bluuebunny/crossref_metadata_2025 huggingface dataset:
OR14-4 Acute sleep disruption does not diminish pulsatile growth hormone secretion in pubertal children
Authors: Amin Rafiul , Faghih Rose T , Genty Jon , Kangarloo Tairmae , Klerman Elizabeth B , Molsberry Samantha , Shaw Natalie D , Calvert Madison
Published: November 2022

Context: Growth hormone (GH) plays a critical role in glucose homeostasis and linear growth during childhood. GH secretion is controlled by multiple neurotransmitters and hormones. Sleep is also a powerful stimulus for GH secretion. In children, GH pulses occur after sleep onset in association with slow-wave sleep (SWS), but it is unclear if undisrupted sleep is required for normal GH secretion. Given the rising incidence of pediatric sleep disorders such as obstructive sleep apnea (OSA) that cause sleep fragmentation, it is critical to determine whether sleep fragmentation during childhood may dysregulate the somatotropic axis.

Objective

To quantify how undisrupted vs fragmented sleep affects GH secretion in children.

Methods

Pubertal subjects (10 M, 9 F; 9.1-14.4 yrs) were randomized to two overnight polysomnographic studies with frequent blood sampling (q10min) to measure GH: fourteen were healthy subjects studied with or without SWS disruption via auditory stimuli (3 sec, 1500 Hz tones, 40-100 dB followed by 18 sec of a 75 dB noise simulating a knock on the door) and five were subjects with OSA studied with or without prescribed continuous positive airway pressure (CPAP); the latter condition was expected to have sleep fragmentation due to untreated OSA. GH pulses were identified using sparse deconvolution. Studies without auditory stimuli or when using CPAP were combined and analyzed as 'undisrupted sleep'. The relationship between GH pulse rate per hour and sleep stage was evaluated using Poisson generalized estimating equations.

Results

In SWS disruption studies, an average of 77.51 ± 13.61 (range 23-190) auditory stimuli were delivered, causing a 40.02 ± 7.78% decrease in SWS in favor of lighter sleep stages. In subjects with OSA, CPAP withdrawal caused a slight increase in the apnea hypopnea index (1.08 ± 0.10 vs. 2.20 ± 1.70 events/hour of sleep, p=0.07) with no change in sleep stage durations. During undisrupted sleep, subjects had an average of 0.91 ± 0.067 GH pulses/hour with a mean pulse amplitude of 10.03 ± 1.00 ng/mL and mean basal secretion rate of 0.26 ± 0.10 ng/ml per min. GH pulses occurred more frequently during SWS (2.3 pulses/hour SWS, amplitude 9.92 ± 2.59 ng/mL) than during any other sleep stage (P < 0.001). Neither form of sleep disruption affected the distribution of GH pulses across sleep stages, GH pulse amplitude and frequency, nor basal GH secretion.

Conclusion

In children, nocturnal GH pulses are temporally associated with SWS. However, neither acute fragmentation of SWS nor nocturnal arousals from OSA altered basal or pulsatile GH secretion, indicating that somatotrophic axis activity is preserved in the face of acute sleep disruption in children.

Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.
OR18-2 Clinical, Hormonal and Genetic Characterization of Familial Central Precocious Puberty
Authors: Argente Jesús , Brito Vinicius , Guimaraes Aline , Latronico Ana Claudia , Leal Andrea , Mendonça Berenice , Montenegro Luciana , Piovesan Maiara , Ramos Carolina , Seraphim Carlos , Tinano Flavia , Canton Ana
Published: November 2022

Context: Familial central precocious puberty (CPP) is a prevalent form (about 27.5%) of precocious puberty. Loss-of-function mutations in two maternally imprinted genes, MKRN3 and DLK1, were identified in families with CPP showing dominant autosomal inheritance with paternal transmission. Maternally transmitted CPP was previously demonstrated in up to 60% of families using pedigree analysis, however, no definitive genetic abnormality has been identified so far.

Objectives

To estimate the prevalence of familial cases in a multiethnic cohort with CPP. To characterize the genetic basis and the mode of inheritance of the affected families. To compare clinical and hormonal features of patients with familial CPP due to different modes of transmission.

Patients and Methods

Clinical and hormonal data were obtained from medical registries of 495 patients with CPP and no brain MRI alterations. Familial CPP was defined as the presence of one or more close relatives with CPP or precocious menarche (≤9 yr). Sanger sequencing of MKRN3 and DLK1 was performed in 427 index cases. Targeted gene panel sequencing was performed in 79 cases, while whole exome sequencing was performed in 101 cases from 36 families

Results

Among 495 index cases, 159 had familial CPP (31%). The mode of transmission of CPP was identified as paternal in 58 (35%), maternal in 59 (38%), indeterminate in 34 (22%), and both maternal and paternal transmission in 8 (5%). Most families with paternal or maternal transmission had 2 generations known to be affected (51 and 77%, respectively). Notably, 67% of index cases with maternally transmitted CPP had their mother affected. In girls with CPP, the median age of thelarche was 6.5 yr in the paternally transmitted group, 6.9 yr in the maternally transmitted group, and 7.3 yr in the indeterminate group (p= 0.547). Median bone age advancement was 2.1, 2.3 and 1.2 yr, respectively (p= 0.013). Basal LH levels were higher in girls with paternally transmitted CPP (p= 0.047). Among those with paternally transmitted CPP, MKRN3 and DLK1 mutations were identified in, respectively, 63.8% and 10.3% of the families.

