Manuel Ramón García-Sáenz

Purpose: Although cabergoline is the treatment of choice for prolactinomas, a non‐negligible proportion of patients show incomplete biochemical and/or tumoral response. Although several baseline factors have been associated with dopamine agonist resistance, their predictive value remains inconsistent. We aimed to evaluate whether baseline clinical, biochemical, and gross tumor burden variables are associated with incomplete biochemical and radiological response to cabergoline in prolactinomas using a predefined composite operational outcome. Methods: We conducted a retrospective observational cohort study at a tertiary care center in Mexico City. Adult patients with prolactinomas treated with cabergoline were included. The primary outcome was incomplete response to cabergoline, defined using a predefined operational composite endpoint requiring both prolactin normalization and at least 30% estimated tumor volume reduction during follow‐up. Follow‐up duration and cabergoline dose exposure were summarized descriptively and component analyses evaluated biochemical and radiological response separately. A sensitivity analysis used at least 30% tumor diameter reduction instead of volume reduction. Baseline characteristics were compared between responders and patients with incomplete response. Multivariable models including only baseline variables were constructed to identify independent baseline factors associated with incomplete response. Because maximal tolerated cabergoline dose and the reasons for dose non‐escalation were not uniformly available, this endpoint was used exclusively as a research classification; non‐attainment was not interpreted as clinical treatment failure or dopamine‐agonist resistance. Results: A total of 226 patients were included. Using the primary volume‐based definition, 140 patients (61.9%) were classified as responders and 86 (38.1%) as having incomplete response. Follow‐up duration from cabergoline initiation to the last clinical assessment was calculable in 225 patients, with a median duration of 107 months (IQR 56.5−153.5). The median cabergoline dose at 12 months was 1.5 mg/week (IQR 1.0−2.0), and 61 patients (27.0%) had received ≥ 2 mg/week at that time. In unadjusted analyses, age, sex, baseline estimated tumor volume, and tumor size category were not associated with incomplete response, whereas baseline prolactin showed only a weak non‐significant trend. In the primary multivariable model, none of the baseline variables independently identified patients with incomplete response. In exploratory component analyses, 140 patients (61.9%) achieved both prolactin normalization and ≥ 30% estimated tumor volume reduction, 14 (6.2%) achieved prolactin normalization only, 46 (20.4%) achieved ≥ 30% estimated tumor volume reduction only, and 26 (11.5%) achieved neither endpoint. Higher baseline prolactin was associated with incomplete biochemical response (adjusted OR 1.90 per log10 increase, 95% CI 1.11−3.25; p = 0.019; AUC 0.624), but no baseline variable was independently associated with incomplete radiological response. Conclusion: Using a composite operational definition of incomplete response to cabergoline, no routinely available baseline clinical, biochemical, or gross tumor burden variable was independently associated with the composite endpoint or with incomplete radiological response. Baseline prolactin was associated only with incomplete biochemical response, and discrimination remained limited. Conventional baseline variables appear insufficient for clinically useful prediction, highlighting the need for more comprehensive models incorporating dynamic treatment‐related, imaging features of tumor invasiveness, and molecular markers.

Background/Objectives: Type 2 diabetes is increasingly recognized as a systemic disorder driven not only by chronic hyperglycemia and insulin resistance, but also by dysregulated interorgan communication. Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as biologically active carriers of proteins, lipids, and microRNAs capable of modulating gene expression in recipient cells. This narrative review integrates clinical, experimental, and translational evidence on EV-associated microRNAs as candidate biomarkers and potential mediators of diabetic complications, with emphasis on diabetic neuropathy, diabetic kidney disease, diabetic retinopathy, and metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: This review was aligned with the SANRA framework and focused on biological plausibility, evidence from tissue and biofluids, biomarker potential, therapeutic implications, and barriers to clinical translation. Studies were additionally interpreted according to biological matrix, EV-carrier specificity, analytical platform, study design, and level of functional validation. Results: Across complications, EV-associated microRNAs appear to participate in shared pathogenic processes, including oxidative stress, inflammation, endothelial dysfunction, fibrosis, angiogenesis, neurodegeneration, and metabolic memory. In diabetic neuropathy, microRNAs such as miR-146a, miR-155, miR-21-5p, and miR-148a-3p have been linked to neuroinflammation, Schwann-cell dysfunction, axonal injury, and neuropathic pain. In diabetic kidney disease, miR-21, miR-29, miR-30, and miR-126 are implicated in podocyte injury, tubulointerstitial fibrosis, albuminuria, and microvascular dysfunction. In diabetic retinopathy, microRNAs including miR-146a, miR-155, miR-21, miR-126, and miR-200b contribute to neurovascular injury, inflammation, barrier disruption, and angiogenesis. In MASLD associated with diabetes, hepatocyte-derived EVs carrying microRNAs such as miR-1 and miR-126a-3p may link hepatic lipotoxicity to endothelial inflammatory and β-cell dysfunction. Conclusions: Although EV-associated microRNAs offer promising opportunities for biomarker discovery, risk stratification, and targeted therapies, clinical translation remains limited by heterogeneity in EV isolation, microRNA quantification, biological matrices, and outcome definitions. Distinguishing EV-associated miRNAs from total circulating extracellular miRNAs remains essential for biological interpretation. Standardized, longitudinal, and externally validated studies are required before these signals can be implemented as actionable tools in precision diabetes care.

