Dopamine agonists are a key tool in the therapeutic arsenal of endocrinologists worldwide. They exert their effects by binding to dopamine‐2 (D2) receptors expressed by pituitary tumour cells to ...modulate hormonal secretion and tumour size. They are the established first‐line treatment for prolactinomas which express high levels of D2 receptors. Growing data support their use as an adjuvant treatment option for other pituitary tumours including growth hormone, adrenocorticotrophic hormones, thyroid hormone secreting adenomas and nonfunctional pituitary tumours, all of which have been shown to express D2 receptors as well, albeit to varying extents. For those pituitary tumours inadequately treated by dopamine agonist alone, combined agonism of D2 and somatostatin receptors represent a new frontier in clinical development. Here we review the development and role of dopamine agonist for the treatment of prolactinomas, the literature supporting their adjuvant use for the treatment of all other pituitary tumours, and recent progress in the development of the next generation of chimeric compounds that target D2 and other receptor subtypes highly expressed on pituitary tumour cells.
While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, ...heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment.
Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models.
We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients’ clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit.
Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.
Summary
Background
Both growth hormone (GH) excess and GH deficiency are associated with abnormalities in body composition and biomarkers of cardiovascular risk in patients with pituitary disorders. ...However, the effects of developing GH deficiency after definitive treatment of acromegaly are largely unknown.
Objective
To determine whether development of GH deficiency after definitive therapy for acromegaly is associated with increased visceral adiposity and biomarkers of cardiovascular risk compared with GH sufficiency after definitive therapy for acromegaly.
Design
Cross‐sectional.
Patients
We studied three groups of subjects, all with a history of acromegaly (n = 76): subjects with subsequent GH deficiency (GHD; n = 31), subjects with subsequent GH sufficiency (GHS; n = 25) and subjects with active acromegaly (AA; n = 20). No study subjects were receiving somatostatin analogues, dopamine agonists or hGH.
Measurements
Body composition (by DXA), abdominal adipose tissue depots (by cross‐sectional CT), total body water (by bioimpedance analysis) and carotid intima‐media thickness (IMT) were measured. Fasting morning serum was collected for high‐sensitivity C‐reactive protein (hsCRP), lipids and lipoprotein levels. An oral glucose tolerance test was performed, and homoeostasis model of assessment‐insulin resistance (HOMA‐IR) was calculated.
Results
Abdominal visceral adipose tissue, total adipose tissue and total body fat were higher in subjects with GHD than GHS or AA (P < 0·05). Subcutaneous abdominal fat was higher, and fibrinogen and IMT were lower in GHD (but not GHS) than AA (P < 0·05). Patients with GHD had the highest hsCRP, followed by GHS, and hsCRP was lowest in AA (P < 0·05). Fasting glucose, 120‐min glucose, fasting insulin, HOMA‐IR and per cent total body water were lower in GHD and GHS than AA (P < 0·05). Triglycerides were higher in GHS than AA (P < 0·05). Lean body mass, mean arterial pressure, total cholesterol, HDL and LDL were comparable among groups.
Conclusions
Development of GHD after definitive treatment of acromegaly may adversely affect body composition and inflammatory biomarkers of cardiovascular risk but does not appear to adversely affect glucose homoeostasis, lipids and lipoproteins, or other cardiovascular risk markers.
Purpose of Review
This article reviews hypopituitarism after TBI, the importance of pituitary hormones, and related controversies, concluding with a suggested patient approach.
Recent Findings
While ...earlier studies focused on increased pituitary deficiencies after moderate-severe TBI, recent studies have focused on deficiencies after mild TBI. There has been increasing focus on the role of growth hormone after injury; growth hormone is the most frequent reported deficiency at 1 year post-TBI, and an area with unresolved questions. While more research is needed to quantify the risk of deficiencies in special populations, and establish the natural history, increasing data indicate an increase in hypopituitarism after other acquired brain injuries; the potential role of pituitary hormone deficiencies after stroke and after COVID-19 infection is an area of active inquiry.
Summary
Given the negative health effects of untreated hypopituitarism and the opportunity to intervene via hormone replacement, it is important to recognize the role of pituitary hormone deficiencies after TBI.
Intra-subject variability (ISV) is the most consistent behavioral deficit in Attention Deficit Hyperactivity Disorder (ADHD). ISV may be associated with networks involved in sustaining task control ...(cingulo-opercular network: CON) and self-reflective lapses of attention (default mode network: DMN). The current study examined whether connectivity supporting attentional control is atypical in children with ADHD. Group differences in full-brain connection strength and brain-behavior associations with attentional control measures were examined for the late-developing CON and DMN in 50 children with ADHD and 50 typically-developing (TD) controls (ages 8-12 years). Children with ADHD had hyper-connectivity both within the CON and within the DMN. Full-brain behavioral associations were found for a number of between-network connections. Across both groups, more anti-correlation between DMN and occipital cortex supported better attentional control. However, in the TD group, this brain-behavior association was stronger and occurred for a more extensive set of DMN-occipital connections. Differential support for attentional control between the two groups occurred with a number of CON-DMN connections. For all CON-DMN connections identified, increased between-network anti-correlation was associated with better attentional control for the ADHD group, but worse attentional control in the TD group. A number of between-network connections with the medial frontal cortex, in particular, showed this relationship. Follow-up analyses revealed that these associations were specific to attentional control and were not due to individual differences in working memory, IQ, motor control, age, or scan motion. While CON-DMN anti-correlation is associated with improved attention in ADHD, other circuitry supports improved attention in TD children. Greater CON-DMN anti-correlation supported better attentional control in children with ADHD, but worse attentional control in TD children. On the other hand, greater DMN-occipital anti-correlation supported better attentional control in TD children.