Conclusions

A significant prevalence (31%) of familial CPP was demonstrated in a multiethnic cohort. Maternally transmitted CPP represented the most frequent form of familial CPP (38%). MKRN3 loss-of-function mutations were responsible for most paternally transmitted CPP cases (63.8%), followed by DLK1 loss-of-function mutations (10.3%).

Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.
RF14 | PSAT114 Conversion from one side of the autoimmune thyroid spectrum to the other: a pediatric clinical challenge
Authors: Almutlaq Nourah , Eugster Erica A , Nebesio Todd D
Published: November 2022

Introduction

Graves disease and Hashimoto thyroiditis represent the two ends of the autoimmune thyroid spectrum. Spontaneous conversion from one to the other is a rare phenomenon, especially in children, and the underlying mechanism is unknown. Changes in the predominance of stimulating versus blocking TSH receptor antibodies (TRAb) has been proposed as a potential etiology.Method: We describe a series of cases of autoimmune thyroid disease in children that converted from one end of the biochemical spectrum to the other Result: Eleven patients of whom 55% were girls and 36% had Down syndrome (DS) were identified. Five (46%) presented with hyperthyroidism (hyper) that spontaneously converted to hypothyroidism (hypo). Four patients (36%) had hypo which converted to hyper while the remaining 2 (18%) presented with Hashitoxicosis (HT) with negative TRAb titers which later converted to hyper. In those who went from hyper to hypo, mean duration of antithyroid drug therapy was 1.8 ± 1.4 years and mean age at initial presentation was 11.0 ± 4.8 years (5-16). Before conversion, all 5 patients had positive TRAb titers with mean of 15.0 ± 4.2 and a mean thyroid peroxidase antibody level of 287.5 ± 389. A period of euthyroidism lasting 2.0 ± 0.8 years was present prior to the development of hypo with a mean TSH of 17.0 ± 25 mU/L (5.8-62). Mean duration of hypo in the second group was 5.0 ± 5.2 years and mean age at initial diagnosis was 6.7 ± 2.8 years (3-10). TSH became suppressed in all 4 patients, TRAb was elevated, and mean free T4 off levothyroxine was 3.3 ± 1.2 ng/dL (2.4-4.6). The two patients with initial HT were 12 ± 2.8 years at diagnosis and converted to hyper after 6.5 ± 0.7 months. Initial mean free T4 was 1.3 ± 0.2 ng/dL and after conversion was 4.6 ± 0.4 ng/dL along with strongly positive TRAb titers (mean of 6.9 ± 6.5). TSH became further suppressed after conversion to hyper (<0.01). More of our patients with DS converted from hypo to hyper than the other direction (75% vs 20%, p=0.01). However, two of them proceeded to have a wavering course between hyper and hypo requiring intensive monitoring and frequent changes in management.

Conclusion

Although oscillating thyroid function in children with autoimmune thyroid disease is uncommon, it is important for parents and providers to be aware of this entity. The natural history of these cases is extremely variable and clinical management is challenging. Our findings suggest that DS may be a risk factor for the phenomenon of vacillating thyroid function in pediatric patients.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:42 p.m. - 12:47 p.m.
RF26 | PMON332 Safety and Efficacy of Treatment with Lonapegsomatropin in Children with Growth Hormone Deficiency at Week 130 in the enliGHten Trial
Authors: Saenger Paul , Nadgir Ulhas , Hofman Paul , Thornton Paul , Chertok Elena D , Aghajanova Elena M , Korpal-Szczyrska Maria , Vlachopapadopoulou Elpis , Malievskiy Oleg , Chaychenko Tetyana , Cappa Marco , Song Wenjie , Mao Meng , Chessler Steven D , Komirenko Allison S , Beckert Michael , Shu Aimee D , Maniatis Aristides K
Published: November 2022

Background

Once-weekly lonapegsomatropin (TransCon hGH) is a long-acting prodrug of somatropin, recently approved for the treatment of pediatric growth hormone deficiency (GHD) by the US FDA. In the pivotal 52-week phase 3 heiGHt trial and the 26-week fliGHt trial, lonapegsomatropin demonstrated safety and efficacy in both treatment-naïve and treatment-experienced children with GHD.

Methods

Results are reported from Week 130 (data snapshot date: September 01, 2021) from the open-label extension trial enliGHten. Upon entry into enliGHten, all participants received lonapegsomatropin via vial/syringe, with subsequent switch to TransCon hGH Auto-Injector when available.

Results

A total of 298 participants (98% of parent trials) continued from the heiGHt or fliGHt trials into enliGHten. At Week 130, 36 participants had completed the trial and 248 participants remain enrolled. The height standard deviation score (SDS) mean (standard deviation [SD]) at Week 130 was -0.64 (0.85) compared with baseline value of -1.56 (0.88) at the start of enliGHten. Participants continued to approach the average parental height SDS mean (SD) of -0.39 (0.77). The annualized height velocity mean (SD) at Week 130 was 9.32 cm/year (0.45). Average IGF-1 SDS mean (SD) at Week 130 was 1.46 (1.18) compared with 0.52 (1.58) at enliGHten baseline. For the 36 participants who had completed the trial, 14 had reached bone age of >14 years (girls) or >16 years (boys), and 24 had completed the study based on investigator judgement that treatment for growth hormone deficiency was no longer necessary. The difference between mean (SD) height SDS at last visit and average parental height SDS was -0.05 (0.75) for the 36 completers, and 61.1% of these participants had met or exceeded the average parental height SDS. The mean (SD) total duration of hGH treatment for participants who completed the trial (including daily treatment and lonapegsomatropin) was 3.53 (0.88) years, and the mean (SD) duration of treatment with lonapegsomatropin was 2.20 (0.66). With continued lonapegsomatropin treatment, the AE profile remained consistent with what was observed in the parent trials, with no new safety signals.

