Daily Endocrinology Research Analysis
Analyzed 100 papers and selected 3 impactful papers.
Summary
Analyzed 100 papers and selected 3 impactful articles.
Selected Articles
1. Genomic characterization of aggressiveness in pituitary neuroendocrine tumors (PitNETs).
In 206 PitNETs, integrated transcriptomic, methylomic, cytogenetic, and mutational profiling linked specific aggressiveness features to lineage-specific omic signatures. A common signature of proliferative transcriptome plus DNA hypermethylation emerged, with LRP1B (novel), TP53, and CDKN2A alterations associated with aggressive behavior, while USP8/GNAS were not. Molecular signatures remained stable over time, supporting a histomolecular definition of aggressiveness.
Impact: This large, lineage-aware multi-omic study reframes aggressiveness in PitNETs with a robust histomolecular signature and identifies LRP1B as a novel gene, informing prognostication and future targeted strategies.
Clinical Implications: A histomolecular definition could refine risk stratification beyond size/invasion and guide surveillance and adjuvant therapy decisions; genetic panels may incorporate LRP1B/TP53/CDKN2A for aggressiveness assessment.
Key Findings
- Aggressive features (rapid progression, post-radiotherapy progression, Ki67≥10%, metastasis, temozolomide use, disease-specific death) mapped to distinct omic signatures.
- A shared aggressiveness signature combined a proliferative transcriptome with DNA hypermethylation across lineages.
- LRP1B (novel for PitNETs), TP53, and CDKN2A alterations associated with aggressiveness, whereas USP8 and GNAS did not.
- Molecular signatures were largely stable over disease course despite evolution towards aggressiveness.
Methodological Strengths
- Large cohort (n=206) with integrated transcriptome, methylome, chromosomal, and mutation data
- Lineage-stratified analyses and longitudinal clonal evolution in a subset (n=7)
Limitations
- Retrospective, non-interventional design limits causal inference
- External prospective validation and clinical utility metrics (e.g., predictive accuracy for outcomes) are pending
Future Directions: Validate signatures prospectively, integrate into prognostic models, and test targeted or adjuvant therapeutic strategies guided by histomolecular risk.
BACKGROUND: Aggressive evolution of PitNETs is rare, metastatic spread even more. Defining aggressiveness and malignancy is challenging, subsequently hard to predict, and to understand. The aim was to provide a molecular definition of aggressiveness using genomic approaches. METHODS: PitNETs from 206 patients were included. Associations between 9 clinicopathological features of aggressiveness and PitNETs' omics were explored. Omics included transcriptome, DNA methylation, chromosomal alterations and mutations. Clonal tumor evolution was monitored in 7 patients. RESULTS: Among the 9 clinicopathological features of aggressiveness, only rapid progression, progression after radiotherapy, Ki67/MIB1 proliferation index ≥10%, temozolomide treatment, metastases and specific death were associated with specific omics signatures, while tumour maximal diameter ≥40mm, cavernous and sphenoid invasion were not. The omic signatures associated with these features of aggressiveness overlapped but remained distinct between corticotroph and mammo-somato-thyrotroph lineages. For each lineage, a common signature of aggressiveness was identified, associating proliferative transcriptome signature and DNA hypermethylation. Alterations in specific genes were associated with aggressive features, - including a novel PitNET gene, LRP1B, and known cancer genes (TP53, CDKN2A) -, while USP8 and GNAS alterations were not. Integration of gene alterations with methylome and transcriptome signatures isolated a subset of molecularly aggressive PitNETs. Molecular signatures were globally stable during the course of the disease, despite evolution towards aggressiveness and potential clonal divergence. CONCLUSION: This systematic analysis of clinicopathological features of aggressiveness using an integrated multiomic approach establishes a histomolecular definition of aggressiveness in PitNETs. Prospective cohorts studies are needed to validate these molecular signatures and establish their prognostic value.
2. Steroids, stress, and body mass index interact to accelerate female pubertal development.
In a 6-year longitudinal cohort of 327 girls, higher prepubertal urinary glucocorticoid, androgen, and progesterone metabolites predicted earlier thelarche, with BMI and stress amplifying effects—advancing onset by about 7 months. Findings shift emphasis beyond estrogens, implicating stress biology and adrenal/ovarian steroid pathways in pubertal timing.
Impact: This study integrates a broad steroid metabolome with psychosocial modifiers to mechanistically explain secular trends in pubertal timing, offering actionable targets for prevention and counseling.
Clinical Implications: Screening for elevated stress and adiposity, coupled with counseling on modifiable behaviors, may help mitigate accelerated pubertal onset; urinary steroid profiling could support risk identification in research settings.
Key Findings
- Doubling of prepubertal urinary glucocorticoid, androgen, and progesterone metabolites associated with earlier thelarche (HRs 1.9, 3.9, and 6.7, respectively).
- High glucocorticoids combined with high BMI and stress advanced thelarche by approximately 7 months.
- Findings implicate stress biology and non-estrogenic steroids in pubertal timing, beyond traditional focus on estrogens and menarche.
Methodological Strengths
- Prospective longitudinal design with survival modeling (Weibull) and interaction testing
- Comprehensive urinary steroidome (36 metabolites) measured before and during puberty
Limitations
- Age at thelarche based on parental report (though correlated with clinical Tanner staging in a subset)
- Observational design limits causal inference; potential residual confounding
Future Directions: Interventional trials targeting stress reduction and adiposity to test modifiability of pubertal timing; validation of urinary steroid panels as predictive biomarkers.
