United States

ENDO 2022

Adrenocortical Carcinoma Management: Practical Tips for Mitotane Therapy

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

technical paper

The Latest Developments in Achondroplasia

Clinical Performance of the Afirma Genomic Sequencing Classifier: Real World Experience and the Optimization of Thyroid Nodule Management

Pathophysiology of Bardet-Biedl Syndrome (BBS): A Syndromic Rare Genetic Disease of Obesity

Introduction:Hypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress or interpersonal difficulty. It is the most prevalent female sexual health problem worldwide, affecting approximately 1 in 10 women, but has limited treatment options despite its substantial health, social, and economic burden. Melanocortin-4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, although, to date, their mechanism of action is unknown. This study aims to use functional MRI to delineate the reproductive neuroendocrine pathways involved and elucidate how MC4R agonists treat HSDD in women.
Methods:We conducted a randomized, double-blinded, placebo-controlled, crossover clinical study, using psychometric, functional neuroimaging and hormonal analyses, to assess the effects of MC4R agonism on sexual brain processing in 31 premenopausal women with HSDD. Participants attended on two occasions, receiving either a subcutaneous injection of an MC4R agonist (Bremelanotide 1.75 mg), or placebo, at each study visit, thereby acting as their own controls.
Results:31 randomized women were included (mean age 32 years, mean duration of HSDD 41 months). MC4R agonism significantly increased self-reported sexual desire for up to 24-hours post administration, compared to placebo (P=0.007). During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity, as well as deactivating the secondary somatosensory cortex, specifically in response to visual erotic videos, compared to placebo (Z=2.3, P<0.05). In addition, MC4R agonism enhanced functional connectivity between the amygdala-insula and amygdala-thalamus during prolonged visual erotic stimuli, compared to placebo (P=0.025). MC4R agonism resulted in a mean increase in LH of 1.1 iU/L (F [1,58] = 13.38, P=0.0005), and FSH of 0.35 iU/L (F [1,60] = 10.97, P=0.0016) across the 300-minute duration of the study, with no effect observed on circulating estradiol or progesterone levels.
Interpretation of results and conclusions:We demonstrate that MC4R agonism deactivates the secondary somatosensory cortex which can reduce the detrimental self-monitoring process often observed in HSDD, thereby increasing sexual desire. Furthermore, cerebellar and supplementary motor area activation by MC4R agonism are associated with increased sexual arousal and sexual motor imagery respectively. Finally, MC4R agonism enhanced functional connectivity between key limbic structures which can be disrupted in HSDD.
In summary, these data identify the previously undescribed neural substrates and connections through which MC4R agonism modulates sexual brain processing to increase sexual desire. These findings provide mechanistic insight for the action of MC4R agonism in sexual behaviour and are relevant to ongoing therapeutic development for HSDD and for MC4R agonist development more widely.
Trial registration: ClinicalTrials.gov identifier NCT04179734.Funding: Investigator-sponsored study funded by AMAG Pharmaceuticals Inc, MRC and NIHR.

Melanocortin-4 Receptor Agonism Enhances Sexual Brain Processing in Women with Hypoactive Sexual Desire Disorder

Background: Delayed hyponatremia is the most common cause for readmission after transsphenoidal surgery (TSS), occurring in up to 35% of patients. Due to lack of reliable predictive risk factors for the development of delayed hyponatremia, some institutions have implemented a post-operative fluid restriction for all patients undergoing TSS. Retrospective studies have demonstrated a reduction in the incidence of hyponatremia and readmission for hyponatremia after implementation of post-operative fluid restriction of varying volumes and duration. To our knowledge, a randomized prospective study on fluid restriction post-TSS has not been published previously. We present an interim analysis of a prospective randomized controlled study comparing two approaches to post-TSS fluid management.Methods: Participants scheduled for TSS were randomly assigned to the control (CON, n=79) or fluid restriction group (FR1, n=38; FR2, n=37). Participants with chronic kidney disease stage III or greater, NYHA class III or IV heart failure, diabetes insipidus on postoperative day (POD) 3, chronic hyponatremia, or untreated adrenal insufficiency or hypothyroidism were excluded. All participants were started on postoperative weight-based intravenous fluids until POD 1 and allowed to drink freely. Participants in the initial fluid restriction group (FR1) were fluid restricted to 1.8 liters/day (2 liters/day if weight > 100 kg) from POD 3 through POD 14. The fluid restriction was changed to 1 liter/day (1.2 liters/day if weight > 100 kg) (FR2) during the study due to an interim analysis suggesting a trend toward a reduction in the incidence of hyponatremia with fluid restriction and new publications advocating for a tighter fluid restriction. Participants in the CON group were instructed to drink ad lib. Serum sodium (Na) levels were checked every 8 hours in the hospital and on POD 3, 7, 10, and 14. Incidence of hyponatremia (Na < 135 mmol/L), severe hyponatremia (Na < 125 mmol/L), and readmissions for hyponatremia were evaluated.Results: There was no significant difference in baseline characteristics between the three groups. 25 participants (31.6%) in CON, 11 (28.9%) in FR1, and 9 (24.3%) in FR2 developed hyponatremia (FR2 vs CON, p=0.556). The incidence of severe hyponatremia was 0% in the FR2 group compared to 7.6% in the CON group (p=0.175). The rate of readmission for hyponatremia was 2.7% in the FR2 group compared to 6.3% in the CON group (p=0.71). There was no difference in the incidence of acute kidney injury or hypernatremia.Conclusion: Preliminary results suggest a trend towards decreased rates of severe hyponatremia with 1L/day post-operative fluid restriction. A higher overall incidence of hyponatremia was noted in this interim analysis compared to previously published retrospective studies and may be related to increased screening in the current study. Further analysis with more participants is needed.

