Hypopituitarism

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

4. PITUITARY AXES

5. ETIOLOGY DEVELOPMENTAL/STRUCTURAL 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 adenom a Parasellar mass ( germinoma , ependymoma , glioma , meningioma, Rathke’s Cyst) Craniopharyngioma Hypothalamic hamartoma , gangliocytoma Pituitary metastases Lymphoma and leukemia

6. ETIOLOGY INFILTRATIVE/INFLAMMATORY Primary hypophysitis Lymphocytic Granulomatous Xanthomatous Secondary Hypohysitis Sarcoidosis Histiocytosis X Infections Wegener’s granulomatosis Takayasu’s disease H emochromatosis 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

20. 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

21. 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

22. Pituitary Apoplexy Radiology

23. 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

24. SHEEHAN’S SYNDROME No correlation between severity of hemorrhage and symptoms R ecognised days to weeks post- partum S econdary hypothyroidism Lactational Failure Secondary Adrenal insufficiency - Lethargy , anorexia , weight loss Typically long interval between obstetric event and diagnosis

25. 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

26. 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

27. 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

28. RADIATION INJURY Pattern of loss – GH>FSH/LH>ACTH>TSH Previously irradiated patients should undergo lifelong periodic anterior pituitary hormone testing

29. EMPTY SELLA SYNDROME Often an incidental MRI finding

30. 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.

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. GONADOTROPHIN DEFICIENCY MEN T estosterone replacement has beneficial effects on body composition, sexual function, mood, behavior & BMD. Treatment is contraindicated in patients with prostate cancer and male breast cancer

40. GONADOTROPHIN DEFICIENCY WOMEN Oestrogen replacement alleviates symptoms of deficiency and is bone protective. It is often given with cyclical/continuous progesterone.

41. 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

42. 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

43. ACTH DEFICIENCY Hydrocortisone is the preferred agent 2 to 3-fold increase in glucocorticoid dose is needed temporarily during intercurrent illness, surgery, etc.

44. 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

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