normal pituitary magnetic resonance scan正常垂体磁共振扫描

Hypothalamic & Pituitary hormones,Eric Lazartigues, Ph.D.Department of P(504) 568-3210,Hypothalamus-Pituitary: Anatomy,Hypothalamus: nervous tissue below thalamusPituitary: small outgrowth of the forebrain, size of half a peaTwo functional partsAdenohypophysis (anterior pituitary)Rathkes pouch ectoderm above mouthNeurohypophysis (posterior pituitary)HypothalamusMove together during development,Hypothalamus-Pituitary:Blood and nerve supplies,HypothalamusHypothalamic neurons release hormones directly into capillary plexus Anterior pituitaryBlood supply from median eminence of hypothalamus portal systemHormones from hypothalamus to pituitarySympathetic/parasympathetic nervesPosterior pituitarySupraoptic and paraventricular nuclei in hypothalamus,Ultradian,0,1,2,3,4,5,6,7,8,amplitude,Frequency,LH,Testosterone,2,4,6,ng/ml,mIU/ml,5,10,15,20,Hr,The pulsatile nature of hormone release from the hypothalamus is critical for maintained optimal responsiveness of the pituitary cells.Pulsatile secretion decreases the extent of down-regulation of pituitary receptors.Continuous release of hypothalamic hormones actually suppresses the secretion of pituitary hormones.,Functions of the HPA,Pituitary releasing hormones,CRH:Corticotrophin releasing hormone (ACTH)TRH:Thyrotrophin releasing hormoneGHRH:GH releasing hormoneSomatostatin:GH inhibitionGnRH:Gonadotrophin (LH, FSH) releasing hormoneDopamine:Prolactin inhibitionVasopressin:ACTH release,Pituitary releasing hormones,Small peptidesActive at relative high concentrationsRapidly degradedLow concentration in peripheral circulationSpecial circulation allows high concentrations to reach targets,Feedback control,Anterior pituitary hormones,Thyrotrophin (TSH),Stimulates:thyroxine synthesisthyroid growthRegulation:TRH: stimulates releaseInhibited by thyroid hormones (T3, T4) feedback inhibitionActs via cAMP,Thyroid Stimulating Hormone: TSH,Thyrotrophs:Thyroid Stimulating Hormone (TSH)Hypothalamic ControlThyrotropin Releasing Hormone (TRH)Target TissueFollicular cells of the Thyroid gland Hormone effects:controls the production of T3 and T4,Endocrine activity of the Thyroid Gland,Follicular cells:T3 and T4Target Tissue;Almost all body tissuesHormone effects:Increases body metabolismIncreases gluconeogenesisIncreases glycolysisIncreases lipolysisIncreased basal metabolic rate (BMR)Increases heart rate and force of contraction,Hypothyroidism,Hypothyroidism (3% of population)endemic goiter: (due to I2 deficiency)Classification: I, II or IIITreatment: Thyroxine (T4) daily (levothyroxine) or combination T3+T4Congenital hypothyroidism (Cretinism): 1:4000 newborns Physical and mental growth and development are greatly retardedTreatment: Thyroxine daily (levothyroxine),Hyperthyroidism,Graves Disease withexophthalmos Temporary treatment:Thyrostatics:Methymazole: inhibit formation of T4Propylthiouracil: prevent conversion T4 to T3Beta blockers:Metoprolol: Management of symptoms onlyPermanent treatment:Surgery: remove whole or part of thyroid131Iodine orally: destroy hyperactive cellsToxic multinodular goiterToxic thyroid adenoma,Corticotrophin (ACTH) secretion,ACTH,CorticotrophsAdrenocorticotropic hormone (ACTH)Hypothalamic ControlCorticotropin releasing hormone (CRH)Target TissueAdrenal cortex, Zona FasciculataHormone affects:control production of glucocorticoids such as cortisol,Endocrine activity of the Adrenal Cortex,Zona glomerulosaMineralocorticoids such as AldosteroneHormonal controlrenin-angiotensin pathwaypermissive effect of ACTH Target tissue:Principle cells of the DCT and collecting ductHormone affects:increases reabsorption of Na+ and water,Endocrine activity of the Adrenal Cortex,Hyper-secretion:Aldosteronism:Hypokalemia, increase in extracellular fluid and blood volume,and hypertension, may also have period of muscular paralysis Hypo-secretion:Addisons disease Mineralocorticoids deficiency, death occurs in four days to two weeks if untreated,Endocrine activity of the Adrenal Cortex,Zona FasciculataGlucocorticoids such as cortisol and cortisoneHormone control:ACTHTarget tissue:Liver