Publications by authors named "Sally Radovick"

89 Publications

Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic.

Front Genet 2021 11;12:697549. Epub 2021 Aug 11.

Division of Pediatric Endocrinology Rutgers Robert Wood Johnson Medical School Child Health Institute of New Jersey, New Brunswick, NJ, United States.

Purpose: Congenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown.

Methods: We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) ( = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups.

Results: First, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband's condition with a monogenic etiology ( mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, = 0.01).

Conclusion: Our findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.
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http://dx.doi.org/10.3389/fgene.2021.697549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386283PMC
August 2021

Clinical research during the COVID-19 pandemic: The role of virtual visits and digital approaches.

J Clin Transl Sci 2021 Mar 8;5(1):e102. Epub 2021 Mar 8.

South Carolina Clinical and Translational Research (SCTR) Institute, Medical University of South Carolina, Charleston, SC, USA.

Clinical trials are a fundamental tool in evaluating the safety and efficacy of new drugs, medical devices, and health system interventions. Clinical trial visits generally involve eligibility assessment, enrollment, intervention administration, data collection, and follow-up, with many of these steps performed during face-to-face visits between participants and the investigative team. Social distancing, which emerged as one of the mainstay strategies for reducing the spread of SARS-CoV-2, has presented a challenge to the traditional model of clinical trial conduct, causing many research teams to halt all in-person contacts except for life-saving research. Nonetheless, clinical research has continued during the pandemic because study teams adapted quickly, turning to virtual visits and other similar methods to complete critical research activities. The purpose of this special communication is to document this rapid transition to virtual methodologies at Clinical and Translational Science Awards hubs and highlight important considerations for future development. Looking beyond the pandemic, we envision that a hybrid approach, which implements remote activities when feasible but also maintains in-person activities as necessary, will be adopted more widely for clinical trials. There will always be a need for in-person aspects of clinical research, but future study designs will need to incorporate remote capabilities.
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http://dx.doi.org/10.1017/cts.2021.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185429PMC
March 2021

Deficiency of arcuate nucleus kisspeptin results in postpubertal central hypogonadism.

Am J Physiol Endocrinol Metab 2021 08 28;321(2):E264-E280. Epub 2021 Jun 28.

Department of Pediatrics, Child Health Institute of New Jersey, Rutgers-Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, New Jersey.

Kisspeptin (encoded by ), a neuropeptide critically involved in neuroendocrine regulation of reproduction, is primarily synthesized in two hypothalamic nuclei: the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). AVPV kisspeptin is thought to regulate the estrogen-induced positive feedback control of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH), and the preovulatory LH surge in females. In contrast, ARC kisspeptin neurons, which largely coexpress neurokinin B and dynorphin A (collectively named KNDy neurons), are thought to mediate estrogen-induced negative feedback control of GnRH/LH and be the major regulators of pulsatile GnRH/LH release. However, definitive data to delineate the specific roles of AVPV versus ARC kisspeptin neurons in the control of GnRH/LH release is lacking. Therefore, we generated a novel mouse model targeting deletion of to the ARC nucleus (Pdyn-Cre/Kiss1 KO) to determine the functional differences between ARC and AVPV kisspeptin neurons on the reproductive axis. The efficacy of the knockout was confirmed at both the mRNA and protein levels. Adult female Pdyn-Cre/Kiss1 KO mice exhibited persistent diestrus and significantly fewer LH pulses when compared with controls, resulting in arrested folliculogenesis, hypogonadism, and infertility. Pdyn-Cre/Kiss1 KO males also exhibited disrupted LH pulsatility, hypogonadism, and variable, defective spermatogenesis, and subfertility. The timing of pubertal onset in males and females was equivalent to controls. These findings add to the current body of evidence for the critical role of kisspeptin in ARC KNDy neurons in GnRH/LH pulsatility in both sexes, while directly establishing ARC kisspeptin's role in regulating estrous cyclicity in female mice, and gametogenesis in both sexes, and culminating in disrupted fertility. The Pdyn-Cre/Kiss1 KO mice present a novel mammalian model of postpubertal central hypogonadism. We demonstrate through a novel, conditional knockout mouse model of arcuate nucleus (ARC)-specific kisspeptin in the KNDy neuron that ARC kisspeptin is critical for estrous cyclicity in female mice and GnRH/LH pulsatility in both sexes. Our study reveals that ARC kisspeptin is essential for normal gametogenesis, and the loss of ARC kisspeptin results in significant hypogonadism, impacting fertility status. Our findings further confirm that normal puberty occurs despite a loss of ARC kisspeptin.
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http://dx.doi.org/10.1152/ajpendo.00088.2021DOI Listing
August 2021

Editorial: Endocrinology and metabolism.

Authors:
Sally Radovick

Curr Opin Pediatr 2021 08;33(4):423

Department of Pediatrics, Robert Wood Johnson Medical School, Bristol Myers-Squibb Children's Hospital, Rutgers Biomedical and Health Sciences, New Brunswick, New Jersey, USA.

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http://dx.doi.org/10.1097/MOP.0000000000001041DOI Listing
August 2021

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

J Endocr Soc 2021 Mar 9;5(3):bvaa205. Epub 2021 Feb 9.

