Journal of Clinical Endocrinology & Metabolism最新文献

{"title":"Increased Prevalence of Germline Pathogenic CHEK2 Variants in Individuals With Pituitary Adenomas.","authors":"Sunita M C De Sousa, Ann McCormack, Andreas Orsmond, Angeline Shen, Christopher J Yates, Roderick Clifton-Bligh, Stephen Santoreneos, James King, Jinghua Feng, John Toubia, David J Torpy, Hamish S Scott","doi":"10.1210/clinem/dgae268","DOIUrl":"10.1210/clinem/dgae268","url":null,"abstract":"<p><strong>Context: </strong>CHEK2 is a cell cycle checkpoint regulator gene with a long-established role as a clinically relevant, moderate risk breast cancer predisposition gene, with greater risk ascribed to truncating variants than missense variants.</p><p><strong>Objective: </strong>To assess the rate and pathogenicity of CHEK2 variants amongst individuals with pituitary adenomas (PAs).</p><p><strong>Methods: </strong>We assessed 165 individuals with PAs for CHEK2 variants. The study population comprised a primary cohort of 29 individuals who underwent germline and tumor whole-exome sequencing, and a second, independent cohort of 136 individuals who had a targeted next-generation sequencing panel performed on both germline and tumor DNA (n = 52) or germline DNA alone (n = 84).</p><p><strong>Results: </strong>We identified rare, coding, nonsynonymous germline CHEK2 variants amongst 3 of 29 (10.3%) patients in our primary cohort, and in 5 of 165 (3.0%) patients overall, with affected patients having a range of PA types (prolactinoma, thyrotropinoma, somatotropinoma, and nonfunctioning PA). No somatic variants were identified. Two variants were definitive null variants (c.1100delC, c.444 + 1G > A), classified as pathogenic. Two variants were missense variants (p.Asn186His, p.Thr476Met), classified as likely pathogenic. Even when considering the null variants only, the rate of CHEK2 variants was higher in our cohort compared to national control data (1.8% vs 0.5%; P = .049).</p><p><strong>Conclusion: </strong>This is the first study to suggest a role for the breast cancer predisposition gene, CHEK2, in pituitary tumorigenesis, with pathogenic/likely pathogenic variants found in 3% of patients with PAs. As PAs are relatively common and typically lack classic autosomal dominant family histories, risk alleles-such as these variants found in CHEK2-might be a significant contributor to PA risk in the general population.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140861044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Thyroid Function on Offspring Neurodevelopment in People Receiving ART Therapy: A Prospective Cohort Study.","authors":"Haofeng Wang, Yuting Peng, Xinru Xia, Yangqian Jiang, Jiangbo Du, Hong Lv, Hongxia Ma, Xiang Ma, Yuan Lin","doi":"10.1210/clinem/dgae046","DOIUrl":"10.1210/clinem/dgae046","url":null,"abstract":"<p><strong>Context: </strong>Adequate maternal thyroid hormone is vital for fetal neurodevelopment. Abnormal thyroid function can cause developmental defects in offspring from spontaneous pregnancies; however, research in assisted reproduction is lacking.</p><p><strong>Objectives: </strong>This work aimed to investigate the association between thyroid disorders and offspring neurodevelopment from assisted reproduction.</p><p><strong>Methods: </strong>In this prospective and longitudinal birth cohort study (Jiangsu, China), we included 729 women who had their thyroid function tested before an assisted reproductive technology cycle and delivered liveborn babies between November 2015 and June 2020. Maternal thyroid function was assessed by measuring thyroid antibodies, free thyroxine, and serum thyrotropin. The third edition Bayley Scales of Infant and Toddler Development screening test (Bayley-III screening test) was used to assess infant neurodevelopment.</p><p><strong>Results: </strong>In multivariable-corrected linear regression analysis, infants of women with subclinical hypothyroidism (SCH) demonstrated a significantly lower receptive communication score (β = -.63; 95% CI, -1.12 to -0.14; P = .013), with stratified analysis showing a significant association among female offspring (β = -.87; 95% CI, -1.59 to -0.15; P = .018) but a null association among male offspring (β = -.44; 95% CI, -1.03 to 0.15; P = .145). No significant differences were found in the assisted pregnancy population with normal thyroid function and positive antibodies according to the diagnostic cutoffs applied to normal pregnant women.</p><p><strong>Conclusion: </strong>SCH in assisted pregnancies correlates with lower communication scores in 1-year-olds, especially in girls. We recommend medication for SCH throughout, regardless of thyroid autoantibody status.