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Hypothalamic Estrogen Receptor α Is Essential for Female Marmoset Sexual Behavior Without Protecting From Obesity.
IF 3 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-05 eCollection Date: 2025-02-04 DOI: 10.1210/jendso/bvaf012
Marissa Kraynak, Molly M Willging, Daniel J Uhlrich, Robert A Shapiro, Matthew T Flowers, Karen A Manning, Sara D John, Samantha M Williams, Lukas J Henjum, Rebecca C Marrah, Hannah R Yohnk, Carter B Berg, Kevin Brunner, Ricki J Colman, Andrew L Alexander, David H Abbott, Jon E Levine

Context: Estrogen receptor α (ERα) in the ventromedial (VMN) and arcuate (ARC) nuclei of female rodent mediobasal hypothalami (MBHs) provides a crucial molecular gateway facilitating estradiol (E2) regulation of sexual behavior, reproductive neuroendocrinology, and metabolic function. In female nonhuman primates (NHPs) and women, however, its hypothalamic counterpart remains unknown.

Objective: We hypothesized that knockdown (KD) of ERα expression in the hypothalamic VMN and ARC of female marmosets would diminish sexual receptivity, while simultaneously disrupting gonadotropic and metabolic homeostasis.

Methods: We ovariectomized (OVX) adult female marmosets of comparable age and weight, immediately replaced E2 at midcycle levels, and approximately 1 month later assigned monkeys to diet-induced obesity (DIO) within group (1) control, receiving scrambled short hairpin RNA (shRNA), or (2) ERαKD, receiving selective ERα gene silencing shRNA. Magnetic resonance imaging-guided neural surgery enabled hypothalamic infusion of viral vector shRNA and subsequent brain immunohistochemistry enabled observer-validated, NIS-elements computer software quantification of ERα knockdown.

Results: ERα expression was significantly diminished in the VMN and ARC, but not the preoptic area (POA), of ERαKD females coincident with elimination of timely female sexual responses, more than 80% loss of female receptivity, modestly elevated gonadotropin levels, hyperglycemia, and diminished calorie consumption. Density and intensity of ERα-expressing cells in the VMN correlated positively with female sexual receptivity and calorie consumption, negatively with timeliness of female sexual responses, and in the ARC, correlated negatively with calorie consumption.

Conclusion: ERα activation in the female NHP MBH is critically important for female sexual behavior and modestly contributes to gonadotropic and metabolic control.

{"title":"Hypothalamic Estrogen Receptor α Is Essential for Female Marmoset Sexual Behavior Without Protecting From Obesity.","authors":"Marissa Kraynak, Molly M Willging, Daniel J Uhlrich, Robert A Shapiro, Matthew T Flowers, Karen A Manning, Sara D John, Samantha M Williams, Lukas J Henjum, Rebecca C Marrah, Hannah R Yohnk, Carter B Berg, Kevin Brunner, Ricki J Colman, Andrew L Alexander, David H Abbott, Jon E Levine","doi":"10.1210/jendso/bvaf012","DOIUrl":"10.1210/jendso/bvaf012","url":null,"abstract":"<p><strong>Context: </strong>Estrogen receptor α (ERα) in the ventromedial (VMN) and arcuate (ARC) nuclei of female rodent mediobasal hypothalami (MBHs) provides a crucial molecular gateway facilitating estradiol (E<sub>2</sub>) regulation of sexual behavior, reproductive neuroendocrinology, and metabolic function. In female nonhuman primates (NHPs) and women, however, its hypothalamic counterpart remains unknown.</p><p><strong>Objective: </strong>We hypothesized that knockdown (KD) of ERα expression in the hypothalamic VMN and ARC of female marmosets would diminish sexual receptivity, while simultaneously disrupting gonadotropic and metabolic homeostasis.</p><p><strong>Methods: </strong>We ovariectomized (OVX) adult female marmosets of comparable age and weight, immediately replaced E<sub>2</sub> at midcycle levels, and approximately 1 month later assigned monkeys to diet-induced obesity (DIO) within group (1) control, receiving scrambled short hairpin RNA (shRNA), or (2) ERαKD, receiving selective ERα gene silencing shRNA. Magnetic resonance imaging-guided neural surgery enabled hypothalamic infusion of viral vector shRNA and subsequent brain immunohistochemistry enabled observer-validated, NIS-elements computer software quantification of ERα knockdown.</p><p><strong>Results: </strong>ERα expression was significantly diminished in the VMN and ARC, but not the preoptic area (POA), of ERαKD females coincident with elimination of timely female sexual responses, more than 80% loss of female receptivity, modestly elevated gonadotropin levels, hyperglycemia, and diminished calorie consumption. Density and intensity of ERα-expressing cells in the VMN correlated positively with female sexual receptivity and calorie consumption, negatively with timeliness of female sexual responses, and in the ARC, correlated negatively with calorie consumption.</p><p><strong>Conclusion: </strong>ERα activation in the female NHP MBH is critically important for female sexual behavior and modestly contributes to gonadotropic and metabolic control.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 3","pages":"bvaf012"},"PeriodicalIF":3.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11795203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Recognition and Management of Ectopic ACTH Secreting Tumors.
IF 3 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-03 eCollection Date: 2025-01-06 DOI: 10.1210/jendso/bvae194
Henrik Elenius, Lynnette K Nieman