Royal Veterinary College, University of London, London, UK.

The designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.
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http://dx.doi.org/10.1210/jendso/bvaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874572PMC
March 2021

Trajectory of Body Mass Index from Ages 2 to 7 Years and Age at Peak Height Velocity in Boys and Girls.

J Pediatr 2021 03 27;230:221-229.e5. Epub 2020 Nov 27.

Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD.

Objective: To examine the associations between body mass index (BMI) at 2-4 years and 5-7 years and age at peak height velocity (APHV), an objective measure of pubertal timing, among boys and girls from predominantly racial minorities in the US that have been historically underrepresented in this research topic.

Study Design: This study included 1296 mother-child dyads from the Boston Birth Cohort, a predominantly Black and low-income cohort enrolled at birth and followed prospectively during 1998-2018. The exposure was overweight or obesity, based on Centers for Disease Control and Prevention reference standards. The outcome was APHV, derived using a mixed effects growth curve model. Multiple regression was used to estimate the overweight or obesity-APHV association and control for confounders.

Results: Obesity at 2-4 years was associated with earlier APHV in boys (B in years, -0.19; 95% CI, -0.35 to -0.03) and girls (B, -0.22; 95% CI, -0.37 to -0.07). Obesity at 5-7 years was associated with earlier APHV in boys (B, -0.18; 95% CI, -0.32 to -0.03), whereas overweight and obesity at 5-7 years were both associated with earlier APHV in girls (overweight: B, -0.24; 95% CI, -0.40 to -0.08; obesity: B, -0.27; 95% CI, -0.40 to -0.13). With BMI trajectory, boys with persistent overweight or obesity and girls with overweight or obesity at 5-7 years, irrespective of overweight or obesity status at 2-4 years, had earlier APHV.

Conclusions: This prospective birth cohort study found that overweight or obesity during 2-7 years was associated with earlier pubertal onset in both boys and girls. The BMI trajectory analyses further suggest that reversal of overweight or obesity may halt the progression toward early puberty.
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http://dx.doi.org/10.1016/j.jpeds.2020.11.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982280PMC
March 2021

High-Fat Diet Alters LH Secretion and Pulse Frequency in Female Mice in an Estrous Cycle-Dependent Manner.

Endocrinology 2020 10;161(10)

Department of Pediatrics, Rutgers University-Robert Wood Johnson Medical School, New Brunswick, New Jersey.

Reproductive fitness in females is susceptible to obesogenic diets. Energy balance and reproduction are tightly regulated, in part, by hypothalamic neurons in the arcuate nucleus (ARC), and high-fat diet (HFD) can steadily increase estradiol levels in rodents. Estradiol regulates the reproductive axis via negative feedback mechanisms in ARC neurons by modulating pulsatile release of the gonadotropin luteinizing hormone (LH). However, it is unclear how the circulating estradiol milieu of adult females interacts with a state of high-caloric fat intake to alter LH pulse dynamics. Here, we used serial tail-tip blood sampling to measure pulsatile LH release at different estrous cycle stages in mice fed a HFD. Starting at 21 days of age, female C57BL/6J mice were freely fed with either regular chow diet (RD) or 60% kcal HFD for 12 weeks. Blood samples were collected once at diestrus, and then again at estrus. LH was measured in 10-minute intervals for 3 hours and analyzed for pulse frequency, amplitude, and mean and basal LH levels. Compared with RD-fed controls, mice fed HFD displayed significantly increased pulse frequency at diestrus, but not at estrus. HFD-fed mice also had lower mean and basal LH levels compared with RD-fed controls, but only during estrus. These data suggest that circulating estradiol can variably contribute to the impact that HFD has on LH pulsatile release and also provide insight into how obesity impacts women's reproductive health when ovarian estradiol levels drastically change, such as during menopause or with hormone replacement therapy.
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http://dx.doi.org/10.1210/endocr/bqaa146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486692PMC
October 2020

Precocious puberty.

Minerva Pediatr 2020 Dec 4;72(6):491-500. Epub 2020 Aug 4.

Unit of Pediatric Endocrinology, Department of Pediatrics, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.

Precocious puberty (PP) is a common reason for referral to pediatric endocrinology clinics, with a strong female predominance. PP is a broad term encompassing benign variants of normal development, gonadotropin-dependent precious puberty (GDPP), and gonadotropin-independent precocious puberty (GIPP). This article reviews the definitions, physiology, clinical presentation, evaluation and treatment of these conditions.
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http://dx.doi.org/10.23736/S0026-4946.20.05970-8DOI Listing
December 2020

SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of Müllerian duct epithelium.

Cell Death Differ 2020 12 22;27(12):3307-3320. Epub 2020 Jun 22.

