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The sodium-glucose co-transporter (SGLT)-2 inhibitor dapagliflozin was recently reported to reduce renal tyrosine hydroxylase (TH) and norepinephrine levels, lowering blood pressure and preventing endothelial dysfunction, in a murine model of neurogenic hypertension. This suggested that dapagliflozin may combat sympathetic nervous system (SNS) hyperactivity, which is known to accompany and aggravate chronic heart failure (CHF). Adrenal G protein-coupled receptor kinase (GRK)-2 upregulation is a major driver of circulating catecholamine (CA) elevation and SNS hyperactivity, especially in CHF. GRK2 severely dysregulates adrenal sympatho-inhibitory α2-adrenergic receptors (ARs), leading to unchecked, chronically elevated CA secretion. Therefore, we hypothesized herein that SGLT2 inhibition with dapagliflozin may lower SNS hyperactivity in the adrenal gland by antagonizing GRK2 actions on α2ARs in adrenal chromaffin cells. We used the rat pheochromocytoma PC12 cell line expressing human α2AAR, as well as freshly isolated adrenal glands from adult male Sprague-Dawley rats treated with dapagliflozin in vivo. We measured circulating norepinephrine (NE) in vivo via RIA, GRK2 &amp; TH expression levels via real-time PCR and immunoblotting, adrenal α2AR density (Bmax) via saturation radioligand binding with [methyl-3H]-rauwolscine, and G protein activation via the GTPγS assay. Dapagliflozin treatment for 7 consecutive days (20 mg/kg/d in drinking water) led to a significant reduction in blood circulating NE levels (217+67 pg/ml, n=6), compared to control, vehicle-treated rats (363+77 pg/ml, n=6, p&lt;.05), suggesting reduced SNS activity. This was accompanied by reduced GRK2 and TH mRNA and protein levels in dapagliflozin-treated rat adrenals vs. vehicle-treated animal-derived glands, indicating reduced adrenal CA synthesis and secretion. Finally, adrenal α2AR density was higher in dapagliflozin- vs. vehicle-treated rats (51.3+7.3 vs. 26.1+8.1 fmol/mg of protein, respectively; n=12 glands from 6 animals per group, p&lt;.05). These results (i.e. GRK2 and TH downregulation) were completely recapitulated in PC12 α2AAR-expressing cells in culture, treated with 5 μM dapagliflozin (or vehicle) for 24 hours. Importantly, α2AR-dependent G protein-mediated signaling towards inhibition of CA secretion was markedly enhanced at 24 hrs post-dapagliflozin application in PC12 cells. This was the result of reduced GRK2-dependent receptor desensitization, since dapagliflozin lacked this effect in cells co-transfected with a GRK2-encoding adenovirus to acutely overexpress GRK2. In conclusion, dapagliflozin exerts a sympatholytic action in the adrenal medulla via downregulation of both TH, which reduces CA biosynthesis, and GRK2, which reduces α2AR desensitization in favor of enhanced inhibition of CA secretion.?? 

ENDO 2021

Dapagliflozin Exerts Adrenal Sympatholysis via G protein-Coupled Receptor Kinase-2 &amp; Tyrosine Hydroxylase Downregulation

