common causes of hypopituitarism and management for the same has been discussed in this presentation

1. Hypopituitarism Diagnosis
and Management
Jeetam Singh Rajput
Jr 3 Internal medicine

2. Moderator:
Prof Sarita Bajaj DM
Director & Head of department
PG Dept of Medicine
MLN Medical college Allahabad

3. Definition

4. Anterior Pituitary
Cell types Hormone synthesize
Acidophilic cells
1. Somatotrophs Growth hormone(GH)
2. Lactotrophs (mammotrophs) Prolactin(PRL)
Basophilic cells
1. Corticotrophs POMC, ACTH, MSH, endorphins, lipotropin
2. Thyrotrophs TSH
3. Gonadotrophs FSH, LH

6. Hormone Features of deficiency
GH Children: growth retardation
Adults: muscle bulk↓
Tendency to hypoglycaemia.
Prolactin Failure of lactation
Gonadotrophins Children: delayed puberty
Female: oligomenorrhoea, infertility,atrophy of breast
& genitalia, los of libido
Male:Impotence,azoospermia,testicular atrophy, loss
of libido
Both sexes: Loss of libido,Loss of body hair
ACTH Weight loss, hypotension, hypoglycaemia, decrease skin
pigmentation, hyponatremia, nausea, vomiting
TSH Weight gain, cold intolerence,fatique, hair loss,
constipation, dry skin, hoarseness,bradycardia, fatigue
Vasopressin Thirst, polyuria

7. Aetiology - Hypopituitarism
1.Developmental/Structural
a) Pituitary dysplasia/Aplasia
b) Encephalocele, congenital empty sella
c) Congenital hypothalamus disorder
i) Septo- optic dysplasia
ii) Prader- willi syndrome
iii) Kallmann syndrome
iv) Laurence-moon-beidl syndrome
2. Neoplastic
a) Pituitary adenoma
b) Parasellar mass( eg: germinoma, glioma,
ependymoma)

8. Contd..
c) Craniopharyngioma
d) Rathke’s cyst
e) Other Tm:- Mets, lymphoma, Leukemia, Meningioma
3. Vascular
a) Pituitary apoplexy
b) Seehan’s syndrome(Postpartum necrosis)
c) Sickle cell disease
d) Arteritis
4. Traumatic
Injury, surgical resection, Radiation damage

9. Contd..
5. Inflammatory
a) Hypophisitis:- Lymhocytic & granulomatous hypophisitis
b) Other causes:- Hemochromatosis,Sarcoidosis, Histiocytosis,
Amyloidosis
6. Infections
a) Fungal(Histoplasmosis)
b) Parasitis(Toxoplasma)
c) Tuberculosis
d) Pnumocystis carinii

10. Septo-Optic Dysplasia
 Hypothalamic dysfunction and hypopituitarism
 may result from dysgenesis of the septum pellucidum or corpus
callosum
 Affected children have mutations in the HESX1 gene
 These children exhibit variable combinations of:
 cleft palate
 syndactyly
 ear deformities
 optic atrophy
 micropenis
 anosmia
 Pituitary dysfunction
 Diabetes insipidus
 GH deficiency and short stature
 Occasionally TSH deficiency

11. Prader Willi Syndrome
• Result from deletion of patternal copy of SRNPN and
NECDIN gene (chr 15q).
• Clinical feature:- Hypogonadotropic Hypogonadism,
Hyperphagia, obesity, muscle hypotonia , mental
retardation, T2DM.

12. Kallman Syndrome
• Defective hypothalamic gonadotropin-releasing hormone
(GnRH) synthesis
• Associated with anosmia or hyposmia due to olfactory bulb
agenesis or hypoplasia
• May also be associated with: color blindness,optic atrophy,
nerve deafness, cleft palate, renal abnormalities,
cryptorchidism
• GnRH deficiency prevents progression
through puberty
• Characterized by
 low LH and FSH levels
 low concentrations of sex steroids

13. Kallman Syndrome
• Males patients
 Delayed puberty and hypogonadism(small testis), including
micropenis
 Long-term treatment:
• human chorionic gonadotropin (hCG) or testosterone
• Female patients
 Primary amenorrhea and failure of secondary sexual
development
 Long-term treatment:
• cyclic estrogen and progestin
• Repetitive GnRH administration restores normal fertility
• Fertility may also be restored by the administration of
gonadotropins or by using a portable infusion pump to deliver
subcutaneous, pulsatile GnRH

14. Laurence-Moon-Bardet-Biedl Syndrome
• Rare autosomal recessive disorder
• Clinical feature:- Retinal degenration, Renal
abnormality, Retardation(Mental), obesity
• other: hexadactyly/ brachydactyly/ syndactyly
• Central diabetes insipidus may or may not be associated
• GnRH deficiency occurs in 75% of males and half of
affected females
• Retinal degeneration begins in early childhood
– most patients are blind by age 30