Ectopic ACTH syndrome (EAS), in which Cushing syndrome is caused by excessive ACTH secretion from a tumor located outside of the pituitary, is associated with an impaired quality of life and an increased mortality rate. Outcomes can be improved with successful tumor localization and resection, which often proves difficult. In order to distinguish EAS from Cushing disease, a significantly more common condition where excessive ACTH is secreted from a pituitary tumor, bilateral inferior petrosal sinus sampling (IPSS) is often necessary. Correct performance and interpretation of IPSS hence becomes crucial to avoid inappropriate future interventions, including surgical procedures. Once an ectopic source of ACTH is confirmed biochemically, identifying the causative tumor is often challenging since they can be located in unexpected areas and potentially be very small. Additionally, EAS carries a risk of severe hypercortisolism, which sometimes needs urgent treatment to avoid disastrous outcomes. The cases here illustrate pitfalls in diagnostic biochemical testing, describe helpful imaging strategies to improve the chances of tumor detection, and review available options to rapidly normalize severe hypercortisolism in critical situations.

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引用次数: 0
Predictive Performance of 2 Immunoassays in Patients with Graves Disease Undergoing Radioiodine Therapy: Prospective Study.
IF 3 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-01-31 eCollection Date: 2025-02-04 DOI: 10.1210/jendso/bvaf016
Marcus Vinícius Rodrigues de Souza, Marcelo Tatit Sapienza, Luciana Pinto Brito, Pedro Afonso Cortez, Suemi Marui

Context: Radioactive iodine (RAI) treatment is a well-established successful treatment for Graves disease (GD) but causes an increment in autoantibodies, particularly TSH receptor antibodies.

Objective: To assess the performance and prognostic role of Immulite thyroid-stimulating immunoglobulin (TSI) and Elecsys thyrotropin receptor antibodies (TRAbs) immunoassays in patients with GD undergoing RAI therapy.

Methods: Clinical and laboratory data of 188 patients (156 GD and 32 toxic nodule goiter), undergoing RAI therapy between January 2018 and January 2022 were prospectively collected over 12 months. Refractoriness was defined as persistent or recurrent hyperthyroidism 6 months post-RAI treatment without levothyroxine. Statistical analysis included descriptive statistics, logistic regression, and generalized estimated equations.

Results: Patients had a mean age of 46.4 years, and 78.2% were women. RAI therapy was indicated in 94.2% due to uncontrolled hyperthyroidism or ATD therapy relapse (median of 35 months). Immulite TSI showed higher clinical sensitivity and accuracy (area under the curve [AUC]: 0.98, sensitivity 92.0%, accuracy 98.4%) than Elecsys TRAb (AUC: 0.97, sensitivity 82.1%, accuracy 91.2%). Successful treatment was achieved in 112 of 126 GD patients (89%). Thyroid volume, 2-hour iodine-131 uptake, free thyroxine and thyroxine levels, Elecsys TRAb, and Immulite TSI were significantly higher in the refractory group (P < 0.05), despite most patients receiving >300 Gy of RAI. Longitudinal thyrotropin evaluation predicted treatment response at 12 months (P = .01), whereas autoantibodies did not.

Conclusion: Refractoriness to RAI therapy was associated with higher levels of Immulite TSI and Elecsys TRAb prior to treatment. Although AUCs for both assays were equivalent, Immulite TSI demonstrated superior clinical sensitivity and accuracy. Despite distinct autoantibody patterns emerging post-RAI, longitudinal monitoring did not predict treatment response after 1 year but indicated persistently high concentrations.

{"title":"Predictive Performance of 2 Immunoassays in Patients with Graves Disease Undergoing Radioiodine Therapy: Prospective Study.","authors":"Marcus Vinícius Rodrigues de Souza, Marcelo Tatit Sapienza, Luciana Pinto Brito, Pedro Afonso Cortez, Suemi Marui","doi":"10.1210/jendso/bvaf016","DOIUrl":"10.1210/jendso/bvaf016","url":null,"abstract":"<p><strong>Context: </strong>Radioactive iodine (RAI) treatment is a well-established successful treatment for Graves disease (GD) but causes an increment in autoantibodies, particularly TSH receptor antibodies.</p><p><strong>Objective: </strong>To assess the performance and prognostic role of Immulite thyroid-stimulating immunoglobulin (TSI) and Elecsys thyrotropin receptor antibodies (TRAbs) immunoassays in patients with GD undergoing RAI therapy.</p><p><strong>Methods: </strong>Clinical and laboratory data of 188 patients (156 GD and 32 toxic nodule goiter), undergoing RAI therapy between January 2018 and January 2022 were prospectively collected over 12 months. Refractoriness was defined as persistent or recurrent hyperthyroidism 6 months post-RAI treatment without levothyroxine. Statistical analysis included descriptive statistics, logistic regression, and generalized estimated equations.</p><p><strong>Results: </strong>Patients had a mean age of 46.4 years, and 78.2% were women. RAI therapy was indicated in 94.2% due to uncontrolled hyperthyroidism or ATD therapy relapse (median of 35 months). Immulite TSI showed higher clinical sensitivity and accuracy (area under the curve [AUC]: 0.98, sensitivity 92.0%, accuracy 98.4%) than Elecsys TRAb (AUC: 0.97, sensitivity 82.1%, accuracy 91.2%). Successful treatment was achieved in 112 of 126 GD patients (89%). Thyroid volume, 2-hour iodine-131 uptake, free thyroxine and thyroxine levels, Elecsys TRAb, and Immulite TSI were significantly higher in the refractory group (<i>P</i> < 0.05), despite most patients receiving >300 Gy of RAI. Longitudinal thyrotropin evaluation predicted treatment response at 12 months (<i>P</i> = .01), whereas autoantibodies did not.</p><p><strong>Conclusion: </strong>Refractoriness to RAI therapy was associated with higher levels of Immulite TSI and Elecsys TRAb prior to treatment. Although AUCs for both assays were equivalent, Immulite TSI demonstrated superior clinical sensitivity and accuracy. Despite distinct autoantibody patterns emerging post-RAI, longitudinal monitoring did not predict treatment response after 1 year but indicated persistently high concentrations.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 3","pages":"bvaf016"},"PeriodicalIF":3.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Assessing and Managing Primary Hyperparathyroidism and Fracture Risk in England: A Survey of Medical Professionals.
IF 3 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-01-28 eCollection Date: 2025-01-06 DOI: 10.1210/jendso/bvae225
Kaiyang Song, Rohit Vijjhalwar, Mo Aye, Alexander N Comninos, Marian Schini, Afroze Abbas, Neil Gittoes, Muhammad Kassim Javaid