Department of Cancer Biology and Genetics, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

During female mammal reproductive tract development, epithelial cells of the lower Müllerian duct are committed to become stratified squamous epithelium of the vagina and ectocervix, when the expression of ΔNp63 transcription factor is induced by mesenchymal cells. The absence of ΔNp63 expression leads to adenosis, the putative precursor of vaginal adenocarcinoma. Our previous studies with genetically engineered mouse models have established that fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), bone morphogenetic protein (BMP)/SMAD, and activin A/runt-related transcription factor 1 (RUNX1) signaling pathways are independently required for ΔNp63 expression in Müllerian duct epithelium (MDE). Here, we report that sine oculis homeobox homolog 1 (SIX1) plays a critical role in the activation of ΔNp63 locus in MDE as a downstream transcription factor of mesenchymal signals. In the developing mouse reproductive tract, SIX1 expression was restricted to MDE within the future cervix and vagina. SIX1 expression was totally absent in SMAD4 null MDE and was reduced in RUNX1 null and FGFR2 null MDE, indicating that SIX1 is under the control of vaginal mesenchymal factors: BMP4, activin A and FGF7/10. Furthermore, Six1, Runx1, and Smad4 gene-dose-dependently activated ΔNp63 expression in MDE within the vaginal fornix. Using a mouse model of diethylstilbestrol (DES)-associated vaginal adenosis, we found DES action through epithelial estrogen receptor α (ESR1) inhibits activation of ΔNp63 locus in MDE by transcriptionally repressing SIX1 and RUNX1 in the vaginal fornix.
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http://dx.doi.org/10.1038/s41418-020-0579-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852590PMC
December 2020

DLG2 variants in patients with pubertal disorders.

Genet Med 2020 08 28;22(8):1329-1337. Epub 2020 Apr 28.

Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Purpose: Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions.

Methods: Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH.

Results: We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH.

Conclusion: The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.
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http://dx.doi.org/10.1038/s41436-020-0803-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510947PMC
August 2020

Controversies surrounding female athletes with differences in sexual development.

J Clin Invest 2020 06;130(6):2738-2740

Department of Pediatrics, Child Health Institute of New Jersey, Rutgers-Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, USA.

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http://dx.doi.org/10.1172/JCI138479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259991PMC
June 2020

Uterine aquaporin expression is dynamically regulated by estradiol and progesterone and ovarian stimulation disrupts embryo implantation without affecting luminal closure.

Mol Hum Reprod 2020 03;26(3):154-166

Laboratory of Human Growth and Reproductive Development, Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.

The study investigated the effect of normal and supraphysiological (resulting from gonadotropin-dependent ovarian stimulation) levels of estradiol (E2) and progesterone (P4) on mouse uterine aquaporin gene/protein (Aqp/AQP) expression on Day 1 (D1) and D4 of pregnancy. The study also examined the effect of ovarian stimulation on uterine luminal closure and uterine receptivity on D4 of pregnancy and embryo implantation on D5 and D7 of pregnancy. These analyses revealed that the expression of Aqp3, Aqp4, Aqp5 and Aqp8 is induced by E2 while the expression of Aqp1 and Aqp11 is induced by P4. Additionally, P4 inhibits E2 induction of Aqp3 and Aqp4 expression while E2 inhibits Aqp1 and Aqp11 expression. Aqp9, however, is constitutively expressed. Ovarian stimulation disrupts Aqp3, Aqp5 and Aqp8 expression on D4 and AQP1, AQP3 and AQP5 spatial expression on both D1 and D4, strikingly so in the myometrium. Interestingly, while ovarian stimulation has no overt effect on luminal closure and uterine receptivity, it reduces implantation events, likely through a disruption in myometrial activity and embryo development. The wider implication of this study is that ovarian stimulation, which results in supraphysiological levels of E2 and P4 and changes (depending on the degree of stimulation) in the E2:P4 ratio, triggers abnormal expression of uterine AQP during pregnancy, and this is associated with implantation failure. These findings lead us to recognize that abnormal expression would also occur under any pathological state (such as endometriosis) that is associated with changes in the normal E2:P4 ratio. Thus, infertility among these patients might in part be linked to abnormal uterine AQP expression.
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http://dx.doi.org/10.1093/molehr/gaaa007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103570PMC
March 2020

Regulation of Pregnancy: Evidence for Major Roles by the Uterine and Placental Kisspeptin/KISS1R Signaling Systems.

Semin Reprod Med 2019 07 23;37(4):182-190. Epub 2020 Jan 23.

Department of Pediatrics, Laboratory of Human Growth and Reproductive Development, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey.

Several studies provide strong evidence suggesting that in addition to central kisspeptin/KISS1R signaling, the peripheral uterine- and placental-based kisspeptin/KISS1R signaling systems are major regulators of pregnancy. Specifically, the evidence suggests that the uterine-based system regulates embryo implantation and decidualization, while both the uterine- and placental-based systems regulate placentation. Uterine kisspeptin and KISS1R regulate embryo implantation by controlling the availability of endometrial glandular secretions, like leukemia inhibitory factor, which are essential for embryo adhesion to the uterine epithelium. As for decidualization, the data suggest that decidualized stromal cells express KISS1R and secrete kisspeptin-inhibiting decidual cell motility and thereby indirectly regulate embryo and placental invasion of the uterus. Similarly, for placentation, placental kisspeptin and KISS1R negatively regulate extravillous trophoblast migration and invasion and thereby directly control placental invasion of the uterus. Having recognized a significant role for the uterine- and placental-based kisspeptin/KISS1R signaling systems regulating pregnancy, the future looks promising for the development of kisspeptin and KISS1R as prognostic and diagnostic markers of pregnancy disorders and the use of kisspeptin as a therapeutic agent in the prevention and treatment of conditions such as recurring implantation failure, recurrent pregnancy loss, and preeclampsia.
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http://dx.doi.org/10.1055/s-0039-3400966DOI Listing
July 2019

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF GROWTH HORMONE DEFICIENCY IN ADULTS AND PATIENTS TRANSITIONING FROM PEDIATRIC TO ADULT CARE.

