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Hypothalamic-Pituitary Axes

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Hypothalamic-Pituitary Axes Hypothalamic Factors Releasing/Inhibiting Pituitary Anterior Pituitary Hormones Circulating ACTH PRL GH Hormones February 11, 2008 LH FSH TSH Posterior Target Pituitary Gland and Hormones Tissue Effects ADH, oxytocin The GH/IGF-I Axis Growth Hormone Somatostatin GHRH Hypothalamus • Synthesized in the anterior lobe of the pituitary gland in somatotroph cells PITUITARY • ~75% of GH in the pituitary and in circulation is Ghrelin 191 amino acid single chain peptide, 2 intra-molecular disulfide bonds GH Weight; 22kD • Amount of GH secreted: IGF-I Women: 500 µg/m2/day Synthesis IGF- I Men: 350 µg/m2/day LIVER Local IGF-I Synthesis CIRCULATION GH Secretion: Primarily Pulsatile Pattern of GH Secretion Regulation by two hypothalamic in a Healthy Adult hormones 25 Sleep 20 Growth - SMS Hormone 15 Somatostatin Releasing GHRH + GH (µg/L) Hormone Inhibitory of 10 Stimulatory of GH Secretion GH Secretion 05 0 GHRH induces GH Somatostatin: Decreases to allow 0900 2100 0900 synthesis and secretion Clocktime GH secretory in somatotrophs Bursts GH From: “Acromegaly” by Alan G. Harris, M.D. 1 Other Physiological Regulators of GH Secretion Pharmacologic Agents Used to Stimulate GH Secretion Amino Sleep Exercise Stress Acids Fasting Glucose Stimulate hypothalamic GHRH or Inhibit Somatostatin Hypothalamus GHRH SMS Hypoglycemia(Insulin) Pituitary L-dopa Arginine Clonidine GHRH + - SMS Pyridostigmine GH Target Tissues Metabolic & Growth Promoting GH Effects IGF-I Insulin-like growth factor I (IGF-I) Major Determinants of Circulating IGF-I Levels • Growth Hormone • 70 amino acid polypeptide Increases IGF-I production in liver, major source of • Produced predominantly in the liver circulating IGF-I • Endocrine and autocrine/paracrine actions • Nutritional Status • Mediates major anabolic and growth-promoting • Age effects of GH • Genetic Factors • Insulin-like effect, independent of GH • Binding proteins • Does not mediate the lipolytic effects of GH • Increased levels in pregnancy and puberty GH & IGF-I Actions GH Secretion & IGF-I Levels Across Lifespan Hypothalamus GHRH SMS GH secretion Anterior Pituitary GH IGF-I levels Bone Fat Muscle Liver Target Tissues IGFBP-1 IGFBP-2 Prepubertal Pubertal Adult <35 yr Adult >35 yr IGFBP-3 IGFBP-4 IGFBP-5 IGFBP-6 IGF-I •GH secretion declines with age Metabolic Anabolism •Serum IGF-I levels also decline with age. Effects Growth 2 Disorders of GH Secretion GH/IGF-I Axis Acromegaly Somatostatin(-) GHRH (+) • GH Excess: GH overproduction by a GH Secreting pituitary tumor - ACROMEGALY PITUITARY GH GH • GH Deficiency: Childhood onset IGF- I Adult onset IGF-I Synthesis IGF- I LIVER Local IGF-I Synthesis CIRCULATION Prevalence of Clinical Features at Biochemical Diagnosis of Acromegaly Diagnosis Acral enlargement and/or coarse features Growth Hormone Sweating Random GH Levels Menstrual Disorders Headache GH Suppression after Oral Glucose: Arthritis Failure of GH to Fall < 1 µg/L Carpal tunnel syndrome Diabetes or impaired glucose intolerance Impaired potency and/or libido Serum IGF-I Level: Hypertension Visual field defect Elevated above age-adjusted normal range Obstructive sleep apnea Galactorrhea Coronary artery disease 0 20 40 60 80 100 Clemmons DR, et al. J Clin Endocrinol Metab. 2003;88:4759-4767. Enlargement of Hands and Feet Current Therapies for Acromegaly Hypertension and heart disease • Primary therapy • Transsphenoidal surgery Headache • Medical therapy Acromegaly Sleep • Adjunctive therapy apnea • Medical therapy • Dopamine agonists • Somatostatin analogs • GH receptor antagonist • Radiotherapy (+ Interim medical therapy) Arthritis Impaired glucose tolerance 3 Targets of the GH/IGF-I Pathway for Medical Role of Surgery for Acromegaly Therapy of GH Producing Pituitary Tumor Somatostatin GHRH – + Somatostatin Analogs (SA) First Line Therapy in Nearly All patients: • Directly inhibit GH secretion GH- Dopamine Agonists (DA) secreting tumor • Potential for cure • Directly inhibit GH secretion • Leads to immediate decline in GH level X GH • Reduces tumor size and relieves mass effect GHR Growth Hormone Receptor IGF-I X antagonist • Surgical complication rate is low (GHR) Antagonist X (pegvisomant) Increased • Blocks the GH receptor, somatic growth negating effects of GH in & metabolic periphery dysfunction • Directly inhibits IGF-I secretion Somatostatin Analogs: Clinical Use Pegvisomant • GH molecule that has been D nal cys tyr mutated to function as a D receptor antagonist trp ala gly cys lys asn phe