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Disorders of the Pituitary Gland as2322@ic.ac.ukTILO'S COVERED I. Endocrine disorders: Summarise II. Function of endocrine glands: Summarise the pathology and pathophysiology the function of the key endocrine glands, of endocrine disorders. including the synthesis, regulation and physiological effects of their hormones. III. Structure of endocrine glands: Explain the structure of the key endocrine glands, with reference to their embryological origins.LECTURE TIMELINE 1. Hypopituitarism 2. Pituitary tumours 3. Disordersof 4. SBAsthroughout Vasopressin the lecture! • Recap on Y1 • Prolactinoma • Panhypopituitarism • GH excess • Vasopressin • Sheehan’ssyndrome • Cushing’sdisease • Diabetes insipidus • Apoplexy • Non-functioning • Psychogenicpolydipsia • SIADHHypopituitarismRecap on Pituitary Dopamine Prolactin CRH ACTH GHRH GH GnRH LH/FSH TRH TSHRecap on Pituitary Dopamine Prolactin CRH ACTH GHRH GH GnRH LH/FSH TRH TSHRecap on Pituitary What happens when this systemfails?Primary vs Secondary Primary disease – gland itself isthe cause (Thyroid, Adrenals, Gonads) Autoimmune destruction Autoimmune destruction, Destruction oftestes (e.g. (Hashimotos,Graves,Tb) trauma mumps)or ovaries (e.g. chemotherapy Secondarydisease– externalfactors (e.g. no signalsfrom Hypothalamus / Anterior pituitary)Primary vs Secondary -ve feedback Testosterone/Oestrogen↓ Primary Hypogonadism LH/FSH↑ Secondary LH/FSH↓ Hypogonadism Testosterone/Oestrogen ↓ Wedon’tmeasureGnRH but that wouldalsobe high!Primary vs Secondary TRH -ve feedback Primary T3/T4↓ Hypothyroidism TSH↑ Secondary TSH↓ Hypothyroidism T3/T4↓ TSH Wedon’tmeasureTRH butthatwould alsobehigh! T3 & T4Primary vs Secondary CRH -ve feedback Primary Cortisol↓ Hypoadrenalism ACTH↑ Secondary ACTH↓ Hypoadrenalism Cortisol↓ ACTH cortisolis regulated by ACTH, aldosterone isNOT (renin-angiotensin) Cortisol Case 1: A 35-year-old woman visits her GP after feeling increasinglyfatigued over the pastnine months.She has also gainedweight despite no major changes in her diet or exercise routine.She mentions feeling unusually cold, often layering upwhile her familycomplains that the house is too warm. She has also noticedthat her periods have become infrequent and unpredictable,with her last one occurring aroundsix months ago. When asked about her personallife, she admits thather interest in intimacy has declined significantly. Recently,she hasstruggled with her vision while driving,particularly noticing thatshe hastrouble seeing cars approaching from either side atjunctions.At work,she finds it harder to focus,and small tasks that used to feel effortless nowseem overwhelming. She wondersif she’s just“burntout”but admits that even time off hasn’t helped. On examination, she appears slightly pale andhas aresting heart rate of 52bpm.Her skin feelscoarse and dry, particularly on her elbows and knees. What is the most likelyunderlyingcause of her symptoms? 1.Hashimotos 3.PCOS thyroiditis 5.Chronicfatigue syndrome 2.Addisons 4.Pituitary adenoma Case 1: A 35-year-old woman visits her GP after feeling increasinglyfatigued over the pastnine months.She has also gainedweight despite no major changes in her diet or exercise routine.She mentions feeling unusually cold, often layering upwhile her familycomplains that the house is too warm. She has also noticedthat her periods have become infrequent and unpredictable,with her last one occurring aroundsix months ago. When asked about her personallife, she admits thather interest in intimacy has declined significantly. Recently,she hasstruggled with her vision while driving,particularly noticing thatshe hastrouble seeing cars approaching from either side atjunctions.At work,she finds it harder to focus,and small tasks that used to feel effortless nowseem overwhelming. She wondersif she’s just“burntout”but admits that even time off hasn’t helped. On examination, she appears slightly pale andhas aresting heart rate of 52bpm.Her skin feelscoarse and dry, particularly on her elbows and knees. What is the most likelyunderlyingcause of her symptoms? 