Purpose: To describe diagnostic approaches and management strategies for patients with primary hyperparathyroidism (PHPT) and recent fracture in England.

Methods: We developed a survey based on a patient at high fracture risk and a new diagnosis of probable PHPT. The survey was circulated among 50 secondary care professionals identified by the Society for Endocrinology Calcium and Bone special interest group. Descriptive statistics, combinatorial, and thematic analyses were employed.

Results: In the patient with hyperparathyroidism and a recent fracture, 54% of respondents favoured a 24-hour urinary calcium: creatinine clearance ratio, with 85% opting to do so after correcting vitamin D levels. Thirty-two percent (16/50) preferred the spot urinary calcium:creatinine clearance ratio, as a random test (56%, n = 9/16). Ninety-six percent of the respondents agreed they would include a fracture risk assessment in their management plan. Eighty-five percent of the respondents selected dual-energy X-ray absorptiometry scans of the lumbar spine, total hip, and femoral neck as the most popular choice. Before initiating antiosteoporotic medications (AOMs), 94% of the respondents preferred correcting vitamin D levels with diverse regimens. IV zoledronate acid was the preferred AOM, and 58% (n = 29/50) supported cinacalcet usage if the patient was ineligible for parathyroid surgery, while 26% (n = 13/50) opposed cinacalcet use entirely. No significant correlation was found between status as an endocrinology consultant or working in a tertiary care hospital and these management preferences.

Main conclusion: This study of National Health Service medical staff identified highly-varied clinical practices in managing PHPT in the setting of high fracture risk, highlighting the need for pragmatic guidelines and wider education.

{"title":"Assessing and Managing Primary Hyperparathyroidism and Fracture Risk in England: A Survey of Medical Professionals.","authors":"Kaiyang Song, Rohit Vijjhalwar, Mo Aye, Alexander N Comninos, Marian Schini, Afroze Abbas, Neil Gittoes, Muhammad Kassim Javaid","doi":"10.1210/jendso/bvae225","DOIUrl":"10.1210/jendso/bvae225","url":null,"abstract":"<p><strong>Purpose: </strong>To describe diagnostic approaches and management strategies for patients with primary hyperparathyroidism (PHPT) and recent fracture in England.</p><p><strong>Methods: </strong>We developed a survey based on a patient at high fracture risk and a new diagnosis of probable PHPT. The survey was circulated among 50 secondary care professionals identified by the Society for Endocrinology Calcium and Bone special interest group. Descriptive statistics, combinatorial, and thematic analyses were employed.</p><p><strong>Results: </strong>In the patient with hyperparathyroidism and a recent fracture, 54% of respondents favoured a 24-hour urinary calcium: creatinine clearance ratio, with 85% opting to do so after correcting vitamin D levels. Thirty-two percent (16/50) preferred the spot urinary calcium:creatinine clearance ratio, as a random test (56%, n = 9/16). Ninety-six percent of the respondents agreed they would include a fracture risk assessment in their management plan. Eighty-five percent of the respondents selected dual-energy X-ray absorptiometry scans of the lumbar spine, total hip, and femoral neck as the most popular choice. Before initiating antiosteoporotic medications (AOMs), 94% of the respondents preferred correcting vitamin D levels with diverse regimens. IV zoledronate acid was the preferred AOM, and 58% (n = 29/50) supported cinacalcet usage if the patient was ineligible for parathyroid surgery, while 26% (n = 13/50) opposed cinacalcet use entirely. No significant correlation was found between status as an endocrinology consultant or working in a tertiary care hospital and these management preferences.</p><p><strong>Main conclusion: </strong>This study of National Health Service medical staff identified highly-varied clinical practices in managing PHPT in the setting of high fracture risk, highlighting the need for pragmatic guidelines and wider education.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvae225"},"PeriodicalIF":3.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Factors Associated With Type 2 Diabetes in Older Japanese With Similar Genetic Risk Scores: The Bunkyo Health Study.
IF 3 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-01-28 eCollection Date: 2025-01-06 DOI: 10.1210/jendso/bvaf019
Thu Hien Bui, Hideyoshi Kaga, Saori Kakehi, Yuki Someya, Hiroki Tabata, Yasuyo Yoshizawa, Hitoshi Naito, Tsubasa Tajima, Naoaki Ito, Satoshi Kadowaki, Yuya Nishida, Ryuzo Kawamori, Hirotaka Watada, Yoshifumi Tamura