The sodium-glucose co-transporter (SGLT)-2 inhibitor dapagliflozin was recently reported to reduce renal tyrosine hydroxylase (TH) and norepinephrine levels, lowering blood pressure and preventing endothelial dysfunction, in a murine model of neurogenic hypertension. This suggested that dapagliflozin may combat sympathetic nervous system (SNS) hyperactivity, which is known to accompany and aggravate chronic heart failure (CHF). Adrenal G protein-coupled receptor kinase (GRK)-2 upregulation is a major driver of circulating catecholamine (CA) elevation and SNS hyperactivity, especially in CHF. GRK2 severely dysregulates adrenal sympatho-inhibitory α2-adrenergic receptors (ARs), leading to unchecked, chronically elevated CA secretion. Therefore, we hypothesized herein that SGLT2 inhibition with dapagliflozin may lower SNS hyperactivity in the adrenal gland by antagonizing GRK2 actions on α2ARs in adrenal chromaffin cells. We used the rat pheochromocytoma PC12 cell line expressing human α2AAR, as well as freshly isolated adrenal glands from adult male Sprague-Dawley rats treated with dapagliflozin in vivo. We measured circulating norepinephrine (NE) in vivo via RIA, GRK2 & TH expression levels via real-time PCR and immunoblotting, adrenal α2AR density (Bmax) via saturation radioligand binding with [methyl-3H]-rauwolscine, and G protein activation via the GTPγS assay. Dapagliflozin treatment for 7 consecutive days (20 mg/kg/d in drinking water) led to a significant reduction in blood circulating NE levels (217+67 pg/ml, n=6), compared to control, vehicle-treated rats (363+77 pg/ml, n=6, p<.05), suggesting reduced SNS activity. This was accompanied by reduced GRK2 and TH mRNA and protein levels in dapagliflozin-treated rat adrenals vs. vehicle-treated animal-derived glands, indicating reduced adrenal CA synthesis and secretion. Finally, adrenal α2AR density was higher in dapagliflozin- vs. vehicle-treated rats (51.3+7.3 vs. 26.1+8.1 fmol/mg of protein, respectively; n=12 glands from 6 animals per group, p<.05). These results (i.e. GRK2 and TH downregulation) were completely recapitulated in PC12 α2AAR-expressing cells in culture, treated with 5 μM dapagliflozin (or vehicle) for 24 hours. Importantly, α2AR-dependent G protein-mediated signaling towards inhibition of CA secretion was markedly enhanced at 24 hrs post-dapagliflozin application in PC12 cells. This was the result of reduced GRK2-dependent receptor desensitization, since dapagliflozin lacked this effect in cells co-transfected with a GRK2-encoding adenovirus to acutely overexpress GRK2. In conclusion, dapagliflozin exerts a sympatholytic action in the adrenal medulla via downregulation of both TH, which reduces CA biosynthesis, and GRK2, which reduces α2AR desensitization in favor of enhanced inhibition of CA secretion.?? 

Dapagliflozin Exerts Adrenal Sympatholysis via G protein-Coupled Receptor Kinase-2 & Tyrosine Hydroxylase Downregulation

technical paper

Background: Cardiometabolic conditions in adulthood are more common in children born SGA1. The relationship of the transcriptome (gene expression) and epigenome (DNA methylation) to birth size and the future development of cardiometabolic disease has not been characterized. Aims: To identify I) the relationship between epigenome at age 0, 7 and 17 years, transcriptome at age 9 years and birth size in a normal population; II) links between the transcriptome and epigenome in childhood and adult cardiometabolic risk. Study Design: Normal children (n=6487) from the Avon Longitudinal Study of Parents and Children were assigned to groups based on birth size using bodyweight (BW) and gestation and divided into groups using the population 10th centile. Adverse cardiometabolic risk at age 17 years was defined by the National Heart Lung and Blood Institute criteria of prehypertension using systolic and diastolic blood pressure as well as HDL and LDL2. Blood transcriptome at age 9 and blood epigenome at age 0, 7, and 17 years and were available from 980 and 947 children, respectively. Hypernetworks were used to integrate differentially expressed genes in the transcriptome (DEGs) and differentially methylated points (DMPs) in the epigenome, identifying functional links. Random Forest, a machine learning approach, was used to determine the predictive value of ‘omic data presented as the area under the curve (AUC) of the receiver operating characteristic. Results: Pre-hypertensive participants at age 17 years were distinguished from normotensive participants and this group was enriched for children born small who caught up by age 7 years (155/611 unhealthy/healthy SGA compared to 1979/12746 in all other BW groups; 1.6-fold, p<1x10-5). This group had a greater height velocity during their catch-up period than the normotensive participants (1.2-fold, p=0.027). Hypernetwork integration of ‘omic data identified a functional relationship between 55 DEGs at age 9 years and DMPs at age 7 years. Random forest analysis was able to accurately predict the presence of pre-hypertensive young adults from the age 9 transcriptome (AUC: 0.973). Using a gene-level contraction of DMPs which map to the 55 DEGs (i.e. cis-DMPs), we demonstrated accurate classification of pre-hypertensive young adults from their blood methylome at age 0 (AUC [95% CI]: 0.92 [0.89-0.95]), 7 (0.90 [0.87-0.93]), and 17 (0.91 [0.88-0.94]) years. Conclusions: Through the integration of transcriptome and epigenome, we have identified a set of genes with an epigenomic and transcriptomic signature which predict pre-hypertension in children born SGA who catch up. Specifically, we have shown that the associated epigenomic signature tracks from birth to early adulthood, indicating the possibility of early detection of risk and primordial prevention. 1 Barker etal. (1988) BMJ 297(6641):134-135. 2 Chobanian etal. (2003) JAMA 289(19):2560-2571.?? 