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139546737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Denosumab-Protection for Bone and Beyond?","authors":"Lorenz C Hofbauer, Martina Rauner","doi":"10.1210/clinem/dgae207","DOIUrl":"10.1210/clinem/dgae207","url":null,"abstract":"","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140319806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Susceptibility, Mendelian Randomization, and Nomogram Model Construction of Gestational Diabetes Mellitus.","authors":"Qiulian Liang, Ming Li, Gongchen Huang, Ruiqi Li, Linyuan Qin, Ping Zhong, Xuekun Xing, Xiangyuan Yu","doi":"10.1210/clinem/dgae200","DOIUrl":"10.1210/clinem/dgae200","url":null,"abstract":"<p><strong>Context: </strong>Gestational diabetes mellitus (GDM) is a pregnancy-complicated disease that poses a risk to maternal and infant health. However, the etiology of the disease has been not yet elucidated.</p><p><strong>Objective: </strong>To detect the genetic susceptibility and construct a nomogram model with significantly associated polymorphisms and key clinical indicators for early prediction of GDM.</p><p><strong>Methods: </strong>Eleven functional single nucleotide polymorphisms (SNPs) screened by genome-wide association study were genotyped in 554 GDM cases and 641 healthy controls. Functional analysis of GDM positively associated SNPs, multivariate mendelian randomization (MVMR), and a GDM early predictive nomogram model construction were performed.</p><p><strong>Result: </strong>rs1965211, rs3760675, and rs7814359 were significantly associated with genetic susceptibility to GDM after adjusting age and prepregnancy body mass index (pre-BMI). It seems that GDM-associated SNPs have effects on regulating target gene transcription factor binding, posttranscriptional splicing, and translation product structure. Besides, rs3760675 can be expression quantitative trait loci and increase the XAB2 mRNA expression level (P = .047). The MVMR analysis showed that the increase of clinical variables of BMI, hemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) had significant causal effects on GDM (BMI-ORMVMR = 1.52, HbA1c-ORMVMR = 1.32, FPG-ORMVMR = 1.78), P < .05. A nomogram model constructed with pre-BMI, FPG, HbA1c, and genotypes of rs1965211, rs3760675, and rs7814359 showed an area under the receiver operating characteristic curve of 0.824.</p><p><strong>Conclusion: </strong>Functional polymorphisms can change women's susceptibility to GDM and the predictive nomogram model based on genetic and environmental factors can effectively distinguish individuals with different GDM risks in early stages of pregnancy.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140856634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Clinical Trial of High-Dose Growth Hormone in a Patient With a Dominant-Negative Growth Hormone Receptor Mutation.","authors":"Nadia Merchant, Lisa Houchin, Kimberly Boucher, Andrew Dauber","doi":"10.1210/clinem/dgae244","DOIUrl":"10.1210/clinem/dgae244","url":null,"abstract":"<p><strong>Context: </strong>Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention.</p><p><strong>Objective: </strong>To determine whether high-dose GH can overcome GH resistance in this specific patient resulting in normal insulin-like growth factor (IGF)-1 levels and improved growth rates.</p><p><strong>Methods: </strong>Single patient trial of ascending doses of GH followed by a dose stable phase: total 12 months of treatment. The patient has a heterozygous variant in the GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature. Daily subcutaneous GH was administered, starting at 50 µg/kg/day and escalating to 250 µg/kg/day until goal IGF-1 achieved. The subject continued on 250 µg/kg/day for a total treatment duration of 12 months. The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the midpoint of the normal range. Secondary endpoints included height velocity and the change in height SDS during the first year of treatment.</p><p><strong>Results: </strong>A dose of GH of 250 µg/kg/day achieved the target IGF-1 level. The patient's annualized height velocity was 8.7 cm/year, an increase of 3.4 cm/year from baseline, resulting in a 0.81 SD gain in height.</p><p><strong>Conclusion: </strong>A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140861248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of High Adiposity on Endometrial Progesterone Response and Metallothionein Regulation.","authors":"Alina R Murphy, Huma Asif, Harun Cingoz, Françoise A Gourronc, James A Ankrum, Aloysius J Klingelhutz, J Julie Kim","doi":"10.1210/clinem/dgae236","DOIUrl":"10.1210/clinem/dgae236","url":null,"abstract":"<p><strong>Context: </strong>Obesity is a disease with deleterious effects on the female reproductive tract, including the endometrium.</p><p><strong>Objective: </strong>We sought to understand the effects of excess adipose on the benign endometrium.</p><p><strong>Methods: </strong>A physiologic in vitro coculture system was developed, consisting of multicellular human endometrial organoids, adipose spheroids, and menstrual cycle hormones. Native human endometrial tissue samples from women with and without obesity were also analyzed. Benign endometrial tissues from premenopausal women ages 33 to 53 undergoing hysterectomy were obtained following written consent at Northwestern University Prentice Women's Hospital, Chicago, Illinois. Gene expression, protein expression, chromatin binding, and expression of DNA damage and oxidative damage markers were measured.