1.Hashimotos 3.PCOS thyroiditis 5.Chronicfatigue syndrome 2.Addisons 4.Pituitary adenoma Panhypopituitarism Definition:‘totalloss of anterior& posterior pituitary function’ Presentations: • Fatigue CRH deficiency • Weightgain • Poorappetite TSHdeficiency • Cold intolerance • Reduced libido • Secondaryamenorrhoea • Reduced pubichairion FSH/LHdeficiency • Depression/lowmood GHdeficiency • Shortstatureinchildren • Inability tobreastfeed Prolactin deficiency hypopituitarism: Causes: Acquired Congenital More common! Rare!– shortstatureand hypoplastic (underdeveloped ant. • Tumours (adenoma, cysts) pituitary onMRI • Radiation (Radiotherapy damage) • Infection (meningitis) • Mutation of transcription factor • Trauma genes (PROP-1) • Inflammation (hypophystitis) • Needed for developmentofAnt. Pituitary • Pituitary apoplexy • Deficiency: GH+ 1 more at least! • Peri-partum infarction (Sheehans) hypopituitarism: Causes: Acquired Congenital More common! Rare!– shortstatureand hypoplastic (underdeveloped ant. • Tumours (adenoma, cysts) pituitary onMRI • Radiation (Radiotherapy damage) • Infection (meningitis) • Mutation of transcription factor • Trauma • Inflammation (hypophystitis) ge•eNeeded for developmentofAnt. Pituitary • Pituitary apoplexy • Deficiency: GH+ 1 more at least! • Peri-partum infarction (Sheehas)Radiotherapy induced hypopituitarism Affects Pituitary Hypothalamus Radiotherapy damage: • Higherdose ->higherrisk Direct e.g.hormone producing pituitary ofHPAaxis damage! tumour • Risk – up to 10 years after so require an annual Indirect e.g.adjacentCNS tumour assessment Case 1: A 35-year-old woman visits her GP after feeling increasingly fatiguedover the past nine months. She has also gainedweight despite no major changes in her dietor exercise routine. She mentionsfeeling unusually cold, often layering upwhile her familycomplains that the house is too warm. She has also noticedthat her periods have become infrequent and unpredictable,with her last one occurring aroundsix months ago. When asked about her personallife, she admits thather interest in intimacy has declinedsignificantly. Recently,she hasstruggled with her vision while driving,particularly noticing thatshe has troubleseeing cars approaching from eitherside atjunctions.At work, she finds it harder to focus, and small tasks that used to feel effortless nowseem overwhelming. She wondersif she’s just“burnt out”butadmits thateven time off hasn’t helped. On examination, she appears slightly pale and has a restingheart rate of 52 bpm.Her skin feels coarse and dry,particularlyon her elbowsandknees. What is the most likelyunderlyingcause of her symptoms? 1.Hashimotos 3.PCOS thyroiditis 5.Chronicfatigue syndrome 2.Addisons 4.Pituitary adenoma Case 1: A 35-year-old woman visits her GP after feeling increasingly fatiguedover the past nine months. She has also gainedweight despite no major changes in her dietor exercise routine. She mentionsfeeling unusually cold, often layering upwhile her familycomplains that the house is too warm. She has also noticedthat her periods have become infrequent and unpredictable,with her last one occurring aroundsix months ago. When asked about her personallife, she admits thather interest in intimacy has declinedsignificantly. Recently,she hasstruggled with her vision while driving,particularly noticing thatshe has troubleseeing cars approaching from eitherside atjunctions.At work, she finds it harder to focus, and small tasks that used to feel effortless nowseem overwhelming. She wondersif she’s just“burnt out”butadmits thateven time off hasn’t helped. On examination, she appears slightly pale and has a restingheart rate of 52 bpm.Her skin feels coarse and dry,particularlyon her elbowsandknees. What is the most likelyunderlyingcause of her symptoms? 