Journal of the Endocrine Society最新文献

Context: Causative factors for ectopic ossifications in X-linked hypophosphatemia (XLH) remain to be elucidated.

Objective: This work aimed to investigate the genotype-phenotype correlations between the phosphate-regulating endopeptidase homologue, X-linked gene (PHEX) and ectopic ossifications in XLH.

Methods: Biochemical data, spinal computed tomography scans, and x-rays of hip/knee joints were retrospectively reviewed. Genetic analysis and the measurement of plasma inorganic pyrophosphate (PP_i)-a potent inhibitor of tissue calcification-were performed. The effect of PHEX mutations on protein function was predicted using nonsense-mediated decay (NMD) and 3-dimensional structure modeling. The index of ossification of the anterior/posterior longitudinal ligament and yellow ligament (OA/OP/OY index) and the sum of the OA/OP/OY index (OS index) were used to quantify the severity of spinal ligament ossification. The severity of the hip/knee osteoarthritis was evaluated by the Kellgren-Lawrence classification.

Results: We examined 24 distinct pathogenic PHEX variants in 28 patients from a study population of 33 individuals in 27 unrelated, nonconsanguineous families. Among the 31 patients whose plasma samples were analyzed for PP_i, 14 patients (45%) showed decreased plasma PP_i concentrations; however, PP_i concentrations did not correlate with mutation type or ectopic ossification. Fibroblast growth factor 23 levels in women with NMD-insensitive mutations trended lower than in men with NMD-sensitive mutations but failed to reach statistical significance. Both models revealed no correlations between PHEX pathogenic variant and ectopic ossification.

Conclusion: Neither modeling found correlates between PHEX pathogenic variants and ectopic ossification. The effects of PP_i on ectopic ossifications in adults with XLH revealed trends that should be investigated with a large sample size.

The thyroid eye disease (TED) of Graves disease is associated with high titers of stimulating TSH receptor antibodies, retro-orbital inflammation, fibroblast release of cytokines and chemokines, and adipogenesis, which in turn leads to proptosis, muscle fibrosis, and dysfunction. Part of this scenario is the induction of fibroblast proliferation and autophagy secondary to synergism between the TSH receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1R). While TED is well associated with thyroid-stimulating antibodies to the TSHR, which is also well expressed on fibroblasts, in fact the TSHR reactome has a variety of TSHR antibodies with varying biological activity. Therefore, we have now evaluated the possible role of neutral TSHR antibodies (N-TSHR-mAbs), directed at the hinge region of the TSHR, which do not induce cell proliferation but are known to have effects on multiple proteins in thyroid cells including stress-related signaling molecules. We examined the consequences of an N-TSHR-mAb acting on TSHR-expressing fibroblasts and found marked cell stress, which initiated signaling pathways involving inflammasome activation. This response ended in widespread cell death by pyroptosis through activation of caspase 8 and gasdermin D. Hence, not only can stimulating TSHR autoantibodies influence TED inflammation but the N-TSHR antibodies, representing more of the reactome, may also exaggerate the retro-orbital inflammatory response seen in TED.

Background: Pregnancy represents an additional challenge to the complex clinical picture of lipodystrophy disorders, and the management of such conditions with related comorbidities has been underreported. This work aims to outline the risk associated with a pregnancy event for women dealing with acquired partial lipodystrophy and the need for diverse but specialized care.

Case: We report on the successful pregnancy outcome of a 28-year-old woman with an acquired partial form of lipodystrophy related to an allogenic bone marrow transplant that occurred at pediatric age. Although metabolic control was challenging, glucose levels progressively improved during the pregnancy, and triglycerides increased less than expected. The periodic monitoring of leptin levels showed a progressive increase with a peak in the third trimester (41.53 ng/mL), followed by a fast decline the day after giving birth, with a lower basal level than the prepregnancy period. However, preterm delivery occurred associated with cardiac complications in the mother.

