Edición 78 - Octubre 2020 / Bibliographic Reviews

Bibliographic Review – Ed. 78

78th ISSUE, OCTOBER 2020

Marco A. Rivarola, MD, Ph.D., and Alicia Belgorosky, MD, Ph.D.

Buenos Aires, Argentina.


Edited by Valeria Rivarola, Ph.D.

NOTE. Endopedonline has been temporarily discontinued in March 2020, coinciding with the initiation of coronavirus pandemic in Argentina. The present issue is a shortened edition, having the intention of maintaining our free service, even though by the way of an abridged issue.



Using Kisspeptin to Predict Pubertal Outcomes for Youth with Pubertal Delay.

Yee-Ming Chan, Margaret F Lippincott, Priscila Sales Barroso, Cielo Alleyn, Jill Brodsky, Hector Granados,  Stephanie Roberts, Courtney Sandler,  Abhinash Srivatsa, and Stephanie B Seminara.

INSTITUTION, Harvard Medical School, Massachusetts General Hospital, Boston, MA. USA.

This paper was published in J. Clin. Endocrinol. Metabol., VOL 105, ISSUE 8, in August 2020.


Context. The management of youth with delayed puberty is hampered by difficulty in predicting who will eventually progress through puberty and who will fail to attain adult reproductive endocrine function. The neuropeptide kisspeptin, which stimulates gonadotropin-releasing hormone (GnRH) release, can be used to probe the integrity of the reproductive endocrine axis.

Objective. Authors sought to determine whether responses to kisspeptin can predict outcomes for individuals with pubertal delay.

Design, Setting, and Participants. They conducted a longitudinal cohort study, in an academic medical center, of 16 children (3 girls and 13 boys) with delayed or stalled puberty.

Intervention and Outcome Measures. Children who had undergone kisspeptin- and GnRH-stimulation tests were followed every 6 months for clinical evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing.

Results. All participants who had responded to kisspeptin with a rise in luteinizing hormone (LH) of 0.8 mIU/mL or greater subsequently progressed through puberty (n = 8). In contrast, all participants who had exhibited LH responses to kisspeptin ≤ 0.4 mIU/mL reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (P = .0002). Moreover, the kisspeptin-stimulation test outperformed GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes.

Conclusion. The kisspeptin-stimulation can assess future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty


First-Trimester Prenatal Dexamethasone Treatment Is Associated With Alterations in Brain Structure at Adult Age.

Annelies van’t Westeinde, Leif Karlsson, Anna Nordenström, Nelly Padilla, and Svetlana Lajic.

INSTITUTION: Department of Women’s and Children’s Health, Karolinska Institutet, Pediatric Endocrinology Unit, Karolinska University Hospital, Stockholm, Sweden

This paper was published in the J. Clin. Endocrinol. Metabol., VOL 105, ISSUE 8, in August 2020.


Context. Prenatal treatment of human disease is rare. Dexamethasone (DEX) is used in pregnancies at risk for congenital adrenal hyperplasia (CAH) to prevent virilization in an affected female fetus. The safety and long-term consequences of prenatal DEX exposure on the brain are largely unknown.

Objective. Authors investigated whether first-trimester prenatal DEX treatment is associated with alterations in brain structure at adult age and if these alterations are associated with DNA methylation, mood, and cognitive abilities.

Design, Setting, and Participants. T1-weighted and diffusion-weighted imaging scans, from a single research institute, are compared between 19 (9 women) first-trimester DEX-treated individuals, at risk of CAH but not having CAH, and 43 (26 women) controls (age range, 16.0-26.4 years).

Results. DEX-treated participants showed bilateral enlargement of the amygdala, increased surface area and volume of the left superior frontal gyrus, and widespread increased radial, mean, and axial diffusivity of white matter, in particular in the superior longitudinal fasciculi and corticospinal tracts. In the DEX-treated group, increased mean and radial diffusivity correlated with increased methylation of the promoter region of the FKBP5 gene (Nair SC, Mol Cell Biol 17:594,1997). There were no group differences in cognition or in scales assessing depression or anxiety, and the treatment and controls. Conclusions. First-trimester prenatal DEX treatment is associated with structural alterations of the brain at adult age, with an accompanying change in gene methylation. The findings add to the safety concerns of prenatal DEX treatment in the context of CAH.