Endocr Pract 2019 Nov;25(11):1191-1232

The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPG). Recommendations are based on diligent reviews of clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. The Executive Summary of this 2019 updated guideline contains 58 numbered recommendations: 12 are Grade A (21%), 19 are Grade B (33%), 21 are Grade C (36%), and 6 are Grade D (10%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 357 citations of which 51 (14%) are evidence level (EL) 1 (strong), 168 (47%) are EL 2 (intermediate), 61 (17%) are EL 3 (weak), and 77 (22%) are EL 4 (no clinical evidence). This CPG is a practical tool that practicing endocrinologists and regulatory bodies can refer to regarding the identification, diagnosis, and treatment of adults and patients transitioning from pediatric to adult-care services with growth hormone deficiency (GHD). It provides guidelines on assessment, screening, diagnostic testing, and treatment recommendations for a range of individuals with various causes of adult GHD. The recommendations emphasize the importance of considering testing patients with a reasonable level of clinical suspicion of GHD using appropriate growth hormone (GH) cut-points for various GH-stimulation tests to accurately diagnose adult GHD, and to exercise caution interpreting serum GH and insulin-like growth factor-1 (IGF-1) levels, as various GH and IGF-1 assays are used to support treatment decisions. The intention to treat often requires sound clinical judgment and careful assessment of the benefits and risks specific to each individual patient. Unapproved uses of GH, long-term safety, and the current status of long-acting GH preparations are also discussed in this document. This updated guideline provides evidence-based recommendations regarding the identification, screening, assessment, diagnosis, and treatment for a range of individuals with various causes of adult growth-hormone deficiency (GHD) and patients with childhood-onset GHD transitioning to adult care. The update summarizes the most current knowledge about the accuracy of available GH-stimulation tests, safety of recombinant human GH (rhGH) replacement, unapproved uses of rhGH related to sports and aging, and new developments such as long-acting GH preparations that use a variety of technologies to prolong GH action. Recommendations offer a framework for physicians to manage patients with GHD effectively during transition to adult care and adulthood. Establishing a correct diagnosis is essential before consideration of replacement therapy with rhGH. Since the diagnosis of GHD in adults can be challenging, GH-stimulation tests are recommended based on individual patient circumstances and use of appropriate GH cut-points. Available GH-stimulation tests are discussed regarding variability, accuracy, reproducibility, safety, and contraindications, among other factors. The regimen for starting and maintaining rhGH treatment now uses individualized dose adjustments, which has improved effectiveness and reduced reported side effects, dependent on age, gender, body mass index, and various other individual characteristics. With careful dosing of rhGH replacement, many features of adult GHD are reversible and side effects of therapy can be minimized. Scientific studies have consistently shown rhGH therapy to be beneficial for adults with GHD, including improvements in body composition and quality of life, and have demonstrated the safety of short- and long-term rhGH replacement. = American Association of Clinical Endocrinologists; = American College of Endocrinology; = alpha-2-HS-glycoprotein; = adult-onset growth hormone deficiency; = arginine; = best evidence level; = bone mineral density; = body mass index; = confidence interval; = childhood-onset growth hormone deficiency; = clinical practice guideline; = C-reactive protein; = diabetes mellitus; = dual-energy X-ray absorptiometry; = evidence level; = Food and Drug Administration; = fixed-dose glucagon stimulation test; = Genetics and Neuroendocrinology of Short Stature International Study; = growth hormone; = growth hormone deficiency; = growth hormone-releasing hormone; = glucagon stimulation test; = high-density lipoprotein; = Hypopituitary Control and Complications Study; = insulin-like growth factor-1; = insulin-like growth factor-binding protein; = isolated growth hormone deficiency; = insulin tolerance test; = Kabi International Metabolic Surveillance; = long-acting growth hormone; = low-density lipoprotein; = leukemia inhibitory factor; = multiple pituitary hormone deficiencies; = magnetic resonance imaging; = procollagen type-III amino-terminal pro-peptide; = pituitary hormone deficiencies; = quality of life; = recombinant human growth hormone; = receiver operating characteristic; = relative risk; = subarachnoid hemorrhage; = standard deviation score; = standardized incidence ratio; = secondary neoplasms; = triiodothyronine; = traumatic brain injury; = vitamin D-binding protein; = World Anti-Doping Agency; = weight-based glucagon stimulation test.
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http://dx.doi.org/10.4158/GL-2019-0405DOI Listing
November 2019

Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK.

Cell Rep 2019 11;29(6):1511-1523.e5

Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Division of Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5' AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin's anti-tumor effects.
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http://dx.doi.org/10.1016/j.celrep.2019.09.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866677PMC
November 2019

Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective.

Horm Res Paediatr 2019 12;92(1):1-14. Epub 2019 Sep 12.

University Children´s Hospital, Tübingen, Germany.

