Handout pituitary Jan 2020.pdf

1/21/20 Disorders of the Learning objectives Hypothalamus A...

1/21/20 Disorders of the Learning objectives Hypothalamus At the end of the lecture, the student should be able to: and the 1. Review the anatomy, development and physiology of the pituitary gland Pituitary Gland 2. Describe the synthesis, secretion, and action of the different anterior and posterior pituitary hormones 3. Organize the various etiologies of hypopituitarism 4. Apply the approach a patient presenting with a sellar mass 5. Identify and diagnose patients with disorders of growth and Anna Angelica Macalalad-Josue, MD, FPCP development IM-Endocrinologist a. Adult GH deficiency b. Acromegaly and gigantism Medicine 2 6. Illustrate the approach to patients with hyperprolactinemia and prolactinoma 7. Demonstrate how to work up a patient with non-functioning pituiary adenoma 8. Discuss disorders of the neurohypophysis – diabetes insipidus, hypodipsic hypernatremia, SIADH Pituitary Gland Cushing’s disease (ACTH producing adenoma)- “master gland” to be discussed under adrenal TSH secreting adenoma – to be discussed under thyroid The anterior and posterior lobes of the pituitary gland and about 1 centimeter in diameter 0.5 to 1 gram in weight adenohypophysis neurohypophysis Taken as the name for the gland because it was from neural tissue believed that it channeled mucus to the nose outgrowth from the from Rathke’s pouch hypothalamus 1  1/21/20 Hypothalamic- Pituitary-(organ) axis Pituitary gland – “Master” gland – Most of the pituitary hormones control other endocrine glands Hypothalamic hormones regulate anterior pituitary Pituitary axes trophic hormones that in turn determine target gland secretion. Peripheral hormones feed back to regulate hypothalamic and pituitary hormones. ANTERIOR PITUITARY HORMONES 2  1/21/20 PROLACTIN PROLACTIN Secretion Action Pulsatile (4-14 secretory pulses q24h) PRL receptor: cytokine receptor family – Highest secretion during REM sleep – Peak : 4am-6am – Lowest: 10am-12nn* – Half life: 50 min (26-47 mins*) Levels decline with age Unique: predominant central control mechanism is INHIBITORY: dopamine tonic induce and maintain decrease reproductive suppress sexual drive/libido suppression of PRL release lactation function (fertility) – Dopamine binds to D2 receptors on lactotrophs Ensure maternal lactation is sustained and not interrupted by pregnancy PRL àé tyrosine hydroxylase à édopamine synthesis à êPRL Inhibit GnRH and LH secretion, impair gonadal steroidogenesis GROWTH HORMONE GROWTH HORMONE Secretion Secretion GHRH – stimulate GH most abundant anterior Ghrelin – stimulate GHRH and GH pituitary hormone Somatostatin [SST] (Somatostatin-release inhibitory Somatostatin (SST or SRIF) factor [SRIF])- inhibits GH – binds to SSTR2 and IGF1- feedbacks to inhibit GH Estrogen – induces GH SSTR5 suppresses GH Glucocorticoids - suppresses GROWTH HORMONE GROWTH HORMONE Secretion Action Pulsatile, highest peak at night with sleep onset Decline with age, parallel to decline in lean muscle mass Reduced in obesity Elevated by: Promotes sodium, potassium, and water retention and – Sleep elevates inorganic phos – Physical stress impairs glucose tolerance by antagonizing insulin action – Trauma – Sepsis – Chronic malnutrition – Prolonged fasting – Beta blockade – α-adrenergic – Dopamine – arginine Linear bone growth 3  1/21/20 Insulin-like growth factors (IGF) ADRENOCORTICOTROPIC HORMONE Physiologic effects Synthesis Corticotroph cells – 20% of the pit cell pop potent growth and differentiation hormone Proopiomelanocortin (POMC) - precursor of Liver – – ACTH β-lipotropin, β-endorphin, éduring