CONTEXT: Estrogens underlie puberty in girls, but the steroid metabolome may also regulate pubertal timing in response to elevated stress and increasing body mass index (BMI). OBJECTIVE: Our objective was to identify steroid metabolome patterns linked to accelerated puberty and test whether BMI and stress markers modify this relationship. METHODS: From the LEGACY Girls Study, a longitudinal cohort followed for 6 years, we selected 327 girls aged 5 to 13 years at baseline to measure 36 steroid metabolites of glucocorticoids, androgens, progesterone, and estrogens in 2 urine samples collected before and during puberty. Parents reported the age at onset of breast development (thelarche), which had a high correlation in the subset with clinically assessed Tanner. Study staff measured height and weight and administered questionnaires, including the Internalizing Composite Scale, a parental proxy of child stress. We estimated hazard ratios (HRs) for the association between doubled steroid metabolites and ages at thelarche, pubarche, and menarche using Weibull survival models, testing interactions with stress and BMI z-scores. RESULTS: Accelerated thelarche was associated with higher prepubertal urinary metabolites of glucocorticoids (HR = 1.9, 95% CI: 1.5-2.5), androgens (HR = 3.9, 95% CI: 2.7-5.6), and progesterone (HR = 6.7, 95% CI: 4.1-10.9). Girls with high glucocorticoid metabolites combined with high BMI and stress reached thelarche 7 months earlier than their counterparts with low measures in these parameters. CONCLUSION: Elevated metabolites of glucocorticoids, androgens, and progesterone are associated with accelerated pubertal onset, and BMI and stress modify this association. Previous studies have focused on estrogens, menarche, and BMI; our results suggest that androgens and stress impact the timing of thelarche as well, explaining secular declines in pubertal timing.
3. The use of denosumab in rare bone diseases in adults: a systematic review from the ECTS Rare Bone Disease Action Group.
This systematic review synthesizes adult data on denosumab for rare bone diseases, noting consistent improvements in pain and lesions with commonly used 120 mg monthly or q3-month dosing over approximately one year. Safety is generally acceptable, but rebound bone turnover and disease recurrence after discontinuation are key concerns; post-denosumab zoledronic acid may mitigate rebound though seldom reported.
Impact: Provides practice-oriented synthesis in an area with sparse adult data, highlighting dosing patterns, safety, and the critical need for planned discontinuation strategies to prevent rebound.
Clinical Implications: Denosumab can be considered for adult rare bone diseases within multidisciplinary care, with proactive plans for discontinuation (e.g., zoledronic acid) and monitoring for hypocalcemia and rebound.
Key Findings
- Pain reduction and lesion improvement or bone formation reported across adult rare bone diseases treated with denosumab.
- Common effective regimens used 120 mg monthly or every 3 months for roughly one year.
- Adverse events were generally mild (asymptomatic hypocalcemia/hypophosphatemia); serious AEs like ONJ or atypical femoral fractures were rare.
- Rebound after discontinuation with disease recurrence is a major concern; post-denosumab zoledronic acid may help but is underreported.
Methodological Strengths
- Targeted systematic evidence synthesis focused on adult rare bone diseases
- Clear synthesis of dosing patterns, safety signals, and discontinuation considerations
Limitations
- Heterogeneous, predominantly non-randomized evidence with small samples
- Limited data on long-term outcomes and standardized discontinuation protocols
Future Directions: Establish rare disease registries and prospective studies to standardize dosing, monitor rebound, and evaluate sequential antiresorptive strategies post-denosumab.
CONTEXT: Rare bone diseases may display a disrupted RANKL-RANK-Osteoprotegerin pathway causing increased osteoclastogenesis and enhanced bone resorption. Although bisphosphonates are commonly used, they often fall short of desired outcomes. Denosumab, an anti-RANKL antibody, provides a promising alternative by swiftly and strongly suppressing bone turnover (faster and more potent suppression of bone resorption than bisphosphonates), though its effects are reversible upon discontinuation. The use of denosumab has been highlighted, especially in pediatric cases but not substantially in adults. EVIDENCE ACQUISITION: A targeted evidence search was conducted to retrieve studies reporting denosumab use in rare bone diseases in adults. EVIDENCE SYNTHESIS: Denosumab administration may lead to pain reduction, lesion reduction or bone formation. Treatment dosage, schedules and duration varied, however, a dose of 120 mg dosed monthly or 3 monthly for almost one year reached the desired treatment effect in most patients. Denosumab is generally well tolerated in adults, with mild common side effects such as (asymptomatic) hypocalcemia and hypophosphatemia. Serious adverse effects such as osteonecrosis of the jaw or atypical femoral fractures are rarely reported. Main concerns regard rebound effect after denosumab discontinuation, with disease recurrence in some cases. Zoledronic acid after discontinuation of denosumab might be advisable, but is seldom reported. CONCLUSIONS: Denosumab is a feasible treatment in adults with rare bone diseases when managed by multidisciplinary teams with knowledge of both the underlying disease and potential surgeries as well as the medical site of treatment. Denosumab discontinuation management is paramount to prevent recurrence and severe complications. The paucity of data supports the need for data collection through rare disease registries for future pertinent evidence-based recommendations.