Physci C144 Presentation Outline - Hypopituitarism - PDF

Pierce Newman and Jordan O’Brien Physci C144 Presentation Outline Hypopituitarism Introduction: Hypopituitarism is defined as the deficiency of one or more pituitary hormones. It can be any of the 6 anterior pituitary hormones (GH, FSH, LH, ACTH, TSH, and prolactin) or the 2 posterior pituitary hor...

Pierce Newman and Jordan O’Brien Physci C144 Presentation Outline Hypopituitarism Introduction: Hypopituitarism is defined as the deficiency of one or more pituitary hormones. It can be any of the 6 anterior pituitary hormones (GH, FSH, LH, ACTH, TSH, and prolactin) or the 2 posterior pituitary hormones (oxytocin and ADH). Epidemiology: Several studies suggest that the incidence and prevalence of hypopituitarism is increasing. Mortality: Several studies show excess mortality in patients with hypopituitarism, with higher mortality in women than men. Causes: Pituitary and hypothalamic mass lesions: Benign pituitary tumors account for most pituitary mass lesions. Pituitary surgery/radiotherapy: A high risk associated with any form of pituitary surgery or radiotherapy is hypopituitarism. Trauma and vascular injury: Injuries and illnesses include but are not limited to traumatic brain injury, pituitary apoplexy, Sheehan’s syndrome, and aneurysmal subarachnoid hemorrhage. Infiltrative: Granulomatous diseases (sarcoidosis, tuberculosis, and histiocytosis X) can involve the pituitary and cause hypopituitarism. Iron overload states can also result in this. Immunological: Lymphocytic hypophysitis is caused by immune mediated infiltration of the anterior pituitary. This occurs in women and is first evident in pregnancy. Genetic: Mutations in one of many transcription factors can lead to congenital hypopituitarism. Clinical Presentation and Diagnosis: Acute Pituitary apoplexy, acute pituitary inflammation, and Sheehan’s syndrome can all cause acute hypopituitarism with high mortality. Presentations include severe retrograde headache and diabetes insipidus. Hydrocortisone treatment is crucial. Chronic Growth Hormone Deficiency (GHD) in childhood: Presents as reduced growth. Chemical assessment of GH – IGF-1 axis and pituitary imaging necessary for diagnosis. GHD in adulthood: Presents as increased fat mass, reduced muscle mass, low energy, and decreased quality of life. Insulin tolerance test is the standard for diagnosis. Gonadotropin deficiency: Presents as menstrual irregularities in women and hypogonadism and infertility in men. Low LH and FSH in women and low testosterone in men required for diagnosis. ACTH deficiency: Presents as lethargy, tiredness, and weight loss. Synacthen test required for diagnosis. TSH deficiency: Presents alongside other deficiencies, difficult to define phenotype; Need to measure serum TSH and free thyroxine concentrations for diagnosis Prolactin deficiency: Prevent adequate lactation in women. Severe hypoprolactinemia is rare, reliable marker of severe hypopituitarism ADH deficiency: Complete central diabetes insipidus – polyuria and polydipsia Diagnosis: Water deprivation test to find hypernatremia and hypotonic polyuria; Copeptin: stable marker of AVP concentration Management: ACTH deficiency: Replacement treatment for cortisol deficiency using hydrocortisone. Need to mimic circadian serum cortisol profile (higher in the morning than night). May lead to androgen deficiency (DHEA included), so DHEA replacement can be beneficial TSH deficiency: GH replacement increases conversion of thyroxine to triiodothyronine – careful monitoring of thyroid function is mandatory as it might uncover central hypothyroidism Gonadotropin deficiency: Women: Replacement: oral estrogen with cyclic addition of progestin to mimic normal menstrual cycle, younger needs higher estrogen dose Men: Teststerone replacement using intramuscular or oral preparations. Spermatogenesis can be induced using chorionic gonadotropin or recombinant FSH – takes months to years GH Deficiency: Daily subcutaneous replacement hormone injections causes reductions in total LDL cholesterol and diastolic BP. May induce diabetes as GH reduces insulin sensitivity Controversies, uncertainties, and future needs: Pathology: Anterior pituitary hormones have varying sensitivity to pathological damage & radiation pathology does not cause diabetes insipidus for unknown reason. Without an explanation to these, new hypopituitarism-avoidance strategies cannot be developed Continuation of care difficulties: transition from pediatric to adult endocrinologist; many patients have untreated hypopituitarism and suffering greatly due to absence of follow-up How it connects to lecture: Discusses the endocrine system and how each hormone effects the body; as well