1.Hashimotos 3.PCOS thyroiditis 5.Chronicfatigue syndrome 2.Addisons 4.Pituitary adenoma Panhypopituitarism: Diagnosis: Externalfactors Serum Hormone affecting Biochemical levels concentration: AKA Blood tests! Dynamic Pituitary • Cortisol – Diurnal! Function • T4 – circulating half- life=6 days • FSH/LH – cyclical in Radiological women • GH/ACTH - pulsatile Panhypopituitarism: Diagnosis: • ACTH (viaCortisol)+ GH – Biochemical released in Insulininduced hypoglycaemia(‘Stress’) • TRH– stimulate TSH Dynamic Pituitary Multiple Blood release Function tests over time, • GnRH – stimulate FSH/ LH underSTRESS! So,give Insulin, TRH +GnRH Radiological -> measurehormonelevels over time Panhypopituitarism: Diagnosis: Biochemical Dynamic Pituitary Function Pituitary MRI: • Better softtissueresolution Radiological Imaging - MRI • Canrevealpathology(apoplexy, adenoma) • Emptysella!Panhypopituitarism Treatments of secondary Prolactin Not treated! disease: replace hormone 1.Confirm via 2. Assess Dynamic PFT QoL GH (NICE 4.Measure guidelines) response via 3.Daily GH QoL↑ / Plasma injection IGF-1 Panhypopituitarism Levothyroxine (T4)oncedaily TSH • Cannot use TSH to adjust dose – low! Intercurrent illness can causean • Aimfor fT4 above middle of ref.range adrenal crisis (dizziness, hypotension,vomiting, weakness ->collapseand death Replace Cortisolusing synthetic glucocorticoids ACTH • Prednisolone 1/day Sick day rules: 1. Steroid alert pendant /bracelet • Hydrocortisone 3/day 2. 2x glucocorticoid dose iffever / illness No fertility Fertility FSH/LH required required 3. Unable to take tablets?-> inject IM Induce + go to A&E Men Topical/IM spermatogenesisvia (replace measure LH/FSH injections testosterone) plasma levels (6-12 months) Women Oral/topical Induceovulationvia carefully timed (replace If uterus intact gonadotrophin oestrogen) +progesterone injections(IVF) Case 2: A 31-year-old woman visits her GP three months after childbirth,concernedaboutpersistent fatigue and weakness.She describes feeling drained throughoutthe day,even after a full night's rest. She has also noticed that she islosing weightwithout trying, despite eating normally. She is struggling with breastfeeding, saying her baby latches properly,but she is barely producing any milk. Additionally,she hasn’t had a period since givingbirth and has a lowsex drive,which she findsunusual. She recalls that her labour was prolongedandcomplicated byheavy bleeding, requiringa blood transfusion before discharge.She initially assumed her symptoms were due to newmotherhood,but as time passes,she feels weaker rather than better. On examination, her blood pressure is 88/60 mmHg, andher pulse is75 bpm.Her BMI is21.5 kg/m² Bloodresults show lowACTH,FSH,LH, TSH, Free T4and9am cortisol What’s the most likely diagnosis to explain her history and presentation? 1.Panhypopituitarism 3.Post-nataldepression 2.Pituitary apoplexy 4.Sheehan’s syndrome Pituitary apoplexy Intra-pituitary haemorrhage, often on abackground of pre-existingpituitarytumour Patientpresentedwith: Sudden Can be precipitated by Anticoagulants;maybe 1 increasein ICP presentation of Pituitary • Suddenonset,severe headache Adenoma! • Bitemporal hemianopia Compressionof • Diplopia(DoubleVision) CN IV,VI • Ptosis (droopingof eyelid) Compressionof CN III Sheehan’s syndrome Post-partum hypopituitarism, secondary to post-partum haemorrhage Symptoms mayappear weeks to months postpartum and are often mistaken for postnatalfatigueordepression. Mechanism: leads tohypotension During pregnancy, lactotrophs, leading to Severe blood loss during and hypoperfusion of pituitaryenlargement delivery (PPH) vitalorgans. Presents as Severe hypotension The enlarged pituitary has causes ischaemia and increased oxygen demand Hypopituitarism -> pituitary infarction → but no direct bloodsupply requires replacement Pituitarycells begin to die. (relies on the hypophyseal therapy portalsystem). Case 2: A 31-year-old woman visits her GP three months after childbirth,concernedabout persistent fatigue and weakness.She describes feeling drainedthroughoutthe day,even after a full night'srest.She has also noticed that she is losing weight without trying,despite eatingnormally. She is struggling with breastfeeding, saying her baby