Does Early Moderate Fluid Restriction Decrease Incidence of Delayed Hyponatremia Following Transsphenoidal Surgery? A Randomized Prospective Trial

Stress exerts a profound impact on reproductive function and disrupts pulsatile luteinizing hormone (LH) secretion. The posterodorsal subnucleus of the medial amygdala (MePD) is an upstream modulator of the hypothalamus pituitary gonadal axis. Stress alters neuronal activity within the MePD, increasing the expression of Urocortin3 (Ucn3) while enhancing the inhibitory output from the MePD to key hypothalamic reproductive centres. Designer receptor exclusively activated by designer drugs (DREADDs) inhibition of MePD Ucn3 neurons prevents psychological stress-induced suppression of LH pulses in female mice. The neurochemical pathways in the MePD responsible for regulating the GnRH pulse generator in the presence of stress remain unknown. We investigate the neurotransmission involved in the neural circuitry responsible for the suppression of GnRH pulse generator activity by MePD Ucn3 neuronal activation. Ucn3-Cre-tdTomato female ovariectomised (OVX) mice were unilaterally injected with AAV-ChR2 and implanted with optofluid cannulae targeting the MePD. Firstly, we optically stimulated MePD Ucn3 neurons with blue light at 10 Hz, 10 mW and monitored the effect on LH pulses. Next, we combined optogenetic activation of MePD Ucn3 neurons with pharmacological antagonism of GABAA or GABAB receptors with bicuculline or CGP, respectively, and observed the effect on LH pulsatility. Finally, during optical activation of MePD Ucn3 neurons we administered a combination of NMDA and AMPA receptor antagonists, AP5 and CNQX respectively, and monitored the effect on pulsatile LH secretion. Optogenetic stimulation of MePD Ucn3 neurons suppressed pulsatile LH secretion compared to controls and administration of aCSF had no effect on LH pulse interval (MePD Ucn3 activation: 36.04 ± 2.49 vs. pre-treatment control period: 17.50 ± 0.67 vs control virus: 21.67 ± 1.67 min; mean ± SEM; p<0.0001; n=12). Intra-MePD infusion of bicuculline (BIC) or CGP during optogenetic stimulation of MePD Ucn3 neurons completely blocked the suppressive effect of MePD Ucn3 neuronal activation on LH pulsatility (MePD Ucn3 activation and BIC: 20.50 ± 2.03 vs. pre-treatment control period: 17.58 ± 0.75 min; MePD Ucn3 activation and CGP: 16.30 ± 0.63 vs. pre-treatment control period: 17.50 ± 0.77 min; n=7-10). Intra-MePD infusion of AP5 + CNQX during optogenetic stimulation of MePD Ucn3 neurons similarly completely blocked the suppressive effect of MePD Ucn3 neuronal activation on LH pulsatility (MePD Ucn3 activation and AP5 + CNQX: 19.58 ± 1.42 min; n=6). Our findings show for the first time that optogenetic stimulation of MePD Ucn3 neurons inhibits GnRH pulse generator activity via GABA and glutamate signalling within the MePD.