puberty, peak 16y/o, decline with – met-enkephalin, – α-melanocyte-stimulating hormone (α-MSH), and age – corticotropin-like intermediate lobe protein (CLIP) Higher in women POMC gene êby glucocorticoid Low with cachexia, malnutrition, and sepsis éby corticotropin releasing hormone (CRH) and Arginine vasopressin (AVP) ADRENOCORTICOTROPIC HORMONE ADRENOCORTICOTROPIC HORMONE Synthesis Synthesis Pulsatile, exhibits a characteristic circadian rhythm peak 6am, nadir midnight é by stress, exercise, acute illness, insulin- induced hypoglycemia Glucocorticoids – negative feedback to ACTH through CRH suppression and POMC gene expression, and release Acute inflammatory or septic insults ADRENOCORTICOTROPIC HORMONE GONADOTROPINS: FSH AND LH Action Synthesis and Secretion HPA axis LH and FSH (like TSH and βHCG) are glycoprotein – maintain metabolic homeostasis and mediate the hormones – α (common to all) and β (unique) neuroendocrine stress response. subunits ACTH – adrenocortical steroidogenesis by sustaining adrenal cell Pulsatile action of GnRH is essential to its action proliferation and function. melanocortin-2 receptor – GPCR – receptor for ACTH 4  1/21/20 GONADOTROPINS: FSH AND LH GONADOTROPINS: FSH AND LH Synthesis and Secretion Action Long acting GnRH agonist- suppress Evokes germ cell development gonadotropins in kids with and maturation, and steroid hormone biosynthesis precocious puberty or men with FSH – ovarian follicle devt and prostate ca ovarian estrogen production Chronic estrogen – inhibitory LH – Leydig cell testosterone Rising estrogen (preovulatory)– synthesis and secretion positive feedback to LH, FSH FSH seminiferous tubule development and regulates Activin – selectively stimulates FSH spermatogenesis Inhibin - selectively inhibits FSH THYROID-STIMULATING HORMONE Synthesis and Secretion 5% of ant. Pituitary cell population TRH – stimulates TSH and PRL Dopamine, SST, glucocorticoids – suppress TSH Hypopituitarism Hypopituitarism Etiology (Table 402-1) Etiology (Table 402-1) Development/structural Development/structural Kallmann syndrome Bardet Beidl syndrome Traumatic Traumatic Leptin and leptin receptor Neoplastic Neoplastic mutations Prader Willi syndrome Infiltrative/inflammatory Infiltrative/inflammatory Vascular Vascular Infections Infections 5  1/21/20 Kallmann syndrome failure of GnRH neurons to migrate properly Migration of the GnRH releasing neurons from the olfactory placode to the hypothalamus. Also listed are the genes which have an influence at each stage of the migration. Hypogonadotropic Hypogonadism sec to Kallman syndrome Kallmann syndrome 15/M Ø undescended testes, but after X-linked form administration of 10,000 U of human chorionic gonadotropin – deficiency of KAL1 gene, for anosmin (hCG), the testes descended and were palpable in the scrotum. Autosomal dominant form Ø His height was 163.9 cm (+1.5 SD [standard deviation]); – mutation in FGFR1 gene Ø Eunuchoid Ø LH was less than 0.3 ng/mL; Long-term treatment Ø FSH 1.2 ng/mL; Ø testosterone level 16 ng/dL. – Males: hCG and Ø After 100 μg of GnRH, Ø plasma LH level (LER-960) was testosteroneàpuberty 0.7 ng/mL Ø FSH level (LER-869) was 2.4 – Females: cyclic estrogen and ng/mL progestin Ø From Styne DM, Grumbach MM. – Fertility: pulsatile GnRH Puberty in the male and female: its physiology and disorders. In: Yen (portable infusion pump) SCC, Jaffe RB, eds. Reproductive Endocrinology, 2nd ed. Philadelphia, PA: WB Saunders; 1986: 313-384.) Prader Willi Prader-Willi syndrome syndrome lack of expression of genes on the paternally inherited chromosome 15q11.2- q13 region hypogonadotropic hypogonadism, a