Hypopituitarism
- 1. HYPOPITUITARISM GUIDE – DR. RAJESH VERMA CANDIDATE – DR. ROHIT MEHTANI
- 2. INTRODUCTION • It is a clinical syndrome of deficiency in pituitary hormone production and secretion. • Panhypopituitarism refers to involvement of all pituitary hormones; however, it is rare. • It may result from disorders involving the pituitary gland, hypothalamus or surrounding structures.
- 3. ANATOMY
- 5. ETIOLOGY • DEVELOPMENTAL/STRUCT URAL – Transcription factor defect – Pituitary dysplasia/aplasia – Congenital Central nervous system mass/encephalocele – Primary empty sella – Congenital hypothalamic disorders • TRAUMATIC – Surgical Resection – Radiation damage – Head injuries • NEOPLASTIC – Pituitary adenoma – Parasellar mass (germinoma, ependymoma, glioma, meningioma, Rathke’s Cyst) – Craniopharyngioma – Hypothalamic hamartoma, gangliocytoma – Pituitary metastases – Lymphoma and leukemia
- 6. ETIOLOGY • INFILTRATIVE/INFLAM MATORY – Primary hypophysitis • Lymphocytic • Granulomatous • Xanthomatous – Secondary Hypohysitis • Sarcoidosis • Histiocytosis X • Infections • Wegener’s granulomatosis • Takayasu’s disease – Hemochromatosis – Transcription factor antibodies • VASCULAR – Pituitary Apoplexy – Pregnancy related – Sickle cell Disease – Arteritis – Aneurysm – Diabetes • INFECTIONS – Fungal (histoplasmosis, aspergillosis) – Parasitic (Toxoplasmosis) – Tuberculosis – Pneumocystis carinii – Viral (CMV)
- 7. ETIOLOGY • FUNCTIONAL – Nutritional – Caloric restriction – Critical illness – Acute illness, CRF, CLD – Drugs – Anabolic Steroids, Estrogen, Dopamine, Thyroxin, GnRH agonists
- 8. CLINICAL FEATURES • Mass lesions - – Space occupying lesions result in headache, visual disturbances and rarely, personality changes, temporal lobe epilepsy, and CSF rhinorrhoea. – Actively secreting tumors can produce a complex picture of combined hormonal excess and deficiency
- 9. Mass lesions
- 10. CLINICAL FEATURES • Growth hormone –Reduced energy and vitality –Reduced muscle mass and strength –Increased central adiposity –Decreased sweating and impaired thermogenesis –Reduced bone mineral density (BMD)
- 11. CLINICAL FEATURES • Adrenocorticotrophic hormone –Fatigue, weakness, anorexia, weight loss, nausea, vomiting, abdominal pain, hypoglycaemia, circulatory collapse; loss of axillary/pubic hair in women
- 12. CLINICAL FEATURES • Gonadotrophins – Men: erectile dysfunction, reduced muscle mass, erythropoiesis, reduced energy and vitality – Women: oligomenorrhoea/amenorrhoea, dyspareunia, breast atrophy – Both: loss of libido, flushes, infertility, regression of sexual characteristics, reduced BMD.
- 13. CLINICAL FEATURES • Thyroid stimulating hormone –Fatigue, apathy, cold intolerance, constipation, weight gain, dry skin, psychomotor retardation. • Antidiuretic hormone –Polyuria, polydipsia, nocturia. • Prolactin –Lactational failure
- 14. • Excessive mortality rates due to cardiovascular disease • Order of diminished trophic hormone reserve function by pituitary compression is usually :- – GH>FSH>LH>TSH>ACTH
- 15. INHERITED PITUITARY DEFICIENCY MUTATION HORMONE DEFICIT Genetic Kallmann’s Syndrome FSH, LH Prader-Willi Syndrome FSH, LH Lawrence-Moon-Biedl Syndrome FSH, LH Receptor GHRH receptor GH CRH receptor ACTH GnRH receptor FSH, LH GPR54 LH, FSH TRH Receptor TSH Leptin receptor LH,FSH Structural Pituitary Aplasia Any Pituitary Hypoplasia Any CNS masses, Encephalocele Any
- 16. INHERITED PITUITARY DEFICIENCY Transcription Factor Defect PITX2 PROP1 GH, PRL, TSH, LH, FSH, +/- ACTH POU1F1(PIT1) PRL, GH, TSH HESX1 GH, PRL, TSH, LH, FSH, ACTH LHX3/4 GH, PRL, TSH, LH, FSH NR0B1 ADRENAL, LH, FSH TBXI9 (TPIT) ACTH Hormone Mutation GH GH FSHβ FSH LHβ LH POMC ACTH TSHβ TSH Leptin LH, FSH Kisspeptin LH,FSH
- 17. POU1F1
- 18. LYMPHOCYTIC HYPOPHYSITIS • Presumed to be autoimmune • Clinical Presentation – Women, during postpartum period – Hyperprolactinemia is seen – Symptoms of Mass effect with headache & visual disturbance – ESR is usually raised
- 19. LYMPHOCYTIC HYPOPHYSITIS • Deficiency of one or more anterior pituitary hormones – Diabetes insipidus • Diagnosis – MRI - may be indistinguishable from pituitary adenoma • Treatment – Corticosteroids – Hormone replacement