as how having a deficit in any of these adversely affects the body Temporal Control of Glucocorticoid Neurodynamics: Implications for Brain Health and Therapeutics By Kalafatakis et. al Vanessa Xayasak and Aria Movassaghi Background on glucocorticoids ● Hypothalamus → CRH → anterior pituitary → ACTH → adrenal cortex → GC ● Glucocorticoids are the main end product of the HPA axis and activates neurons with steroid receptors (GR,MR) in PVN neurons ● GC influence immune functions, metabolic processes, neurotransmission, neural rhythms, memory and emotional behavior Main results ● HPA pulsatility ○ It follows a circadian rhythm with peak GC levels prior to active period followed by a gradual fall during the day to reach nadir levels ○ Underlying HPA pulsatility involves ultradian rhythm characterized by individual pulses of GCs varying in amplitude and duration due to self-sustaining oscillatory activity between the anterior pituitary and adrenal glands ● Dynamics of GCs reaching the brain ○ GCs are affected by factors such as: binding proteins, metabolic rates and differential concentrations and ratios of cortisol within the brain ○ Brain region specific exposure ■ due to variations in enzymatic activity and metabolism ■ prefrontal cortex can enhance local GC presence while other areas, like the circumventricular organs, may have low exposure due to lack of local GC production ● Molecular basis of GC actions within the brain ○ Binding of cortisol and corticosterone to MRs and GRs can modify brain physiology at various levels ○ Aging negatively affects MR expression and substrate binding and chronic stress is associated with down regulation of MR and GR mRNA expression ● GC rhythmicity ○ GC Rhythmicity pattern determines which specific GR’s are activated and how long they are activated for - resulting in different cellular effects ○ Nuclear MR’s are responsible for continuous homeostatic activity, non-nuclear responsible for brain coordinating of acute stress response ○ GR’s responsible for attenuating and terminating stress response in addition to executing neurobehavioral adaptations ● Altered HPA rhythmicity ○ Stress is correlated with the dysregulation of 24h ultradian rhythms, indicative of altered activity of the hypothalamus-pituitary-adrenal (HPA) axis Results interpreted ● potential explanation of the prefrontal dysfunction observed in affective disorders: ○ Disturbance in circadian glucocorticoid fluctuations and the dynamic shifts in GC concentrations ○ HPA axis activity has effects on GC secretion from adrenal glands into the systemic circulation in a pulsatile manner ○ Prolonged or severe stress can disrupt the rhythmicity of glucocorticoid secretion ○ Sleep disruption can interfere with the normal rhythm of cortisol release, potentially leading to elevated or irregular cortisol levels throughout the day. Connection to lecture ● GC’s are recognized by MR’s and GR’s mainly in hippocampus but also in other brain regions, meaning that activation of receptors in certain areas can lead to different effects/different pathways ● Pulsatility of GCs plays an important role in its actions in brain and short term stress mediation ● Disruptions in stress homeostasis and dysregulation of the HPA axis have important health consequences - hyperactivation and hypoactivation can lead to Cushing’s disease and Addison's disease, respectively. Catherine Phelps and Yanyi Qu Interconnection between Circadian Rhythm and Thyroid Function Background Information(HPT) ● Neurons in PVN of hypothalamus secrete TRH from the median eminence ● TRH stimulates for thyrotropes to release thyroid stimulating hormone(TSH) ● TSH stimulates thyroid gland to produce thyroid hormones by binding onto TSH receptor on thyroid follicle cell membrane HPT axis and thyroid hormone activation ● What steps must occur to activate thyroid hormones: ○ Steps prior to thyroid hormones (in HPT) must occur: ○ Must have Thyroglobulin- protein produced by thyroid epithelial cells ● Must have thyroxine-binding globulin (thyroid hormone binding protein)- transports thyroid hormones in blood ● Local activation of thyroid hormone= important mechanism of thyroid hormone action ○ After thyroid hormone enters cell→ it is metabolized by deiodinase enzymes (type 1 and 2- DIO1 and DIO2) Circadian Clocks- Master Pacemaker ● Mammals: circadian rhythm controlled by SCN- suprachiasmatic nucleus ○ Receives light from retina by retinohypothalamic tract ○ Photosensitive ganglion cells- responsible for entrainment ● Mechanism of clockwork ○ Circadian rhythms - generated by transcription and translation feedback loops ○ Two proteins: CLOCK(circadian locomotor output cycles kaput) and BMAL1 heterodimerize- form transcriptional activator