An Epigenomic Signature in Children Born Small for Gestational Age (SGA) With “Catch-up” Growth Is Present From Birth and Predicts Early Adulthood Pre-Hypertension

The pituitary gland regulates key physiological functions, including growth, sexual maturation, reproduction, and lactation. Here, we present a paired single-nuclei (sn) transcriptome and chromatin accessibility characterization of six post-mortem human pituitaries. These samples were from juvenile, adult, and elderly male and female subjects. Well-correlated snRNAseq and snATACseq datasets facilitated robust identification of the major pituitary cell types in each sample. Using latent variable pathway analysis, we uncovered previously unreported coordinated gene expression modules and chromatin accessibility programs for each major cell type as well as an age-specific program across all the endocrine cell types. These largely appear to be congruent between human and mouse datasets. Given the importance of murine models in the study of human pituitary disorders and pituitary physiology, we next sought to compare expression profiles of pituitary cell types in mouse vs. human. Murine and human cell types were well correlated, exemplified by coordinated gene expression programs, especially for undifferentiated stem cells (SCs). In both species, we identified clusters corresponding to naive and committing SCs. All human SC clusters expressed the established SC markers SOX2 and SOX9, as well as genes involved in SC regulatory pathways (WWTR1, YAP1 andPITX2). Additional markers previously reported in murine pituitary SCs were also found in human SC, including WIF1, LGR5, FOS, CDH1, EGFR, LGR4, and WLS. Remarkably, in human, the main naive SC cluster was roughly divided into a high-JUN and a low-JUN expressing subgroup, whereas Jun expression was less pronounced in the murine SC cluster. In both species, committing SC clusters expressed the endocrine markers for POU1F1, TSHB, or POMC, while SCs committing to an intermediate lobe/melanotrope cell identity were distinguishable based on PAX7 expression. In addition, in the human datasets we identify a population of cells as originating from the pars tuberalis. We offer a range of markers that can be utilized for in vivo validation of these cells.Overall, the characterization of the murine and human pituitary SCs strongly suggests the co-existence of subpopulations with different lineage commitments in addition to a single uncommitted SC population. This sn atlas of the human pituitary is a valuable resource that will be made web-accessible.?? 

Single Nucleus Transcriptome and Chromatin Accessibility Landscapes of Human Pituitaries