Urocortin 3 Interaction with GABA and Glutamate in the Posterodorsal Subnucleus of The Medial Amygdala Mediates Suppression of GnRH Pulse Generator Frequency in Female Mice

Kisspeptin neurons in the arcuate nucleus (ARC) of the hypothalamus are considered as the gonadotropin-releasing hormone (GnRH) pulse generator to control the cascade of hormone secretions that constitute the reproductive axis. These neurons typically co-express Neurokinin B and Dynorphin and are thus dubbed KNDy neurons. In addition, KNDy neuron kisspeptin is hypothesized to be a major sensor and regulator of metabolic homeostasis while relaying energy status to the hypothalamic-pituitary-gonad (HPG) axis. However, the direct metabolic impact of KNDy neuron kisspeptin has not been well-characterized. To explore this role, we examined the metabolic profile of our previously established KNDy neuron-specific kisspeptin knock-out mouse model (Pdyn-Cre/Kissfl/fl, or KO). To do so, we performed glucose tolerance tests, EchoMRI body composition analysis, and measured body weight in wild type (WT) control or KO mice fed with either regular chow or a high-fat diet (HFD, 60% kcal fat, Research Diets, New Brunswick, NJ) for 12 weeks post-weaning. At 4 weeks on the HFD, KO females weighed significantly more than HFD WT females, which continued through the remaining 8 weeks. Additionally, we found significantly decreased glucose tolerance and increased fat mass in HFD KO females compared to HFD WT females. However, KO males exhibited no significant differences in body weight, body composition, or glucose tolerance between the genotypes on either diet. This data suggests that KNDy neuron kisspeptin is critical for metabolic homeostasis and preventing metabolic dysfunction when challenged with a high-fat diet. Our findings further suggest a sexual dimorphism whereby KNDy neuron kisspeptin performs this action predominantly in females.

Absence of Kisspeptin in KNDy Neurons of Mice Causes Sexually Dimorphic Metabolic Dysfunction on a High-Fat Diet

Introduction: Loss-of-function (LOF) germline variants in the SDHx genes (SDHA, SDHB, SDHC, and SDHD), encoding the succinate dehydrogenase subunits, are a rare cause for pituitary tumors in the setting of various familial tumor syndromes. Occasional case reports have highlighted SDHx mutations in isolated pituitary tumors (including one case of Cushing's disease, CD). The actual frequency of SDHx variants as genetic drivers of pituitary tumors, however, remains elusive.
Aim: We sought to determine the frequency of germline SDHx variants in a large cohort of CD patients.
Methods: Of the 245 unrelated CD patients studied (139 females, 56.7%; 230 pediatric, 93.9%), 184 underwent whole-exome sequencing (WES) of peripheral blood and 27 of them underwent additional tumor WES. Forty-three additional germline samples and 92 tumor samples underwent Sanger sequencing of specific genes. Rare variants of uncertain significance (VUS), likely pathogenic or pathogenic variants of the SDHx genes were reviewed. Immunocytochemistry was used to analyze protein expression in tumor samples.
Results: Germline heterozygous variants of SDHA (three missense and one frameshift) and SDHD (two missense) were identified in six patients (four female; mean age of 8.8±2.2 years at onset of CD and 11.5±2.6 years at diagnosis). The variants were inherited in all 5 cases where parental germline samples were available. We found the following SDHA variants: Case 1 carried p.A21T (absent from gnomAD), Case 2 carried p.L74Ffs*9 (absent from gnomAD), Case 3 carried p.I235T (allele frequency, MAF=0.0100% in gnomAD exomes), and Case 4 carried p.H424Q (MAF=0.0056% in gnomAD exomes). Two patients (Cases 5 and 6) carried the SDHD missense VUS c.53C>T, p.A18V (MAF= 0.0068% in gnomAD exomes). Case 6 had a maternal family history of familial isolated pituitary adenomas, but an SDHD variant of paternal origin; disease presentation was apparently sporadic in the rest of cases. Case 2 displayed somatic loss of heterozygosity (LOH) for the SDHA variant, while no LOH was found in the three other cases tested. Somatic hotspot variants were absent in all tumors tested in USP8 (5/5 cases), USP48 (4/4 cases), and BRAF (4/4 cases). All patients carried microadenomas and achieved remission after one transsphenoidal surgery. Case 4 was diagnosed with a Crooke's cell corticotropinoma and also carried germline VUS in DICER1 and TSC2. In all three tumors tested, SDHx subunit expression was reduced: SDHB reduced in Cases 2, 4, and 5; SDHA reduced in Cases 2 and 4; absent SDHD in Case 2, and absent SDHC in case 5.
Conclusion: Altogether, SDHx variants were found in 2.4% of the cohort (2.6% of pediatric patients). Our findings suggest that germline SDHx variants are a rare but significant genotype associated with isolated sporadic Cushing's disease.
* JLM and CAS contributed equally.