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.
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http://dx.doi.org/10.1159/000502231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979443PMC
April 2020

Inter-generational link of obesity in term and preterm births: role of maternal plasma acylcarnitines.

Int J Obes (Lond) 2019 10 22;43(10):1967-1977. Epub 2019 Jul 22.

Department of Population, Family and Reproductive Health, Center on the Early Life Origins of Disease, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.

Background/objectives: Acylcarnitines, intermediates of fatty acid oxidation, are known to be involved in obesity and insulin resistance. Since maternal prepregnancy overweight or obesity (OWO) is a recognized major risk factor for offspring OWO, we hypothesized that maternal plasma acylcarnitines may play a role in inter-generational OWO.

Subjects/methods: This study included 1402 mother-child pairs (1043 term, 359 preterm) recruited at birth from 1998-2013 and followed prospectively up to age 18 years at the Boston Medical Center. The primary outcomes were child OWO defined as BMI ≥ 85th percentile for age and sex. The primary exposures were maternal prepregnancy OWO defined as BMI ≥ 25 kg/m and maternal acylcarnitine levels measured in plasma samples collected soon after delivery using liquid chromatography-tandem mass spectrometry (LC-MS) in a targeted manner.

Results: Approximately 40% of the children in this study were OWO by age 5. Maternal OWO had a significant association with childhood OWO, both in term and preterm births. β-hydroxybutyryl-carnitine (C4-OH) levels were significantly and positively associated with child OWO among term births after adjustment for potential confounders and multiple-comparisons. Children born to OWO mothers in the top tertile C4-OH levels were at the highest risk of OWO: OR = 3.78 (95%CI: 2.47, 5.79) as compared with those born to non-OWO mothers in the lowest tertile (P for interaction of maternal OWO and C4-OH = 0.035). In a four-way decomposition of mediation/interaction analysis, we estimated that C4-OH levels explained about 27% (se = 0.08) of inter-generational OWO risk (P = 0.001). In contrast, these associations were not observed in preterm births.

Conclusions: In this U.S. urban low-income birth cohort, we provide further evidence of the inter-generational link of OWO and reveal the differential role of C4-OH in explaining the inter-generational obesity between term and preterm births. Further investigations are warranted to better understand and prevent the inter-generational transmission of OWO.
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http://dx.doi.org/10.1038/s41366-019-0417-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900290PMC
October 2019

Editorial: Endocrinology and metabolism.

Authors:
Sally Radovick

Curr Opin Pediatr 2019 08;31(4):523

Department of Pediatrics, Robert Wood Johnson Medical School, Bristol Myers-Squibb Children's Hospital, Rutgers Biomedical and Health Sciences, Rutgers University, New Brunswick, New Jersey, USA.

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http://dx.doi.org/10.1097/MOP.0000000000000788DOI Listing
August 2019

Uterine Gα signaling, in a progesterone-dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse.

FASEB J 2019 08 15;33(8):9374-9387. Epub 2019 May 15.

Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA.

A nonreceptive uterus is a major cause of embryo implantation failure. This study examined the importance of the Gα-coupled class of GPCRs as regulators of uterine receptivity. Mice were created lacking uterine Gα and Gα; as a result, signaling by all uterine Gα-coupled receptors was disrupted. Reproductive profiling of the knockout females revealed that on d 4 of pregnancy, despite adequate serum progesterone (P4) levels and normal P4 receptor (PR) expression, there was no evidence of PR signaling. This resulted in the down-regulation of heart and neural crest derivatives expressed 2, Kruppel-like factor 15, and cyclin G1 and the subsequent persistent proliferation of the luminal epithelium. Aquaporin (Aqp) 11 was also potently down-regulated, whereas /AQP5 expression persisted, resulting in the inhibition of luminal closure. Hypertrophy of the myometrial longitudinal muscle was also dramatically diminished, likely contributing to the observed implantation failure. Further analyses revealed that a major mechanism which uterine Gα signaling induces PR signaling is through the transcriptional up-regulation of leucine-rich repeat-containing GPCR 4 (). LGR4 was previously identified as a trigger of PR activation and signaling. Overall, this study establishes that Gα signaling, in a P4-dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse, and disruption of such signaling results in P4 resistance.-de Oliveira, V., Schaefer, J., Calder, M., Lydon, J. P., DeMayo, F. J., Bhattacharya, M., Radovick, S., Babwah, A. V. Uterine Gα signaling, in a progesterone-dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse.
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http://dx.doi.org/10.1096/fj.201900026RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662978PMC
August 2019

Growth hormone therapy in children; research and practice - A review.

Growth Horm IGF Res 2019 02 26;44:20-32. Epub 2018 Dec 26.

New York University Winthrop Hospital, 101 Mineola Boulevard, Mineola, NY 11201, USA. Electronic address:

Short stature remains the most common reason for referral to a pediatric Endocrinologist and its management remains a challenge. One of the main controversies is the diagnosis of idiopathic short stature and the role of new technologies for genetic investigation of children with inadequate growth. Complexities in management of children with short stature includes selection of who should receive interventions such as recombinant human growth hormone, and how should this agent dose be adjusted during treatment. Should anthropometrical data be the primary determinant or should biochemical and genetic data be used to improve growth response and safety? Furthermore, what is considered a suboptimal response to growth hormone therapy and how should this be managed? Treatment of children with short stature remains a "hot" topic and more data is needed in several areas. These issues are reviewed in this paper.
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http://dx.doi.org/10.1016/j.ghir.2018.12.004DOI Listing
February 2019

Strategy for early identification of prediabetes in lean populations: New insight from a prospective Chinese twin cohort of children and young adults.