Obesity, almond shape eyes, down-turned mouth hyperphagia-obesity (food seeking with and straight borders of inner excessive weight gain) legs. b Straight borders of ulnar side of hands and scares chronic muscle hypotonia, mental from skin picking. c Active and healing skin lesions on retardation, and adult-onset diabetes scalp mellitus 6  1/21/20 ACQUIRED HYPOPITUITARISM ACQUIRED HYPOPITUITARISM Acquired cause Hypothalamic Infiltration Disorders Hypothalamic sarcoidosis, histiocytosis X, amyloidosis, and Inflammatory Lesions Infiltration Disorders hemochromatosis; DI is the most common presenting symptom Cranial Irradiation Hypogonadotropic hypogonadism with hyperPRL Inflammatory Lesions TB, opportunistic fungal infections assoc with AIDs, tertiary Lymphocytic Hypophysitis syphilis Granulomatous conditions, sarcoidosis Pituitary Apoplexy Cranial Irradiation Hormone insufficiency correlates with radiation dose Hypopituitarism occurs over 5-15 years Empty Sella GH> LH/FSH>TSH>ACTH Lymphocytic postpartum; Hypophysitis Presents with hyperPRL and a pituitary mass sequential order of hormone loss is usually Diffuse lymphocytic infiltration of the pituitary Tx. Several months of glucocorticoid treatment GH → FSH/LH → TSH → ACTH. Enhanced axial and coronal T1-weighted MRI of a typical ACQUIRED HYPOPITUITARISM large pituitary tumor with a "snowman" configuration (coronal) and marked enhancement with contrast. This tumor has not undergone Pituitary Apoplexy -Acute intrapituitary hemorrhagic vascular event apoplexy. -may occur spontaneously in a preexisting adenoma; postpartum (Sheehan’s syndrome); or in association with diabetes, hypertension, sickle cell anemia, or acute shock -an endocrine emergency that may result in severe hypoglycemia, hypotension and shock, CNS hemorrhage, and PITUITARY APOPLEXY Enhanced T1-weighted axial death and coronal MRI showing a -Severe headache with signs of meningeal irritation, bilateral large pituitary tumor that has visual changes, ophthalmoplegia, and, in severe cases, recently undergone ischemic cardiovascular collapse and loss of consciousness apoplexy showing a necrotic Empty Sella -often an incidental MRI finding, (hypointense) center and ring of gadolinium enhancement -usually have normal pituitary function, implying that the (hyperintense), ie, the surrounding rim of pituitary tissue is fully functional "pituitary ring sign." There is -Hypopituitarismmay develop insidiously a small area of hemorrhagic blush in the center of the necrosis. Hormone Replacement Learning objectives Therapy for Adult At the end of the lecture, the student should be able to: 1. Review the anatomy, development and physiology of the pituitary Hypopituitarism gland (Table 402-3) 2. Describe the synthesis, secretion, and action of the different anterior and posterior pituitary hormones 3. Organize the various etiologies of hypopituitarism 4. Apply the approach a patient presenting with a sellar mass 5. Identify and diagnose patients with disorders of growth and development a. Adult GH deficiency b. Acromegaly and gigantism 6. Illustrate the approach to patients with hyperprolactinemia and prolactinoma 7. Demonstrate how to work up a patient with non-functioning pituiary adenoma 8. Discuss disorders of the neurohypophysis – diabetes insipidus, hypodipsic hypernatremia, SIADH 7  1/21/20 Hypothalamus Optic chiasm HYPOTHALAMIC, Pituitary Temperature dysregulation Loss of red perception Hypogonadism Appetite and thirst disorders Bitemporal hemianopia Hypothyroidism Superior or bitemporal PITUITARY, AND Obesity Growth failure; Diabetes insipidus field defect Adult hyposomatotropism