The polygenic New Zealand obese (NZO) mouse model displays the characteristics of early type 2 diabetes: fasting hyperglycemia, hyperinsulinemia, and insulin resistance. The expression of the ATP-sensitive potassium (KATP) channels in the β cells was reported to be reduced. To define at the cellular level the role of the KATP channel function for the altered insulin secretion of NZO mice. We measured the plasma membrane potential, KATP channel currents, cytosolic Ca2+ concentration ([Ca2+]i), and insulin secretion of NZO mouse islets and β cells in comparison with those of metabolically healthy NMRI mice. The potassium current of NZO β cells had half the extent of that of NMRI β cells and remained so in the presence of the KATP channel opener, diazoxide. The KATP channel blocker, tolbutamide, reduced the currents to the same low level. At low glucose and in the presence of diazoxide, the plasma membrane potential of NZO β cells was less polarized, and consequently, [Ca2+]i was higher in NZO β cells than in NMRI β cells. The depolarization and [Ca2+]i increase by tolbutamide were not different. Insulin secretion of the NZO islets was higher than that of NMRI islets at low glucose and in the presence of diazoxide, but was lower than that of NMRI islets in the presence of tolbutamide and of high glucose. The higher insulin secretion at basal glucose, but not the lower stimulated secretion of NZO islets, is at least partly due to the reduced expression of the KATP channels.
The manifestations of common disorders can infrequently obscure the presence of very rare conditions that share similar clinical findings. Polycystic ovary syndrome (PCOS) is a common disorder characterized by hyperandrogenism, ovulatory dysfunction, and/or polycystic ovarian morphologic features. A key component of the Rotterdam PCOS diagnostic criteria is the exclusion of other conditions that can mimic the signs and symptoms of PCOS. Compared to PCOS, androgen-producing tumors are rare neoplasms that originate in either the ovaries or adrenals and appear in only about 0.2% of people with hyperandrogenism. Ovarian steroid cell tumors (OSCTs) are an exceptionally rare subset of this class that represents less than 0.1% of all ovarian neoplasms. OSCTs are often hormonally active and classically cause the sudden and severe onset of secondary virilizing characteristics. In the case presented here, we describe a postmenopausal patient who was referred for management of PCOS but ultimately found to have an OSCT. A detailed history elicited a worsening of symptoms after menopause that raised the suspicion of a virilizing tumor; however, the clinical challenge was to determine whether the patient had both PCOS and an OSCT or whether the OSCT had been "causing" PCOS all along. This required careful scrutiny of the patient's 24-year clinical course and a comprehensive literature review in an effort to distinguish the manifestations of an OSCT from those of PCOS.
The mammary gland undergoes extensive reorganization during pregnancy, lactation, and involution. During involution, mass apoptosis of epithelial cells and infiltration of immune cells return the gland to a state similar to the nulliparous female. However, the postinvolution gland has structural differences to the nulliparous gland, which may provide protection against breast cancer. Changes associated with parity are hormone dependent and could be vulnerable to endocrine-disrupting chemicals, particularly those that are estrogen receptor (ER) agonists. We evaluated the effects of ethinyl estradiol (EE2), a pharmaceutical ER agonist, administered during pregnancy and lactation on the structure and steroid function of the postinvolution mammary gland. CD-1 mice were exposed to vehicle or EE2 (20 μg/kg/day) from pregnancy day 9 until weaning. An unexposed nulliparous group was included for comparison. Five weeks after exposure, we evaluated the mammary glands for treatment effects on tissue architecture, proliferation, immune cell populations, and steroid function. EE2 exposure reduced the parity-driven effects on mammary gland epithelial volume, with more modest (nonsignificant) effects on mammary gland functional components including a reduction in resident macrophages, an increase in ER- and a decrease in progesterone receptor-expressing cells. EE2 exposure also restricted maternal and pup growth during the exposure period and delayed pup eye opening. These results suggest that EE2 exposure during pregnancy and lactation disrupts some of the typical changes of parity seen in the mammary gland. This pharmaceutical may provide insights into effects of other estrogenic endocrine-disrupting chemicals on the maternal mammary gland.