The pituitary gland is the major endocrine organ that produces and secretes hormones in response to hypothalamic signals to regulate important processes like growth, reproduction, and stress. The anterior pituitary adapts to metabolic and reproductive needs by exhibiting cellular plasticity, resulting in altered hormone production and secretion. The adipokine, leptin, serves a critical role to couple energy status to pituitary function. We have recently reported that the cell fate determinant, Musashi, functions as a post-transcriptional regulator of target mRNA translation in the mouse pituitary and have speculated that Musashi may modulate pituitary cell plasticity. However, the underlying mechanisms governing such pituitary plasticity are not fully understood. Musashi is an mRNA binding protein that is required for self-renewal, proliferation, and to control the differentiation of stem and progenitor cells. We have recently shown that Musashi is expressed in Sox2+ pituitary stem cells and surprisingly, we also found Musashi expression in all differentiated hormone expressing cell lineages in the adult anterior pituitary. The role of Musashi in these mature differentiated cells is unknown. We have observed that a range of critical pituitary mRNAs, including the lineage specification transcription factors Prop1 and Pou1f1, as well as hormone mRNAs including Tshb, Prl, and Gnrhr, all contain consensus Musashi binding elements (MBEs) in their 3’ untranslated regions (3’ UTRs). Using RNA electrophoretic mobility shift assays (EMSAs) and luciferase mRNA translation reporter assays we show that Musashi binds to these mRNAs and exerts inhibitory control of mRNA translation. Moreover, we determined that leptin stimulation opposes the ability of Musashi to exert translational repression of the Pou1f1 and Gnrhr 3’ UTRs. This de-repression does not require regulatory phosphorylation of Musashi on two conserved C-terminal serine residues. Interestingly in the same cell assay system, Musashi exerts translational activation of the Prop1 3’ UTR. We observed that this translational activation requires Musashi phosphorylation on the two regulatory C-terminal serine residues, consistent with the requirement for regulatory phosphorylation to drive translational activation of Musashi target mRNAs during Xenopus oocyte cell maturation. The distinction between MBEs in 3’ UTRs that exert repression (Pou1f1, Prl, Tshb, and Gnrhr) and the Prop1 3’ UTR that directs translational activation is under investigation. We propose that Musashi acts as a bifunctional regulator of pituitary hormone production and lineage specification and may function to maintain pituitary hormone plasticity in response to changing organismal needs.?? 

The Musashi1 RNA-Binding Protein Functions as a Leptin-Regulated Enforcer of Pituitary Cell Fate and Hormone Production

The pituitary gland harbors a population of stem cells. However, role and regulation of these cells remain poorly understood. We recently established organoids from mouse pituitary as a novel research tool to explore pituitary stem cell biology (Cox et al., J. Endocrinol. 2019; 240:287-308). In general, organoids represent 3D in vitro cell configurations that develop and self-organize from (single) tissue stem cells under well-defined culture conditions that typically mirror the stem cell niche and/or embryogenic processes. Organoids reliably recapitulate key aspects of the original organ, including of its stem cell compartment. Moreover, organoids are long-term expandable while retaining these properties. We demonstrated that pituitary organoids originate from the resident (SOX2+) stem cells, largely phenocopy these cells and retain the stemness phenotype during expansive culture. Interestingly, the organoids show confident in vivo translatability and, when developed from transgenically damaged gland, recapitulate the activation status of the stem cells as observed in situ following injury. Now, we found that the organoids also mirror the stem cells’ phenotype and biology in physiological conditions in which the stem cell compartment is either activated or compromised. Organoids from the neonatal maturing pituitary reproduce phenotypical and functional aspects of its activated stem cells, whereas organoids from aging gland mimic the declined functional state of the stem cells in old pituitary. Interestingly, this functional decay was found to be reverted during organoid culture, indicating that the old pituitary stem cells retain intrinsic functionality but are in vivo restrained by an obstructive microenvironment, not present in the organoid culture. Indeed, using single-cell transcriptomics and in vivo analysis, we found that the aging pituitary suffers from a prevailing inflammatory state (inflammaging) which appears to raise the threshold for stem cell activation. Interestingly, comparison of young and old pituitary led us to the discovery of pituitary stem cell activators. Finally, we found that activated parameters of organoid formation are also observed when tumorigenesis takes place in the gland, again mimicking the in situ stem cell activation that is occurring in this perturbed, pathological condition.Taken together, we identified, and applied, our new pituitary organoid model as advanced and powerful tool to gain profound insight into pituitary stem cell behavior across life and disease, which is expected to eventually translate into restorative and rejuvenative tactics when pituitary function is compromised by damage or age. In this context, our single-cell transcriptome database has strong potential to unveil appealing targets.?? 