Sleep disorders Scotoma Hypoadrenalism OTHER SELLAR Behavioral dysfunction Autonomic dysfunction Blindness MASSES Cavernous sinus Ophthalmoplegia with or without ptosis or diplopia Facial numbness Brain Loss of red perception Bitemporal hemianopia Superior or bitemporal field defect Frontal lobe Scotoma Personality disorder Blindness Anosma EVALUATION OF SELLAR MASSES EVALUATION OF SELLAR MASSES MRI MRI – Pituitary macroadenoma Note the large enhancing mass in the region of the sella that is growing up into and displacing the optic chiasm and hypothalamus. Surgical resection demonstrated a large pituitary adenoma. T1-weighted with gadolinium sagittal (left) and coronal (right) MRI EVALUATION OF SELLAR MASSES EVALUATION OF SELLAR MASSES Ophthalmologic Evaluation Laboratory investigation visual field assessment using perimetry techniques initial hormonal evaluation for a pituitary incidentaloma Early diagnosis reduces the risk of optic atrophy, vision 1. basal prolactin (PRL) loss, or eye misalignment 2. insulin-like growth factor (IGF) I 3. 24-h urinary free cortisol (UFC) and/or overnight oral dexamethasone (1 mg) suppression test 4. FSH, LH 5. thyroid function tests –TSH, FT4 8  1/21/20 EVALUATION OF SELLAR MASSES EVALUATION OF SELLAR MASSES Treatment – Transsphenoidal surgery Treatment – Radiation Indications: – Correction of hormonal Adjunct to surgery of medical therapy secretion (except prolactinoma) relatively slow onset of action, hence is – mass lesions that impinge on surrounding structures usually reserved for postsurgical – expanding pituitary mass management: treat residual tumor accompanied by persistent headache, progressive Highest rate of pituitary hormone – visual field defects, cranial insufficiency that develops 5-10 years after nerve palsies, hydrocephalus, and, – occasionally, intrapituitary hemorrhage and apoplexy optimal balance between maximal tumor resection and preservation of anterior pituitary function SELLAR MASSES Hypothalamic lesions Craniopharyngiomas – benign suprasellar cystic masses; from Rathke’s pouch; common in the young 6 – Extremely high PRL concentration may saturate their months after ability to detect very high PRL levels childbirth or MRI discontinuation of – should be done in all patients with HyperPRL – Prolactinoma or a sellar mass (causing a “stalk effect”) can breast-feeding 50 y/o postmenopausal woman with galactorrhea co-exist with other causes of hyperPRL with hx of herpes zoster 12 mo prior Atrophic hypopigmented scars right side, T4 dermatome 10  1/21/20 Discontinue drug x 3d Thyroid/Steroid hormone PROLACTINOMA or switch (olanzapine, replacement aripirprazole) If PRL do not normalize after D/Cà do an MRI Etiology and Prevalence to r/o a prolactinoma Asymptomatic but with long term Female:male ratio Treatment hypogonadism – replace with estrogen – 20:1 for microprolactinoma; or testosterone GOAL: normalize PRL levels alleviate suppressive – 1:1 macroprolactinoma effects on gonadal function, halt galactorrhea, Renal Mixed tumors (co-secreting tumors) preserve bone mineral density. transplantation – GH+PRL, ACTH+PRL, TSH+PRL (rare) Classification by size: Prolactinoma: Dopamine – Microadenoma 1cm, usually invasive Mass or Adenoma – surgery Granulomatous or – Giant >4cm hypophysitis - steroids PROLACTINOMA PROLACTINOMA Signs and Symptoms Treatment Asymptomatic and Fertility not desired: No Tx Monitor PRL and MRI 11  1/21/20 PROLACTINOMA PROLACTINOMA Treatment - Medical Treatment – Medical : Dopamine Agonists Dopamine agonist (DA) therapy CABERGOLINE BROMOCRIPTINE – lower prolactin levels Long acting; High D2 receptor Short acting, preferred