</p><p><strong>Results: </strong>Under high adiposity conditions, endometrial organoids downregulated endometrial secretory phase genes, suggestive of an altered progesterone response. Progesterone specifically upregulated the metallothionein (MT) gene family in the epithelial cells of endometrial organoids, while high adiposity significantly downregulated the MT genes. Silencing MT genes in endometrial epithelial cells resulted in increased DNA damage, illustrating the protective role of MTs. Native endometrium from women with obesity displayed increased MT expression and oxidative damage in the stroma and not in the epithelium, indicating the cell-specific impact of obesity on MT genes.</p><p><strong>Conclusion: </strong>Taken together, the in vitro and in vivo systems used here revealed that high adiposity or obesity can alter MT expression by decreasing progesterone response in the epithelial cells and increasing oxidative stress in the stroma.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140865729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The European Network for the Study of Adrenal Tumors Staging System (2015): A United States Validation.","authors":"Letizia Maria Ippolita Jannello, Reha-Baris Incesu, Simone Morra, Lukas Scheipner, Andrea Baudo, Mario de Angelis, Carolin Siech, Zhe Tian, Jordan A Goyal, Stefano Luzzago, Francesco A Mistretta, Matteo Ferro, Fred Saad, Shahrokh F Shariat, Felix K H Chun, Alberto Briganti, Derya Tilki, Sascha Ahyai, Luca Carmignani, Nicola Longo, Ottavio de Cobelli, Gennaro Musi, Pierre I Karakiewicz","doi":"10.1210/clinem/dgae047","DOIUrl":"10.1210/clinem/dgae047","url":null,"abstract":"<p><strong>Objective: </strong>To test the ability of the 2015 modified version of the European Network for the Study of Adrenal Tumors staging system (mENSAT) in predicting cancer-specific mortality (CSM), as well as overall mortality (OM) in adrenocortical carcinoma (ACC) patients of all stages, in a large-scale, and contemporary United States cohort.</p><p><strong>Methods: </strong>We relied on the Surveillance, Epidemiology, and End Results (SEER) database (2004-2020) to test the accuracy and calibration of the mENSAT and subsequently compared it to the 8th edition of the American Joint Committee on Cancer staging system (AJCC).</p><p><strong>Results: </strong>In 858 ACC patients, mENSAT accuracy was 74.7% for 3-year CSM predictions and 73.8% for 3-year OM predictions. The maximum departures from ideal predictions in mENSAT were +17.2% for CSM and +11.8% for OM. Conversely, AJCC accuracy was 74.5% for 3-year CSM predictions and 73.5% for 3-year OM predictions. The maximum departures from ideal predictions in AJCC were -6.7% for CSM and -7.1% for OM.</p><p><strong>Conclusion: </strong>The accuracy of mENSAT is virtually the same as that of AJCC in predicting CSM (74.7% vs 74.5%) and OM (73.7% vs 73.5%). However, calibration is lower for mENSAT than for AJCC. In consequence, no obvious benefit appears to be associated with the use of mENSAT relative to AJCC in US ACC patients.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139546794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Underpinnings of Fasting and Oral Glucose-stimulated Based Insulin Sensitivity Indices.","authors":"Sufyan Suleman, Anne L Madsen, Lars H Ängquist, Mikkel Schubert, Allan Linneberg, Ruth J F Loos, Torben Hansen, Niels Grarup","doi":"10.1210/clinem/dgae275","DOIUrl":"10.1210/clinem/dgae275","url":null,"abstract":"<p><strong>Context: </strong>Insulin sensitivity (IS) is an important factor in type 2 diabetes (T2D) and can be estimated by many different indices.</p><p><strong>Objective: </strong>We aimed to compare the genetic components underlying IS indices obtained from fasting and oral glucose-stimulated plasma glucose and serum insulin levels.</p><p><strong>Methods: </strong>We computed 21 IS indices, classified as fasting, OGTT0,120, and OGTT0,30,120 indices, using fasting and oral glucose tolerance test (OGTT) data in 2 cohorts. We used data from a family cohort (n = 313) to estimate the heritability and the genetic and phenotypic correlations of IS indices. The population cohort, Inter99 (n = 5343), was used to test for associations between IS indices and 426 genetic variants known to be associated with T2D.</p><p><strong>Results: </strong>Heritability estimates of IS indices ranged between 19% and 38%. Fasting and OGTT0,30,120 indices had high genetic (ρG) and phenotypic (ρP) pairwise correlations (ρG and ρP: 0.88 to 1) The OGTT0,120 indices displayed a wide range of pairwise correlations (ρG: 0.17-1.00 and ρP: 0.13-0.97). We identified statistically significant associations between IS indices and established T2D-associated variants. The PPARG rs11709077 variant was associated only with fasting indices and PIK3R rs4976033 only with OGTT0,30,120 indices. The variants in FAM63A/MINDY1, GCK, C2CD4A/B, and FTO loci were associated only with OGTT0,120 indices.