latches properly,but she is barely producing any milk. Additionally,she hasn’t had a period since giving birth and has a low sex drive,which she finds unusual. She recalls that her labour was prolongedand complicated by heavy bleeding,requiring a bloodtransfusion before discharge.She initially assumed her symptoms were due to newmotherhood,but as time passes,she feels weaker rather than better. On examination, her blood pressure is 88/60mmHg,andher pulse is 75 bpm.Her BMIis 21.5 kg/m² Bloodresults show low ACTH, FSH,LH, TSH,Free T4and9am cortisol What’s the most likely diagnosis to explain her history and presentation? 1.Panhypopituitarism 3.Post-nataldepression 2.Pituitary apoplexy 4.Sheehan’s syndrome Case 2: A 31-year-old woman visits her GP three months after childbirth,concernedabout persistent fatigue and weakness.She describes feeling drainedthroughoutthe day,even after a full night'srest.She has also noticed that she is losing weight without trying,despite eatingnormally. She is struggling with breastfeeding, saying her baby latches properly,but she is barely producing any milk. Additionally,she hasn’t had a period since giving birth and has a low sex drive,which she finds unusual. She recalls that her labour was prolongedand complicated by heavy bleeding,requiring a bloodtransfusion before discharge.She initially assumed her symptoms were due to newmotherhood,but as time passes,she feels weaker rather than better. On examination, her blood pressure is 88/60mmHg,andher pulse is 75 bpm.Her BMIis 21.5 kg/m² Bloodresults show low ACTH, FSH,LH, TSH,Free T4and9am cortisol What’s the most likely diagnosis to explain her history and presentation? 1.Panhypopituitarism 3.Post-nataldepression 2.Pituitary apoplexy 4.Sheehan’s syndromeCase 3: A 50-year-oldwomanwitha historyof acraniopharyngiomatreated with surgeryandradiotherapy presentswithworseningfatigue, nausea, and dizziness. Shedeniesexcessivethirst orpolyuria. Blood testsshow: •9 AMcortisol:100 nmol/L(low) •ACTH: Low •FreeT4: 9pmol/L(low) •TSH: 0.5mU/L(normal) SAQ:Whatdoes thisbiochemical profileindicate, and how doesit differ fromprimaryendocrine gland failure?Case 3: The patient isstartedonhydrocortisone and levothyroxine. A few months later, she develops achest infection and presents with worsening fatigue anddizziness. VSAQ :What shouldshe havedone differently inmanagingher illness?Case 3: The patient isstartedonhydrocortisone and levothyroxine. A few months later , she develops achest infection and presents with worsening fatigue anddizziness. VSAQ :What shouldshe havedone differently inmanagingher illness? SBA: Sherecovers but asks ifher levothyroxine dose should also be adjustedduring illness. Yesit should bedoubled Yesit should behalved Yesit should bestopped No Menti Code: 1901 1734 Pituitary TumoursPituitary Tumours Pituitary Pituitary Cell Type Tumour HormoneTumour classification Radiological (MRI) • Size Most important Microadenoma <1cm (10mm) part! Macroadenoma >1cm (10mm) • Sellar or suprasellar • Compressingoptic chiasm or Function not • Invading cavernoussinus or • Excess secretion ofa specific not pituitary hormone eg prolactinoma Benign orMalignant • No excess secretion of • Pituitarycarcinoma veryrare pituitary hormone (Non- (<0.5%of pituitarytumours) FunctioningAdenoma) • Mitotic index measuredusing Ki67 index – benign is <3% • Pituitaryadenomascan have benign histology but display malignant behaviour Case 4: A29-year-oldman presentswith lowlibido, erectile dysfunction, and fatigue. Hehas nosignificant medical historybutreports difficulty gainingmusclemass despiteregularexercise. Blood tests reveal: •Serum prolactin: 7,200mU/L(elevated). •Testosterone: 5.0nmol/L(low). •LH&FSH: Low. •TSH& free T4: Normal. Whatis themostlikelymechanismbywhichhyperprolactinemialeads tolowtestosterone? A)Prolactinincreasesdopamine release, whichsuppresses testosteroneproduction. B)Prolactinstimulatesaromataseactivity,increasingoestrogen levelsand reducingtestosterone. C) Prolactininhibitskisspeptinrelease, leadingtoreducedGnRHandLH/FSHsecretion. D) Prolactindirectlyinhibitstestosteronesynthesisin Leydig cells. Kisspeptin – Y1 refresher 1. Prolactinbinds PRLreceptors onthehypothalamic kisspeptinneurones, inhibiting kisspeptin release. 