Background/Objectives: This cross-sectional study aimed to validate the Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) against bioelectrical impedance analysis (BIA) in 204 adults. Methods: We evaluated CUN-BAE and body mass index (BMI) as continuous predictors of body fat percentage, total fat mass, and visceral fat. Results: BMI showed stronger correlations with visceral fat (r = 0.941 vs. 0.850) and total fat mass (r = 0.968 vs. 0.828),while CUN-BAE showed a slightly stronger correlation with body fat percentage (r = 0.918 vs. 0.884), the parameter it was designed to estimate. CUN-BAE displayed only a weak correlation with muscle mass (r = 0.153), supporting its specificity for adiposity assessment, whereas BMI showed a moderate correlation with muscle mass (r = 0.551), reflecting its weight-dependent nature. Conclusions: Overall, BMI remains a practical marker of absolute fat mass and visceral adiposity, while CUN-BAE may provide a more refined estimate of relative body fat percentage. Tool selection should be guided by the clinical objective and interpreted as complementary rather than competing measures.

Introduction: Flushing is a common clinical symptom characterised by transient cutaneous vasodilation and erythema, frequently accompanied by a sensation of heat. Although often benign, it may signal endocrine, neuroendocrine, autonomic, inflammatory, pharmacologic, or neoplastic disorders. Objectives: To provide an integrated review of the neuroendocrine and vascular mechanisms underlying flushing and to propose a structured, clinically applicable diagnostic approach based on symptom patterns and pathophysiological pathways. Methods: A narrative review of the literature was conducted, focusing on thermoregulatory physiology, neuroendocrine signalling, vascular control, and clinical conditions associated with flushing. Evidence from experimental, observational, and clinical studies was synthesised to develop a mechanistic framework and a stepwise diagnostic algorithm integrating clinical features and targeted laboratory evaluation. Results: Flushing arises from disruption of central thermoregulatory integration involving hypothalamic nuclei, peripheral sensory pathways, and vasoactive mediators, including oestrogens, serotonin, catecholamines, vasoactive intestinal peptide, prostaglandins, substance P, and histamine. Neurotransmitters help modulate the vascular response, which is further influenced by endothelial function and autonomic tone. Conclusions: Flushing is a multifactorial symptom reflecting integrated neuroendocrine and vascular dysregulation rather than an isolated cutaneous phenomenon. Recognising the distinction between wet and dry flushing and applying a mechanism‐based diagnostic framework may improve diagnostic accuracy and facilitate earlier identification of clinically important underlying disorders.

Insulin therapy remains essential for the management of diabetes mellitus; however, conventional subcutaneous injection continues to impose significant physical, psychological, and behavioral barriers that negatively affect treatment adherence and metabolic outcomes. Injection-related pain, fear of needles, local tissue complications, and psychological insulin resistance contribute to delayed insulin initiation, inadequate dose titration, and suboptimal glycemic control worldwide. In response, alternative insulin delivery routes (including oral, pulmonary, nasal, and transdermal strategies) have been explored to reduce invasiveness and improve patient experience. Among these, transdermal insulin delivery has emerged as a particularly promising approach due to its potential to bypass gastrointestinal degradation, provide controlled absorption, and enhance patient acceptance. Recent advances in microneedle-based systems and needle-free jet injectors have enabled effective transdermal insulin administration by overcoming the skin barrier while minimizing pain and discomfort. This narrative review synthesizes current evidence on insulin delivery technologies with a specific focus on transdermal and needle-free systems. We discuss the biological and physicochemical challenges of insulin transport, the mechanisms underlying emerging delivery platforms, and clinical evidence regarding metabolic efficacy, glycemic variability, and patient-reported outcomes. The integration of these technologies with continuous glucose monitoring is also explored. Finally, we address translational challenges and future perspectives, highlighting the role of needle-free insulin delivery as a patient-centered strategy to improve adherence and metabolic control in diabetes care.

Sellar and sphenoidal meningoceles are rare entities that can lead to neurological, ophthalmological, and endocrine complications. We report the case of a 28-year-old man with a giant sellar meningocele who presented with chronic headache and bitemporal hemianopsia but with preserved pituitary function at diagnosis. Magnetic resonance imaging revealed a large defect of the sellar floor with herniation of meninges and displacement of the optic chiasm and pituitary gland. The patient underwent endoscopic transsphenoidal repair. Within 24 hours, he developed arginine vasopressin (AVP) deficiency requiring long-term desmopressin therapy, which persisted beyond 6 months, fulfilling the criteria for permanent AVP deficiency. No other pituitary hormone deficits were observed. Visual field impairment did not improve after surgery, although further deterioration was prevented. This case underscores that adult sellar meningoceles can present with intact anterior pituitary function but still carry a risk of isolated permanent AVP deficiency after surgical repair. To our knowledge, this is among the largest adult sellar meningoceles reported with preserved anterior pituitary function at presentation and subsequent permanent isolated AVP deficiency, emphasizing the need for careful perioperative counseling and long-term endocrine follow-up.