Context: Genome-wide association studies have identified numerous single-nucleotide variations (SNVs, formerly single-nucleotide polymorphisms) linked to type 2 diabetes (T2D), thus improving the accuracy of genetic risk scores (GRS) in predicting T2D.

Objective: This study aimed to investigate the association between the novel GRS and the prevalence of T2D and clarify the characteristics that differentiate individuals with and without T2D with similar genetic risk.

Methods: This cross-sectional study analyzed 1610 Japanese individuals aged 65 to 84 years. GRS were calculated using 110 SNVs associated with T2D in Japanese, and GRS classified individuals as having low, average, or high risk for T2D. The characteristics of participants with or without diabetes were compared by sex at each risk level.

Results: The prevalences of T2D were 7.8%, 14.7%, and 16.7% at low-, average-, and high-risk levels, respectively. The odds ratios at the high- and average-risk levels were significantly higher than those at the low-risk level, even after adjusting for confounding factors. The diabetes group had a higher visceral fat area (VFA) and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) value, but a lower insulinogenic index, than the nondiabetes group across all risk levels. In the nondiabetes group, the II decreased significantly as GRS increased, but the HOMA-IR and Matsuda index values showed no association. In men with diabetes, VFA tended to decrease with higher GRS.

Conclusion: A higher GRS was significantly associated with increased T2D prevalence in older Japanese individuals. Our data demonstrated that the contribution of VFA to the development of diabetes varies with genetic risk.

{"title":"Factors Associated With Type 2 Diabetes in Older Japanese With Similar Genetic Risk Scores: The Bunkyo Health Study.","authors":"Thu Hien Bui, Hideyoshi Kaga, Saori Kakehi, Yuki Someya, Hiroki Tabata, Yasuyo Yoshizawa, Hitoshi Naito, Tsubasa Tajima, Naoaki Ito, Satoshi Kadowaki, Yuya Nishida, Ryuzo Kawamori, Hirotaka Watada, Yoshifumi Tamura","doi":"10.1210/jendso/bvaf019","DOIUrl":"10.1210/jendso/bvaf019","url":null,"abstract":"<p><strong>Context: </strong>Genome-wide association studies have identified numerous single-nucleotide variations (SNVs, formerly single-nucleotide polymorphisms) linked to type 2 diabetes (T2D), thus improving the accuracy of genetic risk scores (GRS) in predicting T2D.</p><p><strong>Objective: </strong>This study aimed to investigate the association between the novel GRS and the prevalence of T2D and clarify the characteristics that differentiate individuals with and without T2D with similar genetic risk.</p><p><strong>Methods: </strong>This cross-sectional study analyzed 1610 Japanese individuals aged 65 to 84 years. GRS were calculated using 110 SNVs associated with T2D in Japanese, and GRS classified individuals as having low, average, or high risk for T2D. The characteristics of participants with or without diabetes were compared by sex at each risk level.</p><p><strong>Results: </strong>The prevalences of T2D were 7.8%, 14.7%, and 16.7% at low-, average-, and high-risk levels, respectively. The odds ratios at the high- and average-risk levels were significantly higher than those at the low-risk level, even after adjusting for confounding factors. The diabetes group had a higher visceral fat area (VFA) and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) value, but a lower insulinogenic index, than the nondiabetes group across all risk levels. In the nondiabetes group, the II decreased significantly as GRS increased, but the HOMA-IR and Matsuda index values showed no association. In men with diabetes, VFA tended to decrease with higher GRS.</p><p><strong>Conclusion: </strong>A higher GRS was significantly associated with increased T2D prevalence in older Japanese individuals. Our data demonstrated that the contribution of VFA to the development of diabetes varies with genetic risk.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvaf019"},"PeriodicalIF":3.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetics in Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency and Clinical Implications.
IF 3 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-01-28 eCollection Date: 2025-02-04 DOI: 10.1210/jendso/bvaf018
Paola Concolino, Henrik Falhammar

Of all congenital adrenal hyperplasia (CAH), 95% to 99% is 21-hydroxylase deficiency (21OHD), an autosomal recessive disease. 21OHD is due to an insufficiency of 21-hydroxylase enzyme, which is encoded by the CYP21A2 gene and involved in cortisol and aldosterone production. The clinical presentation differs widely from severe classic to mild nonclassic CAH. 21OHD represents one of the most complex and at the same time intriguing topics in human genetics and its molecular diagnosis involves ongoing challenges. To provide a meticulous presentation of the topic, we searched the past and present literature, including original articles and reviews from PubMed, ScienceDirect, Web of Science, Embase, and Scopus, using search terms for genetics of 21OHD, 21OHD variants, molecular diagnosis of 21OHD, and 21OHD genetic testing. We offer a comprehensive review focusing on recent developments, new concepts, and conclusions.