</p><p><strong>Conclusion: </strong>Even though the IS indices mostly share a common genetic background, notable differences emerged between OGTT0,120 indices. The fasting and OGTT-based indices have distinct associations with T2D risk variants. This work provides a basis for future large-scale genetic investigations into the differences between IS indices.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140861250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Oral Bisphosphonate Drug Holiday on Mortality Following Hip Fracture.","authors":"Miriam T Y Leung, Justin P Turner, Clara Marquina, Jenni Ilomaki, Tim Tran, J Simon Bell","doi":"10.1210/clinem/dgae272","DOIUrl":"10.1210/clinem/dgae272","url":null,"abstract":"<p><strong>Context: </strong>Current clinical guidelines recommend a drug holiday after extended use of oral bisphosphonates. However, no studies have investigated the effect of drug holidays before hip fractures on postfracture mortality.</p><p><strong>Objective: </strong>This work aimed to investigate the effect of a drug holiday on postfracture mortality in patients with extended use of oral bisphosphonates.</p><p><strong>Methods: </strong>This retrospective, population-based cohort study took place among all patients with hip fractures in Victoria, Australia, from 2014 to 2018. Patients were adherent to oral alendronate or risedronate for 5 years or more prior to hip fracture. Group-based trajectory modeling categorized patients into different bisphosphonate usage after 5-year good adherence. The main outcome measure was postfracture mortality.</p><p><strong>Results: </strong>We identified 365 patients with good adherence (medication possession ratio ≥80%) to oral alendronate/risedronate for 5 years or more. Most patients (69%) continued to use oral bisphosphonates until admission for hip fracture; 17% had discontinued for 1 year and 14% had discontinued for 2 years. Postfracture mortality was higher in patients who had discontinued risedronate for 1 year (hazard ratio [HR] 2.37; 95% CI, 1.24-4.53) and 2 years (HR 3.08; 95% CI, 1.48-6.41) prior to hip fracture. No increase or decrease in postfracture mortality was observed in patients who had discontinued alendronate for 1 year (HR 0.59; 95% CI, 0.29-1.18) or 2 years (HR 1.05; 95% CI, 0.57-1.93) prior to hip fracture.</p><p><strong>Conclusion: </strong>Postfracture mortality is higher in people who discontinue risedronate, but not alendronate, for 1 or 2 years after being adherent to treatment for at least 5 years. The type of bisphosphonate may be a factor to consider when planning drug holidays.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140867255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Distinct Antiandrogen Exposures on the Plasma Metabolome in Feminizing Gender-affirming Hormone Therapy.","authors":"Rebecca Shepherd, Lachlan M Angus, Toby Mansell, Bridget Arman, Bo Won Kim, Katherine Lange, David Burgner, Jessica A Kerr, Ken Pang, Jeffrey D Zajac, Richard Saffery, Ada Cheung, Boris Novakovic","doi":"10.1210/clinem/dgae226","DOIUrl":"10.1210/clinem/dgae226","url":null,"abstract":"<p><strong>Context: </strong>The plasma metabolome is a functional readout of metabolic activity and is associated with phenotypes exhibiting sexual dimorphism, such as cardiovascular disease. Sex hormones are thought to play a key role in driving sexual dimorphism.</p><p><strong>Objective: </strong>Gender-affirming hormone therapy (GAHT) is a cornerstone of transgender care, but longitudinal changes in the plasma metabolome with feminizing GAHT have not been described.</p><p><strong>Methods: </strong>Blood samples were collected at baseline and after 3 and 6 months of GAHT from transgender women (n = 53). Participants were randomized to different anti-androgens, cyproterone acetate or spironolactone. Nuclear magnetic resonance-based metabolomics was used to measure 249 metabolic biomarkers in plasma. Additionally, we used metabolic biomarker data from an unrelated cohort of children and their parents (n = 3748) to identify sex- and age-related metabolite patterns.</p><p><strong>Results: </strong>We identified 43 metabolic biomarkers altered after 6 months in both anti-androgen groups, most belonging to the very low- or low-density lipoprotein subclasses, with all but 1 showing a decrease. We observed a cyproterone acetate-specific decrease in glutamine, glycine, and alanine levels. Notably, of the metabolic biomarkers exhibiting the most abundant \"sex- and age-related\" pattern (higher in assigned female children and lower in assigned female adults, relative to assigned males), 80% were significantly lowered after GAHT, reflecting a shift toward the adult female profile.</p><p><strong>Conclusion: </strong>Our results suggest an anti-atherogenic signature in the plasma metabolome after the first 6 months of feminizing GAHT, with cyproterone acetate also reducing specific plasma amino acids. This study provides novel insight into the metabolic changes occurring across feminizing GAHT.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140874982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}