Conclusions

Children and adolescents treated with lonapegsomatropin showed continued improvement of height SDS through their 3rd year of therapy. Lonapegsomatropin continued to demonstrate a safety profile comparable to that of daily somatropin therapy.

Presentation: Monday, June 13, 2022 12:30 p.m. - 12:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
LBMON231 Virilization Secondary To Androgen Producing Ovarian Serous Cystadenoma
Authors: De Guzman Vernon Joseph , Vargas-Jerez Julia , Zahra Tasneem
Published: November 2022

Background

Ovarian cystadenomas are classically considered as 'non-functional' tumors and among the most common benign ovarian neoplasms. Most of these tumors are asymptomatic and found incidentally on pelvic examination or with ultrasound. In rare circumstances these tumors may present as functional with secretions of excess androgens that subsequently produce virilizing features.

Clinical Case

A 59 year old Hispanic female G3P3(3003) presented to the clinic for receding hairline and facial hair for a duration of almost 2 years. Her medical history included total abdominal hysterectomy, due to fibroids, syphilis treated in Dominican Republic, Obesity, Vitamin D deficiency. On examination patient had hirsutism and significant hair growth on the abdomen, axilla, chest and extremities. The clitoris was enlarged, had frontal blading and increased abdominal circumference. Initial laboratory studies showed total testosterone was elevated [264 ng/mL] and free testosterone was high normal [4.2 pg/mL], DHEA-Sulfate normal [29.2 ug/mL], CA 125 unremarkable [5 U/mL]. Repeat labs were done showed elevated total testosterone and free testosterone [276 ng/mL and 4.7 pg/mL respectively] Normal levels of DHEA [87ng/dL] and DHEA-sulfate [ug/mL], 17-Hydroxyprogesterone [64 ng/mL], FSH normal [41.7 IU/L], LH normal [26.6 IU/L], morning cortisol level was normal [ 7.1 ug/mL] and a normal response to 1 mg dexamethasone suppression test. Transvaginal/Transabdominal ultrasound showed a left adnexa of 11.7×5.5×8.3 cm and simple cystic mass with no internal septations or nodularity and unremarkable right adnexa. Imaging by CAT scan showed a 9 cm left adnexal mass likely cystadenoma with unremarkable liver, spleen, pancreas and adrenals. Considering the laboratory, imaging findings and onset of symptoms the androgen production favors left adnexal cyst as the origin and not from the adrenals. Patient then underwent bilateral salphingoophorectomy without any complications and pathology reports revealed left serous cystadenoma. During her 2 week and 3 month post op follow up, patient reports no improvement of her hirsutism and virilization while repeat labs postoperatively showed normalization of total [15 ng/mL] and free testosterone [1.5 ng/mL].

Conclusion

In conclusion, we report a rare case of androgen producing ovarian serous cystadenoma with virilizing features. References: 1. Wasay Nizam, Shah A, Cornwell E., Naab, Tammey, Williams Mallory. Postmenopausal virilization secondary to large ovarian cystadenoma with stromal hyperthecosis. 2021.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
LBMON233 Hormonebayes: A Novel Bayesian Toolbox For Analysis Of Pulsatile Hormone Dynamics
Authors: Voliotis Margaritis , Abbara Ali , Prague Julia K , Veldhuis Johannes D , Dhilo Waljit S , Tsaneva-Atanasova Krasimira
Published: November 2022

The hypothalamus is the central regulator of reproductive hormone secretion. Pulsatile secretion of gonadotropin releasing hormone (GnRH) is fundamental to physiological stimulation of the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Furthermore, GnRH pulsatility is altered in common reproductive disorders such as polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea (HA). LH is measured routinely in clinical practice using an automated chemiluminescent immunoassay method and is the gold standard surrogate marker of GnRH. LH can be measured at frequent intervals (e. g., 10 minutely) to assess GnRH/LH pulsatility. However, this is rarely done in clinical practice because it is resource intensive, and there is no user-friendly and accessible method for computational analysis of the LH data available to clinicians. Here we present hormoneBayes, a novel open-access Bayesian framework that can be easily applied to reliably analyze serial LH measurements to assess LH pulsatility. The framework utilizes parsimonious models to simulate hypothalamic signals that drive LH dynamics, together with state-of-the-art (sequential) Monte-Carlo methods to infer key parameters and latent hypothalamic dynamics. We show that this method provides estimates for key pulse parameters including inter-pulse interval, secretion and clearance rates and identifies LH pulses in line with the current gold-standard deconvolution method. We show that these parameters can distinguish LH pulsatility in different clinical contexts including in reproductive health and disease in men and women (e. g., healthy men, healthy women before and after menopause, women with HA or PCOS). A further advantage of hormoneBayes is that our mathematical approach provides a quantified estimation of uncertainty. Our framework will complement methods enabling real-time in-vivo hormone monitoring and therefore has the potential to assist translation of personalized, data-driven, clinical care of patients presenting with conditions of reproductive hormone dysfunction.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
LBMON273 Not All Men Are Created Equal
Authors: van Rooyen Desmaré , Atkin Stephen L , Swart Amanda C
Published: November 2022

Background

Clinical assessment of androgens in the diagnosis of androgen excess, hypogonadism, androgen replacement or suppressive therapy and in anti-doping practices is generally limited to a few C19 steroids. More accurate evaluations may be gained with comprehensive steroid analysis. The aim of this study was to determine all major circulating adrenal and gonadal steroids together with the adrenal C11-oxy C19 steroids.