Results: A total of 12 studies were retrieved concerning women aged 14 to 38 years with various lipodystrophy phenotypes. Diabetes and hypertriglyceridemia were the most common comorbidities. Most women had successful pregnancies despite gestational complications (including miscarriages), preterm and emergency deliveries, and newborns undergoing partum or postpartum transient or chronic complications.

Conclusion: Lipodystrophy disorders expose both mothers and children to very high risk. Intensive monitoring and care of all potential clinical complications should be planned and carried out by a multidisciplinary team before, during, and after the pregnancy. Leptin secretion during pregnancy should be investigated more deeply in these patients.

Background: Levothyroxine (LT4) is recommended to be ingested in a fasting state, 30-60 minutes before breakfast to avoid interactions with food and drugs. In clinical practice, we noticed that this instruction may be inconvenient for patients. Therefore, we aimed to evaluate patient experiences and preferences concerning the recommended fasting administration of LT4.

Methods: Patients using LT4 were invited to complete a questionnaire. Regression analyses were performed to identify patient characteristics associated with taking LT4 close to or together with food and/or interfering drugs, feeling burdened with postponing breakfast, and preferring nonfasting LT4 ingestion.

Results: Of 463 invited patients, 410 completed the questionnaire (88.6%). Of these, 76.8% was female and median age was 57 years (interquartile range: 43-67). Nearly all patients (97.3%) reported to have received instruction on fasting LT4 ingestion, but only 30% adhered to this. Nonfasting LT4 intake was associated with use of co-medication (odds ratio [OR], 2.82; 95% CI, 1.77-4.47), treatment duration >1 year (OR, 1.76; 95% CI, 1.02-3.04), and male sex (OR, 1.67; 95% CI, 1.03-2.70). Approximately half of the patients reported being burdened with postponing breakfast and the majority (60.5%) expressed their preference for nonfasting LT4 ingestion. Interestingly, 25% omitted breakfast and 13.4% forgot their medication because of the fasting requirement. Furthermore, the majority (68.2%) of patients that used interfering drugs stated not to be instructed to separate these drugs from LT4.

Conclusion: This study highlights the burden associated with fasting LT4 ingestion, leading to nonadherence, irregular LT4 intake, and omitting breakfast. Given the clear preferences towards nonfasting LT4 ingestion, further research into alternative nonfasting administration methods is warranted.

Background: Autonomously functioning thyroid nodules (AFTNs) constitute 5% to 7% of thyroid nodules and represent the second most common cause of hyperthyroidism following Graves' disease. Currently, radioactive iodine (RAI) and surgery are the standard treatment options, and both incur a risk of postprocedural hypothyroidism and other surgery and radiation-related complications.

Methods: This work aimed at assessing the efficacy of radiofrequency ablation (RFA) as an alternative treatment option for resolving hyperthyroidism and the nodule volume rate reduction (VRR) and its associated adverse events.

Results: A total of 22 patients underwent RFA for a solitary AFTN. Seventy-two percent (n = 16) had subclinical hyperthyroidism, 9% (n = 2) had overt hyperthyroidism, and 18% (n = 4) were biochemically euthyroid on antithyroid medication. Average pretreatment TSH was 0.41 mIU/L (SD = 0.98) and free T4 1.29 ng/dL (SD = 0.33). Following a single RFA session, hyperthyroidism resolved in 90.9% (n = 20) and average VRR (61.13%) was achieved within 3 to 6 months following the ablation. Except for 1 nodule, none of the nodules grew during the follow-up period (16.5 months). Two patients (9%) developed transient tachycardia requiring short-term beta-blocker therapy, and 2 developed mild hypothyroidism requiring levothyroxine therapy. Two patients developed recurrent hyperthyroidism and elected to undergo lobectomy and repeat RFA respectively. No serious adverse effects were noted in this cohort.

Conclusion: RAI and/or surgery represent the standard of care for toxic adenomas, but RFA shows excellent efficacy and safety profile. Therefore, at centers with RFA expertise, it should be considered an alternative treatment strategy, avoiding radiation and surgery-related complications.