Excerpts Selected from this Article.
Taken together, these findings show that first-trimester DEX exposure results in altered brain structure at adult age, which is associated with epigenetic changes in a promotor region of the FKBP5 gene (Nair SC, Moll Cell Biol 17:594,1997). Despite structural changes, authors could not detect significant differences in cognition or mood in the DEX-treated participant compared to controls in this particular cohort. However, subthreshold associations and a lack of participation of participants with higher anxiety strongly suggest that research on more DEX-treated individuals is needed to exclude an effect of prenatal treatment on cognition and behavior at adult age. The findings do contribute to concerns about the safety of prenatal DEX treatment in the context of CAH, and of prenatal GC treatment in general. The fact that authors changes in brain structure that persists into adult age, and changes in methylation, known to be of epigenetic nature, further strengthens the concern and points toward a decision that early prenatal treatment should not be used in fetuses that do not benefit from the treatment per se. The findings have implications for the clinical management of CAH and warrant the development of methods for earlier prenatal diagnosis in both sexes to avoid unnecessary treatment in healthy babies.


A Bayesian Approach to Diagnose Growth Hormone Deficiency in Children: Insulin-Like Growth Factor Type 1 Is Valuable for Screening and IGF-Binding Protein Type 3 for Confirmation.

TH Inoue-Lima.a, GA Vasques Ga,b, M Nakaguma.a, LP Britoa, BB Mendonçaa, IJP Arnholda, AAL Jorgea,b

aUnidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular (LIM/42), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil.bUnidade de Endocrinologia Genetica (LIM/25), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil.

This paper was published in Horm Res Padiatr, 2020, Aug, 14:1-9.


Background: The utility of insulin-like growth factor type 1 (IGF-1) is well established in the diagnosis of growth hormone deficiency (GHD), whereas IGF-binding protein type 3 (IGFBP-3) has a more controversial role. Most studies evaluated the value of these peptides by assessing their sensitivity and specificity but not considering the low prevalence of GHD among short children (<2%).

Objective: To evaluate the utility of basal IGF-1 and IGFBP-3 values in the GHD diagnosis process with a Bayesian approach, based on pre- and post-test probability.

Methods: We determined ROC curves, sensitivity, specificity, and positive and negative predictive values for IGF-1 and IGFBP-3 obtained from patients with GHD (n = 48) and GH-sufficient children (n = 175). The data were also analyzed by classifying the children into early childhood and late childhood (girls and boys younger and older than 8 and 9 years, respectively).

Results: The area under the curve (AUC) of the receiver operating characteristic curve of IGF-1-SDS (standard deviation score) was greater than that of IGFBP-3-SDS (AUC 0.886 and 0.786, respectively, p = 0.001). In early childhood, the AUC of IGFBP-3-SDS was significantly improved (0.866) and similar to IGF-1-SDS (0.898). IGF-1-SDS, in comparison to IGFBP-3-SDS, had a greater sensitivity (92 vs. 45.8%, respectively), lower specificity (69 vs. 93.8%, respectively), and lower positive predictive value (5.7 vs. 13.1%, respectively), with similar negative predictive values.

Conclusion: IGF-1-SDS is a useful screening tool in the diagnosis of GHD. Although IGFBP-3-SDS lacks sensitivity, its high specificity supports the role to confirm GHD in short children, especially in early childhood. This strategy could simplify and reduce the necessity of a second laborious and expensive GH stimulation test to confirm the diagnosis of GHD.



Alterations of the GH/IGF-I Axis and Gut Microbiome after Traumatic Brain Injury: A New Clinical Syndrome?

K.C.J. Yuen, B.E. Masel, K.L. Reifschneider, M. Sheffield-Moore, R.J. Urban, R. Piles.

INSTITUTION. FRCP (UK) Neuroendocrinology, FACE, Burrow, Pituitary Center. Phoenix, AZ, 85013, USA.

Published in the J Clin Endocrinol Metabol 105, Sept 2020.


Context. Pituitary dysfunction with abnormal growth hormone (GH) secretion and neurocognitive deficits are common consequences of traumatic brain injury (TBI). Recognizing the comorbidity of these symptoms is of clinical importance; however, efficacious treatment is currently lacking.

Evidence Acquisition. A review of studies in PubMed published between January 1980 to March 2020 and ongoing clinical trials were conducted using the search terms “growth hormone,” “traumatic brain injury,” and “gut microbiome.”

Evidence Synthesis. Increasing evidence has implicated the effects of TBI in promoting an interplay of ischemia, cytotoxicity, and inflammation that renders a subset of patients to develop postinjury hypopituitarism, severe fatigue, and impaired cognition and behavioral processes. Recent data have suggested an association between abnormal GH secretion and altered gut microbiome in TBI patients, thus prompting the description of a hypothesized new clinical syndrome called “brain injury associated fatigue and altered cognition.” Notably, these patients demonstrate distinct characteristics from those with GH deficiency from other non-TBI causes in that their symptom complex improves significantly with recombinant human GH treatment, but does not reverse the underlying mechanistic cause as symptoms typically recur upon treatment cessation.