Methods

Serum androgens, mineralocorticoids, glucocorticoids, progesterones and C11-oxy steroids were determined in 71 healthy men, 18-35yrs, using ultra-performance convergence-chromatography tandem mass spectrometry. Data was analysed using GraphPad Prism Version 9.3.1.

Results

Profiles and inter-individual steroid concentrations differed considerably. Testosterone (25.2 nM) was detected in all subjects while dehydroepiandrosterone (DHEA) was undetectable in 18% of the subjects. Comparing subjects with DHEA, 11.14 (3.178-52.73) nM and those without DHEA identified steroids differing significantly (p≤0. 001; q values ≤5%): 11-OHA4 (4. 0 ±0.3 vs 1.6±0.3 nM), 16-hydroxyprogesterone (0.7±0. 07 vs 0.3 ±0.1 nM), corticosterone (15.5±1.8 vs 3.8±1.1 nM), 11-dehydrocorticosterone (4.5±0.3 vs 2±0.5nM), cortisol, (357±21.2 vs 157.9±29.3 nM) and cortisone (57.9±2.4 vs 35.3 ±5.4 nM). Dihydrotestosterone (∼4.3 nM) and 11-hydroxytestosterone (∼0.5 nM) were detected at comparable concentrations, however, at a frequency of 25% and >90%, respectively (in both groups). 11-ketotestosterone levels were also comparable but below the limit of accurate quantification while present in ∼50% of the subjects. Epitestosterone levels were comparable (0.2±0. 02 vs 0.1±0. 03 nM), but higher in younger subjects 18-25 yrs (p<0. 05).

Conclusions

Analysis of gonadal and adrenal steroids indicate greater circulating steroid heterogeneity than previously thought. Data shows that the often-disregarded adrenal C11-oxy C19 steroids contributed to 16% of the androgen profile. Furthermore, given that the C19 steroids were 1.8-fold lower in men without measurable DHEA, the functional oxyandrogens, 11-ketotestosterone and 11-hydroxytestosterone, would be of particular physiological importance due to their androgenic activity. Absence of measurable DHEA showed an overall modulated adrenal steroidogenic flux in these men, evident in the attenuated glucocorticoid production. Data underscores the modulatory role of cytochrome P450 11β-hydroxylase in these individuals, potentially impacting on diagnostic testing and evaluation.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
LBODP089 Effects Of Low-dose Oral Micronised Progesterone On Sleep, Psychological Distress And Breast Development In Transgender Individuals Undergoing Feminising Hormone Therapy: A Prospective Controlled Study
Authors: Nolan Brendan J , Frydman Aviva S , Leemaqz Shalem Y , Carroll Meg , Grossmann Mathis , Zajac Jeffrey D , Cheung Ada S
Published: November 2022

Objective

The role of micronised progesterone in hormone regimens for transgender individuals undergoing feminising hormone therapy remains uncertain. We aimed to determine the effect of oral micronised progesterone (progesterone) on sleep quality, psychological distress and breast development in transgender individuals undergoing feminising hormone therapy. Design: Prospective case-control study. Twenty-three transgender individuals on stable estradiol treatment newly commencing 100mg oral progesterone (n=23) and controls continuing standard care (n=19) were assessed over 3 months.

Methods

Pittsburgh Sleep Quality Index (PSQI), Kessler psychological distress scale (K10), and Tanner stage to assess breast development were assessed at 0 and 3 months. Non-parametric ANCOVA were used to compare differences between groups.

Results

Compared with controls over 3 months, there was no difference in PSQI (P=0.35), K10 (P=0.64) or Tanner stage (P=0.42). There was no significant difference in the proportion of individuals with clinically significant improvement in PSQI (25% vs. 22%, P=0.84). One individual had a significant deterioration in psychological distress that improved following cessation of progesterone.

Conclusions

Low-dose progesterone was not associated with changes in sleep quality, psychological distress, or breast development over three months follow-up, though there was significant inter-individual variability. Larger, placebo-controlled trials are required to further evaluate different doses of progesterone in feminising hormone therapy regimens.

Presentation: No date and time listed
ODP403 Diversity of Estrogen-Responsive Genes in Endometriotic Lesions
Authors: Izawa Masao , Taniguchi Fuminori
Published: November 2022

Background

Endometriosis has been accepted as an estrogen-dependent disease for more than two decades. So far, estrogen modulators that targeting estrogen depletion in endometriotic lesions have been expected as the first option of treatments to improve the symptoms associated with endometriosis. However, the limits of treatment are becoming apparent.

Objective

As the background of limits, we hypothesized the heterogeneity of genetic and/or epigenetic environments in endometriotic lesions (1). To test our hypothesis, we examined the expression profile of estrogen-responsive genes using endometriotic stromal cells as a model. Patients: Institutional Review Boards approved this project. We obtained informed consent from all patients. The chocolate cyst lining in the ovaries of patients with endometriosis was the source of endometriotic tissue. As a control, the eutopic endometrial tissues were obtained from uteri of premenopausal women who had uterine leiomyoma.

Methods

Stromal cells were prepared from endometriotic and endometrial tissues. ESR1 and ESR2 expression were evaluated using RT-PCR (2). For RNA-seq analysis of estrogen-responsive genes, total cellular RNAs from endometriotic cells treated with or without 10nM estradiol for 8hr were prepared. Following the quality control (concentration>50ng/ul, RIN>9), RNA samples were used for polyA+ selected library preparation and the strand-specific RNA-seq (NovaSeq, DNBSEQ-G400, 20M paired- end (PE) reads and 2×150bp PE/sample). Estrogen-responsive genes were extracted using RNA-seq bioinformatics analysis. Genes with adjusted p-values < 0. 05 and absolute log2 fold changes > 1 were extracted as estrogen-responsive genes (DESeq2 BP). Principal component analysis (PCA) was used to visualize sample-to-sample distances. Differential gene GO enrichment analysis was performed (GOseq. v1.34.1).