Context: Neurodevelopmental impairments are common among survivors of extremely preterm birth, particularly in males. Hyperactivation of the hypothalamic-pituitary-gonadal (HPG) axis has been suggested as an underlying cause, but this has been poorly investigated.

Objective: Establish levels and temporal changes in circulating androgens in extremely preterm infant males.

Methods: Observational cohort study analyzing cord blood serum (n = 25) and postnatal plasma (n = 13) collected from day 0 until week 11 from infant males born at 22.8-27.9 weeks gestational age. Testosterone and dihydrotestosterone (DHT) were determined using gas chromatography mass spectrometry, sex hormone-binding globulin (SHBG) with an enzyme-linked immunosorbent assay, and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) with the Luminex xMAP multiplex assay.

Results: Testosterone and DHT levels were higher on day 0 (median 4.27 and 0.30 ng/mL) than in cord blood (0.15 and 0.01 ng/mL) (P < .001 for both). Levels of the hormones then declined rapidly until day 5 (median 0.16 and 0.12 ng/mL), then remained relatively constant throughout the study period. Median levels of testosterone and DHT across the whole study period were approximately 6-fold higher than reported in utero levels. FSH and LH showed similar postnatal patterns as the androgens. SHBG steadily increased over time, and, as a result, the fraction of bioavailable testosterone declined with infant postnatal age.

Conclusion: The HPG axis is activated immediately after birth in extremely preterm infant males, resulting in an androgen pulse occurring several months earlier than during a normal pregnancy. The long-term implications of high androgen exposure during a sensitive neurodevelopmental period warrant further studies.

Context: Renin is a marker of blood volume. There is no consensus on the validity of plasma renin measurement for adjusting mineralocorticoid (MC) substitution in patients with primary adrenal insufficiency (PAI).

Objective: This work aimed to investigate if plasma renin could be used to adjust MC substitution in patients with PAI.

Methods: A total of 150 patients with at least one measurement of plasma renin followed for PAI at 2 tertiary expert centers between 2008 and 2022 were retrospectively included. As supraphysiological hydrocortisone might have additional MC activity, we integrated the individual hydrocortisone dose to obtain the MC equivalent dose (Eq-MC). Renin less than 20 mIU/L was considered oversubstituted, renin between 20 and 60 mIU/L as correctly substituted, and renin over 60 mIU/L as undersubstituted.

Results: The mean dose of fludrocortisone was 82.3 ± 46 μg/day. Plasma renin was abnormal in 56.7% of cases (7 patients oversubstituted and 78 patients undersubstituted). Abnormalities in electrolyte levels were observed in only 12.7% of patients. Plasma renin correlated negatively with sodium (P < .01) and systolic blood pressure (P = .026), and positively with potassium (P < .01). Doses changes in Eq-MC had a statistically significant effect on renin levels (P = .0037), with an increase of MC dose correlating with a decrease in renin level and vice versa; no correlation was observed using electrolytes or blood pressure.

Conclusion: Plasma renin correlates with electrolytes and blood pressure. While dose changes significantly alter renin levels, electrolytes and blood pressure do not, suggesting that renin may provide more information about MC replacement therapy than electrolytes and blood pressure.

Context: Patients with aggrecan (ACAN) deficiency present with dominantly inherited short stature, as well as early-onset joint disease.

Objective: The objective of this study was to evaluate the efficacy and safety of recombinant human GH (rhGH) on linear growth in ACAN-deficient children.

Methods: Open-label, single-arm, prospective study over 3 years recruiting 10 treatment-naïve patients with heterozygous mutations in ACAN, age ≥2 years, prepubertal, and normal IGF-I concentration. Patients were treated with rhGH (initially, 50 mcg/kg/day). Main outcomes were change in (Δ) height SD score (HtSDS) and height velocity (HV).