2. This resultsina reductionofGonadotrophin ReleasingHormone(GnRH) secretionintotheportal circulation. 3. This leadstoless FSHand LHsecretion by gonadotrophsintheanteriorpituitary. 4. This leadsto less testosteroneand oestrogen production, resultingin irregular menstrualcycles and decreased libido. Prolactinoma Pituitary tumourthat secretes an excessof prolactin,leading togonadal dysfunction Presentation /Symptoms: DuetoKisspeptininhibition -> ↓GnRH-> ↓LH/FSH-> • Irregular menstrualcycle ↓Oestrogen/Testosterone (Oligo/Amenorrhoea) • Decreased libido Excess milk productionfrom • Nipple discharge (Galactorrhoea) Lactotrophs • Headache Prolactinoma -> raisesICP If amale: • Erectiledysfunction • Decreased hair growth+ muscle mass LackofTestosterone • Decreased libido • Subfertility No LH/FSH -> nospermatogenesisProlactinoma Othercausesofan elevated prolactin Physiological • Pregnancy/breastfeeding • Stress: exercise, seizure, venepuncture Pathological • Nipple/chestwallstimulation • Primaryhypothyroidism • Polycystic ovarian Iatrogenic (medication) syndrome • Antipsychotics • Selective serotoninre-uptake inhibitors • Chronic renal failure • Anti-emetics • Highdose oestrogen • Opiates Prolactinoma Investigations: Treatment: First Line: Bloods First line: D2 • UsuallyserumPRL>5000 (Dopamine) receptor mU/L agonists Onceconfirmed true Optic Pituitary e.g. Cabergoline elevationofPRL+ Chiasm prolactinoma clinical featuresof raised PRL-> Pituitary MRI If medical doesn’t work: Transsphenoidal Pituitary Surgery –> remove thetumour Case 4: A29-year-oldman presentswith lowlibido, erectile dysfunction, and fatigue. Hehas nosignificant medical historybutreports difficulty gainingmusclemass despiteregularexercise. Blood tests reveal: •Serum prolactin: 7,200mU/L(elevated). •Testosterone: 5.0nmol/L(low). •LH&FSH: Low. •TSH& free T4: Normal. Whatis themostlikelymechanismbywhichhyperprolactinemialeads tolowtestosterone? A)Prolactinincreasesdopamine release, whichsuppresses testosteroneproduction. B)Prolactinstimulatesaromataseactivity,increasingoestrogen levelsand reducingtestosterone. C) Prolactininhibitskisspeptinrelease, leadingtoreducedGnRHandLH/FSHsecretion. D) Prolactindirectlyinhibitstestosteronesynthesisin Leydig cells. Case 4: A29-year-oldman presentswith lowlibido, erectile dysfunction, and fatigue. Hehas nosignificant medical historybutreports difficulty gainingmusclemass despiteregularexercise. Blood tests reveal: •Serum prolactin: 7,200mU/L(elevated). •Testosterone: 5.0nmol/L(low). •LH&FSH: Low. •TSH& free T4: Normal. Whatis themostlikelymechanismbywhichhyperprolactinemialeads tolowtestosterone? A)Prolactinincreasesdopamine release, whichsuppresses testosteroneproduction. B)Prolactinstimulatesaromataseactivity,increasingoestrogen levelsand reducingtestosterone. C)Prolactininhibits kisspeptinrelease,leading to reducedGnRHandLH/FSHsecretion. D) Prolactindirectlyinhibitstestosteronesynthesisin Leydig cells. Case 4: A29-year-oldman presentswith lowlibido, erectile dysfunction, and fatigue. Hehas nosignificant medical historybutreports difficulty gainingmusclemass despiteregularexercise. Blood tests reveal: •Serum prolactin: 7,200mU/L(elevated). •Testosterone: 5.0nmol/L(low). •LH&FSH: Low. •TSH& free T4: Normal. His MRIis shownontheright. Whatis themostappropriate initial treatment forthis patient’s condition? 1.Radiotherapy 2.Cabergoline 3.Transsphenoidal 4.Topical pituitarysurgery testosterone Case 4: A29-year-oldman presentswith lowlibido, erectile dysfunction, and fatigue. Hehas nosignificant medical historybutreports difficulty gainingmusclemass despiteregularexercise. Blood tests reveal: •Serum prolactin: 7,200mU/L(elevated). •Testosterone: 5.0nmol/L(low). •LH&FSH: Low. •TSH& free T4: Normal. His MRIis shownontheright. Whatis themostappropriate initial treatment forthis patient’s condition? 