Results

1) wild type ERα mRNA expression in endometriotic cells was one-tenth of that in endometrial cells. wild type ERβ1 and the splice variant ERβ2 mRNAs were expressed in endometriotic cells at a comparable level of the ERα. 2) PCA suggested the presence of at least two cell types in endometriotic cells. 3) Cluster analysis of gene expression suggested the presence of 2 cell types: endometriotic cells with or without GATA6 expression (3). 4) Estrogen-responsive genes were significantly different among the cells examined. 4) Differential gene GO enrichment analysis suggested the diversity of gene expression profiles depending on the cells.

Conclusion

In the hope of overcoming the limits of endocrine-targeted therapy in endometriosis, we examined the estrogen-responsive genes in endometriotic cells. The finding suggests the diversity of estrogen-responsive genes in endometriotic lesions. References(1) Fertil Steril (2019) 111: 327–39. (2) Reprod Sci (2016) 23: 871-6. (3) Am J Reprod Immunol (2019) 81: e13078.

Presentation: No date and time listed
ODP405 Effects of Gonadotrope-Specific Knockout of Creb on HPG Axis Function in Mice
Authors: Hausken Krist , Quinn Alyssa , Kim Han , Boehm Ulrich , Carroll Rona , Kaiser Ursula
Published: November 2022

Background and Objective

Reproduction is regulated by FSH and LH, which are synthesized and secreted by pituitary gonadotropes in response to pulsatile hypothalamic GnRH in a frequency dependent manner. Low and high GnRH pulse frequencies preferentially increase Fshb and Lhb expression, respectively, mediated by preferential coupling to Gαs-PKA-Creb and Gαq-PKC-MAPK-AP1 signaling cascades in vitro. The mouse Fshb proximal promoter contains a half-AP1/half-CRE recognition motif that binds Creb in vitro, and mutation of this half-CRE results in loss of preferential GnRH stimulation of Fshb at low pulse frequencies in immortalized gonadotrope LβT2 cells. Therefore, the purpose of this study was to identify the direct role of Creb on gonadotropin regulation in vivo. We hypothesized that gonadotrope-specific deletion of Creb would influence pubertal timing and/or fertility due to reduced Fshb expression.

Methods and Results

Gonadotrope-specific Creb knockout (Creb1 fx/fx / Gnrhr GRIC/+; Creb KO) and control (Creb1 fx/fx) mice were generated by Cre-Lox recombination and markers for pubertal onset were evaluated. We observed no differences in body weights of Creb KO and littermate control mice in either females or males from postnatal day (PND) 21 to 3 months of age (n=9/genotype/sex). The age of vaginal opening, a marker of puberty onset in female mice, was not significantly different between female Creb KO (PND 28.4±0.5; n=21) and littermate control (PND 29.5±0.6; n=17) mice. Similarly, the age of first estrus, determined by vaginal lavage and cytology, was not significantly different between Creb KO mice (PND 37.6±1.9; n=9) and littermate controls (PND 36.6±2.2; n=8). Estrous cyclicity was normal over a three-week period in Creb KO and control mice, which spent similar amounts of time in diestrus/metestrus, proestrus, or estrus. Male Creb KO mice tended to show preputial separation at a younger age (PND 28.8±0.3; n=19) compared to littermate control (PND 29.6±0.3; n=22) mice, but the difference did not reach statistical significance (p=0. 06).

Conclusions

Deletion of Creb from pituitary gonadotropes did not affect the timing of pubertal onset in female mice, but we did observe a trend for male Creb KO mice to have advanced puberty, as measured by preputial separation. Normal pubertal timing does not preclude potential effects of Creb-mediated gonadotropin regulation on folliculogenesis, spermatogenesis, or fertility (including litter size), for which studies are ongoing.

Presentation: No date and time listed
ODP406 Effects of hormone replacement therapy on memory cognitive function in postmenopausal women: a systematic review and meta-analysis
Authors: Chen Yan , Chen Lin , Yao Jin , Chen Prof Gang
Published: November 2022

Objective

To investigate the effect of hormone replacement therapy (HRT) on memory cognitive function in postmenopausal women.

Methods

PubMed, Cochrane, Embase, Chinese Biomedical Literature Database (CBM)and web of ClinicalTrials.gov were systematically searched for randomized controlled trials comparing the effect of HRT on memory function in postmenopausal women to Placebo. The primary outcome of interest is memory cognitive function (measured by tests used in the study). We assessed pooled data by using random-effects model.

Results

Ten studies with 2818 participants were finally eligible for inclusion in the analysis. Compared with placebo, HRT showed no significant differences on logical memory including both immediate (weighted mean difference [WMD] 0.34, 95% CI: -0.73, 1.40) and delayed(0.99, 95% CI: -0.51, 2.48) recall in postmenopausal women, also no differences on short-delay (-0. 00, 95% CI: -0.37, 0.37) or long-delay (-0.19, 95% CI: -0.69, 0.31) recall of California Verbal Learning Test, but yielded an a mean reduction in digit span forward of -0.20 (95%CI: -0.36,-0. 03), with no significant difference in digit span total scores (-0.67, 95% CI: -1.58, 0.24) or backward (-0.10, 95%CI: -0.26, 0. 05). In women within 5 years of menopause, HRT still shows no harmful or beneficial effects on immediate (WMD 0.45, 95% CI: -0.75, 1.65) or delayed recall (WMD 1. 03, 95% CI: -0.93, 3. 00) of logical memory, but no detrimental effects on digit span forward (WMD -0.11, 95% CI: -0.72, 0.50).

