS is linked to reduced estradiol production, the study indicates that ovarian tissue may still contribute to circulating estradiol levels in affected women.

Study of hypothalamic-pituitary-testicular axis in Egyptian post-COVID-19 patients

ABSTRACT Background SARS-CoV-2, was identified as a global pandemic by the World Health Organization a few months after the first epidemic. It penetrates host cells through angiotensin-converting enzyme 2 receptors and spreads by respiratory droplets. Testes are among the several tissues that have high expression levels of ACE-2 receptors. The current study aimed to evaluate the hypothalamic-pituitary-testicular axis integrity among Egyptian post-COVID-19 patients. Methods This is a cross-sectional study that included patients with a history of COVID-19 infection, at least 3 months from the onset of COVID-19. A detailed clinical history was obtained, and a thorough examination was performed. Laboratory tests included FBG, total testosterone, free testosterone, bioactive testosterone, FSH, LH, prolactin, E2, albumin, and SHBG. Testicular ultrasonography was performed. The data were statistically analyzed. Results Eighty male patients were evaluated with a mean age of 35.53 ± 10.35 years. The mean serum total testosterone was 5.48 ± 1.65 ng/ml. Low testosterone was detected in 2.8% of the patients. High LH levels were detected in 17/80 patients (21.3%). High FSH levels were detected in 4/80 patients (5%). Six patients had elevated serum E2 level. The mean serum prolactin value was 10.90 ± 5.66 ng/ml. Fourteen patients had elevated prolactin levels. The mean serum T/LH ratio was 3.28 ± 1.52. The ratio of T/LH was decreased in eight COVID-19 patients (10%). In COVID-19 patients, a statistically significant negative correlation was found between age and free testosterone (FT) (r=-0.381, p < 0.001), bioavailable testosterone (Bio. T) (r=-0.375, p = 0.001), and androgen index (A. index) (r=-0.446, p < 0.001). Conclusion The data of the current study suggest that COVID-19 infection might deteriorate pituitary – gonadal axis. The prevalence of low testosterone in COVID-19 male survivors is low. The risk of hypogonadism is increased with advanced age. More studies are required to confirm the relationship between COVID-19 infection and male gonadal function.

LHCGR inactivating variants: single center experience and systematic review of phenotype-genotype of 46,XY and 46,XX patients.

The data on Leydig cell hypoplasia (LCH) resulting from biallelic Luteinizing hormone/chorionic gonadotropin receptor (LHCGR) inactivating variants is limited to case series. We aim to describe our patients and perform systematic review of the patients with LHCGR inactivating variants in the literature. Detailed phenotype and genotype data of three patients from our centre and 85 (46,XY: 67; 46,XX: 18) patients from 59 families with LHCGR-inactivating variants from literature were described. Three 46,XY patients (age 6-18 years) from our center, with two reared as females, had two novel variants in LHCGR. Systematic review (including our patients) revealed 72 variants in 88 patients. 46,XY patients (n = 70, 56 raised as females) presented with pubertal delay (n = 41) or atypical genitalia (n = 17). Sinnecker score ≥3 (suggesting antenatal human chorionic gonadotropin (hCG) inaction) was seen in 80% (56/70), and hCG-stimulated testosterone was low (<1.1 ng/mL) in 77.4% (24/31), whereas puberty/postpubertal age, high luteinizing hormone (LH) (97.6%, 41/42) and low (<1.0 ng/mL) basal testosterone (94.9%, 37/39) was observed in most. Follicle stimulating hormone was elevated in 21/51 of these patients. Variants with <10% receptor function were exclusively seen in cohorts with Sinnecker 4/5 (10/15 vs 0/5, P = 0.033). 46,XX patients (n = 18) presented with oligo/amenorrhea and/or anovulatory infertility and had polycystic ovaries (7/9) with median LH of 10 IU/L (1.2-38). In summary, this study comprehensively characterizes LHCGR variants, revealing genotype-phenotype correlations and informing clinical management of LCH. In 46,XY LCH patients, pubertal LH inaction is uniform with variable severity of antenatal hCG inaction. Few mutant LHCGR have differential actions for LH and hCG.

Infrared thermography technique for detecting estrus in Surti does

The present study evaluated the potential of the infrared thermography technique for estrus detection in Surti does. Based on the presence of estrus-specific behaviour, physiological signs as well as higher LH, FSH, estrogen and lower progesterone hormone concentration, 24 Surti does were divided into two groups, viz. estrus and non- estrus does. Recording of surface temperatures, rectal and tympanic temperatures was done using an Infrared thermal camera (FLIR T420), digital thermometer and infrared non-contact tympanic thermometer, respectively. It was concluded that temperatures of the vulva, rectal surface, rectal and tympanic temperatures are significantly higher in estrus does. Further, a strong, significant positive correlation was observed between vulvar and pudendal, rectal surface temperatures, rectal temperature as well as tympanic temperature. Thus, it may be concluded that the infrared thermography technique holds the potential for detecting estrus in Surti does.