1.Radiotherapy 2.Cabergoline 3.Transsphenoidal 4.Topical pituitarysurgery testosterone Case 4: A29-year-oldman presentswith lowlibido, erectile dysfunction, and fatigue. Hehas nosignificant medical historybutreports difficulty gainingmusclemass despiteregularexercise. Blood tests reveal: •Serum prolactin: 7,200mU/L(elevated). •Testosterone: 5.0nmol/L(low). •LH&FSH: Low. •TSH& free T4: Normal. Heisstarted on cabergoline, adopamine agonist. Whatis themechanismbywhichdopamine agonists reduceprolactinlevels? A)Binding todopamine D2receptorson lactotrophcells, inhibiting prolactinrelease. B)Increasing hypothalamickisspeptinsecretion, restoringLHand FSHproduction. C) EnhancingpituitaryGnRHreceptorsensitivity, increasinggonadotropinsecretion. D) Blocking prolactinreceptors inthe hypothalamus, preventing afeedback loop. Case 4: A29-year-oldman presentswith lowlibido, erectile dysfunction, and fatigue. Hehas nosignificant medical historybutreports difficulty gainingmusclemass despiteregularexercise. Blood tests reveal: •Serum prolactin: 7,200mU/L(elevated). •Testosterone: 5.0nmol/L(low). •LH&FSH: Low. •TSH& free T4: Normal. Heisstarted on cabergoline, adopamine agonist. Whatis themechanismbywhichdopamine agonists reduceprolactinlevels? A)BindingtodopamineD2 receptorsonlactotroph cells,inhibiting prolactinrelease. B)Increasing hypothalamickisspeptinsecretion, restoringLHand FSHproduction. C) EnhancingpituitaryGnRHreceptorsensitivity, increasinggonadotropinsecretion. D) Blocking prolactinreceptors inthe hypothalamus, preventing afeedback loop.Acromegaly Presentation duetoexcess secretionof GH fromfunctional pituitary adenoma Causes Non-pituitary Presentation /Symptoms tolook for: tumours(pancreatic, • Increased hand size (ring fit issues) Pituitary Adenoma lung, adrenal) -> • Increased feet size (shoe fitissues) ectopicGH • Large, coarse facial features (nose / jaw) • Large tongue (macroglossia) GHhypersecretion • Snoring/obstructive sleep apnoea • Sweatiness IGF-1 hypersecretion • Headache Growth and • Joint pain development of • Impaired glucose tolerance / Diabetes bodytissues • Hypertension Acromegaly Investigations: Treatment: 1.First Line: Bloods First line: • GH pulsatile – so randommeasurement unhelpful Transsphenoidal • Elevatedserum IGF-1 Pituitary Surgery –> remove the 2.T o confirm: tumour OGTT–failed suppressionof GH Priortosurgerytoshrink ‘paradoxical tumour/ cannot have rise’ surgery: Octreotide (Somatostatin analogue) 3.Once Blocks GH secretion from tumour confirm GH Pituitary MRI to Rare: use D2 agonists, as someGH tumours visualisetumour can co-secrete Prolactin excess:Case 5: A 42-year-old man presents with progressiveenlargement ofhandsand feet, coarseningof facial features, sweating, andjoint pain overthe pastfewyears. His wife alsoreports thathe snores more atnight. On examination,he has: •Prominent supraorbital ridges and jaw enlargement (prognathism) •Thickened skin and oilycomplexion •Hypertension What isthemost likely diagnosis,andhow is it confirmed biochemically?Case 5: A 42-year-old man presents with progressiveenlargement ofhandsand feet, coarseningof facial features, sweating, andjoint pain overthe pastfewyears. His wife alsoreports thathe snores more atnight. On examination,he has: •Prominent supraorbital ridges and jaw enlargement (prognathism) •Thickened skin and oilycomplexion •Hypertension What isthemost likely diagnosis,andhow is it confirmed biochemically? Biochemical tests to confirm diagnosis: •ElevatedIGF-1 levels Acromegaly levels fail to suppress afterglucoseadministration(GH suppressiontest).Cushing’s syndrome Symptoms: The presentationresulting from an excess of cortisol Common features inSBAs: • Fat padsedabdominal striae • Round/moonface • Centripetal obesity Lemon on a stick!Cushing’s disease! Corticotroph adenoma Ix: 1. 24h urine free cortisol↑ secreting ACTH -> high Cortisol! 2. Late night cortisol ↑ (saliva/ blood) – loss ofdiurnal ACTH dependent! 