Mild autonomous cortisol secretion (MACS) has an increasing prevalence with age and is associated with cardiometabolic comorbidity and increased mortality. Current guidelines recommend the majority of patients with MACS be managed conservatively, with select people referred for laparoscopic adrenalectomy. There are currently no licensed medications for MACS. We aimed to systematically review the literature to map out the current available evidence on the use of medical therapy in the treatment of MACS and to assess the research gap. Additionally, we sought to establish the outcome measurements used, to inform the design of future prospective clinical trials. We searched MEDLINE and EMBASE from conception as well as clinical trial registries to detect all original studies of medical treatments in MACS. Titles and abstracts were screened and full articles reviewed. A total of 5369 results were found from the search strategy. Thirteen studies met the inclusion criteria, of which 8 were conference abstracts and 5 full-text studies were included in the final analysis. This included 2 studies of metyrapone and 3 studies that used mifepristone. Common outcome measures included blood pressure, glucose measurements, weight, and side effect data. There is a considerable knowledge gap with regard to the medical management of MACS. Current available evidence consists of a handful of small, heterogeneous studies with a suggestion of a potential benefit in initiating mifepristone or metyrapone in this cohort. Our results highlight the urgent need for larger, prospective studies. To support this, we have provided suggestions for outcome measures.
Multiple endocrine neoplasia type 1 (MEN1) is a hereditary tumor predisposing syndrome, characterized by typical neuroendocrine tumors in parathyroid, pituitary, and endocrine pancreas tissues ("3P"). MEN1 is also associated with non-neuroendocrine cancers, which are less studied. To assess the prevalence of certain non-neuroendocrine cancers associated with MEN1 in Finnish patients and compare the findings with a local control population. Retrospective registry-based cohort study. 113 MEN1 patients (51 males) treated at Oulu University Hospital between 1982 and 2023, with an average follow-up of 56 patient-years, were compared to a local control population (n = 1 045 520 males, average follow-up of 73 patient-years). Data were analyzed using descriptive statistics, survival curves, and Cox regression models. Seven women with MEN1 (11.5%) had breast cancer (BC), 7 (6.2%) with papillary thyroid carcinoma (PTC), and 5 (4.4%) with renal cancers (RC). The mean age at BC diagnosis was 49 years compared to 60 in the general Finnish population. The hazard ratio (HR) for BC in female MEN1 patients was 3.79 (95% CI: 1.66-8.60) compared to controls. Pathogenic variants in established BC risk genes were not present in our MEN1 patients. The HR for PTC and RC were 9.37 (3.59-24.41) and 7.80 (2.74-22.25), respectively. This study demonstrates a significantly increased prevalence of BC, PTC, and RC in MEN1 patients compared to the Finnish general population. The findings support earlier BC screening in women with MEN1 and highlight the need for further research into non-neuroendocrine cancer risks in these patients.
Osteoporosis is a progressive disease characterised by changes in bone structure leading to fragility fractures. In Singapore, it is a significant health concern with a high prevalence, and is expected to increase as the population ages. These consensus statements aim to provide scientifically grounded recommendations for the management of osteoporosis, to standardise its management in Singapore and promote multidisciplinary collaboration. An expert panel comprising 18 representatives from 10 Singapore medical bodies developed consensus statements based on current evidence and through multiple online meetings. Each panellist voted on each statement independently using a 3-point Likert scale (Agree, Neutral, Disagree). Consensus (total ratings of "Agree") was set a priori at ≥80%, with statements not reaching this threshold excluded for lacking consensus. The expert panel reached consensus on 80 consensus statements. These include 10 statements on screening, risk factors, and fracture risk assessment; 7 statements on initial bone mineral density testing; 5 on the indications for pharmacotherapy; 20 on osteoporosis pharmacotherapy; 24 on treatment targets, treatment monitoring, and follow-up bone mineral density testing; and 14 statements on the prevention and management of medication-related osteonecrosis of the jaw. The consensus statements in this paper guide clinicians in using the latest evidence and expert opinion to inform appropriate diagnostic and therapeutic approaches for the management of osteoporosis. These statements are not intended to replace current guidelines, but rather to support clinical decision-making and help develop individualised, patient-centred management plans based on the patient's demographics, clinical characteristics, and preferences.