and general body cellsHormone affects:Stimulates gluconeogenesis by the liverDecreased glucose utilization by cells,Endocrine activity of the Adrenal Cortex,Hormone effects:Elevated blood glucose levelsReduction of protein stores in all body cells except the liverincreased plasma protein levelspromote lipolysis and beta oxidation of fatHelps body recover from stressPrevention of inflammation,Endocrine activity of the Adrenal Cortex,Hypo-secretionAddisons disease - glucocorticoid deficiencyperson becomes highly susceptible to disease and deteriorating effects of stressACTH stimulation test (tetracosactide)Hyper-secretion:Cushings Syndromemobilization of fat from lower body to the thoracic and upper abdominal regions giving raise to “Buffalo Torso”,Long,Loop,Long,Loop,Cortisol,Cortisol,Corticotroph,ACTH,CRH,HYPOTHALAMUS,CRH,Cortisol,Short,Loop,STRESS,- Infection,- Trauma,- Surgery,Sleep/wake,ACTH,Hypoglycemia,a-MSH,Stress overcomes negative feedback regulation,- Pain, Cold,Anterior Pituitary Hormones: Stimulation Testing,ACTH (ATHAR, COSYNTROPIN) - Not used clinically to treat adrenal insufficiency due to expense - Used for stimulation testing. ACTH (IV ACTH should result in in peak plasma levels of glucocorticoids in 3-60 min - Tx myasthenia gravis Adverse Effects (Prolonged use): Suppression of hypothalamic pituitary-adrenal axis, immunosupression, hypertension Drug Interactions: natriuretic and diuretic effects of diuretics. Use with K+-depleting diuretics can produce severe hypokalemia.Contraindications: Surgery, 1o adrenal insufficiency, heart failure TRH/TSH (Thyrotropin; recombinant human TSH (THYROGEN) Not commonly used to treat thyroid disorders but are used to distinguish between hypothalamic-pituitary-thyroid gland dysfunction.,Endocrine activity of the Adrenal Cortex,Zona reticularisProduces small amounts of androgens, mostly dehydroepiandrosterone (DHEA), DHEA may be converted into estrogensHormone Control:Believed to be ACTHTarget tissue:General body cells,Endocrine activity of the Adrenal Cortex,Hyper-secretion:Adrenogenital SyndromeCongenital Adrenal hyperplasia:11b-hydroxylase deficiency (90-95%)Salt wasting crises in infancy virilization of female infantsSex assignment issues and controversies,Gonadotropic hormones,GnRH: pulsatile secretionCyclical secretion LH, FSHFemales: ovary LH: ovulation, corpus luteumFSH: dvpt follicle, oestradiol and progesteroneMales: testes LH: Leydig cells: testosteroneFSH: Sertoli cells: spermatogenesisFSH: inhibin: negative feedback,GnRH and analogs,Decapeptide half-life of 2-4 min. Pulsatile secretion, arcuate nucleus Continuous secretion: downregulation (clinical use) Diagnostic use: synthetic GnRH, Gonadorelin (FACTREL) stimulation testing: pituitary can secret LH/FSH? Therapeutic uses: Management of infertilty: promote physiological cycle Suppression of gonadotropin secretion: non-pulsatile GnRH-dependent precocious puberty: before 8-9 year-old Endometriosis, Uterine leiomyomata (fibroids) estrogen-sensitive fibrous growths Pharmacological castration (paraphilia): triptorelin (TRELSTAR),GnRH and analogs (continued),Side Effects (chronic non-pulsatile administration)Females: Typical symptoms of menopause: hot flashes, sweats, headaches and bone density. Depression, libido, generalized pain, vaginal dryness, and breast atrophy may also occur. Men: Testicular atophy, sweats, edema, gynecomastia, libido, hematocrit, bone density,Both: dizziness, vertigo, insomnia, and headache Drug-drug Interactions: Androgen therapy: DECREASE EfficacyDiscontinue nasal decongestants Contraindications: Pregnancy, breast-feeding, osteoporosis, undiagnosed abnormal vaginal bleeding,GnRH antagonists,Ganirelix (ANTAGON) and cetrorelix (CETROTIDE) Mechanism of Action: Inhibit the secretion of LHFSH in a dose dependent manner. Administer subcutaneously Use: Inhibit premature (LH) surges in women undergoing controlled ovarian hyperstimulation with FSH and hCG, followed by subsequent assisted insemination or reproductive technology (ART) procedures Adverse effects: nausea and headaches. Contraindications: primary ovarian failure, pregnancy, breast