An unusual case of 17-hydroxylase deficiency presenting with short stature

17α-Hydroxylase and 17,20-lyase are enzymes encoded by the CYP17A1 gene and are necessary for the production of cortisol and sex steroids. Females with 17α-hydroxylase deficiency usually present with primary amenorrhea and delayed puberty accompanied by hypertension and electrolyte imbalance. Here, we report the case of a 14-year-old female patient who presented with severe short stature and delayed puberty without any complaint suggestive of 17-hydroxylase enzyme deficiency. Laboratory test results showed low cortisol and dehydroepiandrosterone sulfate (DHEA-S) along with high luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Turner syndrome was excluded after genetic analysis showed a 46,XX karyotype, and 17α-hydroxylase deficiency was diagnosed by detecting a c.1319G>A (p.Arg440His) variation/alternation in the patient's CYP17A1 gene.

Targeted inhibition of kisspeptin neurons reverses hyperandrogenemia and abnormal hyperactive LH secretion in a preclinical mouse model of polycystic ovary syndrome.

Do hyperactive kisspeptin neurons contribute to abnormally high LH secretion and downstream hyperandrogenemia in polycystic ovary syndrome (PCOS)-like conditions and can inhibition of kisspeptin neurons rescue such endocrine impairments? Targeted inhibition of endogenous kisspeptin neuron activity in a mouse model of PCOS reduced the abnormally hyperactive LH pulse secretion and hyperandrogenemia to healthy control levels. PCOS is a reproductive disorder characterized by hyperandrogenemia, anovulation, and/or polycystic ovaries, along with a hallmark feature of abnormal LH hyper-pulsatility, but the mechanisms underlying the endocrine impairments remain unclear. A chronic letrozole (LET; aromatase inhibitor) mouse model recapitulates PCOS phenotypes, including polycystic ovaries, anovulation, high testosterone, and hyperactive LH pulses. LET PCOS-like females also have increased hypothalamic kisspeptin neuronal activation which may drive their hyperactive LH secretion and hyperandrogenemia, but this has not been tested. Transgenic KissCRE+/hM4Di female mice or littermates Cre- controls were treated with placebo, or chronic LET (50 µg/day) to induce a PCOS-like phenotype, followed by acute (once) or chronic (2 weeks) clozapine-N-oxide (CNO) exposure to chemogenetically inhibit kisspeptin cells (n = 6 to 10 mice/group). Key endocrine measures, including in vivo LH pulse secretion patterns and circulating testosterone levels, were assessed before and after selective kisspeptin neuron inhibition and compared between PCOS groups and healthy controls. Alterations in body weights were measured and pituitary and ovarian gene expression was determined by qRT-PCR. Acute targeted inhibition of kisspeptin neurons in PCOS mice successfully lowered the abnormally hyperactive LH pulse secretion (P < 0.05). Likewise, chronic selective suppression of kisspeptin neuron activity reversed the previously high LH and testosterone levels (P < 0.05) down to healthy control levels and rescued reproductive gene expression (P < 0. 05). N/A. Ovarian morphology was not assessed in this study. Additionally, mouse models can offer mechanistic insights into neuroendocrine processes in PCOS-like conditions but may not perfectly mirror PCOS in women. These data support the hypothesis that overactive kisspeptin neurons can drive neuroendocrine PCOS-like impairments, and this may occur in PCOS women. Our findings complement recent clinical investigations using NKB receptor antagonists to lower LH in PCOS women and suggest that pharmacological dose-dependent modulation of kisspeptin neuron activity may be a valuable future therapeutic target to clinically treat hyperandrogenism and lower elevated LH in PCOS women. This research was supported by NIH grants R01 HD111650, R01 HD090161, R01 HD100580, P50 HD012303, R01 AG078185, and NIH R24 HD102061, and a pilot project award from the British Society for Neuroendocrinology. There are no competing interests.

O-059 ART in PCOS

Abstract Polycystic Ovarian Syndrome affects an estimated 8 – 13% of women of reproductive age (WHO). It is the commonest cause of anovulation and infertility. The high AMH, LH, Insulin resistance and hyperandrogenism seen in PCOS women contributes to infertility along with poor oocyte quality and reduced endometrial receptivity. ART procedures are recommended as the third line of treatment after ovulation induction, IUI or ovarian drilling. Prior to IVF, metabolic assessment and lifestyle adjustments with weight management must be done. Adjuvant agents such as metformin melatonin, myoinositol and Vitamin-D have been tried to improve IVF outcomes. Mild stimulation is an option in patients as high risk for ovarian hyperstimulation syndrome (OHSS). Conventional stimulation with low dose FSH, GnRH antagonist down regulation, agonist trigger with freezing of all embryos, significantly reduces risk of OHSS without compromising cumulative live birth rates. Adjustments for stimulation protocols may need to be made for BMI, insulin resistance and AMH. In vitro maturation can be considered in patients with prior severe OHSS, though the results may be inferior. ART in PCOS patients is challenging and even after pregnancy is achieved, there may be a higher risk of adverse obstetric outcomes.