Background: Estrogen plays a crucial role in adipose tissue homeostasis, influencing fat distribution, lipid metabolism, and insulin sensitivity. Through estrogen receptor (ER) activation, particularly ERα, estradiol (E2) regulates adipogenesis, inhibits adipocyte hypertrophy, and promotes insulin signaling. It enhances lipid oxidation, reduces lipogenesis, and suppresses pro-inflammatory cytokine production, thereby maintaining metabolic health. Primary ovarian insufficiency (POI), characterized by estrogen deficiency before the age of 40, disrupts this regulatory network, leading to adverse metabolic effects. Objetives: This review examines the effects of estrogen on adipose tissue, lipid metabolism, and carbohydrate metabolism, with a particular focus on clinical evidence in women with POI. Methods: A narrative review of the metabolic alterations associated with POI, emphasizing the molecular, biochemical, and metabolic mechanisms underlying estrogen deficiency, with a special focus on adipose tissue. Results: Women with POI exhibit increased visceral fat accumulation, reduced lean mass, and alterations in adipokine secretion, resembling the metabolic phenotype of postmenopausal women. The decline in estrogen levels contributes to central adiposity, impaired lipid metabolism, and insulin resistance, exacerbating the risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). The loss of estrogenic regulation leads to enhanced lipolysis in visceral fat, raising free fatty acid flux to the liver, promoting hepatic steatosis, and worsening insulin resistance. Studies indicate that POI patients have significantly higher total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides compared to age-matched controls, reinforcing their heightened CVD risk. Reduced sex hormone-binding globulin (SHBG) levels increase free androgen availability, aggravating central fat deposition. These metabolic disturbances can potentially accelerate atherosclerosis and vascular aging, increasing morbidity and mortality in POI patients. Conclusions: Understanding the role of estrogen in adipose tissue and its disruption in POI highlights the importance of early intervention. Although the available evidence is limited and largely extrapolated from menopause studies, strategies such as hormone replacement therapy, lifestyle modifications, and lipid profile optimization are essential to mitigate metabolic consequences and improve long-term health outcomes in women with POI.

Context: Genetic tests are part of the routine clinical approach to syndromic and nonsyndromic phenotypes of neuroendocrine neoplasms (NENs). Current data on phenotype–genotype associations in NENs, however, do not accurately represent all populations. Objective: To describe the frequency, inventory, and clinical associations of germline defects associated with multiple types of NENs in a Mexican cohort. Methods: Blood DNA from Mexican adults with NENs was analyzed with a 53-gene next-generation sequencing panel developed ad hoc (n = 90) or Sanger sequencing (n = 2). Single nucleotide variants, indels, and structural variants were identified, classified, and subjected to orthogonal confirmation. When possible, tumor samples and blood DNA from additional family members were tested using Sanger sequencing. Results: Ninety-two probands (70.7% women, 51.5% sporadic) were included; 16 carried pathogenic or likely pathogenic (P/LP) variants and were significantly younger at disease onset than the rest (29.6 ± 10.7 vs 40 [21.5-51.5] years, P = .0384). Likely driving variants were identified in three-quarters of Von Hippel Lindau syndrome cases, one-third of multiple endocrine neoplasia (MEN) type 1, one-quarter of early-onset acromegaly/gigantism, and individual cases of Cushing's disease, MEN2A, and medullary thyroid carcinoma. One patient with clinical MEN1 associated with an SDHA variant and 1 with a pituitary tumor and neurofibromatosis type 1 were also identified. Probands with familial disease were more likely to carry P/LP variants than sporadic cases (26.7 vs 8.5%, P = .0282). Conclusion: P/LP variants were identified in 17.4% of individuals with NENs. Our research provides a view of the landscape of NEN drivers in a population not previously characterized.

Neurosarcoidosis (NS) is a rare form of sarcoidosis, with isolated hypothalamic-pituitary involvement being exceptionally uncommon. We report a 20-year-old woman presenting with polyuria, galactorrhea, amenorrhea, and substantial weight loss. Hormonal evaluation revealed hypopituitarism with arginine-vasopressin deficiency and hyperprolactinemia. Magnetic resonance imaging demonstrated pituitary stalk thickening and suprasellar extension, initially suggestive of hypophysitis. High-dose glucocorticoid therapy resulted in partial regression of the pituitary lesion but persistence of suprasellar involvement, prompting a transcranial stereotactic biopsy. Histopathological analysis confirmed isolated NS with noncaseating granulomas. The patient was treated with rituximab after partial response to glucocorticoids, achieving significant clinical and radiological improvement, although hormonal axis recovery was not observed. Hormone replacement therapy remains necessary. The case met the criteria for definitive type b NS, as no extraneural involvement was identified. This case underscores the diagnostic challenges of isolated NS and highlights the importance of considering histopathological confirmation in patients without systemic manifestations to guide treatment. Glucocorticoids are first-line therapy, but rituximab may be effective as a second-line option for refractory cases. Early diagnosis and tailored therapy are essential to improving outcomes in this rare and challenging condition.