Results: Ten patients (6 females) enrolled with median chronological age (CA) of 5.6 years (range, 2.4-9.7). Baseline median HtSDS, HV, and bone age/CA were -2.5 (range, -4.3 to -1.1), 5.2 cm/year (range, 3.8 to 7.1), and 1.2 (range, 0.9 to 1.5), respectively. The cumulative median ΔHtSDS over 3 years was +1.21 (range, +0.82 to +1.94). Median HV increased to 8.3 cm/year (range, 7.3-11.2), 7.7 cm/year (range, 5.9-8.8), and 6.8 cm/year (range, 4.9-8.6) during years 1, 2, and 3, respectively. The median Δ predicated adult height was +6.8 cm over 3 years. Four female subjects entered puberty; nevertheless, median Δbone age/CA was -0.1. No adverse events related to rhGH were observed.

Conclusion: Linear growth improved in a cohort of ACAN-deficient patients treated with rhGH, albeit somewhat attenuated in older participants who entered puberty. Longitudinal follow-up is needed to assess the long-term efficacy of rhGH and adult height outcome.

Context: For Muslim patients on levothyroxine (L-T4) therapy, the best approach for L-T4 intake during Ramadan fasting remains unclear.

Objective: We compared 2 practical approaches for L-T4 intake during Ramadan.

Methods: We randomly assigned 69 patients (21 males, 48 females, median age 44 years) with differentiated thyroid cancer (DTC) who underwent thyroidectomy in the past and are on stable LT4 doses to 2 arms. Arm A (33 patients) ingested their pre-Ramadan L-T4 dose at the evening meal and ate immediately. Arm B (36 patients) increased their pre-Ramadan dose by 25 µg if their regular L-T4 dose was ≤150 µg/day or by 50 µg if their pre-Ramadan dose was >150 µg/day and ate immediately.

Results: At the beginning of Ramadan (baseline), the median thyrotropin (TSH) level and the numbers of patients in euthyroidism, subclinical hyperthyroidism (Shyper), or subclinical hypothyroidism (Shypo) were comparable between the 2 arms (P = .69 and P = .65, respectively). At the end of Ramadan, in arm A there were 17 (51.5%), 3 (9.1%), and 13 (39.4%) patients in euthyroidism, Shyper, and Shypo compared with 17 (47.2%), 14 (38.9%), and 5 (13.9%) patients, respectively, in arm B (P = .005). The mean ± SD TSH levels in arms A and B at the end of Ramadan were 5.6 ± 6.0 mU/L and 1.67 ± 2.6 mU/L, respectively (P = .0001).

Conclusion: No overt thyroid dysfunction developed but there were more cases of Shypo in arm A and Shyper in arm B. Arm B achieved desirable levels of TSH (normal or slightly suppressed) in 86% of cases and might be a preferable approach, especially for patients who need TSH suppression (eg, DTC).

The Endocrine Society formally addressed the issue of retirement for its members for the first time in a Workshop held on June 4 at ENDO 2024 in Boston, Massachusetts. Preparation for the workshop included 4 steps: (1) completion of a survey; (2) advice from a retirement expert; (3) extensive literature review; and (4) multiple pre-workshop discussions among the presenters. The survey found that retired endocrinologists are involved in a wide variety of professional and nonprofessional activities. The retirement expert and the literature review outlined several concepts underlying a successful retirement and the questions and decisions needed during the planning process. The presenters described several illustrative examples of retirement activities. A "Piece of My Mind" essay in the Journal of the American Medical Association written by the moderator (C.B.) expressed ethical considerations made feasible by the independence of her retirement status. The first presenter (A.R.) noted that the time available during retirement allowed mentorship, teaching in foreign countries and other institutions, and participation on international committees. The second speaker (K.F.) commented that expertise gained during practice of Endocrinology can be used for expert legal, pharmaceutical, and financial opinions. She also noted that volunteering for professional or nonprofessional groups provides an avenue for "giving back" to others. The final presenter (R.S.) stated that retirement provides an opportunity to embark on new clinical endeavors, such as managing patients via telemedicine in rural underserved areas. In summary, retirement is an important phase of a career and can be highly rewarding and enjoyable.