complex and repress transcription of E-box(CLOCK and BMAL1) ○ Second feedback loop: positively stimulate transcription of E-box ● Transcription-translation feedback loops of circadian clock genes drive rhythmic expression of many clock-controlled genes Circadian regulation of HPT axis ● Evidence of TSH rhythms (circadian clock regulates HPT axis and thyroid function) ○ Human blood TSH levels exhibit a clear daily rhythm ○ TSH continues to be released during sleep deprivation- 2x as high as humans with a night of normal sleep ● Mechanism of Ultradian TSH rhythms ○ Unclear ○ Discrepancy- some wild type rat studies have not reported the same daily variations in TSH plasma levels ○ Experimental conditions: subjects used are nocturnal rodents which can alter experiments ○ Many experiments reveal rhythmic activity of TSH and thyroid hormone in rats Thyroid Hormone and Gene Expression ● Thyroid hormone deficiency and excess affect the circadian clock o Hypothyroidism: shortened the period of circadian activity rhythms in rats o Hyperthyroidism: lengthen the period of circadian activity rhythm in rats and hamsters ● Chronic alterations in thyroid status affect the circadian clock and metabolic function in the peripheral region tissues (heart and brain (not in SCN)) shown in gene expression o Tissue-specific thyroid hormone receptor regulation o Hyperthyroidism and hypothyroidism affect the expression patterns of circadian clock genes (Per2, Bmal1, Rev-erba and Rora) and clock-controlled genes (Pdk4 and Ucp3) in the heart o Thyroidectomy (hypothyroidism) affects the expression of PER2 in the bed nucleus of the stria terminalis, amygdala, and does not affect the SCN clock Circadian clocks in thyroid nodules and thyroid cancer. ● Thyroid nodules are defined as any discrete mass in the thyroid gland o Represent an abnormal growth of thyroid cells in the thyroid gland o Benign: like healthy human thyroid tissue, robust circadian oscillation of clock genes has been observed o Malignant ▪ Well-differentiated thyroid cancer: upregulation of BMAL1 and downregulation CRY2 detected in tissue samples ▪ Poor-differentiated thyroid cancer: dramatic changes and drop-down ● Circadian clock machinery in the thyroid gland could be altered during malignant transformation Seasonal rhythms and thyroid function ● The hormone melatonin released by the pineal gland provides an endocrine representation of seasonal information by reflecting night length o Knockout mice revealed that negative regulation of pars tubralis-derived TSH via MT1 melatonin receptor ● PT- TSH → ependymal cells of hypothalamus→ induce DIO2 → generation of T3 from T4 hormone activation → the springtime signal (seasonal reproduction) ● How to prevent Pars distalis-derived TSH overactivity o has tissue-specific N-glycans and forms macro-TSH complexes with immunoglobulin G (IgG) and albumin, which are unable to stimulate the thyroid gland Gabbi Richardson, Chloe Reese “The Impact of Acute Stress Physiology on Skilled Motor Performance: Implications for Policing” by Anderson et. al Background/Introduction ● Stress: a stimulus that is perceived to threaten homeostasis ● Physiological stress response: autonomic response initiated by brain to return body to homeostasis ● Previous studies on police focus on cognitive responses to high stress environments, not muscular impairments ● HPA Axis: parvocellular neurons in PVN release CRH → corticotropes in anterior pituitary, release ACTH → adrenal cortex, release glucocorticoids (GCs, i.e. cortisol) ● ANS: SNS and PSNS divisions, only SNS (“fight/flight”) relevant to acute stress; activated by higher order brain regions How Acute Stress Modifies Skilled Motor Performance ● General example: if escaping from aggressor, have no problem running away, but struggle to unlock a door ● Lesions to red nucleus, corticospinal tract, motor cortex, and/or striatum cause difficulties reaching with their arms for food pellets (skilled motor movement) ● High stress caused similar deficits when reaching for food, but allowed mice to move with greater speed ⇒ tradeoff between speed and accuracy during high stress ○ Possibly due to suppression of somatosensory feedback How Repeated Acute Stress Manifests as Chronic Stress ● Repeated HPA stimulation → GR downregulation → reduced negative feedback → prolonged brain exposure to GCs → neurological disease ● Acute psychological stress increased muscle tension in cashiers, while chronic trapezius muscle tension in chocolate factory workers caused chronic shoulder pain ● Application: police officers found to have high cortisol levels, so at risk for musculoskeletal deficits due to chronic stress Stress Physiology of Police and Impact on Skilled Motor Performance ● During