No prior meta-analysis has systematically assessed efficacy and safety of C-type natriuretic peptide (CNP) analogs within the context of evolving understanding of FGFR3 biology and achondroplasia natural history. To evaluate the safety and efficacy of CNP analogs in children with achondroplasia and contextualize clinical outcomes and natural history. Systematic review of randomized control trials and real-world studies evaluating the safety and efficacy of CNP analogs (vosoritide and navepegritide) in children aged <18 years with genetically confirmed achondroplasia was performed. Coprimary outcomes of interest were adverse events (AEs) and changes from baseline in annualized growth velocity (AGV) at the end of the trials. Secondary outcomes included changes from baseline in height Z-score, standing height, and upper-to-lower body segment (ULS) ratio. Eleven studies (N = 542) were included, of which 4 RCTs (n = 326) with low overall risk of bias were meta-analyzed. Overall and serious AE rates were comparable between CNP analogs and placebo, except for higher relative risks of injection site reactions (1.65), urticaria (4.04), and swelling (3.57). C-type natriuretic peptide analogs significantly increased mean differences in AGV (1.36 cm/year; 95% CI: 1.05-1.68; P < .00001) and standing height (1.24 cm; 95% CI: 0.47-2.01; P = .002), without short-term effect on ULS ratio. Real-world studies demonstrated sustained growth benefits with infrequent serious AEs or treatment discontinuations. C-type natriuretic peptide analogs provide slight but statistically meaningful improvements in linear growth in children with achondroplasia with acceptable short-term safety profile. Long-term studies are needed to define optimal timing of therapy on adult height, functional outcomes, and achondroplasia-related complications.
Insulin resistance (IR) is more prevalent in men than in women, but evidence directly linking IR to fracture risk in older men remains limited. To evaluate the association between insulin resistance (IR), estimated using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and the triglyceride-glucose (TyG) index, and fracture risk in older men. Data from 5994 men (≥65 years) in the MrOS cohort were analyzed. A total of 5416 participants were included in the HOMA-IR analysis and 5384 in the TyG index analysis. Fractures were self-reported and confirmed radiographically. Participants were grouped into quartiles based on IR indices, and fracture outcomes were evaluated during a mean follow-up of 12.2-13.6 years using Cox models. A U-shaped association was observed in the HOMA-IR analysis, with Q3 vs Q1 showing a lower hazard ratio (HR) for any fracture (HR 0.82, 95% CI 0.70-0.97). Similarly, in the TyG index analysis, Q3 vs Q1 was associated with lower risks of any fracture (HR 0.84, 95% CI 0.72-0.98) and major osteoporotic fracture (MOF) (HR 0.80, 95% CI 0.65-0.99). No associations were found for hip or vertebral fractures, and results were unchanged in sensitivity analyses excluding T2DM. Older community-dwelling men in Q3 of HOMA-IR and TyG had modestly lower risks of any clinical fracture and MOF, but associations were inconsistent across quartiles and fracture types. Further studies in other populations are needed to confirm these findings.