Conclusion. The reviewed data describe the importance of alterations of the GH/insulin-like growth factor I axis and gut microbiome after brain injury and its influence in promoting neurocognitive and behavioral deficits in a bidirectional relationship and highlight a new clinical syndrome that may exist in a subset of TBI patients in whom recombinant human GH therapy could significantly improve symptomatology. More studies are needed to further characterize this clinical syndrome.


Latin American consensus: children born small for gestational age.

Margaret CS Boguszewski, Veronica Mericq, Ignacio Bergada, Durval Damiani, Alicia Belgorosky, Peter Gunczler, Teresa Ortiz, Mauricio Llano, Horacio Domene, Raúl Calzada-León, Armando Blanco, Margarita Barrientos, Patricio Procel, Roberto Lanes, Orlando Jaramillo.

This paper was published in Hormone Research in Paediatrics. Free PMC article


Background: Children born small for gestational age (SGA) experience higher rates of morbidity and mortality than those born appropriate for gestational age. In Latin America, identification and optimal management of children born SGA is a critical issue. Leading experts in pediatric endocrinology throughout Latin America established working groups in order to discuss key challenges regarding the evaluation and management of children born SGA and ultimately develop a consensus statement.

Discussion: SGA has defined as birth weight and/or birth length greater than 2 standard deviations (SD) below the population reference mean for gestational age. SGA refers to body size and implies length-weight reference data in a geographical population whose ethnicity is known and specific to this group. Ideally, each country/region within Latin America should establish its own standards and make relevant updates. SGA children should be evaluated with standardized measures by trained personnel every 3 months during year 1 and every 6 months during year 2. Those without catch-up growth within the first 6 months of life need further evaluation, as do children whose weight is ≤ -2 SD at age 2 years. Growth hormone treatment can begin in SGA children > 2 years with short stature (< -2.0 SD) and a growth velocity < 25th percentile for their age, and should continue until final height (a growth velocity below 2 cm/year or a bone age of > 14 years for girls and > 16 years for boys) is reached. Blood glucose, thyroid function, HbA1c, and insulin-like growth factor-1 (IGF-1) should be monitored once a year. Monitoring insulin changes from baseline and surrogates of insulin sensitivity is essential. Reduced fetal growth followed by excessive postnatal catch-up in height, and particularly in weight, should be closely monitored. In both sexes, the gonadal function should be monitored especially during puberty.

Summary: Children born SGA should be carefully followed by a multidisciplinary group that includes perinatologists, pediatricians, nutritionists, and pediatric endocrinologists since 10% to 15% will continue to have weight and height deficiency through the development and may benefit from growth hormone treatment. Standards/guidelines should be developed on a country/region basis throughout Latin America.


Phase 3 Trial of a Small-volume Subcutaneous 6-Month Duration Leuprolide Acetate Treatment for Central Precocious Puberty. 

Karen O Klein,  Analía Freire,  Mirta Graciela Gryngarten,  Gad BEugster,  Nelly Mauras.

INSTITUTION: Rady Children’s Hospital and University of California, San Diego, California 92123.

Published in The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 10, 1 October 2020, dgaa479.


Context: Gonadotropin-releasing hormone agonists (GnRHas) are standard of care for central precocious puberty (CPP). A 6-month subcutaneous injection has recently been approved by the Food and Drug Administration.

Objective. Determine efficacy, pharmacokinetics, and safety of 6-month 45-mg subcutaneous leuprolide acetate for CPP.

Design. Phase 3 multicenter, open-label, single-arm study.

Setting. 25 sites in 6 countries.

Subjects. 64 GnRHa-naïve children with CPP (age: 7.5 ± 0.1 years) received study drug: 59 completed the study.

Intervention(s). 2 doses of 45-mg subcutaneous leuprolide acetate (0.375 mL) at 0 and 24 weeks; children were followed for 48 weeks.

Main Outcome Measure(s). Percentage of children with serum luteinizing hormone (LH)

Results. 54/62 (87%) children achieved poststimulation LH

Conclusions. A small volume of 45-mg subcutaneous leuprolide acetate administered at a 6-month interval effectively suppressed pubertal hormones and stopped or caused regression of pubertal progression. This long-acting GnRHa preparation of leuprolide acetate is a new, effective, and well-tolerated therapy for children with CPP.

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