Diabetes Res Clin Pract 2018 Dec 9;146:101-110. Epub 2018 Oct 9.

Department of Population, Family and Reproductive Health, Center on the Early Life Origins of Disease, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Division of General Pediatrics & Adolescent Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Aims: To identify certain subgroups in young and lean populations, who may be at a high risk of developing prediabetes/diabetes, which is not captured by current BMI-based screening algorithms.

Methods: Incidence of prediabetes/diabetes was assessed using oral glucose tolerance tests among 1859 children and 1073 young adults from a prospective Chinese twin cohort.

Results: Over a 6-year follow-up, 507 (27.3%) children and 293 (27.3%) adults developed prediabetes/diabetes. Of the 800 incidents, 737(92.1%) and 644(80.5%) were lean at baseline and follow-up, respectively. Baseline fasting glucose in the top tertile of the normal range was associated with an increased risk of prediabetes/diabetes: odds ratio, 1.85 (95% CI 1.32-2.59) and 3.29 (95%CI 2.10-5.17) among normal weight and underweight children, respectively, and 2.74 (95% CI 1.78-4.23) and 3.08 (95% CI 1.69-5.58) among normal weight and overweight/obese adults, respectively, compared with the low tertile of fasting glucose.

Conclusions: We showed that majority incident cases of prediabetes/diabetes were not overweight/obese (at baseline), who would have been missed by traditional screening algorithm emphasizing overweight/obesity. Our findings revealed that an upper end of normal fasting glucose was a simple and robust predictor of future higher risk of prediabetes/diabetes in this young and lean population.
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http://dx.doi.org/10.1016/j.diabres.2018.10.003DOI Listing
December 2018

KISS1/KISS1R in Cancer: Friend or Foe?

Front Endocrinol (Lausanne) 2018 3;9:437. Epub 2018 Aug 3.

Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States.

The gene encodes KISS1, a protein that is rapidly processed in serum into smaller but biologically active peptides called kisspeptins (KPs). KISS1 and the KPs signal via the G-protein coupled receptor KISS1R. While KISS1 and KPs are recognized as potent positive regulators of the reproductive neuroendocrine axis in mammals, the first reported role for KISS1 was that of metastasis suppression in melanoma. Since then, it has become apparent that KISS1, KPs, and KISS1R regulate the development and progression of several cancers but interestingly, while these molecules act as suppressors of tumorigenesis and metastasis in many cancers, in breast and liver cancer they function as promoters. Thus, they join a small but growing number of molecules that exhibit dual roles in cancer highlighting the importance of studying cancer in context. Given their roles, KISS1, KPs and KISS1R represent important molecules in the development of novel therapies and/or as prognostic markers in treating cancer. However, getting to that point requires a detailed understanding of the relationship between these molecules and different cancers. The purpose of this review is therefore to highlight and discuss the clinical studies that have begun describing this relationship in varying cancer types including breast, liver, pancreatic, colorectal, bladder, and ovarian. An emerging theme from the reviewed studies is that the relationship between these molecules and a given cancer is complex and affected by many factors such as the micro-environment and steroid receptor status of the cancer cell. Our review and discussion of these important clinical studies should serve as a valuable resource in the successful development of future clinical studies.
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http://dx.doi.org/10.3389/fendo.2018.00437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085450PMC
August 2018

Impairments in the reproductive axis of female mice lacking estrogen receptor β in GnRH neurons.

Am J Physiol Endocrinol Metab 2018 11 24;315(5):E1019-E1033. Epub 2018 Jul 24.

Department of Pediatrics, Rutgers-Robert Wood Johnson Medical School , New Brunswick, New Jersey.

The effect of estrogen on the differentiation and maintenance of reproductive tissues is mediated by two nuclear estrogen receptors (ERs), ERα, and ERβ. Lack of functional ERα and ERβ genes in vivo significantly affects reproductive function; however, the target tissues and signaling pathways in the hypothalamus are not clearly defined. Here, we describe the generation and reproductive characterization of a complete-ERβ KO (CERβKO) and a GnRH neuron-specific ERβKO (GERβKO) mouse models. Both ERβKO mouse models displayed a delay in vaginal opening and first estrus. Hypothalamic gonadotropin-releasing hormone (GnRH) mRNA expression levels in both ERβKO mice were similar to control mice; however female CERβKO and GERβKO mice had lower basal and surge serum gonadotropin levels. Although a GnRH stimulation test in both female ERβKO models showed preserved gonadotropic function in the same animals, a kisspeptin stimulation test revealed an attenuated response by GnRH neurons, suggesting a role for ERβ in normal GnRH neuron function. No alteration in estrogen-negative feedback was observed in either ERβKO mouse models after ovariectomy and estrogen replacement. Further, abnormal development of ovarian follicles with low serum estradiol levels and impairment of fertility were observed in both ERβKO mouse models. In male ERβKO mice, no differences in the timing of pubertal onset or serum luteinizing hormone and follicle-stimulating hormone levels were observed as compared with controls. Taken together, these data provide in vivo evidence for a role of ERβ in GnRH neurons in modulating puberty and reproduction, specifically through kisspeptin responsiveness in the female hypothalamic-pituitary-gonadal axis.
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http://dx.doi.org/10.1152/ajpendo.00173.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293171PMC
November 2018

Early Life Weight Gain and Development of Childhood Asthma in a Prospective Birth Cohort.