Diagnosing SHOX gene variations is important because growth hormone treatment is an approved option for affected children. Subtle clinical and radiological abnormalities were reported in SHOX deficiency associated with idiopathic short stature (ISS). Whether systematic or phenotype-based molecular screening should be performed remains debated. To determine whether simple radiological features on left-hand radiography could serve as indicators for molecular analysis of the SHOX gene, and to compare these with published clinical/radiological scores. This retrospective study included 266 patients diagnosed with ISS who underwent SHOX gene analysis without any predefined selection criteria at the Pediatric Endocrinology Unit of Angers University Hospital from 2016 to 2023, aiming to determine the rate of SHOX gene variations. We also included 33 ISS patients diagnosed with a SHOX gene variation between 2005 and 2015 to refine sensitivity analyses. Systematic screening using MLPA identified SHOX gene variations in 9.8% of ISS children and sequencing in MLPA-negative subjects detected an additional 6%. Variations occurred in the coding regions in one-third and in the enhancer regions in two-thirds. A cutoff of 147° for the convexity of the distal radial metaphysis showed sensitivity/specificity of 89%/50%. A cutoff of 128° for pyramidalization of the carpal row yielded sensitivity/specificity of 86%/49%. Combining both criteria yielded 91% sensitivity and 70% specificity. Previous scores proposed by Rappold and Binder had sensitivity/specificity of 36%/51% and 81%/10%, respectively. Systematic molecular screening by MLPA and sequencing is recommended to detect all SHOX gene variants in children with ISS.
Thyroid hormone levels vary by age, sex, and genetic background; yet most clinical reference ranges (RRs) do not account for these factors, potentially leading to misclassification of thyroid status and missed associations with metabolic disorders. The aim of this study was to evaluate the impact of newly established age- and sex-specific reference ranges for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) on the prevalence of thyroid statuses and their associations with metabolic disorders. Cross-sectional observational studies were conducted, and we enrolled over 8000 participants who underwent thyroid status evaluation with Abbott and Siemens assay kits. We compared the prevalence of different thyroid statuses and corresponding metabolic disorders based on the new RRs with that based on the manufacturers' RRs. New RRs significantly altered the prevalence of several thyroid statuses. Subclinical hypothyroidism increased in middle-aged individuals using Abbott kits but decreased in older individuals using Siemens kits. Syndrome of inappropriate secretion of TSH (SITSH, high FT4 with normal or elevated TSH) increased significantly with both kits when applying the new RRs. SITSH, defined by the new RRs, was significantly associated with increased risks of hypertension (Abbott: odds ratio [OR] 2.00; Siemens: OR 1.70) and diabetes (Abbott: OR 2.65; Siemens: OR 1.68), whereas no such associations were observed using the manufacturers' RRs. Age- and sex-specific RRs corrected the misclassification of thyroid status and uncovered a previously underdiagnosed group (SITSH) associated with cardiometabolic risks. These findings support the importance of new RRs for diagnostic accuracy and clinical risk stratification.
The intrauterine environment strongly influences children's health and development. Distinct cardiovascular biomarkers have been linked to birth weight and later weight gain, with correlations observed in maternal and umbilical cord serum. To describe (1) maternal cardiovascular biomarker patterns during the second and third trimesters and (2) potential associations between these biomarkers and offspring weight at birth and at 1 year of age. Within the LIFE Child Study, serum samples from 86 healthy mothers at 24 and 36 gestational weeks and cord blood at birth were analyzed using the Olink® Target 96 Cardiovascular III panel. Statistical analyses (Wilcoxon test, Spearman correlation, multivariate regression) were performed in R. Community-based cohort, Leipzig, Germany. Eighty-six mother-child pairs from the LIFE Child cohort. Mothers had no pregnancy complications, and all newborns had birth weights between 2500 and 4500 g. Offspring body weight at 1 year of age. Of 92 maternal serum biomarkers, 88 were detectable. Seventy biomarkers increased significantly from 24 to 36 weeks (P < .004). Several biomarkers measured at the 36th gestational week correlated with birth weight and 1-year weight. After adjustment for maternal age, body mass index, and offspring sex, no associations remained with birth weight. However, maternal paraoxonase 3 (PON3) [P = .037, 95% confidence interval (CI): -0.52, -0.02] and integrin subunit β 2 (ITGB2) (P = .038, 95% CI: 0.04, 1.12) were significantly associated with child weight at 1 year. In our cohort, maternal PON3 and ITGB2 were independently associated with early postnatal growth, potentially implicating these biomarkers in fetal programming.