3. Failuretosuppresscortisolafter oral dexamethasone (shouldhave neg feedbackreaction Tx: 1. Confirmedhypercortisolism -> measureACTH 2. Ifhigh -> PituitaryMRINon-functioning Pituitary Adenomas No specifichormone secreted! • Often present with visual disturbance (bitemporal hemianopia) • Can present with hypopituitarism • Serum PRL can be raised (as dopamine cannot travel down stalk!) Tx: Trans-sphenoidal surgery forlarger tumours (esp. ifvisual disturbance!)Disorders of VasopressinPosterior Pituitary Posterior pituitary – anatomically continuous with Hypothalamus! Hormones produced inhypothalamus (stored in Post.Pit.) Arginine Concentrates Vasopressin (AVP) urine via water aka Anti-diuretic reabsorption in Hormone(ADH) collecting duct Oxytocin Stimulates Milk ejection (+ Contractions inpregnancy)Posterior Pituitary Optic Chiasm PosteriorPituitary = ‘Bright Spot’on MRI Bright Absence canbe normal,not Spot always present Stimulation of vasopressin release Risein plasma osmolality (↑Bloodconcentration), sensedby osmoreceptors • Increase in plasmaosmolality (concentration) sensed by osmoreceptors • Osmoreceptorsare specialsensory receptors in the hypothalamus Code: 1901 SBA 1734 Whichof thefollowing is the primary physiologicalaction of argininevasopressin(AVP)? A)Inhibition of aldosteronerelease B)Stimulationofsodiumexcretioninthekidneys C)Stimulationofwaterreabsorptionin therenalcollectingducts D) Stimulationof reninreleasefromtheJGA E)Stimulationofglucose reabsorptioninthe proximal tubuleSBA Whichof thefollowing is the primary physiologicalaction of argininevasopressin(AVP)? A)Inhibition of aldosteronerelease B)Stimulationofsodiumexcretioninthekidneys C)Stimulation ofwater reabsorptionin therenalcollecting ducts E)Stimulationofglucose reabsorptioninthe proximal tubuleVasopressin MoA 2 1 5 4 3 7 6 Case 6: A 48-year-old motheroftwoteenagechildren seesher GPto discuss some symptoms thathave been troubling her.For the last fewmonths,she has hadvery disrupted sleep. Shehas nodifficulty falling asleep butwakes up at leastthreetimes per night needing to pass urine. She alsonoticesthat beforeshegoesback tosleep, she needs to drink alarge glassofwater because she is sothirsty. She works as aschool administrator andhasnoticed thatsheisalsopassing urinefrequently in the daytime, having toleaveher desktogotothe toiletatleast six times per day.Shehas alarge bottle ofwater ather deskatworkand fills this up several times perday. Her bloodresultscome back.She has a fasting glucose of5.4mmol/L,HbA1c of 36mmol/mol(<42), anda serum sodium of 148mmol/L (135-145). What is the most likelydiagnosis? 1. 2.Type 2Diabetes 3.Diabetes 4.Type 1 Psychogenic mellitus insipidus Diabetes AVP Disorders Presentation causedby hyposecretion of / insensitivity to AVP /ADH Most commonly Osmotic caused by Othersymptoms: symptoms: Diabetes Urine: • Polyuria • Very dilute (hypo-osmolar) mellitus! • Large volume • Nocturia Plasma: • Polydipsia • Concentrated (hyper-osmolar) • Thirst – extreme! • ↑ Na+ (hypernatremia) • Glucose normal (R/O T2DM) In Diabetes Insipidus – due to issue with AVP! 2types: AVP AVP resistance deficiencyAVP Disorders AVP-Deficiency AVP-Resistance • Issue in Hypothalamus / • Can make AVPasnormal Posterior Pituitary • Issue in Kidney (collecting duct) – • Unable to make AVP unable to respond toAVP Causes: Causes: • Acquired: Traumatic Brain injury; • Congenital: RARE (e.g. mutation Pituitarysurgery / tumours/ metastases; Autoimmune; in V2 receptor gene / AQP2) Granulomatousinfiltration • Acquired: Drugs (e.g. Lithium) • Congenital: RAREAVP DisordersAVP Disorders AVP Disorders AVP-Deficiency AVP-Resistance • Hardtotreat successfully(BUTrare) • ReplaceVasopressin • Stop anycausative drugs • Desmopressin • Selective for V2receptor • Either Tablet or Intranasal• Thiazide diuretics • Combined withNSAIDe.g. Ibuprofen • To reduce urinevolume /rate of kidney urine production Case 6: A 48-year-old motheroftwoteenagechildren seesher GPto discuss some symptoms thathave been troubling her.For the last fewmonths,she has had very disrupted sleep.She hasnodifficultyfalling asleep but wakesup at least threetimes pernight needingtopass urine. She also noticesthat beforeshegoesback tosleep, she needs todrinkalarge glassof water because she is sothirsty. She works as aschool administrator andhasnoticed thatsheisalso passingurinefrequently inthe daytime, having toleave her desktogo tothe toiletatleastsix times per day. She has alarge bottle of water ather deskat workand fills thisup several times perday. Her bloodresults come back.Shehasa fasting glucose of5.4mmol/L, HbA1c of 36mmol/mol (<42), and aserumsodium of 148mmol/L(135-145). Wh1. isthe mostlikely diagnosis? 