Conclusion

This review suggests that HRT do not improve verbal memory in postmenopausal women, may even impair some domains of short-term memory. HRT may thus not be a potential therapeutic strategy to prevent memory decline in postmenopausal women.

Presentation: No date and time listed
ODP407 Effects of Leptin and Ghrelin on Ovarian Steroidogenesis and Involvement of BMP Action in Rat Granulosa Cells.
Authors: Nakano Yasuhiro , Kashino Chiaki , Hasegawa Toru , Iwata Nahoko , Soejima Yoshiaki , Suyama Atsuhito , Yamamoto Koichiro , Otsuka Fumio
Published: November 2022

Leptin and ghrelin are the two major hormones which regulate food intake and energy balance. They have also been reported to have pleiotropic functions, including the modulation of ovarian function via the hypothalamic-pituitary-ovarian system or in a direct manner to the ovaries. Blood leptin levels increase over the menstrual cycle and peak at the time of the luteinizing hormone (LH) surge. Leptin secreted from adipocytes acts on the hypothalamus and pituitary gland to stimulate the secretion of GnRH and gonadotropins. In the ovaries, high levels of leptin inhibit follicle-stimulating hormone (FSH)-induced steroid secretion and follicular development. Ghrelin, secreted by the stomach, has been reported to modulate GnRH secretion in the hypothalamus and to affect FSH and LH secretion, as well as steroidogenesis in the ovaries. Knockout of these hormones leads to impaired fertility. However, the mechanism of the direct effects of leptin and ghrelin on the ovaries has not been well elucidated. In the present study, we investigated the effects of leptin and ghrelin on the ovarian steroidogenesis using primary culture of rat granulosa cells, by focusing on the ovarian bone morphogenetic protein (BMP) system, which plays an important role in follicular development and steroidogenesis and acts as a luteinizing inhibitor. The results showed that treatment with leptin (1 to 300 ng/mL) did not affect either estradiol (E2) or progesterone (P4) production, but enhanced FSH-induced P4 production at low concentrations (10 ng/mL). On the other hand, treatment with ghrelin (1 to 300 nM) did not affect E2 and P4 production, but enhanced FSH-induced P4 production in a concentration-responsive manner. The mRNA levels of the follicular steroid synthases (StAR, P450scc, 3βHSD, 20αHSD) were examined. Leptin treatment enhanced 3βHSD mRNA levels. Both leptin treatment and ghrelin treatment decreased FSH-induced 20αHSD mRNA levels. However, both treatments decreased FSH-induced cAMP production. In addition, leptin treatment tended to suppress the transcriptional activity of Id-1 induced by BMP-6. Collectively, these results indicate that both leptin and ghrelin enhance FSH-induced P4 production by suppressing BMP signaling in rat granulosa cells. It was thus suggested that leptin and ghrelin which regulate food intake and energy balance can also act as endogenous regulators for the modulation of P4 synthesis and luteinizing process by ovarian follicles.

Presentation: No date and time listed
ODP411 Frequency of hyperandrogenism in Mexican adult women with type 1 diabetes mellitus: a pilot study.
Authors: García-Sãenz Manuel , Ramírez-Rentería Claudia , Ferreira-Hermosillo Aldo , López-Juãrez Nitzia G , Lobaton-Ginsberg Miry
Published: November 2022

Background

Hyperandrogenism has been described with different frequencies in populations of women and adolescents with type 1 diabetes (T1D). Ethnic differences account for variation in genetic causes as well as clinical and metabolic parameters for diagnosis. We aimed to evaluate clinical, laboratory and imaging tests of a sample of adult women with T1D in order to calculate a valid sample size for further studies in our population, which presents a high prevalence of metabolic syndrome.

Materials and methods

we included the first patients from a group of 55 women with T1D between the ages of 18 and 45. Blood samples were performed in the early follicular phase and ultrasound in the follicular phase. Ferriman-Gallwey score was evaluated by two independent trained observers. We excluded patients with hysterectomy or oophorectomy or continuous use of hormonal contraceptives in the last 3 months or previous cosmetic treatments. Non-parametric tests were calculated using SPSS v 21. 0 with a p<0. 05. Results are expressed in medians and interquartile ranges (IQR) or percentages.

Results

27 women had full workup, their median age was 32 years (IQR 25-40), the age of diagnostic of T1D was 13.5 years (IQR 10-20), 55.5% had a BMI >25 kg/m2, HbA1c was 8.6% (IQR 7.3-10) and used 0.83 UI insulin/kg/day (IQR 0.62-1. 06). Using the Rotterdam criteria 40.7% had PCOS, and 33.3% by stricter criteria based in hyperandrogenemia (AE-PCOS and NIH). A Ferriman-Gallwey score of 9 or higher was agreed in 40.7% of the cases with a inter-observer kappa of 77% (p<0. 001), 22.8% had elevated total testosterone, and 14.8% had DHEA-S above the upper limit of normal for age, the 55.6% had ultrasonographic criteria for PCOM. We eliminated 4 cases with 17-OHP progesterone of > 2. 0ng/mL, and 1 with undiagnosed primary ovarian insufficiency. A sample size of 41 is needed to achieve a power of 80% in this setting. Insulin doses were higher in patients with SOP compared with other patients (1. 06IU/kg/day in patients with PCOS and 0.73IU/kg/day in patients without PCOS, p=0. 013, IC -0.59; -0. 07).