Adenomyosis is an intractable gynecological disorder that can give rise to severe pelvic pain, heavy menstrual bleeding, and infertility, predominantly affecting women of reproductive age. The limited efficacy of current pharmacological interventions in certain cases-particularly those resistant to hormone therapies-underscores the urgent need for deeper mechanistic insights and the development of novel therapeutic strategies. Progress in this field, however, has been hampered by the scarcity of suitable experimental models, as adenomyosis is primarily a human disease. In this study, we demonstrate a preclinical platform for therapeutic evaluation using a mouse model of mechanically induced adenomyosis, which recapitulates the key pathological features observed in humans. By integrating high-resolution three-dimensional (3D) tissue imaging, we successfully visualized the invagination and expansion of adenomyosis lesions spatiotemporally. This approach enabled the clear-cut and efficient assessment of progestin efficacy in situ. We propose that the combination of a mechanistically relevant mouse model and advanced 3D histological analysis constitutes a concise and robust system for therapeutic validation and compound screening, thereby facilitating the discovery of effective treatments for adenomyosis.
The association of iodine nutritional status with thyroid function in iodine-replete countries is controversial and more sensitive biomarkers than urinary iodine concentration is required. To evaluate the use of scalp hair and serum iodine concentration as measure of iodine status through their association with thyroid indices. A nationwide survey was conducted between 2016 and 2023. Iodine concentration in serum (SIC), hair (HIC), urine (UIC) and estimated 24-hour urinary iodine excretion (eUIE), dietary iodine intake (DII) as well as serum TSH, FT4, and FT3 concentrations, thyroid antibody (ThAb) was measured in Japanese adults. The median UIC in 2771 adults was 295.0 μg/L and within the WHO's adequacy range of iodine intake. The high iodine intake assessed by UIC, eUIE and SIC was associated with higher TSH and lower thyroid hormone levels. Urinary iodine concentration, eUIE and DII were higher in the group with a high TSH level. The subjects with positive ThAbs had significantly higher SIC, DII, TSH and slightly lower FT4 levels. The median HIC correlated positively but weakly with SIC, eUIE and DII, while SIC correlated modestly with eUIE, UIC and weakly with DII. The 5th percentile of the SIC reference (49.9 μg/L) coincided with the threshold value of median UIC (<100 μg/L) for iodine deficiency by WHO. Higher iodine intake results in changes of TSH and thyroid hormones within their referenced range. Serum and hair iodine concentrations might be feasible indicators for a population's iodine intake and further research is needed to validate their availability.
Classic congenital adrenal hyperplasia (CAH) is a rare genetic condition characterized by impaired cortisol and aldosterone synthesis. Historical management required glucocorticoid (GC) therapy to replace cortisol and, often, to suppress excess ACTH and adrenal androgens. However, supraphysiologic GC doses can lead to substantial complications. This study aimed to characterize the clinical burden associated with CAH and quantify the degree to which CAH- and/or GC-related complications manifest. Retrospective cohort analyses were conducted using administrative claims data from MarketScan® Research Databases (1/1/2020-12/31/2022) to quantify the burden of CAH- and/or GC-related complications among insured patients with CAH in the United States compared with a matched cohort. A total of 719 patients with CAH receiving GC therapy were matched 1:5 with 3595 individuals based on age, sex, payer, region, and enrollment duration. Patients with CAH had significantly higher rates of predominantly GC-related complications, including cardiovascular/circulatory diseases, type 2 diabetes, hypertension, hyperglycemia, metabolic complications, obesity, and osteoporosis (all P < .05). Patients with CAH demonstrated significantly higher rates and risks of nearly all CAH-related complications compared with matched controls (P < .05). Rates and risks of nearly all complications categorized as both CAH- and GC-related were significantly higher among patients with CAH (P < .05). Rates were consistently higher in adults than pediatric patients, underscoring the progressive and cumulative nature of CAH- and GC-related morbidity. Individuals with CAH experience higher rates and risks of CAH- and/or GC-related complications, highlighting the considerable burden associated with CAH and supraphysiologic GC treatment. Higher complication rates in adults emphasize the need for early and effective management of CAH. Novel non-GC therapies may enable GC dose reduction while maintaining androgen control, potentially mitigating these complications.