Lanreotide • GH Receptors are blocked. phe lys • GH does not fall, but GH trp val actions are blocked. Somatostatin-14 Thr cys GH • IGF-I levels fall and clinical lys symptoms of thr D acromegaly improve cys ser thr phe phe cys phe D trp Functional Octreotide GHR lys IGF-I Dimerization Amino acids common to Thr Is Prevented cys thr native hormone & analog. ol Levels Fall Goals of Therapy Etiologies of Clinical Syndromes of Growth Hormone Deficiency Hypothalamic Disease: • Biochemical control GHRH Deficiency GH suppression IGF-I normalization Pituitary Disease: Failure to Secrete GH • Relieve signs and symptoms GH • Reduce tumor size & mass effect Failure to generate IGF-I peripherally • Preserve pituitary function Liver & • Deficiencies of GH or IGF-I Other receptors in liver; IGF-I not • Minimal side effects Tissue produced; GH resistance, GH not low. IGF-I 4 Clinical Consequences of Adult Etiologies of Adult Onset of GH Deficiency Onset GH Deficiency Cause N=1034 Percent • Increased cholesterol and increased levels of some Pituitary tumor 53.9 cardiovascular risk markers eg. CRP. Craniopharyngioma 12.3 • Abnormal body composition; increased central body fat. Idiopathic 10.2 CNS tumor 4.4 • Decreased bone density Empty sella syndrome 4.2 • Decreased quality of life Sheehan’s syndrome 3.1 Head trauma 2.4 Therapy of GH Deficiency: Hypophysitis 1.6 • Requires daily subcutaneous injections of human growth Surgery other than for pituitary treatment 1.5 hormone. (Some newer formulations may be longer acting) Granulomatous diseases 1.3 • Effect in GH deficient adults; Modest improvements in the effects of GH deficiency listed above. Irradiation other than for pituitary treatment 1.1 Other 4.0 Abs R, et al. Clin Endocrinol (Oxf) 1999;50:703-713. Regulation of Prolactin Secretion Hyperprolactinemia Stimulated by: Suppressed by: • Defined as excess serum prolactin: Prolactin >20 µg/L in men or >25 µg/L in women • Sleep • Dopamine • Food Hypothalamus Under • Most common endocrine disorder of the • Stress hypothalamic-pituitary axis • Pregnancy Tonic Inhibition • Nursing • Prevalence: 0.4% in unselected normal adult • Breast population stimulation • Many different etiologies • Prolactinomas are the most frequent cause of hyperprolactinemia Pathological Causes of Hyperprolactinemia Pharmacologic Causes of Hyperprolactinemia • Antihypertensives • Antipsychotics Pituitary/Hypothalamic Other Causes • Phenothiazines • Verapamil Disorders • Primary hypothyroidism • Butyrophenones • Methydopa • Prolactinoma • Seizures • Atypicals • Reserpine • Antidepressants • Acromegaly • Polycystic ovary disease • GI Medications • Tricyclics • Other sellar masses • Neurogenic causes • MAO inhibitors • Chlorpromazine • Infiltrative disorders (chest wall trauma or • SSRIs • Metoclopramide • Hypothalamic and pituitary surgery, herpes zoster) • Other stalk disease or damage • Renal insufficiency • Domperidone • Cocaine • Opiates • Cirrhosis • H2 blockers? • Protease Inhibitors? • Medications 5 Clinical Manifestations of Hyperprolactinemia Treatment of Hyperprolactinemia Hyperprolactinemia: Suppresses gonadotropins • Dopamine agonist therapy is primary treatment for - leads to varying degrees of gonadal dysfunction. almost all patients • Surgery and radiation therapy ocassionally used Women Men • Careful follow-up without treatment is an option for patients • Oligo-amenorrhea • Decreased libido if they • Infertility • Erectile dysfunction • do not have a macroadenoma • Galactorrhea • Gynecomastia • are asymptomatic • Estrogen deficiency • Galactorrhea • have normal gonadal function • Acne/hirsuitism • Infertility • are not seeking fertility • Osteopenia • Osteopenia Dopamine Agonists used to treat Hyperprolactinemia: Treatment Goals Hyperprolactinemia/Prolactinomas • Restore gonadal function • Bromocriptine • Improvement in sexual dysfunction • Fertility • Cabergoline • Resolve galactorrhea (if bothersome) • Reduce/stabilize tumor size • Reverse mass effects • Preserve/restore pituitary function • Normalize PRL level Pituitary Tumors Evaluation of the Patient for Pituitary Disease Nearly All Benign • History and Physical examination Can be: Non-secreting • Laboratory: Pituitary hormone overproduction and Hormone Secreting hypopituitarism Prolactin Growth Hormone • Prolactin ACTH- Cushing’s • Free T4, TSH TSH, LH, FSH • Cortisol, ACTH Cause Disease: • GH, IGF-I Problems related to: Excess hormone • LH, FSH, testosterone Pressure of tumor on: optic nerves, other surrounding • Pregnancy test • MRI Or normal pituitary - pituitary insufficiency • Visual fields 6.
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