Novel Pituitary Organoid Model as Powerful Tool to Unravel Pituitary Stem Cell Biology Across Ages and Disease

Exosomes, small extracellular vesicles carrying lipids, proteins, DNA and RNA, enable intercellular communication. Pituitary-derived exosomes have not been well validated, and as no human pituitary cell lines are available, we characterized exosomes derived from rat somatotroph tumor cells (GH1 and GH3). Rat FR and H9C2 cells were used as non-pituitary controls. Exosomes were isolated from serum-free culture supernatants by combining ultrafiltration and ultracentrifugation to eliminate hormone contamination. Derived exosomes were analyzed by NanoSight to visualize, size, and count particles. Exosomal proteins were extracted and exosome markers including TSG101, ALIX, CD63, HSP70, HSP90 detected by Western Blot. The exosome inhibitor GW4869 (10 µM, 30 h) reduced exosome release (up to 81%), whereas treating cells with hydrocortisone (0.1 µM, 72 h) increased exosome production (up to 42%) in GH1 and GH3 cells. Exosomal shuttle RNA characterized by RNA-Seq showed distinct pituitary vs non-pituitary exosome RNA profiles. Selected miRNAs assessed in exosomes and corresponding cells by qRT-PCR validated exosomal RNA-seq and suggested that miRNA signatures in exosomes and in respective cells of origin were concordant. Next, we explored downstream signaling of GH1-derived exosomes (GH1-exo) in vitro and in vivo and studied biological actions in normal hepatocytes and in malignant cells. As evidenced by mRNA-seq, GH1-exo distinctly altered signaling pathways in rat primary hepatocytes, vs pathways elicited by GH or PRL (0.5 µg/mL, 24 h). GH1-exo, FR-exo or vehicle were intravenously injected to 4-week-old female Wistar rats twice weekly for 4 weeks (5*109 exo/200 g, n=3), and livers dissected for mRNA-seq. Among GH1-exo specifically regulated genes, EIF2AK/ATF4, involved in cAMP responses and amino acid biosynthesis, were attenuated. In hepatocytes, GH1-exo suppressed up to 65% of nascent protein synthesis and reduced forskolin (10 µM)-stimulated cAMP activity by 19%, while GH (0.01-1 µg/mL) did not affect this pathway. Notably, GH1-exo also attenuated malignant cell motility. Both GH1-exo incubation or GH1 cell co-culture (48 h) suppressed migration, invasion and wound healing of HCT116 cancer cells by up to 70%. In contrast, treatment with rGH (0.5 µg/mL) increased HCT116 motility. Intravenous administration of GH1-exo (1010 exo/mouse, twice a week for 5 weeks) decreased metastatic tumor volume by 40% in nude mice harboring splenic HCT116 implants (5*105 cells/mouse, n=10), and especially abrogated hepatic metastases. mRNA-seq of GH1-exo treated HCT116 cells vs controls indicated dysregulated p53 and MAPK pathways, which may partially explain mechanisms underlying motility attenuation. The results elucidate novel biological actions of somatotroph adenoma cell-derived exosomes and suggest exosomes as non-hormonal messengers produced by pituitary tumors.?? 

Pituitary Somatotroph Adenoma Cell-Derived Exosomes: Characterization of Novel Non-Hormonal Functions