- 21. PITUITARY APOPLEXY • Hemorrhagic infarction of a pituitary adenoma/tumor • Considered a neurosurgical emergency • Presentation: – Hypoglycemia – Hypotension & shock – CNS hemorrhage – Severe headache – Meningismus – Visual changes – ophthalmoplegia
- 22. PITUITARY APOPLEXY • Risk factors: – Diabetes – Radiation treatment – Warfarin use • Symptoms may occur immediately or may develop over 1-2 days • Diagnose with CT/MRI • Treatment: – Surgical – Trans-sphenoid decompression – Medical therapy – if symptoms are mild • Corticosteroids
- 24. SHEEHAN’S SYNDROME • Named after British Pathologist, Harold Leeming Sheehan, who described specific association with PPH • Ischemic pituitary necrosis after substantial blood loss during childbirth
- 25. SHEEHAN’S SYNDROME • No correlation between severity of hemorrhage and symptoms • Recognised days to weeks post-partum – Secondary hypothyroidism – Lactational Failure – Secondary Adrenal insufficiency - Lethargy, anorexia, weight loss – Typically long interval between obstetric event and diagnosis
- 26. HEAD TRAUMA • Partially or totally damaged by birth trauma, cranial hemorhhage, fetal asphyxia, or breech delivery • Head trauma may lead to sella turcica fracture, pituitary stalk section, trauma induced vasospasm, or ischemic infarction
- 27. HEAD TRAUMA • Most common traumatic cause is iatrogenic neurosurgical trauma • Transient or permanent diabetes insipidus and varying degrees of anterior pituitary dysfunction • Hypopituitarism usually manifests within a year after the insult
- 28. RADIATION INJURY • Causes atrophy of the pituitary gland along with damage to hypothalamic synthesis of hypophysiotropic hormones • Radiation dose exposure, time interval after completion of radiotherapy, & distance of pituitary from central energy field correlate with development of pituitary hormone deficits
- 29. RADIATION INJURY • Pattern of loss – GH>FSH/LH>ACTH>TSH • Previously irradiated patients should undergo lifelong periodic anterior pituitary hormone testing
- 30. EMPTY SELLA SYNDROME Often an incidental MRI finding
- 31. EMPTY SELLA SYNDROME • Usually have normal pituitary function – Implying that the surrounding rim of pituitary tissue is fully functional • Hypopituitarism may develop insidiously when >90% tissue is compressed.
- 32. EMPTY SELLA SYNDROME • Primary empty sella may develop as a consequence of congenital weakness of the diaphragm • Pituitary masses may undergo clinically silent infarction with secondary development of a partial or totally empty sella by cerebrospinal fluid (CSF) filling the dural herniation. • Rarely, functional pituitary adenomas may arise within the rim of pituitary tissue, and these are not always visible on MRI
- 34. DIAGNOSIS • Thorough clinical examination including visual field charting is essential • Simultaneous measurements of basal anterior pituitary and target organ hormone levels • Dynamic/provocative tests are necessary to assess GH secretory reserve and ACTH-adrenal axis
- 35. HORMONE TEST BLOOD SAMPLE INTERPRETATION Growth Hormone INSULIN TOLERANCE TEST – regular insulin(0.05-0.15 U/kg iv) GHRH TEST – 1 ug/kg iv L-ARGININE TEST – 30 g iv over 30 min L-DOPA TEST – 500 mg PO -30, 0, 30, 60, 120 min for glucose and GH 0, 15, 30, 45, 60, 120 min for GH 0, 30, 60, 120 min for GH 0, 30, 60, 120 min for GH Glucose<40, GH should be >3ug/dl Normal response is GH>3 ug/dl Normal response is GH>3 ug/dl Normal response is GH>3 ug/dl
- 36. HORMONE TEST BLOOD SAMPLE INTERPRETATION Prolactin TRH TEST – 200-500 ug iv 0, 20 and 60 min for TSH and PRL Normal PRL >2 ug/L and increase >200% of baseline TSH BASAL THYROID FUNCTION TESTS – T3, T4, TSH TRH TEST – 200-500 ug IV Basal measurements 0, 20, 60 min for TSH and PRL Low free thyroid hormone with normal/low TSH TSH should increase by >5 mIU/L unless thyroid hormone levels are increased