{"title":"Genetics in Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency and Clinical Implications.","authors":"Paola Concolino, Henrik Falhammar","doi":"10.1210/jendso/bvaf018","DOIUrl":"10.1210/jendso/bvaf018","url":null,"abstract":"<p><p>Of all congenital adrenal hyperplasia (CAH), 95% to 99% is 21-hydroxylase deficiency (21OHD), an autosomal recessive disease. 21OHD is due to an insufficiency of 21-hydroxylase enzyme, which is encoded by the <i>CYP21A2</i> gene and involved in cortisol and aldosterone production. The clinical presentation differs widely from severe classic to mild nonclassic CAH. 21OHD represents one of the most complex and at the same time intriguing topics in human genetics and its molecular diagnosis involves ongoing challenges. To provide a meticulous presentation of the topic, we searched the past and present literature, including original articles and reviews from PubMed, ScienceDirect, Web of Science, Embase, and Scopus, using search terms for genetics of 21OHD, 21OHD variants, molecular diagnosis of 21OHD, and 21OHD genetic testing. We offer a comprehensive review focusing on recent developments, new concepts, and conclusions.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 3","pages":"bvaf018"},"PeriodicalIF":3.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11795198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Glycemia, Insulin Sensitivity, and Secretion Improve 3 Months Post-sleeve Gastrectomy in Youth With Type 2 Diabetes.
IF 3 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-01-28 eCollection Date: 2025-02-04 DOI: 10.1210/jendso/bvaf020
Tyler J Dobbs, Melanie G Cree, Alex J Bailey, Amy D Baumgartner, Justin Garrish, Cecelia Diniz-Behn, Laura Pyle, Megan M Kelsey, Amy S Shah, Thomas H Inge, Petter Bjornstad, Kristen J Nadeau

Context: Metabolic bariatric surgery reduces weight in youth with severe obesity; however, its impacts on youth-onset type 2 diabetes (T2D) are unclear.

Objective: We evaluated short-term outcomes in youth with T2D 3 months after vertical sleeve gastrectomy (VSG).

Design: Longitudinal, observational study in the Impact of Metabolic surgery on Pancreatic, Renal, and cardiOVascular hEalth in youth with T2D study (IMPROVE-T2D).

Setting: Academic medical university and children's hospital.

Participants: Fourteen youth with T2D [mean age ± SD 16.8 ± 1.4 years; 50% female, pre-VSG hemoglobin A1c (HbA1c) 6.6 ± 0.2%; diabetes duration 17.6 ± 13.8 months; age at diabetes diagnosis 15.9 ± 1.4 years; body mass index (BMI) 46.7 ± 2 kg/m2].

Interventions: Participants underwent a mixed-meal tolerance test (MMTT), body composition, and indirect calorimetry before and 3 months after VSG.

Main outcomes: Glycemic control (HbA1c, diabetes medications), insulin sensitivity (Matsuda Index, Homeostasis Model of Insulin Sensitivity, oral minimal model), and secretion (C-peptide model).

Results: After VSG, weight and BMI decreased (25.2 ± 5.6 kg [19%], -8.7 ± 2 kg/m2 [18%], respectively, P < .001). Body fat decreased (4.5%, P = .012), with reductions of 14.1 ± 5.4 kg of fat mass (P = .005) and 4.5 kg of fat-free mass (P = .034). HbA1c decreased from 6.6 ± 0.2% to 5.7 ± 0.2% (P = .003), with 86% of participants no longer requiring diabetes medications. Glucose was lower throughout the MMTT, with insulin, C-peptide, free fatty acids, glucagon-like peptide-1, and peptide-YY significantly changing postsurgery (P < .05 for all). Insulin sensitivity and insulin secretion rate during the MMTT significantly improved.

Conclusion: Three months post-VSG, youth showed significant improvements in weight, body composition, insulin sensitivity and secretion, and glycemic control, with most no longer requiring diabetes medications.