Background: In a prior Phase III, randomized-withdrawal study, osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided rapid and sustained normalization of mean urinary free cortisol (mUFC) in most patients (pts) with CD. Now, we report efficacy and safety results from another Phase III study of osilodrostat in pts with CD that included an upfront, double-blind, randomized, placebo-controlled phase (LINC 4: NCT02697734). Methods: Adults with CD with mUFC >1.3 x ULN were randomized 2:1 to osilodrostat 2 mg bid or matching placebo for a 12-week (W) double-blind period, with dose adjustments at W2, 5 and 8 (range 1-20 mg bid) based on efficacy and tolerability; dose matching and adjustments were managed by independent endocrinologists. From W12 to W48, all pts received open-label osilodrostat, with dose adjustments permitted (range 1-30 mg bid). At W48, pts could enter an optional extension. Primary endpoint: proportion of randomized pts in each arm who received ≥1 treatment dose with mUFC ≤ULN at W12. Results: 73 pts were randomized and received osilodrostat (n=48) or matching placebo (n=25; baseline median [range] mUFC 2.5 x ULN [0.7-12.5] vs 2.2 x ULN [0.2-18.9]). 77% of osilodrostat recipients achieved mUFC ≤ULN at W12 vs 8% of placebo recipients (OR 43.4; 95% CI 7.1-343.2; P<0.0001). At W36, 81% (95% CI 69.9-89.1) of osilodrostat recipients had mUFC ≤ULN (key secondary endpoint). Median time to first controlled mUFC response was 35 days (95% CI 34‒52) for pts randomized to osilodrostat. Median duration of osilodrostat exposure at data cut-off (Feb 25, 2020) was 71.7 vs 62.3 weeks for pts randomized to osilodrostat and placebo (median [IQR] dose 4.7 [3.8-9.0] vs 6.0 mg/day [3.7-9.7]). Up to W12, 3 osilodrostat pts discontinued, 1 because of an AE (arthralgia), vs 0 with placebo. The most common (≥30%) AEs occurring by W12 were decreased appetite (38% osilodrostat vs 16% placebo), arthralgia (35% vs 8%) and nausea (31% vs 12%). AEs related to hypocortisolism and adrenal-hormone-precursor accumulation occurred in 15% vs 0% and 44% vs 36% of osilodrostat and placebo pts; most were grade 1/2 and resolved with dose reduction/interruption and/or concomitant medication. During the overall study period, the most common (≥30%) AEs occurring on osilodrostat treatment were arthralgia (45%), decreased appetite (45%), fatigue (38%), nausea (37%) and headache (33%). Improvements in cardiovascular- and metabolic-related parameters, including systolic and diastolic blood pressure and HbA1c, were observed with osilodrostat treatment at W12 and W48.?Conclusion: Osilodrostat was superior to placebo at normalizing mUFC levels at W12 (77% vs 8%). Improvements in mUFC levels were sustained at W36. Few pts discontinued because of AEs; hypocortisolism-related AEs were infrequent and manageable. We conclude that osilodrostat is a highly effective and well-tolerated treatment for pts with CD.?? 

Osilodrostat Is an Effective and Well-Tolerated Treatment for Cushing's Disease (CD): Results From a Phase III Study With an Upfront, Randomized, Double-Blind, Placebo-Controlled Phase (LINC 4)

Metopirone Treatment in Endogenous Cushing's Syndrome
Results from a Prospective Multicenter, Open-Label, Phase III/IV Study: PROMPT

Background: Based on the CHIASMA OPTIMAL study, oral octreotide capsules (OOC) were recently approved in the US as a long-term maintenance therapy for patients with acromegaly previously responding to injectable octreotide or lanreotide, somatostatin receptor ligands (SRLs). Results on longer-term efficacy and safety of OOC from the first 48 weeks of the open-label extension (OLE) of this study are presented here. Methods: Eligible patients had the option to enroll in the OLE of CHIASMA OPTIMAL following the double-blind placebo-controlled (DPC) period; 90% of patients who received OOC in the DPC period enrolled. All patients entering the OLE were initiated on a 60 mg/day dose of OOC and titrated up or down based on insulin-like growth factor I (IGF-I) level and/or acromegaly signs or symptoms. End points in the OLE were exploratory and included the proportion of patients who completed week 48 of the OLE, the proportion who completed as responders (defined as average IGF-I ≤1.0 × upper limit of normal [ULN] at weeks 46/48), and changes in IGF-I from baseline of DPC and OLE until week 48 of the OLE; multiple imputation (MI) was used for missing data. Results: Forty patients entered the OLE (n=20 each; OOC and placebo). Median exposure to OOC in the OLE was > 1 year for those who had been on placebo in the DPC and ≤ 21 months for those who had been on OOC. Dosing of OOC at the end of their participation in the OLE was 40 mg, n=3; 60 mg, n=10; and 80 mg, n=27. In those who received OOC during the DPC, 90% (n=18) completed 48 weeks of the OLE. Of responders at the end of the DPC period (n=14), 92.6% maintained response at OLE week 48. In patients from the OOC group who completed the DPC on study drug, average IGF-I using MI was 0.91 and 0.90 × ULN at OLE baseline and week 48, respectively. The mean change in IGF-I from the baseline of the DPC to OLE week 48 was 0.06 × ULN in patients who completed the DPC on OOC (n=19). In those who received placebo during the DPC, 70% (n=14) completed 48 weeks of the OLE. Of responders at the end of the DPC (n=5), 100% maintained response at OLE week 48. In patients from the placebo group who completed the DPC and did not revert to prior injectable therapy (n=9), the average IGF-I values were 1.09 and 0.87 × ULN at OLE baseline and week 48 respectively, using MI. The mean change in IGF-I from the baseline of the DPC to OLE week 48 was 0.08 × ULN in patients who completed the DPC on placebo (n=9). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal; most were mild or moderate. The incidence of TEAEs was similar between patients who were on OOC or placebo during the DPC. The safety profile during the OLE did not show new concerns with increased duration of drug exposure. Conclusion: Long term maintenance of biochemical response to OOC is durable as assessed following ≤ 21 months of treatment. The OOC safety profile in the extension study is consistent with that of injectable SRLs but without injection-related AEs.?? 