feedingAbarelix (PLENAXIS) Indication: Prostate cancer to prevent adverse consequences of tumor growth. Distribution limited (hypersensitivity reactions).,Clinical use of FSH/LH,Diagnostic uses:a. Pregnancy: hCG detection in urine or plasma b. Timing of ovulation: occurs 36 hours after the onset of LH surge c. Diseases of Male and Female Reproductive Systems Low LH and FSH: hypogonadotrpoic hypogonadism : hypothalamic or pituitary disease High LH and FSH: primary gonadal diseasesTherapeutic Uses of Gonadotropins: Purified from the urine of pregnant women or postmenopausal womenhCG (PREGNYL, NOVAREL, PROFASI) mimics action of LHMenotropins (PERGONAL, REPRONEX): equal amount LH and FSH Recombinant FSH: rFSH: follitropin a (GONAL-F) and follitropin b (PUREGON, FOLLISTIM) Female infertility in combo with ART: Anovulation, Polycystic Ovary disease Adverse effects: multiple pregnancies and ovarian hyperstimulation syndrome (OSS)Male Infertility Secondary to gonadotropin deficiency, cryptorchidismMost common side effect is gynecomastia,Prolactin,Secreted by lactotrophsLactationInhibits reproductive hormone secretionRelease inhibited by dopamineAnimals: osmoregulation, growthStalk transection prolactinNo therapeutic useHyperprolactinemia:Women: galactorrhea, amenorrhea, infertilityMen: loss of libido, impotence, infertilityRx: surgery, radiation, D2 agonists,Pharmacological Treatment of Prolactin excess: DA agonists,Bromocriptine interacts with D2R on lactotrophs - Note only 7% reaches circulation do first-pass metabolism by the liver. Longer acting version (PARLODEL-LAR) Pergolide (PERMAX) off label treatmentCabergoline (DOSTINEX) ergoline-derived dopamine agonist .More potent and longest half-lifeMechansism of Action: Shrink pituitary PRL-secreting tumors, lower circulating PRL levels, and restore ovulation in approximately 70% of women with microadenomas and 30% of women with macroadenomaSide Effects: Nausea, headaches, orthostatic hypotensionDrug-drug Interactions: May effects of anti-hypertensives, and effectiveness of dopamine antagonists such as the antipsychotics and the phenothiazine-type antiemetics,Growth hormone,Promotes growth: skeleton, muscles, visceraEffects mediated by somatomedins (e.g. IGF1, 2.)Released at night during growthVariety of metabolic effectsAnabolic, positive nitrogen balanceAnti-insulinStimulated by GHRH, stress, exerciseInhibited by somatostatin,Physiological Effects of GH,Growth Hormone Deficiency,Children: Dwarfism. Most common is isolated idiopathic Insulin-stimulated hypoglycemia induced GH 90% have overt pituitary hypofunction due to disease, pituitary adenoma or iatrogenic Insulin-stimulated hypoglycemia induced GH 3 g/L,9 year old Peruvian girl (80 cm) with GH receptor defect,Primary Therapeutic Objective Clinical Condition Growth Growth failure in pediatric patients : Growth hormone deficiency Prader-Willi syndrome Turner syndrome Small for age with failure to catch up by age 2Idiopathic short stature in pediatric patientsImproved metabolic state, Growth hormone deficiency in adultslean body mass, sense of well-being lean body mass, weight, AIDS-related muscle wasting and physical enduranceImproved GI functionShort bowel syndrome in patients receiving specialized nutritional support,Clinical Uses of Recombinant Human Growth Hormone,GH SUPPLEMENTATION Somatropins GH preparations whose sequence matches native hGH. Somatrem: GH derivative with an additional methionine at the amino terminus.Side effects: hyperglycemia (may be contraindicated in diabetes) and increased intracranial pressure.Additional approved uses of GH therapy: “Social use” short stature within “normal” ranges, bodybuilding, athletes, ageing. GHRH LIKE ACTIONSsermorelin peptide that corresponds to the first 29 amino acids of GHRH. - Used diagnostically to Decrease serum GH levels - Tx Children with 3o (hypothalamic deficiency)Side effect: angina, flushingIGF-1 THERAPY For Pts with GH Receptor mutationMecasermin: complex of recombinant human IGF-1 (rhIGF-1) and recombinant human insulin-like growth factor-binding protein-3 (rhIGFBP-3). Clinical response