{"title":"Glycemia, Insulin Sensitivity, and Secretion Improve 3 Months Post-sleeve Gastrectomy in Youth With Type 2 Diabetes.","authors":"Tyler J Dobbs, Melanie G Cree, Alex J Bailey, Amy D Baumgartner, Justin Garrish, Cecelia Diniz-Behn, Laura Pyle, Megan M Kelsey, Amy S Shah, Thomas H Inge, Petter Bjornstad, Kristen J Nadeau","doi":"10.1210/jendso/bvaf020","DOIUrl":"10.1210/jendso/bvaf020","url":null,"abstract":"<p><strong>Context: </strong>Metabolic bariatric surgery reduces weight in youth with severe obesity; however, its impacts on youth-onset type 2 diabetes (T2D) are unclear.</p><p><strong>Objective: </strong>We evaluated short-term outcomes in youth with T2D 3 months after vertical sleeve gastrectomy (VSG).</p><p><strong>Design: </strong>Longitudinal, observational study in the Impact of Metabolic surgery on Pancreatic, Renal, and cardiOVascular hEalth in youth with T2D study (IMPROVE-T2D).</p><p><strong>Setting: </strong>Academic medical university and children's hospital.</p><p><strong>Participants: </strong>Fourteen youth with T2D [mean age ± SD 16.8 ± 1.4 years; 50% female, pre-VSG hemoglobin A1c (HbA1c) 6.6 ± 0.2%; diabetes duration 17.6 ± 13.8 months; age at diabetes diagnosis 15.9 ± 1.4 years; body mass index (BMI) 46.7 ± 2 kg/m<sup>2</sup>].</p><p><strong>Interventions: </strong>Participants underwent a mixed-meal tolerance test (MMTT), body composition, and indirect calorimetry before and 3 months after VSG.</p><p><strong>Main outcomes: </strong>Glycemic control (HbA1c, diabetes medications), insulin sensitivity (Matsuda Index, Homeostasis Model of Insulin Sensitivity, oral minimal model), and secretion (C-peptide model).</p><p><strong>Results: </strong>After VSG, weight and BMI decreased (25.2 ± 5.6 kg [19%], -8.7 ± 2 kg/m<sup>2</sup> [18%], respectively, <i>P</i> < .001). Body fat decreased (4.5%, <i>P</i> = .012), with reductions of 14.1 ± 5.4 kg of fat mass (<i>P</i> = .005) and 4.5 kg of fat-free mass (<i>P</i> = .034). HbA1c decreased from 6.6 ± 0.2% to 5.7 ± 0.2% (<i>P</i> = .003), with 86% of participants no longer requiring diabetes medications. Glucose was lower throughout the MMTT, with insulin, C-peptide, free fatty acids, glucagon-like peptide-1, and peptide-YY significantly changing postsurgery (<i>P</i> < .05 for all). Insulin sensitivity and insulin secretion rate during the MMTT significantly improved.</p><p><strong>Conclusion: </strong>Three months post-VSG, youth showed significant improvements in weight, body composition, insulin sensitivity and secretion, and glycemic control, with most no longer requiring diabetes medications.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 3","pages":"bvaf020"},"PeriodicalIF":3.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11795195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Perceived Stress During Late Pregnancy and Infant Body Composition at 1 Month.
IF 3 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-01-28 eCollection Date: 2025-01-06 DOI: 10.1210/jendso/bvae222
Xiaoran Yang, Sandrah P Eckel, Luis E Maldonado, Tingyu Yang, Xinci Chen, Mario Vigil, Claudia M Toledo-Corral, Genevieve F Dunton, Brendan H Grubbs, Laila Al-Marayati, Deborah Lerner, Nathana Lurvey, Rima Habre, Shohreh F Farzan, Theresa M Bastain, Carrie Breton

Context: Worldwide, obesity remains one of the most challenging crises with children being one of the most susceptible populations. The effect of maternal stress during pregnancy on newborn body composition, measured by fat mass and lean mass has, not been extensively studied.

Objectives: We evaluated the association between perceived stress during late pregnancy and infant adiposity at 1 month and assessed effect modification by infant sex and preterm birth.

Methods: Mother-infant dyads (N = 138) were included from the ongoing MADRES cohort. Maternal perceived stress during late pregnancy was measured by the 10-item Perceived Stress Scale (PSS), as a cumulative score, during the third trimester. Infant adiposity measures, collected at 1 month by EchoMRI, included weight, fat mass (FM), and lean mass with FM-related ratios derived. Multivariable linear regression models with interaction terms were performed.

Results: Most mothers reported low to moderate stress (mean ± SD PSS: 13.2 ± 5.6) during late pregnancy. A 1-SD higher PSS was associated with higher FM% (FM (g)/weight (g): β = 0.78%; 95% CI, 0.13-1.44) but we did not find significant associations for the other adiposity measures. Statistically significant effects of perceived stress on FM-related measures were observed in male infants and preterm infants (both P for interaction <.05) but were null among female infants or term infants.

Conclusion: In this predominately low-income Hispanic population, perceived stress during late pregnancy was associated with higher FM-related body composition measures during early infancy; this association was stronger among male and preterm infants compared to the overall population and other subgroups.