Youth suicide is increasing in the United States, with deaths among younger people of color driving this upward trend. For more than four decades, American Indian and Alaska Native (AIAN) communities ...have suffered disproportionate rates of youth suicide and years of productive life lost compared to other U.S. Races. The National Institute of Mental Health (NIMH) recently funded three regional Collaborative Hubs to carry out suicide prevention research, practice, and policy development with AIAN communities in Alaska and rural and urban areas of the Southwestern United States. The Hub partnerships are supporting a diverse array of tribally-driven studies, approaches, and policies with immediate value for increasing empirically driven public health strategies to address youth suicide. We discuss unique features of the cross-Hub work, including: (a) long-standing Community-Based Participatory Research processes that led to the Hubs’ innovative designs and novel approaches to suicide prevention and evaluation, (b) comprehensive ecological theoretical approaches that contextualize individual risk and protective factors in multilevel social contexts; (c) unique task-shifting and systems of care approaches to increase reach and impact on youth suicide in low-resource settings; and (d) prioritization of strengths-based approaches. The work of the Collaborative Hubs for AIAN youth suicide prevention is generating specific and substantive implications for practice, policy, and research presented in this article at a time when youth suicide prevention is a dire national priority. Approaches also have relevance for historically marginalized communities worldwide.
Context: Anorexia nervosa and normal-weight hypothalamic amenorrhea are characterized by hypogonadism and hypercortisolemia. However, it is not known whether these endocrine abnormalities result in ...reductions in adrenal and/ or ovarian androgens or androgen precursors in such women, nor is it known whether relative androgen deficiency contributes to abnormalities in bone density and body composition in this population.
Objective: Our objective was to determine whether endogenous androgen and dehydroepiandrosterone sulfate (DHEAS) levels: 1) are reduced in women with anorexia nervosa and normal-weight hypothalamic amenorrhea, 2) are reduced further by oral contraceptives in women with anorexia nervosa, and 3) are predictors of weight, body composition, or bone density in such women.
Design and Setting: We conducted a cross-sectional study at a general clinical research center.
Study Participants: A total of 217 women were studied: 137 women with anorexia nervosa not receiving oral contraceptives, 32 women with anorexia nervosa receiving oral contraceptives, 21 normal-weight women with hypothalamic amenorrhea, and 27 healthy eumenorrheic controls.
Main Outcome Measures: Testosterone, free testosterone, DHEAS, bone density, fat-free mass, and fat mass were assessed.
Results: Endogenous total and free testosterone, but not DHEAS, were lower in women with anorexia nervosa than in controls. More marked reductions in both free testosterone and DHEAS were observed in women with anorexia nervosa receiving oral contraceptives. In contrast, normal-weight women with hypothalamic amenorrhea had normal androgen and DHEAS levels. Lower free testosterone, total testosterone, and DHEAS levels predicted lower bone density at most skeletal sites measured, and free testosterone was positively associated with fat-free mass.
Conclusions: Androgen levels are low, appear to be even further reduced by oral contraceptive use, and are predictors of bone density and fat-free mass in women with anorexia nervosa. Interventional studies are needed to confirm these findings and determine whether oral contraceptive use, mediated by reductions in endogenous androgen levels, is deleterious to skeletal health in such women.
Background:
Research on sustaining community-based interventions is limited. This is particularly true for suicide prevention programs and in American Indian and Alaska Native (AIAN) settings. Aiming ...to inform research in this area, this paper sought to identify factors and strategies that are key to sustain suicide prevention efforts in AIAN communities.
Methods:
We used a modified Nominal Group Technique with a purposeful sample of N = 35 suicide prevention research experts, program implementors and AIAN community leaders to develop a list of prioritized factors and sustainability strategies. We then compared this list with the Public Health Program Capacity for Sustainability Framework (PHPCSF) to examine the extent the factors identified aligned with the existing literature.
Results:
Major factors identified included cultural fit of intervention approaches, buy in from local communities, importance of leadership and policy making, and demonstrated program success. Strategies to promote these factors included partnership building, continuous growth of leadership, policy development, and ongoing strategic planning and advocacy. All domains of the PHPCF were representative, but additional factors and strategies were identified that emerged as important in AIAN settings.
Conclusions:
Sustaining effective and culturally informed suicide prevention efforts is of paramount importance to prevent suicide and save lives. Future research will focus on generating empirical evidence of these strategies and their effectiveness at promoting program sustainability in AIAN communities.
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