physical/psychosocial aspects of police work, there was increased stress reactivity under active duty settings ○ Increased cardiovascular stress responses of police officers during heightened physical demand, potential threat, and periods of anticipation ○ The most severe acute stressor was unpredictable situations ● High levels of stress reactivity recorded during virtual lethal use of force training ● Repeated stressful training results in cumulative physiological effects such as increased HR, observed before scenario (anticipatory) and increases with stress escalation ● Increased physiological response and decreased shooting skill under high stress conditions such as a heavily armed person compared to low threat conditions such as an unarmed target ○ Decreased accuracy, faster reaction times, and more false positives Discussion ● Following stressful events (real-world and simulated), there was significant physiological activation among police officers ● Repeated and prolonged exposure to occupational stress manifests into chronic stress and impacts skill performance under acute stress ● Presence of stress-induced decay in skilled motor performance among officers ● Motor skill deterioration was significant in situations with physical/physiological stress ● Suggested Evidence-Informed Training to Reduce Skill Deficits in Acute Stress Situations ○ Can be virtual or scenario-based, both training formats produced realistic physiological stress responses ○ Training induces skill-appropriate stress thus improving performance deficits ■ Inducing stress overrides natural/unconditioned responses that may endanger officers during real incidents ○ Motor skill training was suggested ■ Learn fundamental motor skills under no stress, increase skill complexity, once mastered progress to applying skills in situations with increased levels of stress Learning & Memory Under Stress: Implications for the Classroom Overview ● Context & Duration of Stress determine its Effects on Memory (enhancing or impairing), which occur through both Physiological & Endocrine changes incited by a stressful encounter. Emotionally arousing memories tend to be stronger than neutral ones. Physiological + Endocrine Background ● Stress elicits a well coordinated response with numerous mediators; two main ones are 1) Rapid Autonomic Nervous System (ANS) [Physiological] Triggers release of catecholamines (ex: noradrenaline -NA) from adrenal medulla and locus coeruleus (brain) activating physiological “fight or flight” response. Affect neural functioning in learning/memory regions of the brain (ex: hippocampus, amygdala, & Prefrontal Cortex - PFC) 2) Slow hypothalamus-Pituitary-Adrenal Axis (HPA axis) [Endocrine] Triggers release of corticosteroids (ex: cortisol) from adrenal cortex. Peak levels 20-30 minutes after stressor onset. Enters brain binding to 2 different receptors: ● glucocorticoid receptors (GR) ○ ubiquitous throughout brain ○ Mainly Slow-Genomic action: 60-90 minute after stress onset involving long lasting DNA changes through translation & transcription, decreases neural excitability in amygdala & hippocampus long after stress ○ Revert acute effects of stress + reestablish homeostasis ● mineralocorticoid receptors (MR) ○ Concentrated in learning/memory regions ○ Mainly Non-Genomic action: develops rapidly & enhances neural excitability in amygdala + hippocampus ○ Support memory formation Effects on Memory Formation & Retrieval ● Stress affects memory in a time-dependent manner, enhancing formation around time of stressful encounter but impairing memory retrieval and acquisition of information encoded long after stressful event. Effects are dependent on NA & cortisol interactions in the amygdala and thus are stronger for emotional than neutral learning material. ○ NA is crucial for the impairing effects of cortisol which relies on NA-activation of amygdala Effects on Memory Consolidation, Reconsolidation, & Misinformation ● Stress after reactivation of memory trace interfered with later memory performance test ● The Misinformation Effect: Highly arousing information learned during stress resulted in robust memories resistant to being updated by subsequent misinformation. Misinformation less often incorporated if participants were stressed before the presentation of misinformation Stress Alters the way we Learn: Effects on Memory Quality ● Stress studies on memory largely focused on the hippocampus but revealed multiple memory systems ● Stress in rodents shifted memory processing from flexible cognitive to rigid habit-based systems. This shift didn't hamper learning but affected performance when blocked, indicating its adaptive nature. Humans under stress leaned towards habit-based memory over