One-Year Outcomes of the Open-Label Extension of CHIASMA OPTIMAL, a Phase 3 Study of Oral Octreotide Capsules in Acromegaly

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists Reduce Fluid Intake in Primary Polydipsia

Background: Studies comparing the timing and pace of puberty in overweight/obese girls (OW/OB) vs normal weight girls (NW) have produced conflicting results; some suggest earlier activation of the central components of the reproductive axis in OB while others are more consistent with a peripheral source of estrogen (e.g. adipose tissue) driving puberty in OB. Importantly, there have been no longitudinal assessments of both clinical and biochemical pubertal markers in OB vs. NW. Methods: 90 healthy pre-menarchal girls (26 OW/OB, 54 NW) from the community, aged 8.2-14.7 years, completed 2.8 ± 1.7 (mean, SD) study visits over the course of 4 years. Visits included dual-energy x-ray absorptiometry to calculate percent total body fat (TBF), Tanner staging, breast ultrasound for morphological staging (BMORPH; stages A-E), pelvic ultrasound, hand x-ray (bone age, BA), blood tests for reproductive hormones, and urine collection to determine a vaginal maturation index (VMI), an index of estrogen exposure in urogenital epithelial cells. Menarchal status was determined at each visit and via follow-up questionnaires. The effect of TBF on hormones and markers of estrogen action, the pace of breast maturation, and age at menarche were determined using a mixed, multi-state, or Cox proportional hazards model, respectively. Mixed and Cox models controlled for BMORPH at visit 1 (V1) and race. Results: NW girls were older than OW/OB (11.3 vs. 10.2 yrs, p&lt;0.01) at V1, more likely to be non-Hispanic White (66 vs. 40%, p=0.03), and had more advanced breast morphology BMORPH (p&lt;0.01). LH, E2, VMI, BA, and ovarian and uterine volume increased with time with no effect of TBF. There was an interaction between time and TBF for FSH, INHB, E1, Total T, Free T, and A’dione (p&lt;0.05): levels were initially similar in all TBF groups, but after 1 yr, levels increased in girls with higher TBF, plateaued in girls with mid-range TBF, and decreased in girls with lower TBF. Girls with higher TBF progressed through BMORPH stage D (corresponding to growth/arborization of the breast ductal system), more slowly than girls with lower TBF but achieved menarche at a younger age (risk 1.04x higher per 1 unit increase in TBF). Conclusions: Intensive reproductive phenotyping of girls during the pubertal transition reveals that both the neuroendocrine and ovarian components of the axis are generally preserved in girls with higher TBF but that the axis appears to be activated earlier than in girls with lower TBF. In late puberty, however, girls with higher TBF demonstrate subtle differences in standard hormonal (e.g. serum FSH, INHB, and androgen) and clinical (e.g. delayed growth of breast bud) markers of puberty. Investigation of the mechanistic basis for these differences and their potential clinical consequences for girls with higher TBF deserves further study.?? 

Dapagliflozin Exerts Adrenal Sympatholysis via G protein-Coupled Receptor Kinase-2 & Tyrosine Hydroxylase Downregulation

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An Epigenomic Signature in Children Born Small for Gestational Age (SGA) With “Catch-up” Growth Is Present From Birth and Predicts Early Adulthood Pre-Hypertension

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