Isolated Cushing’s Disease Associated With Rare Germline SDHx Variants

The pituitary gland controls responses to changing physiological requirements during growth, pregnancy, puberty, and stress. Synthesis and secretion of appropriate pituitary hormones in response to changing organismal demands is mediated through a remarkable capacity for cellular plasticity of the distinct hormone-producing cells. The mechanisms governing pituitary cellular plasticity are not fully understood. We hypothesize that plasticity in the adult tissue is mediated through similar mechanisms to those that occur during embryonic and postnatal pituitary development. The Prophet of Pit1(Prop1), a paired-like homeodomain transcription factor, is the earliest pituitary-specific transcription factor and is highly expressed in pituitary progenitor cells where it controls lineage commitment to the distinct hormone-producing cell types.  Our recent work has identified post-transcriptional regulation of pituitary gene expression in the adult tissue via the stem cell determinant, mRNA binding protein, Musashi. The full-length mouse Prop1 (mProp1) mRNA 3' untranslated region (UTR) contains 24 consensus binding elements for Musashi (MBEs) and demonstrates Musashi1-dependent translational activation in vitro. Specifically, the terminal mProp1 3' UTR MBE directs 40% of Musashi1-mediated translation activation, and mutational disruption of this terminal MBE abolishes all Musashi1-dependent translational activation. Immunoprecipitation of Musashi-mRNA complexes from adult mouse pituitaries confirmed Musashi1-mProp1 mRNA association in adult tissue. The gene sequence data for the human Prop1 (hPROP1) mRNA 3' UTR is incomplete in the Ensembl and RefSeq databases. Using published RNA sequencing datasets, we identified an expressed full-length hPROP1 mRNA 3' UTR of 6996 nucleotides with 54 predicted consensus MBEs, suggesting that the human PROP1 mRNA, like the murine Prop1 mRNA, may be subject to Musashi-dependent translational control. Our findings are consistent with the hypothesis that the Musashi protein exerts evolutionarily conserved control of Prop1 mRNA translation to facilitate plasticity of anterior pituitary function.

Regulation of the Pituitary Cell Lineage Regulator Prop1 by the Stem Cell Determinant Musashi

Heart Rate Variability (HRV) results from the autonomic nervous system activity, it is a non-invasive marker of cardiac autonomic function. Loss of parasympathetic function (PNS) and sympathetic (SNS) override, reflected in decreased HRV, is one of the earliest subclinical manifestations of cardiac autonomic dysfunction. Lower HRV is associated with increased risk of cardiac events in adults.
We aimed to characterize HRV in normal weight and overweight children with and without dysglycemia and to investigate the determinants of HRV in these youth, including body composition, glycemia measures, beta-cell function and inflammatory markers.
We evaluated 94 adolescents (50 males/44 females), age 15 ± 2.1 years; 21 normal weight with normal glucose tolerance (NW-NGT), 23 overweight with NGT (OW-NGT) and 50 overweight with impaired glucose regulation (OW-IGR) including prediabetes (n= 27) and type 2 diabetes (n= 23). They underwent assessment of anthropometrics, body composition (DXA scan), inflammatory markers (hs-CRP and TNF-α), fasting labs and 2-hour oral glucose tolerance test (OGTT) with determination of glucose and insulin concentration. EndoPat was used to measure HRV: frequency-domain indices [high-frequency (HF) reflecting PNS, low-frequency (LF) reflecting both PNS and SNS, and LF/HF (higher is worse) estimating the ratio between SNS and PNS] and time-domain indices [the inter-beat interval of normal sinus beats (NN) and the standard deviation of NN (SDNN) measuring overall HRV, the square root of the mean squared difference of successive NN (RMSSD) and the NN intervals differing by more than 50 milliseconds (NN50) measuring PNS activity].
LF/HF was higher in the OW-IGR group compared with NW and OW-NGT (p=0.005). After controlling for sex, race and Tanner stage, fasting glucose (FBG) negatively correlated with NN (r=-0.22,p=0.04), SDNN (r=-0.21,p=0.05), RMSSD (r=-0.3,p=0.004), NN50 (r=-0.27,p=0.01) and HF (r=-0.26,p=0.02). LF/HF was positively related to FBG (r=0.39,p<0.001), 2hr-glucose (r=0.31,p=0.004) and HbA1c (r=0.22,p=0.04), and negatively with the insulinogenic index (r=-0.27,p=0.02), but not fasting insulin or HOMA-IR; LF/HF also correlated with percent body fat (r=0.22,p=0.04), hs-CRP (r=0.33,p=0.002) and TNF-α (r=0.38,p=0.006).
In a linear regression model with LnLF/HF as the dependent variable and percent body fat, hs-CRP, FBG and HOMA-IR as the independent variables, FBG (beta=0.39,p=0.003) and hs-CRP (beta=0.21,p=0.09) were the significant determinants of LnLF/HF independent of age, sex, race and Tanner stage as covariates (R²= 0.23,p=0.013).
Youth with impaired glucose metabolism have evidence of early subclinical cardiac autonomic dysfunction with decreased HRV, loss of parasympathetic function and sympathetic overdrive as reflected by lower time-domain indices, lower HF and higher LF/HF, related to glycemia and systemic inflammation.

Adrenocortical Carcinoma Management: Practical Tips for Mitotane Therapy

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