affinity when pregnancy is desired – decrease tumor size (improve mass effects) 0.5-1mg 1-2x weekly Start low, 0.625–1.25 mg – Restore gonadal function for patients Preferred because of higher efficacy at bedtime with a snack harboring symptomatic prolactin-secreting May be effective in patients the gradually increase microadenomas or macroadenomas resistant to bromocriptine Side effects of Dopamine Agonists: If achieved, may be withdrawn after 2 years, then Less adverse effects and drug intolerance Constipation, nasal stuffiness, dry monitor carefully for recurrence mouth, nightmares, insomnia, vertigo More expensive, less Nausea, vomiting accessible (in the Phils) Reduced dose Intravaginal administration of bromo Gadolinium-enhanced MRI (sagittal view) showing a 40 mm pituitary macroprolactinoma in a 41-year-old man before (A) and PROLACTINOMA after (B) 2-month treatment with cabergoline Treatment – Surgery and Radiotherapy Surgery Indications: – Dopamine resistance (max doses, no tumor shrinkage >50%, no restoration of fertility) or intolerance – presence of an invasive macroadenoma with compromised vision that fails to improve after drug treatment – Malignant prolactinoma Radiotherapy: – aggressive tumors that do not respond to maximally tolerated dopamine agonists and/or surgery, malignant prolactinoma 12  1/21/20 PITUITARY DWARFISM PITUITARY DWARFISM (Growth Failure) Etiology it is the disease caused by decreased secretion of Congenital deficiency of GH - Genetic disorders GH by pituitary gland or decreased sensitivity of - Defect of pituitary gland development (aplasia, hypoplasia) peripheral tissues to this hormone and leads to Acquired deficiency of GH growth retardation. - trauma, neoplasms (craniopharyngioma), infection Peripheral resistance for GH - Pathology of GH receptors (Laron’s syndrome) - Biologically inactive GH No demonstratable etiology (idiopathic hypopituitarism) (The latter is more frequent in males than in females) Clinical manifestations. The height of adult men is less than 130 cm, and adult women is less than 120 cm. 1. Child is born with normal weight and height. 2. Growth retardation can be observed since 3 – 4 years (the increasing of the height is not more than 1 cm per year). 3. The patient, despite small size, has normal body proportions. 4. Mental develoment is normal. 5. Secondary hypothyroidism. 6. Secondary adrenal insufficiency. 7. Puberty will not appear because of a lack of gonadotropic hormons (secondary hypogonadism). 8. The passport age is not corresponding with biologic age. Jyoti Amge's, 15 y.o., 9. In patients with isolated GH deficiency the patients born December 16, 1993 have normal pituitary function (other than lack og a resident of Nagpur, India GH), undergo normal puberty, and have normal reproductive capacity ADULT GH DEFICIENCY (AGHD) Presentation and Diagnosis acquired hypothalamic or pituitary somatotrope damage Clinical features: – Impaired quality of life – Body composition changes – Reduced exercise capacity – Cardiovascular risk factors Increased body fat mass Central fat deposition Born Karl Kosiczky on September 21 1918 in Prakendorf, Hungary (now in Slovakia), he Increased waist-to-hip ratio stopped growing at the age of four and was diagnosed with pituitary dwarfism. Karl Slover, Decreased lean body mass who has died aged 93, was a member of the "Singer Midgets" vaudeville troupe and played several roles as a Munchkin in the 1939 film classic The Wizard of Oz. 13  1/21/20 ADULT GH DEFICIENCY (AGHD) ADULT GH DEFICIENCY(AGHD) Imaging and Laboratory Treatment Imaging and PE Laboratory – Pituitary: mass or structural Evoked GH