2.Type 2 Diabetes 3.Diabetes 4.Type 1 Psychogenic mellitus insipidus Diabetes polydipsia Menti Case 7: Code: 1901 1734 A 19-year-old female studentpresentswith increasedpolydipsiaand polyuriasince childhood.She has a fluid intake of 6to 8litres anda frequency of micturitionof20to 25 times ina 24-hour period.She denies anypsychiatric historyand thereis noevidenceof dehydration, neurologicalabnormalities,or head trauma.She’s alsohad recurrent episodes ofnausea since childhood, as well as recurrent headaches.Her friends at university have noticedshe neverleavesanywhere without her water bottle, andoften has to goto the toiletwhilstoutside. O/E,there are nosignificantfindings.Herblood resultsare significant for aNa+of 124mmol/L (rr: 135-145mmol/L). Her HbA1c is normal.A waterdeprivationtestwith ddAVP is conducted,and her urine osmolalitygoes up from 75mOsm/kg H2O to810 mOsm/kg H2O. Gi1.n thehistoryand 2.Thiazideions, whattreatm ntwould youoffer? id Desmopressin diuretics Saline infusion restriction Psychogenic Polydipsia Excessive fluid intake bypatientin absence of physiological stimuli to drink Similar presentation toDiabetes Insipidus: Osmotic symptoms: • Polydipsia (extreme) • Polyuria • Nocturia BUTnoproblem with AVP! • Often seen in patients with psychiatric /neurodevelopmental disorders • The patient drinks allthe time, so passes large volumes of dilute urine Psychogenic Polydipsia Excessivefluid intake by patientin absence of physiologicalstimuli to drink DI vs PP - diagnosis How to distinguish? 1. Water Deprivation T est Noaccess to fluids; over time measure: • Urine volume • Urine concentration (osmolality) • Plasma concentration(osmolality) Weigh regularly! • Stoptest if >3% body weight loss • Marker of significant dehydration! DI vs PP - diagnosis How to distinguish? 2. Give ddAVP(desmopressin) WorkslikeAVP! • AVP-Deficiency (CDI): response toddAVP -> urine concentrates • AVP-Resistance (NDI): no increase in urine osmolality with ddAVP, as kidneys cannot respond Case 7: A 19-year-oldfemalestudentpresentswith increased polydipsiaandpolyuriasince childhood. She has afluid intakeof6to8 litres and afrequencyof micturitionof 20 to25times ina24-hour period. Shedenies anypsychiatrichistoryandthereis noevidenceof dehydration, neurological abnormalities, orhead trauma. She’salsohadrecurrent episodes ofnauseasincechildhood, as well asrecurrent headaches. Her friendsat university have noticed shenever leaves anywhere without her waterbottle, and often has togoto the toilet whilst out. O/E, therearenosignificant findings. Her bloodresultsaresignificant fora Na+ of124mmol/L(rr: 135-145mmol/L). HerHbA1cis normal. Awaterdeprivation test withddAVP is conducted,and her urineosmolalitygoesup from 75mOsm/kg H2Oto810 mOsm/kg H2O. Giventhe history andinvestigations, whattreatmentwould youoffer? 3.IV hypertonic 4.Fluid 1. 2.Thiazide Saline infusion restriction Desmopressin diuretics SIADH Excessproduction of AVP/ADH,leading to excessive fluid retention Syndrome of Inappropriate Causes: ADH • CNS: headtrauma,stroke, tumour • Lungs: Pneumonia,bronchiectasis Too much AVP results in: • Malignancy:Small Cell LungCancer • Reduced Urine output -> • Drugs: Carbamazepine, SSRIs • Idiopathic highurine osmolality • Water retention -> low plasma osmolality Management: • Fluid restrict • Consequently, dilutional • Can use Vasopressin antagonist (e.g. hyponatraemia (↓ Na+) Vaptan) – binds V2 receptors but expensiveContact Details Name: Amelia Shabir Email: as2322@ic.ac.uk Feedback Form