Ann Am Thorac Soc 2018 10;15(10):1197-1204

3 Center on Early Life Origins of Disease, Department of Population, Family, and Reproductive Health, and.

Rationale: The prevalence of childhood asthma has been increasing worldwide in parallel with childhood obesity.

Objectives: We investigated whether there is a temporal relationship between early life weight gain (reflecting growth velocity) and early life body mass index (BMI) attained status (reflecting accumulative weight) with future risk of asthma in the Boston Birth Cohort.

Methods: This report includes 1,928 children from the Boston Birth Cohort with a mean age of 7.8 years (standard deviation, 3.3 yr), enrolled at birth and followed prospectively. Asthma was defined using physician diagnosis code (International Classification of Diseases, Ninth Revision, Clinical Modification code 493.xx) in children 2 years and older. We categorized the children by their weight gain trajectory on the basis of changes in z-scores: slow (less than -0.67), on track (-0.67 to 0.67), rapid (0.67-1.28), and extremely rapid (>1.28); and by their BMI attained status (underweight, normal weight, and overweight) during the first 4, 12, and 24 months. Poisson regression models with robust variance estimation were applied to examine the relationship between early life weight gain/attained BMI and asthma.

Results: During the first 4 months of life, 37% had on-track weight grain, 22% had slow weight gain, 15% had rapid weight gain, and 26% had extremely rapid weight gain. At 4 months, 61% were normal weight, 7% were underweight, and 32% were overweight. In adjusted analyses, extremely rapid early life weight gain during the first 4 and 24 months of life were each associated with increased risks of asthma (risk ratio, 1.34 for extremely rapid weight gain at 4 months; 95% confidence interval [CI], 1.06-1.70; risk ratio, 1.32 for extremely rapid weight gain at 24 months; 95% CI, 1.00-1.75) Similarly, overweight at 4, 12, and 24 months were each associated with an increased risk of asthma. Analyses that further adjusted for birthweight or preterm birth showed similar findings.

Conclusions: In this predominantly urban U.S. low-income minority birth cohort, excessive early life weight gain and overweight status were both associated with an increased risk of asthma in childhood.
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http://dx.doi.org/10.1513/AnnalsATS.201712-921OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321993PMC
October 2018

The 3 World Conference on Kisspeptin, "Kisspeptin 2017: Brain and Beyond":Unresolved questions, challenges and future directions for the field.

J Neuroendocrinol 2018 Apr 14:e12600. Epub 2018 Apr 14.

Centre for Neuroendocrinology and Department of Physiology, University of Otago School of Biomedical Science, Dunedin, 9054, New Zealand.

The 3 World Conference on Kisspeptin, "Kisspeptin 2017: Brain and Beyond" was held March 30-31 at the Rosen Centre Hotel in Orlando, Florida, providing an international forum for multidisciplinary scientists to meet and share cutting-edge research on kisspeptin biology and its relevance to human health and disease. The meeting built upon previous world conferences focused on the role of kisspeptin and associated peptides in the control of gonadotropin-releasing hormone (GnRH) secretion and reproduction. Based on recent discoveries, the scope of this meeting was expanded to include functions of kisspeptin and related peptides in other physiological systems including energy homeostasis, pregnancy, ovarian and uterine function, and thermoregulation. In addition, discussions addressed the translation of basic knowledge of kisspeptin biology to the treatment of disease, with the goal of seeking consensus about the best approaches to improve human health. The two-day meeting featured a non-traditional structure, with each day starting with poster sessions followed by lunch discussions and facilitated large-group sessions with short presentations to maximize the exchange of new, unpublished data. Topics were identified by a survey prior to the meeting, and focused on major unresolved questions, important controversies, and future directions in the field. Finally, career development activities provided mentoring for trainees and junior investigators, and networking opportunities for those individuals with established researchers in the field. Overall, the meeting was rated as a success by attendees and covered a wide range of lively and provocative discussion topics on the changing nature of the field of "kisspeptinology" and its future. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/jne.12600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461527PMC
April 2018

Growth Hormone Research Society perspective on biomarkers of GH action in children and adults.

Endocr Connect 2018 Mar 26;7(3):R126-R134. Epub 2018 Feb 26.

Aarhus University HospitalAarhus, Denmark

Objective: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly.

Participants: GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry.

Evidence: Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs.

Consensus Process: Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process.

Conclusions: The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly.
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http://dx.doi.org/10.1530/EC-18-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868631PMC
March 2018

Pituitary Hypoplasia.

Endocrinol Metab Clin North Am 2017 06 22;46(2):247-257. Epub 2017 Feb 22.