Discussion and conclusions

Our population shows a high frequency of hyperandrogenism, which affects the patients reproductive capabilities, but also may be related to adverse metabolic outcomes. Hyperandrogenism may be related to PCOS, but also to undiagnosed comorbidities, which require further endocrine evaluation. More awareness is needed in the diagnosis of these conditions in our population.

Presentation: No date and time listed
ODP414 Incidence of Suicidal Events in Transgender Patients with Initiation of Gender Affirming Hormone Therapy
Authors: Elliott Karma-Jaya , Grotzke Marissa
Published: November 2022

Objectives

Our study aims to evaluate objective markers of suicidal events to further evaluate the relationship between incidence of suicidal events and initiation of gender affirming hormone therapy (HT).

Introduction

Transgender individuals are at higher risk for suicide compared with non-transgender individuals. Previous studies have revealed that a much higher percentage (18–45%) of transgender persons have attempted suicide in their lifetime, compared with the general population (4.6%).

Methods

We performed a retrospective chart review of adults at the local Veterans Administration (VA) from January 1, 2008 to December 31, 2020 of patient charts that include ICD-9 and ICD-10 code of F64. X, transgender, male-to-female transgender, female-to-male transgender, gender dysphoria, gender identity disorder, non-binary. Charts were reviewed for incidences of suicidal events defined as requiring hospitalizations, mental health crisis interventions, suicide attempts, and suicide completion. Charts were also reviewed for HT initiation, and mental health medication prescriptions. Data was compared using McNemar's Test or Chi Squared as appropriate.

Results

106 patients were found with the ICD codes with an average age of 50 years (standard deviation (SD) 15). Of those, 93 (88%) have previously been prescribed or are currently prescribed HT with an average age of initiation of 41 years (SD 14). Among all patients studied 98 (92%) were diagnosed with a mental health disorder, 57 (54%) had a history of suicidal event, and 50 (47%) had history of mental health medication prescription. Of persons on HT 49 (53%) had a suicidal event prior to the initiation of hormone therapy compared with 31 (33%) who had suicidal events after initiation of HT which was statistically significant (p<0. 001). The most common suicidal event was hospitalization (41), followed by crisis interventions (27), suicide attempt (3), and suicide completion (1). Of all patients on HT: 39 (42%) had no suicidal events pre or post-HT, 5 (5%) had no suicidal events pre-HT but did have suicidal events post-HT, 23 (25%) had suicidal events pre-HT and no suicidal events post-HT, and 26 (28%) had suicidal events pre and post-HT (p<0. 001).

Conclusions

Among transgender patients at our local VA on HT the incidence of suicidal event prior to initiation of HT was higher than that after initiation of HT. History of suicidal event prior to initiation of HT predicted future incidence of suicidal event after initiation of HT. Potential confounders include mental health evaluation and treatment prior to initiation of HT, limited duration of follow up, age at HT initiation, and initiation of new mental health medication prescriptions. References: Marshall E, Claes L, Bouman WP, et al. (2016). Non-suicidal self-injury and suicidality in trans people: A systematic review of the literature. Int Rev Psychiatry.28, 58–69

Presentation: No date and time listed
ODP416 Increased Ovarian Volume in Young Girls: A Marker of Impending Hyperandrogenism or Normal Variant?
Authors: Golob Laura , Chattha Asma , Pittock Siobhan
Published: November 2022

Ovarian volume increases with age in childhood with reported volumes from 0.6 cm 3 in neonates to approximately 6 cm 3 by 12 years old. There are no precise normal ranges defined based on age or Tanner stage in childhood; therefore, interpretation of ovarian volume can be challenging. The surgical and medical implications of ovarian enlargement are important as it can help predict ovarian torsion. It has been reported that a higher ovarian volume ratio (OVR) (ratio of larger to contralateral ovary) may be a strong predictor of ovarian torsion. A study evaluating premenarchal girls 3-14 years old showed OVR of 7.6 Vs 1.4 in those with and without torsion respectively. There is also an association between current or eventual development of hyperandrogenism and enlarged ovaries in adolescents. Seven girls, five to nine years old presented for care between 2013 and 2021 with at least one ovary large for pubertal status (volume ranging from 6 to 38 mL). Of these, 6 had bilateral enlargement. Presentation was for abdominal pain from ovarian torsion (5/7) or concerns for early puberty (2/7). Family history of PCOS was positive in 4/7. All girls were prepubertal or in early puberty (Tanner stage I-II for breast and pubic hair). All had normal body mass indices (BMI), none had reported hirsutism, acne or stigmata of Mc-Cune Albright syndrome. Pelvic ultrasound revealed large ovaries without discrete ovarian cysts or masses, 2/7 had decreased blood flow with one of these having heterogeneity related to prior torsion. Thyroid function tests, prolactin, gonadotropins, androgen levels and tumor markers were normal when measured. Bone age was checked and normal in five cases. Follow up ranged from 0-8 years, none required pubertal suppression for progressive precocious puberty. One case was diagnosed with PCOS at age 17 years after an initial presentation of ovarian torsion. PCOS is associated with oligo/anovulation and a risk for development of metabolic syndrome. Earlier detection of PCOS, particularly in the early pubertal age group may alter the trajectory of the complications with close monitoring potentially decreasing eventual metabolic risks. Since PCOS is associated with larger ovarian volumes (>10mL in the adolescent population), detection of this enlargement in early puberty may portend later development of PCOS. It is also conceivable that premenarchal girls presenting with ovarian enlargement may signify a specific hyperandrogenic phenotype. While it is possible that larger ovarian volumes are variants of normal, larger retrospective studies and ideally, prospective, long term follow up investigations are required to determine a relationship between them and eventual hyperandrogenic and metabolic phenotypes.