is monitored Serum IGF-1 levels.,Treatment of GH insufficiency (all SC or IM) :,Growth hormone release,06:00,06:00,24:00,18:00,12:00,Normal,Acromegaly,Periosteal Bone growth Excess soft tissueEnlarged organs.CardiomyopathyOften diabeticInfertile? GH PRL,Growth Hormone Excess,Don Fermin y Urieta (1870-1913)“The Giant of Aragon”229 cm tall,Hyper-secretion:During childhood causesGigantism (up to 8 9 ft.)During Adulthood causesAcromegaly:Enlargement of the small bones of the hand and feetEnlargement of the cranium, nose, and lower jawTongue, liver, and kidneys become enlarged,Drug TypeDosingOctreotide Short-actingSubcutaneous 3 times/day; dose range of 50-500 mgOctreotide LAR Long-actingIntramuscular every 28 days; dose range of 10-40 mgLanreotide depot Long-actingIntramuscular every 7-14 daysLanreotide autogel Long-actingDeep subcutaneous every 28 days,Octreotide (SANDOSTATIN) 8 amino acid derivative of somatostatin that preferentially binds to SS receptors on GH-secreting tumors.Lanreotide (SOMATULINE-LA) slow release, long-acting octapeptide causes prolonged GH suppression. Most effective for patients with non-pituitary tumours Side effects: Inhibits gastrointestinal and pancreatic function Long-term use causes digestive problems such as loose stools, nausea, and gas 25% of patients develop gallstonesArrhythmias, sinus bradycardia, and conduction disturbancesDrug Interactions: Cyclosporine bioavailability,SOMATOSTATIN (SS) ANALOGS,GROWTH HORMONE ANTAGONISTS: Pegvisomant (SOMAVERT) GH analog bindsreceptor but does not induce receptor dimerization or Jak/Stat signaling. Adverse Effects: No negative feedback at the pituitary or hypothalamus: May endogenous GH levels. May also see excessive tumor growth. Contraindications: IV therapy, breast feeding,DOPAMINE-RECEPTOR AGONISTS (see Prolactine section)- Bromocriptine (Parlodel) Cabergoline. (DOSTINEX) Long-acting oral agonist Paradoxically reduce GH secretion from pituitary tumorsSide effects: nausea and hypotension Contraindications: Patients with hypertensivedisorders of pregnancy (preeclampsia, eclampsia),Posterior pituitary hormones (1),Vasopressin/Antidiuretic hormone (ADH)Produced by SON and PVN magnocellular neuronsConserves water - concentrates urine Water reabsorption by collecting tubuleDeficiency: diabetes insipidusExtreme thirst and polyuria plasma sodium and osmolalityExcess: inappropriate ADH “water intoxication” (SIADH),Vasopressin Receptors: Location & Functions,Diseases Affecting the Vasopressin System,AVP hyposecretion:Diabetes insipidus: large volume of diluted urineCentral DI: insufficient secretion (trauma HP axis, idiopathic)Rx: Desmopressin: increase urine osmolality (test vs. NDI)Chlorpropamide (oral sulfonylurea): potentiates low AVPCarbamazepine and clofibrate (rarely): reduce polyuriaNephrogenic DI: insufficient response (congenital or acquired)Many forms are drud-related: lithiumX-linked NDI: mutation V2 receptor geneAutosomal recessive and dominant NDI: mutation aquaporin 2Rx: Amiloride: blocks uptake of Lithium Thiazide: non-lithium related DI: reduce polyuria Indomethacin: (?) decrease PG and enhance AVP effects,Diseases Affecting the Vasopressin System,AVP hypersecretion:SIADH: impaired H2O excretion, hyponatremia, hypo-osmolalityCauses: malignancies, lung/CNS diseasesPsychotropic , sulfonylureas, vinca alkaloids: Drug-induced SIADHRx: water restriction, hypertonic saline, loop diureticsDemeclocycline: inhibit AVP action in collecting ductsLithium: mild efficacy, irreversible damages (chronic), low TIOther water retaining states: Congestive HF, cirrhosis, nephrotic syndrome: hypovolemia hypovolemiaAVP releasehyponatremia Need for orally active V2 receptor antagonists,Posterior pituitary hormones (2),OxytocinIn the periphery:Milk let-downUterine contractionSexual intercourse (orgasm ?)In the brain:Sexual arousalBondingvarious behaviors, including social recognition,bonding, anxiety, trust, and maternal behaviors.,Stretch,Induction of labor oxytocin (PITOCIN,) is treatment of choice to induce labor. Due to short half-life it is given as IV drip -(start at 2-10 mU/min then increase up