It has been suggested that consumption of saccharin, a widely used artificial sweetener, decreases insulin sensitivity in rodents and humans, but studies show conflicting results. To investigate if saccharin affects insulin sensitivity in a proof-of-concept study in humans using hyperinsulinemic-euglycemic clamp. In an open-label pilot study, we recruited 14 overweight participants without diabetes who were mean 60.5 (SD 4.1) years of age and had a body mass index of 27.6 (SD 0.7). Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was determined before and after consumption of 5 mg/kg saccharin/day for 3 months. Blood was collected for analysis of diabetes-related biomarkers. Stool samples were collected before, during, and after saccharin consumption for microbiota profiling by 16S rRNA gene sequencing. Thirteen of the 14 participants (6 men, 7 women) completed the study. There was no change in insulin sensitivity (mean M value difference [ΔM] -0.1, P = .85) or body weight (mean difference -0.1 kg, P = .70) after consumption of saccharin. However, the mean glycated hemoglobin decreased from 38.7 mmol/mol (SD 3.0) at visit 1 to 36.8 (SD 3.4) at visit 4 (P = .003). Overall, there was no change in composition or richness of the gut microbiota at the end of the study. This study did not demonstrate an association between saccharin intake and impaired insulin sensitivity in adult, overweight participants without diabetes assessed by hyperinsulinemic-euglycemic clamp.
Early prediction of ovarian reserve is essential to improve fertility counseling in girls with Turner syndrome (TS). This work aimed to examine the occurrence of puberty and longitudinal hormone patterns in girls with TS, and to take an initial step toward developing a prediction model for ovarian function. Main outcome measures included thelarche, menarche, and age of premature ovarian insufficiency (POI). A retrospective cohort study was conducted of girls with TS. Levels of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), antimüllerian hormone (AMH), inhibin B, and information on karyotype and puberty were extracted from the medical records. A joint model combining a Cox survival model and 2 linear mixed-effects models for FSH and AMH was used to model the association between POI and longitudinal hormone values. A total of 365 girls were included, of whom 287 had available data on pubertal development. In this patient cohort, 43% had monosomy 45,X, 17% had mosaic 45,X/46,XX, 18% had an isochromosome X, and 22% had an "other" karyotype in lymphocytes. Girls with spontaneous puberty had lower FSH and higher AMH before age 8 years compared to girls without spontaneous puberty. The joint model showed that lower AMH is significantly related to POI, while FSH was not significantly related to POI. The individual predicted risks on POI come with large uncertainty. AMH and FSH patterns contribute to understanding ovarian reserve at an early age in girls with TS. Creating a prediction model remained challenging and more data are needed.
Since 2020, growth hormone (GH) therapy administered using electronic drug delivery devices (GROWJECTORTM L) linked to a smartphone application (Melon NikkiTM) has been approved in Japan. Real-world data generated through this system enable evaluation of treatment adherence among pediatric patients receiving GH therapy. To assess adherence to home-based GH self-injection using a smartphone application linked to an electronic injection device and identify factors associated with adherence. Observational study. Real-world data were collected and analyzed, including home injection patterns, GH dosage, and changes in height and body mass index over the first year of therapy. Factors significantly associated with adherence outcomes were evaluated using statistical analyses. We enrolled a cohort of Japanese pediatric patients with various indications for GH therapy who used an electronic injection device connected to the Melon NikkiTM application. Injection adherence declined after the second month in patients with GH deficiency and after the fourth month in patients born small for gestational age, particularly among those with variable injection times. Multivariate analysis showed that cumulative app usage up to 24 weeks is an independent factor that significantly contributes to an increase in the cumulative injection rate. Use of the application was associated with better adherence during initial 8 weeks. Use of a smartphone application linked to an electronic injection device may support adherence maintenance during the early phase of GH therapy. These findings provide clinically relevant insights that may inform patient guidance and adherence-focused interventions.