{"title":"Perceived Stress During Late Pregnancy and Infant Body Composition at 1 Month.","authors":"Xiaoran Yang, Sandrah P Eckel, Luis E Maldonado, Tingyu Yang, Xinci Chen, Mario Vigil, Claudia M Toledo-Corral, Genevieve F Dunton, Brendan H Grubbs, Laila Al-Marayati, Deborah Lerner, Nathana Lurvey, Rima Habre, Shohreh F Farzan, Theresa M Bastain, Carrie Breton","doi":"10.1210/jendso/bvae222","DOIUrl":"10.1210/jendso/bvae222","url":null,"abstract":"<p><strong>Context: </strong>Worldwide, obesity remains one of the most challenging crises with children being one of the most susceptible populations. The effect of maternal stress during pregnancy on newborn body composition, measured by fat mass and lean mass has, not been extensively studied.</p><p><strong>Objectives: </strong>We evaluated the association between perceived stress during late pregnancy and infant adiposity at 1 month and assessed effect modification by infant sex and preterm birth.</p><p><strong>Methods: </strong>Mother-infant dyads (N = 138) were included from the ongoing MADRES cohort. Maternal perceived stress during late pregnancy was measured by the 10-item Perceived Stress Scale (PSS), as a cumulative score, during the third trimester. Infant adiposity measures, collected at 1 month by EchoMRI, included weight, fat mass (FM), and lean mass with FM-related ratios derived. Multivariable linear regression models with interaction terms were performed.</p><p><strong>Results: </strong>Most mothers reported low to moderate stress (mean ± SD PSS: 13.2 ± 5.6) during late pregnancy. A 1-SD higher PSS was associated with higher FM% (FM (g)/weight (g): β = 0.78%; 95% CI, 0.13-1.44) but we did not find significant associations for the other adiposity measures. Statistically significant effects of perceived stress on FM-related measures were observed in male infants and preterm infants (both <i>P</i> for interaction <.05) but were null among female infants or term infants.</p><p><strong>Conclusion: </strong>In this predominately low-income Hispanic population, perceived stress during late pregnancy was associated with higher FM-related body composition measures during early infancy; this association was stronger among male and preterm infants compared to the overall population and other subgroups.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvae222"},"PeriodicalIF":3.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetics and Epigenetics of Human Pubertal Timing: The Contribution of Genes Associated With Central Precocious Puberty. 人类青春期时间的遗传学和表观遗传学:与中枢性性早熟相关的基因的贡献。
IF 3 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-01-21 eCollection Date: 2025-01-06 DOI: 10.1210/jendso/bvae228
Ana Pinheiro Machado Canton, Delanie Bulcao Macedo, Ana Paula Abreu, Ana Claudia Latronico

Human puberty is a dynamic biological process determined by the increase in the pulsatile secretion of GnRH triggered by distinct factors not fully understood. Current knowledge reveals fine tuning between an increase in stimulatory factors and a decrease in inhibitory factors, where genetic and epigenetic factors have been indicated as key players in the regulation of puberty onset by distinct lines of evidence. Central precocious puberty (CPP) results from the premature reactivation of pulsatile secretion of GnRH. In the past decade, the identification of genetic causes of CPP has largely expanded, revealing hypothalamic regulatory factors of pubertal timing. Among them, 3 genes associated with CPP are linked to mechanisms involving DNA methylation, reinforcing the strong role of epigenetics underlying this disorder. Loss-of-function mutations in Makorin Ring-Finger Protein 3 (MKRN3) and Delta-Like Non-Canonical Notch Ligand 1 (DLK1), 2 autosomal maternally imprinted genes, have been described as relevant monogenic causes of CPP with the phenotype exclusively associated with paternal transmission. MKRN3 has proven to be a key component of the hypothalamic inhibitory input on GnRH neurons through different mechanisms. Additionally, rare heterozygous variants in the Methyl-CpG-Binding Protein 2 (MECP2), an X-linked gene that is a key factor of DNA methylation machinery, were identified in girls with sporadic CPP with or without neurodevelopmental disorders. In this mini-review, we focus on how the identification of genetic causes of CPP has revealed epigenetic regulators of human pubertal timing, summarizing the latest knowledge on the associations of puberty with MKRN3, DLK1, and MECP2.

人类青春期是一个动态的生物学过程,由GnRH的脉动性分泌的增加所决定,这种增加是由尚未完全了解的不同因素引发的。目前的知识揭示了刺激因素的增加和抑制因素的减少之间的微调,其中遗传和表观遗传因素已被明确的证据表明在青春期开始的调节中起关键作用。中枢性性早熟(CPP)是由GnRH脉冲性分泌的过早再激活引起的。在过去的十年中,CPP的遗传原因的鉴定已经大大扩展,揭示了青春期时间的下丘脑调节因子。其中,与CPP相关的3个基因与涉及DNA甲基化的机制有关,强化了表观遗传学在该疾病中的重要作用。Makorin Ring-Finger Protein 3 (MKRN3)和Delta-Like Non-Canonical Notch Ligand 1 (DLK1)这两个常染色体母体印迹基因的功能缺失突变被描述为CPP的相关单基因原因,其表型仅与父系遗传相关。MKRN3已通过不同的机制被证明是下丘脑对GnRH神经元抑制输入的关键组成部分。此外,在伴有或不伴有神经发育障碍的散发性CPP女孩中发现了罕见的甲基cpg结合蛋白2 (MECP2)的杂合变异,MECP2是一种x连锁基因,是DNA甲基化机制的关键因素。在这篇小型综述中,我们重点关注CPP遗传原因的鉴定如何揭示了人类青春期时间的表观遗传调控因子,总结了青春期与MKRN3、DLK1和MECP2相关的最新知识。
{"title":"Genetics and Epigenetics of Human Pubertal Timing: The Contribution of Genes Associated With Central Precocious Puberty.","authors":"Ana Pinheiro Machado Canton, Delanie Bulcao Macedo, Ana Paula Abreu, Ana Claudia Latronico","doi":"10.1210/jendso/bvae228","DOIUrl":"10.1210/jendso/bvae228","url":null,"abstract":"<p><p>Human puberty is a dynamic biological process determined by the increase in the pulsatile secretion of GnRH triggered by distinct factors not fully understood. Current knowledge reveals fine tuning between an increase in stimulatory factors and a decrease in inhibitory factors, where genetic and epigenetic factors have been indicated as key players in the regulation of puberty onset by distinct lines of evidence. Central precocious puberty (CPP) results from the premature reactivation of pulsatile secretion of GnRH. In the past decade, the identification of genetic causes of CPP has largely expanded, revealing hypothalamic regulatory factors of pubertal timing. Among them, 3 genes associated with CPP are linked to mechanisms involving DNA methylation, reinforcing the strong role of epigenetics underlying this disorder. Loss-of-function mutations in Makorin Ring-Finger Protein 3 (<i>MKRN3</i>) and Delta-Like Non-Canonical Notch Ligand 1 (<i>DLK1</i>), 2 autosomal maternally imprinted genes, have been described as relevant monogenic causes of CPP with the phenotype exclusively associated with paternal transmission. <i>MKRN3</i> has proven to be a key component of the hypothalamic inhibitory input on GnRH neurons through different mechanisms. Additionally, rare heterozygous variants in the Methyl-CpG-Binding Protein 2 (<i>MECP2</i>), an X-linked gene that is a key factor of DNA methylation machinery, were identified in girls with sporadic CPP with or without neurodevelopmental disorders. In this mini-review, we focus on how the identification of genetic causes of CPP has revealed epigenetic regulators of human pubertal timing, summarizing the latest knowledge on the associations of puberty with <i>MKRN3</i>, <i>DLK1</i>, and <i>MECP2</i>.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvae228"},"PeriodicalIF":3.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Measurements of Iodination in Thyroglobulin: A Step Toward the Next Generation of Thyroid Cancer Monitoring.
IF 3 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-01-21 eCollection Date: 2025-02-04 DOI: 10.1210/jendso/bvaf015
Anthony Maus, Chris Thompson, Stefan K G Grebe