The role of mesenchymal stem cell therapy in ameliorating diabetes-induced ovarian damage in albino rats: Histological, biochemical and immunohistochemical studies

Background Diabetes mellitus (DM) is a chronic disease causing a variety of complications that can damage most organs, including the gonads. Diabetes was reported to be effectively treated using mesenchymal stem cells (MSCs). Objective The objective of the work was to demonstrate the therapeutic role of stem cells in cases of ovarian damage due to diabetes. Materials and methods Eighteen adult female albino rats were divided evenly into three groups. The control group received an injection of 1 ml of saline intraperitoneally (i.p.). The streptozotocin (STZ)-treated group: that was given 60 mg/kg per body weight (i.p.) of STZ to induce DM, which was slaughtered after 4 weeks. The STZ+stem cell-treated group that got STZ then was allowed to recover for 4 weeks and then underwent an intravenous injection of one million MSC before being sacrificed. Measurements of blood glucose, serum estradiol (E2), follicular-stimulating hormone (FSH), and luteinizing hormone (LH) were performed. Histological examination with hematoxylin and eosin, Masson stain, and immunohistochemical investigation for proliferating cell nuclear antigen (PCNA) were performed on the ovarian sections. Results and conclusion The STZ-induced DM group showed high glucose, FSH, and LH levels and decreased the E2 levels. Also, the inflammation, degeneration, and decreased PCNA immune expression of the ovary development in the STZ-induced DM group were observed. The treatment with the MScs reversed the effect of DM on glucose, FSH, LH, and E2. Additionally, the MScs improved the pathological alterations by increasing PCNA immune expression in the ovary. It was concluded that MSCs can effectively treat diabetes-induced ovarian damage.

Intrauterine insemination timing models-LH can only take you so far.

Can an optimal LH threshold algorithm accurately predict timing of ovulation for natural cycle-intrauterine insemination (NC-IUI)? A retrospective cohort study (2018-2022) including 2467 natural cycles. Ovulation timing for these cycles was determined using a previously developed AI model. Two LH thresholds, low and high, were determined in the LH algorithm. Being below the low threshold meant that ovulation is likely to occur in ≥ 4days, suggesting another daily blood test. Between the two thresholds meant that ovulation was likely in 2-3days, suggesting IUI the next day. Above the high threshold meant that ovulation will likely occur tomorrow, suggesting performing IUI on the same day. The optimal LH model with a high threshold of 40 mIU/ml and a low threshold of 11 mIU/ml succeeded in correctly predicting timing for IUI (day - 1, - 2 relative to ovulation) in 75.4% (95%CI 75.3-75.4). In 23.1% (95%CI 23.0-23.2), the algorithm predicted "error," suggesting performing insemination when in fact it would have been performed on a non-optimal day (0 or - 3). A previously described 3-hormone-based (LH, estradiol, progesterone) AI model performed significantly better in all parameters (93.6% success rate, 4.3 "error" rate). An LH threshold model, representing common practice, evaluating all possible high and low LH threshold combinations, was successful in accurately scheduling timing for IUI in only 75% of cases. Integrating all three hormones as performed in the AI model may have an advantage in accurately predicting the optimal time for IUI, over the use of LH only.

Clustering Identifies Subtypes With Different Phenotypic Characteristics in Women With Polycystic Ovary Syndrome.

Hierarchical clustering (HC) identifies subtypes of polycystic ovary syndrome (PCOS). This work aimed to identify clinically significant subtypes in a PCOS cohort diagnosed with the Rotterdam criteria and to further characterize the distinct subtypes. Clustering was performed using the variables body mass index (BMI), luteinizing hormone (LH), follicle-stimulating hormone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), testosterone, insulin, and glucose. Subtype characterization was performed by analyzing the variables estradiol, androstenedione, dehydroepiandrosterone, cortisol, anti-Müllerian hormone (AMH), total follicle count (TFC), lipid profile, and blood pressure. Study participants were girls and women who attended our university hospital for reproductive endocrinology screening between February 1993 and February 2021. In total, 2502 female participants of European ancestry, aged 13 to 45 years with PCOS (according to the Rotterdam criteria), were included. A subset of these (n = 1067) fulfilled the National Institutes of Health criteria (ovulatory dysfunction and hyperandrogenism). Main outcome measures included the identification of distinct PCOS subtypes using cluster analysis. Additional clinical variables associated with these subtypes were assessed. Metabolic, reproductive, and background PCOS subtypes were identified. In addition to high LH and SHBG levels, the reproductive subtype had the highest TFC and levels of AMH (all P < .001). In addition to high BMI and insulin levels, the metabolic subtype had higher low-density lipoprotein levels and higher systolic and diastolic blood pressure (all P < .001). The background subtype had lower androstenedione levels and features of the other 2 subtypes. Reproductive and metabolic traits not used for subtyping differed significantly in the subtypes. These findings suggest that the subtypes capture distinct PCOS causal pathways.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. To clarify associations of sex hormones with these outcomes. Systematic literature review to July 2019, with bridge searches to March 2024. Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. Observational study design, heterogeneity among studies, and imputation of missing data. Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).