- 37. HORMONE TEST BLOOD SAMPLE INTERPRETATION ACTH INSULIN TOLERANCE TEST – regular insulin(0.05-0.15 U/kg iv) CRH TEST– 1 ug/kg iv at 8 AM METYRAPONE TEST– 30mg/kg at midnight STANDARD ACTH STIMULATION TEST – Cosyntropin 0.25 mg im or iv LOW DOSE ACTH TEST – 1 ug iv 3-DAY ACTH STIMULATION TEST – 0.25 mg cosyntropin iv over 8 h each day -30, 0, 30, 60, 120 min for glucose and cortisol 0, 15, 30, 45, 60, 90, 120 min for ACTH & cortisol Plasma 11- deoxycortisol and cortisol at 8 AM; ACTH can also be measured 0, 30, 60 min for cortisol and aldosterone 0, 30, 60 min for cortisol Glucose<40, Cortisol should increase by >7ug/dl or to >20 ug/dl Basal ACTH increases 2- to 4-fold & peaks at 20- 100 pg/ml. Cortisol >20- 25 ug/dl Plasma cortisol should be <4 ug/dl to assure an adequate response. Normal response is 11- deoxycortisol >7.5 ug/dl or ACTH >75 pg/ml Cortisol > 21 ug/dl & aldosterone > 4ng/dL above baseline Cortisol > 21 ug/dL Cortisol > 21 ug/dL
- 38. HORMONE TEST BLOOD SAMPLE INTERPRETATION LH, FSH LH, FSH, TESTOSTERONE, ESTROGEN GnRH TEST – 100 ug iv Basal measurements 0, 30, 60 min for LH & FSH Basal LH & FSH should be increased in postmenopausal women Low testosterone levels with low FSH & LH indicate pituitary insufficiency LH should increase by 10 IU/L and FSH by 2 IU/L Normal responses are variable Multiple hormones COMBINED ANTERIOR PITUITARY TESTS: GHRH (1ug/kg), CRH (1 ug/kg), GnRH (100 ug), TRH (200 ug) are given iv -30, 0, 15, 30, 60, 90, 120 min for GH, ACTH, cortisol, LH, FSH, and TSH Combined or individual releasing hormone responses must be elevated in the context of basal target gland hormone values
- 39. TREATMENT • Hormone replacement therapy • It should mimic physiological hormone production • Those with glucocorticoid replacement require dose adjustments during stressful events like acute illness, pregnancy, surgery, dental procedures, trauma, and acute hospitalization
- 40. TSH DEFICIENCY • Thyroxine is the treatment of choice. • ACTH deficiency should be treated if present before initiating thyroxine replacement. • TSH monitoring is unhelpful • Long term over treatment may result in AF & reduction in bone mineral density
- 41. GONADOTROPHIN DEFICIENCY MEN • Testosterone replacement has beneficial effects on body composition, sexual function, mood, behavior & BMD. • Treatment is contraindicated in patients with prostate cancer and male breast cancer
- 42. GONADOTROPHIN DEFICIENCY WOMEN • Oestrogen replacement alleviates symptoms of deficiency and is bone protective. • It is often given with cyclical/continuous progesterone.
- 43. GH DEFICIENCY • Human GH 0.2-0.3 mg s.c. is given daily, titrating the dose every 4-6 weeks • Side effects include headache, arthralgia, myalgia, fluid retention. • Absolute contraindications are active malignancy, benign intracranial hypertension and proliferative diabetic retinopathy
- 44. VASOPRESSIN DEFICIENCY • In mild Diabetes Insipidus, (urine output <4l/day), adequate oral fluid intake is sufficient • In severe forms desmopressin is the treatment of choice • Hyponatremia is a common side effect
- 45. ACTH DEFICIENCY • Hydrocortisone is the preferred agent • 2 to 3-fold increase in glucocorticoid dose is needed temporarily during intercurrent illness, surgery, etc.
- 46. TROPHIC HORMONE DEFICIT HORMONE REPLACEMENT ACTH Hydrocortisone (10-20 mg A.M. ; 5-10 mg P.M.) Cortisone acetate (25 mg A.M. ; 12.5 mg P.M.) Prednisone (5 mg A.M.) TSH L-Thyroxine (0.075-0.15 mg daily) FSH/LH MALES Testosterone enanthate (200 mg IM every 2 weeks) Testosterone skin patch (5 mg/day) FEMALES Conjugated estrogen (0.65-1.25 mg qd for 25 days) Progesterone (5-10 mg qd) on days 16-25 Estradiol skin patch (0.5 mg, every other day) FOR FERTILITY – menopausal gonadotropins, human chorionic gonadotropins GH ADULTS – Somatotropin (0.1-1.25 mg SC qd) CHILDREN – Somatotropin (0.02-0.05 mg/kg/day) VASOPRESSIN Intranasal Desmopressin (5-20 ug twice daily) Oral 300-600 ug qd
- 47. THANK YOU
Editor's Notes
- #15: GH – 50% ACTH – 10-30 PRL – 10-30% TSH – 5%
- #18: PROP1 mutations may be fully manifest only in adulthood. Seen in 30-50% of patients with combined pituitary insufficiency Hesx1/rpx – critical for corpus development and associated with structural brain defects POU1F1 – early growth failure with or without hypothyroidism Reiger Syndrome – Pitx2 mutation – normal or ectopic posterior pituitary
- #19: 49 kd cytosolic protein – 70% 68kd &43 kd membrane antigen – 30%