Thyroglobulin (Tg) is a 330-kDa homodimeric protein that that is the prohormone of thyroid hormones triiodothyronine (T3) and thyroxine (T4). The most critical steps of thyroid hormone synthesis by Tg are iodination and fusion of specific tyrosine residues that are in close proximity to each other in the folded Tg protein. The degree of Tg iodination has been studied widely to determine if it is correlated with thyroid autoimmune disease with mixed results, but these efforts have been limited by the lack of an effective quantitative technique. Simultaneously, the treatment of thyroid cancer has undergone a shift toward partial thyroidectomies, thus undermining the value of Tg measurements. A possible alternative to established monitoring techniques is measurement of Tg iodination states as it has been shown that tumor-derived Tg has significantly lower iodine content. Such measurements require a thorough understanding of normal iodination status. In this study, state-of-the-art liquid chromatography-tandem mass spectrometry (LC-MS/MS) instrumentation is used to perform bottom-up proteomics experiments and identify iodinated residues within commercially available Tg. Using this technique, sequence coverages greater than 90% were achieved, which resulted in identification of previously identified and novel hormone synthesis and donor sites. Based on the results of these discovery experiments, 5 iodination sites were selected for targeted quantitative LC-MS/MS measurements, which suggested that hormone synthesis occurs predominantly at Y24 and Y2766. The results presented herein lay the foundation for routine measurements of iodinated residues, which has the potential to overcome the limitations of current monitoring techniques and benefit patient care.

{"title":"Measurements of Iodination in Thyroglobulin: A Step Toward the Next Generation of Thyroid Cancer Monitoring.","authors":"Anthony Maus, Chris Thompson, Stefan K G Grebe","doi":"10.1210/jendso/bvaf015","DOIUrl":"10.1210/jendso/bvaf015","url":null,"abstract":"<p><p>Thyroglobulin (Tg) is a 330-kDa homodimeric protein that that is the prohormone of thyroid hormones triiodothyronine (T3) and thyroxine (T4). The most critical steps of thyroid hormone synthesis by Tg are iodination and fusion of specific tyrosine residues that are in close proximity to each other in the folded Tg protein. The degree of Tg iodination has been studied widely to determine if it is correlated with thyroid autoimmune disease with mixed results, but these efforts have been limited by the lack of an effective quantitative technique. Simultaneously, the treatment of thyroid cancer has undergone a shift toward partial thyroidectomies, thus undermining the value of Tg measurements. A possible alternative to established monitoring techniques is measurement of Tg iodination states as it has been shown that tumor-derived Tg has significantly lower iodine content. Such measurements require a thorough understanding of normal iodination status. In this study, state-of-the-art liquid chromatography-tandem mass spectrometry (LC-MS/MS) instrumentation is used to perform bottom-up proteomics experiments and identify iodinated residues within commercially available Tg. Using this technique, sequence coverages greater than 90% were achieved, which resulted in identification of previously identified and novel hormone synthesis and donor sites. Based on the results of these discovery experiments, 5 iodination sites were selected for targeted quantitative LC-MS/MS measurements, which suggested that hormone synthesis occurs predominantly at Y24 and Y2766. The results presented herein lay the foundation for routine measurements of iodinated residues, which has the potential to overcome the limitations of current monitoring techniques and benefit patient care.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 3","pages":"bvaf015"},"PeriodicalIF":3.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Journal of the Endocrine Society
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