Presentation: No date and time listed
ODP417 Kisspeptin directly stimulates estrogen and progesterone secretion from human granulosa cells.
Authors: Sitticharoon Chantacha , Sririwichitchai Rungnapa , Keadkraichaiwat Issarawan , Maikaew Pailin , Churintaraphan Malika
Published: November 2022

Kisspeptin is a peptide hormone that has a central role to stimulate gonadotropin-releasing hormone secretion from the hypothalamus. Furthermore, it was shown to have peripheral roles on enhancing CYP19 (aromatase) expression and aromatase secretion from human granulosa cells (1). The objectives of this study were to determine direct effects of kisspeptin treatment on estrogen and progesterone secretion from human granulosa-like tumor cell line (KGN). KGN cells (n=3) were treated with 10 nM follicle stimulating hormone (FSH); 100, 1,000, and 10,000 nM kisspeptin; and FSH together with different doses of kisspeptin for 24 hours. Estrogen and progesterone concentrations in supernatant were measured by enzyme immunoassay kits. The results showed that FSH treatment alone (P<0. 05) and FSH together with 100 (P<0. 01), 1,000 (P<0. 001), and 10,000 (P<0. 001) nM kisspeptin increased estrogen concentrations in supernatants when compared to control. Kisspeptin treatment alone did not increase estrogen concentrations in supernatant when compared to control. Interestingly, kisspeptin treatment at 1,000 (P<0. 01) and 10,000 (P<0. 01) nM together with FSH enhanced estrogen concentrations in supernatant when compared to FSH treatment alone. Furthermore, FSH treatment alone (P<0. 05) and FSH together with kisspeptin at doses of 1,000 (P<0. 001) and 10,000 (P<0. 05) nM increased progesterone concentrations in supernatant when compared to control. All doses of kisspeptin did not increase progesterone concentrations in supernatant when compared to control. Only 1,000 nM kisspeptin together with FSH enhanced progesterone secretion in supernatant when compared to FSH alone (P<0. 01). Taken together, FSH stimulated estrogen and progesterone secretion from human granulosa cells and kisspeptin enhanced these effects in addition to the effects of FSH alone. Further studies are required to determine whether kisspeptin treatment can restore the functions of unresponsive or partially responsive granulosa cells of aging humans to secrete estrogen and progesterone as well as kisspeptin is useful in augmenting infertility treatment. Reference: (1) Qin L, Sitticharoon C, Petyim S, Keadkraichaiwat I, Sririwichitchai R, Maikeaw P, et al. Exp Biol Med (Maywood). 2021;246(8): 996-1010.

Presentation: No date and time listed
ODP421 Patterning the Antero-posterior and Dorso-ventral Axes of the Female Reproductive Tract is Dependent on Amhr2+ Mesenchyme in Mice
Authors: Jia Shuai , Zhao Fei
Published: November 2022

The functional properties of the female reproductive tract organs are dependent on establishing the correct organ-specific epithelial morphologies and differentiation. At the early stage, XX embryos possess the progenitors for both male and female reproductive tracts, also known as the Wolffian and Müllerian ducts. The two ducts are surrounded by their own distinct mesenchymes. During sexual differentiation, the XX embryo eliminates the Wolffian duct and maintains the Müllerian duct, which eventually gives rise to the oviduct, uterus, cervix, and vagina in an antero-posterior fashion. Our previous study revealed that the Wolffian duct mesenchyme was not eliminated in the XX embryo. Instead, it becomes a unique mesenchymal population localized at the mesometrial (dorsal) side of the uterus, contrary to the residence of the Müllerian duct mesenchyme-derived cells at the anti-mesometrial (ventral) side. It has been well-established that epithelial morphogenesis is regulated by its surrounding mesenchyme. Therefore, a subsequent question is how the two different mesenchymes contribute to the morphogenesis of the female reproductive tract. The Müllerian duct mesenchyme uniquely expresses Amhr2. To investigate the functional significance of the Müllerian duct mesenchyme in vivo, we designed the Amhr2-Cre; Rosa-DTA genetic cellular ablation model to partially remove Amhr2+ Müllerian duct mesenchyme in the female reproductive tract. After partially ablating the Amhr2+ Müllerian duct mesenchyme, the oviduct became shorter and lost its characteristic coiling. Oviductal epithelial proliferation was significantly reduced, which contributed to the defective oviductal elongation and coiling. Surprisingly, the regionalization of the oviduct into the infundibulum, ampulla, and isthmus was not affected in the ablation group, suggesting that oviductal coiling and regionalization are two uncoupled events. The uterus looked shorter in the ablation group. Histology analysis further revealed the disorganization of the lumen shape. Normally, the lumen shape of the neonatal uterus forms an ellipse with the long axis parallel to the dorso-ventral axis. In the ablation group, however, the uterine shape was irregular and the long axis of the lumen became perpendicular to the dorso-ventral axis. These results demonstrate that Amhr2+ mesenchyme is indispensable for the morphological patterning of the female reproductive tract along both the antero-posterior and dorso-ventral axes. To investigate the mechanisms underlying the morphological defects in the ablation group, we are in the process of investigating cellular events that have been implicated in the female reproductive tract patterning: cellular apoptosis, proliferation, and orientation of cell division. Taken together, our study provides a novel model to understand how the mesenchyme patterns the female reproductive tract in place. This work was supported by NIH grant R00 HD096051.

Presentation: No date and time listed