Department of Pediatrics, Child Health Institute of New Jersey, Rutgers-Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 89 French Street, Room 4212, New Brunswick, NJ 08901, USA.

This article summarizes pituitary development and function as well as specific mutations of genes encoding the following transcription factors: HESX1, LHX3, LHX4, POU1F1, PROP1, and OTX2. Although several additional genetic defects related to hypopituitarism have been identified, this article focuses on these selected factors, as they have been well described in the literature in terms of clinical characterization of affected patients and molecular mechanisms of action, and therefore, are very relevant to clinical practice.
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http://dx.doi.org/10.1016/j.ecl.2017.01.003DOI Listing
June 2017

Weight Gain in Infancy and Overweight or Obesity in Childhood across the Gestational Spectrum: a Prospective Birth Cohort Study.

Sci Rep 2016 07 15;6:29867. Epub 2016 Jul 15.

Department of Population, Family and Reproductive Health, Center on Early Life Origins of Disease, Johns Hopkins University Bloomberg School of Public Health, Baltimore, USA.

This study aimed to investigate the optimal degree of weight gain across the gestational spectrum in 1971 children enrolled at birth and followed up to age 7 years. Weight gain in infancy was categorized into four groups based on weight gain z-scores: slow (<-0.67), on track (-0.67 to 0.67), rapid (0.67 to 1.28), and extremely rapid (>1.28). Underweight and overweight or obesity (OWO) were defined as a body mass index ≤5(th) and ≥85(th) percentile, respectively, for age and gender. In our population, OWO was far more common than underweight (39.7% vs. 3.6%). Weight gain tracked strongly from age 4 to 24 months, and was positively associated with OWO and an unfavorable pattern of metabolic biomarkers, although the degree of weight gain for the risk was different across gestational categories. Extremely rapid weight gain led to a particularly high risk of OWO among children born early term and late preterm: odds ratio: 3.3 (95% confidence interval: 1.9 to 5.5) and 3.7 (1.8 to 7.5), respectively, as compared to those with on track weight gain. Our findings suggest that monitoring and ensuring optimal weight gain across the entire gestational spectrum beginning from birth represents a first step towards primary prevention of childhood obesity.
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http://dx.doi.org/10.1038/srep29867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945912PMC
July 2016

Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production.

J Biol Chem 2016 May 21;291(20):10562-70. Epub 2016 Mar 21.

Departments of Medicine and.

Metformin is the most commonly prescribed oral anti-diabetic agent worldwide. Surprisingly, about 35% of diabetic patients either lack or have a delayed response to metformin treatment, and many patients become less responsive to metformin over time. It remains unknown how metformin resistance or insensitivity occurs. Recently, we found that therapeutic metformin concentrations suppressed glucose production in primary hepatocytes through AMPK; activation of the cAMP-PKA pathway negatively regulates AMPK activity by phosphorylating AMPKα subunit at Ser-485, which in turn reduces AMPK activity. In this study, we find that metformin failed to suppress glucose production in primary hepatocytes with constitutively activated PKA and did not improve hyperglycemia in mice with hyperglucagonemia. Expression of the AMPKα1(S485A) mutant, which is unable to be phosphorylated by PKA, increased both AMPKα activation and the suppression of glucose production in primary hepatocytes treated with metformin. Intriguingly, salicylate/aspirin prevents the phosphorylation of AMPKα at Ser-485, blocks cAMP-PKA negative regulation of AMPK, and improves metformin resistance. We propose that aspirin/salicylate may augment metformin's hepatic action to suppress glucose production.
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http://dx.doi.org/10.1074/jbc.M116.719666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865906PMC
May 2016

Altered somatotroph feedback regulation improves metabolic efficiency and limits adipose deposition in male mice.

Metabolism 2016 Apr 8;65(4):557-68. Epub 2015 Dec 8.

Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, New Brunswick, NJ 08901.

Several transgenic mouse models with disruption in the growth hormone (GH) axis support the role of GH in augmenting metabolic homeostasis. Specifically, interest has focused on GH's lipolytic properties and ability to affect adipose deposition. Furthermore, both GH and insulin growth factor 1 (IGF-1) may also play a direct or indirect role in adipose development. The somatotroph insulin-like growth factor-1 receptor knockout (SIGFRKO) mouse with only a modest increase in serum GH and IGF-1 demonstrates less adipose tissue than controls. In order to characterize the metabolic phenotype of SIGFRKO mice, histologic analysis of fat depots confirmed a smaller average diameter of adipocytes in the SIGFRKO mice compared to controls. These changes were accompanied by an increase in lipolytic gene expression in fat depots. Indirect calorimetry performed on 6-8week old male mice and again at 25weeks of age demonstrated that SIGFRKO mice, at both ages, had a higher VO2 and increased energy expenditure when compared with controls. The calculated respiratory exchange ratio (RER) was lower in the younger SIGFRKO mice compared to controls. No differences in food consumption or in either ambulatory or total activity were seen between SIGFRKO and control mice in either age group. These studies highlight the role of GH in adipose deposition and its influence on the expression of lipolytic genes resulting in an altered metabolic state, thus providing a mechanism for the decrease in weight gain seen in the SIGFRKO mouse model.
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http://dx.doi.org/10.1016/j.metabol.2015.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331908PMC
April 2016
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