N-(phosphonomethyl)glycine (glyphosate) is the most sprayed herbicidal chemical in the world. Although glyphosate is considered safe in humans and higher animals due to its targeting of the shikimate pathway found only in plants and microorganisms, recent in vivo and in vitro studies show evidence of toxicity across a range of systems, including the vertebrate brain. Given that developing brains with immature blood-brain barriers can be especially sensitive to environmental contaminants, here we test the effects of embryonic exposure to environmental levels of glyphosate or its commercial formulation, Roundup®. Embryonic zebrafish exposed to an environmental concentration of Roundup (10 µg/L acid equivalent) from 10 to 48 hours postfertilization (hpf) showed defects in morphology, respiratory capacity, and hatching at 48 hpf as well as changes in locomotion, light-startle response, and thigmotaxis behaviors at 5 days postfertilization (dpf), with some effects lasting in the juvenile. To understand neurodevelopmental changes underlying these behavioral abnormalities, we tested for changes to the timing of neurogenesis and conducted bulk RNA sequencing. We found increased neurogenesis and uncovered dysregulation of axonogenesis pathways, which was confirmed using immunohistochemistry. Finally, to test if axonal deficits might manifest as dysregulation of neuronal circuits, we observed changes in phospho-extracellular signal-regulated kinases levels and Ca2+ dynamics as indicators of activity disruptions at 5 dpf following embryonic exposure to Roundup. These results suggest that Roundup at current environmental levels may not be safe for organismal exposure, and glyphosate toxicity warrants closer attention.
Medical treatment of Cushing syndrome (CS) with steroidogenesis inhibitors or ACTH-directed agents is typically given using a titration strategy to achieve "normal" exposure to cortisol, as determined by a 24-hour urine free cortisol (UFC) measurement. This approach generally achieves similar serum cortisol levels across the day and fails to provide a normal diurnal pattern of cortisol. Chronotherapy addresses this problem through weighted afternoon/evening dosing of cortisol-lowering drugs. Additionally, because of day-to-day variability of cortisol production, patients may be undertreated on days of higher cortisol production and overtreated on days of lower cortisol production. A "block and replace" strategy is an alternative approach in which consistent biochemical glucocorticoid deficiency is the goal, with added glucocorticoid replacement to provide physiologic diurnal exposure to cortisol. Recently, the term mild autonomous cortisol secretion (MACS) has been used to describe patients without clinical features of CS who fail to suppress cortisol after 1 mg dexamethasone. MACS includes individuals with an adrenal mass(es) who may have hypertension, type 2 diabetes mellitus, and/or osteoporosis. The role of medical vs surgical treatment of MACS is currently debated. We here review the advantages and disadvantages of each approach to medical treatment of CS and MACS, concluding that "block and replace" deserves wider consideration, especially in patients who have severe disease, and to avoid adrenal insufficiency in those with highly variable UFC, or are taking agents that may cause adrenal insufficiency. Conversely, in those with mild disease, chronotherapy normalizes nighttime cortisol exposure while reducing drug burden.
In 2023, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved fezolinetant (Veozah® in the United States, Veoza® in Europe), a novel neurokinin 3 receptor (NK3R) antagonist and first-in-class nonhormonal drug for treating moderate to severe menopausal vasomotor symptoms (VMS). While its efficacy and safety have been demonstrated through the SKYLIGHT and MOONLIGHT programs, concerns were highlighted regarding a potential increased risk of neoplasms. Although regulatory agencies initially dismissed that risk, emerging data from meta-analysis and pooled analysis consistently showed a significant increase in the risk of nonbenign neoplasms. These findings raise important questions regarding a potential causal link between NK3R antagonists and cancer. By blocking NK3R, fezolinetant can reduce kisspeptin secretion, a ubiquitous peptide known for its antimetastasis function. Furthermore, NK3R blockade may induce compensatory activation of the neurokinin 1 receptor (NK1R), which has been implicated in tumor proliferation, angiogenesis, and metastasis. Because of these mechanistic concerns, long-term safety studies and investigations on the NK3R pathway are essential to clarify the neoplastic risk profile of fezolinetant. This review is based on a PubMed/MEDLINE search using specific keywords, complemented by screening of regulatory documents and citation tracking.