hippocampal memory, impacting task performance. Stress altered the balance between memory systems governing behavior, favoring habits over goal-directed actions Stress and Memory in the Classroom ● Stress significantly affects children's memory and learning. It boosts learning but disrupts memory recall and update. Stress shifts memory towards rigid, habit-like patterns, impacting problem-solving. ● Strategies needed: educate about stress impact, add emotions in learning, avoid strong stressors before exams. Stress affects memory retrieval and learning style, but practice helps ● Context matters: better memory when learning and recall happen in the same setting, potentially lessening stress effects on memory Outline for Diet and Depression Presentation - Nataly Opoyan Objective of paper: Showing the role of diet in improving or worsening psychiatric conditions and mental disorders, the main target of the paper is using depressive symptoms as the metric of comparison. Two Types of Diets: Mediterranean or Anti-Inflammatory Diet High in phytochemicals, vitamins, nutrients, omega-3 fatty acids, and poly/monounsaturated fats Anti-inflammatory, reduce oxidative stress and improve gut microbiome Western or Inflammatory Diet High in caloric density, trans and saturated fats, and gastrointestinal carbohydrates and sugars Pro-inflammatory and worsens gut microbiome Absence of vitamins/nutrients/O-3 FAs → increase in oxidative stress There are 9 modulatory biological pathways that can have potential impact (in the study): - - - - - - - - Inflammatory Response Neuropsychiatric disorder patients showcased high inflammation levels Causes: Psychological (i.e. early life adversities) or physiological stressors (i.e. smoking) can cause this Treatments: Pharmaceutical: NSAIDs (non-steroidal anti-inflammatory drugs, i.e. ibuprofen), cytokine inhibitors, and antibiotics Dietary Intervention: Mediterranean diet (i.e. inclusion of salmon → more DHA and EPA → antiinflammatory Oxidative Stress The imbalance between oxidative and antioxidant processes can result in cellular injury to lipids, proteins, and DNA. Depressed Patients: High oxidative stress markers, low antioxidant markers Treatments: Pharmaceutical: Antidepressants shown to reduce oxidative stress markers Dietary Intervention: Mediterranean diet (i.e. increase in Vitamin C and E → increase antioxidants → reduce oxidative stress markers) Mitochondrial Dysfunction Disrupted oxidative phosphorylation and impairments in mitochondrial ATP generation may lead to depression. A bad diet can lead to depressive symptoms: High-fat diets are associated with abnormal mitochondrial biogenesis → i.e. inflammation, and insulin resistance. Treatments: Dietary intervention: Caloric restriction → increase in mitochondrial biogenesis markers KETO DIET → increase mitochondrial uncoupling Alterations in Gut Microbiota Changes in gut microbiota can impact mental health. Western diet microbiota → mimics depressive symptoms (i.e. high anxiety, bad memory) Treatments: Prebiotics and probiotics → reduce chronic stress-induced changes and inflammation caused by WEST DIET. MED DIET intervention →improved cognitive function and ↓ inflammatory markers Tryptophan-Kynurenine Metabolism Tryptophan: amino acid essential in dietary consumption. Tryptophan is converted into serotonin → most antidepressants and anxiolytic medications target serotonin (SSRIs) ↓ TRP bioavailability with WEST DIET. Treatments: Caloric restrictions & Diet: black tea, probiotics, resveratrol → MORE neuroprotective kynurenic acid metabolite produced. HPA (Adrenal) Axis Excess glucocorticoid secretion is seen in a majority of depressed patients. Causes: Early childhood traumas can cause permanent disruptions in the HPA axis. Treatments: MED DIET → increase in vitamins, O-3 FAs, phytochemicals, and probiotics reduced serum glucocorticoid levels. Hippocampal Neurogenesis and BDNF BDNF (brain-derived neurotrophic factor): neurotrophin with ↑expression in the hippocampus, involved in synaptic plasticity and cell metabolism. ↓ BDNF level → major depressive patterns WEST DIET: impairs neurogenesis and ↓BDNF levels MED DIET: preserve hippocampal function and ↑ Obesity Positive feedback between obesity and depression → WEST DIET increases depressive symptoms Reduced levels of reward signaling, mood, and diet-regulating neurotransmitters (serotonin) with WEST DIET. Treatments: Caloric restriction/weight loss and/ or MED DIET can ↓ symptoms. Epigenetics Can affect DNA methylation age → related to depression and other disorders in adults Nutrition is a large aspect of environmental influences in epigenetics Undernutrition → demethylation changes that increase risk for neuropsychiatric disorders in adulthood.