15. Hypopituitarism
(Acquired Causes)
1. Neoplastic
2. Vascular
Pituitary Apoplexy, sheehan’s syndrome
3. Infiltrative/inflammatory disorder
Lymphocytic hypophysitis
4. Trauma, Cranial irradiation,Surgical resection
5. Empty Sella syndrome
6. Infections

16. Order of hormone deficiencies
• GH
• Gonadotropins (FSH, LH)
• TSH
• ACTH
• Prolactin
• Posterior pituitary hormones

17. Pituitary adenoma(Non functioning)
• Consist of 10% of all intracranial neoplasm.
• 25-35% are nonfunctioning .
• Most of them arise from gonadotropin cells & monoclonal in
origin.
• Most of them are macroadenoma.
• Usually discovered because of space-occupying effects, or
inadvertently.

18. Management of nonfunctioning pituitary adenoma
Non functioning pit. adenoma
MRI differential diagnosis
Asses pituitary function
Nonfunctioning
pituitary
adenoma
Macroadenoma
Transspenoidal surgery
Follow up: MRI at 1,2,5 year
Reasses if symptomatic
Microadenoma
Observe
MRI and hormone testing
every 6 month for 2yr, anually
thereafter, hormone
replacement if required

19. Pituitary Apoplexy
• Spontaneous hemorrhage in pituitary adenoma/tumor
• Considered as a neurosurgical emergency
• Presentation:
Variable onset of severe headache
Nausea and vomiting
Meningismus
Vertigo
 Visual defects
 Altered consciousness
• Symptoms may occur immediately or may develop
over 1-2 days

20. Pituitary Apoplexy
• Risk factors:
DM, HTN
Sicle cell anemia
Anticoagulant use:- Warfarin, Heprin
• Usually resolve completely
• Transient or permanent hypopituitarism is possible
undiagnosed acute adrenal insufficiency
• Diagnose with CT/MRI
• Differentiate from leaking aneurysm
• Treatment:
If visual defects and altered consciousness then
Surgical – Transsphenoidal decompression
• Medical therapy – if symptoms are mild
Corticosteroids

21. Normal MRI imaging of Pituitary
T 1 image sagittal section T1 image coronal section

22. Pituitary Apoplexy
Coronal & sagittal section of brain(MRI) showing pituitary haemorrhage

23. Sheehan’s Syndrome
• Infarction of pituitary after substantial blood loss during
childbirth
• Incidence: 3.6%
• No correlation between severity of hemorrhage and
symptoms
• Severe: recognised month to years postpartum period
– Lethargy, anorexia, weight loss, unable to breast feeding

24. Sheehan’s Syndrome
• Typically long interval between obstetric event and
diagnosis( months to years)
• Of total patients:
 50% permanent amenorrhea
 The rest had scanty-rare menses
 Mostly lactation was poor to absent
• Dx: MRI empty sella turcica
• T/t: Hormone replacement &
Corticosteroids

25. Lymphocytic Hypophysitis
• Etiology
Presumed to be autoimmune
• Clinical Presentation
Women, during postpartum period
Mass effect (sellar mass)
Deficiency of one or more anterior pituitary hormones
 ACTH deficiency is the most common
• Diagnosis
MRI - may be indistinguishable from pituitary adenoma
↑ ESR
• Treatment
Non compressive symptoms→Hormone support + Steroid
Compressive symptoms→ Surgery(TSS)

26. Lymphocytic Hypophysitis
HPE of Pituitary MRI brain (coronal & sagittal section)

27. Trauma
• The pituitary may be partially or totally damaged by birth
trauma, cranial hemorrhage, fetal asphyxia, or breech
delivery.
• Head trauma can lead to direct pituitary damage by
1) Sella turcica fracture,
2) Pituitary stalk section
3) Trauma-induced vasopasm, or ischemic infarction
• The most common traumatic cause of compromised pituitary
function in the adult is iatrogenic neurosurgical trauma.

28. • Hypopituitarism following head trauma usually appears within a
year after the insult.
• Virtually all patients with subsequent pituitary failure have a
history of loss of consciousness following trauma.
• 1/2 pt has documented skull fracture.
• 1/3rd
of these patients have demonstrable signs of hypothalamic
or post pituitary hemorrhage (or both) or ant lobe infarction on
MRI.
• Diabetes insipidus is the most common endocrine disorder,
encountered in about 30% of these patients, later on other
hormone deficiency may also occurs.
• 75% of patients have evidence of hypopituitarism, and the degree
of pituitary failure correlates with severity of head trauma.

29. Cranial Irradiation
• Children and adolescents, are more susceptible to pituitary &
hypothalamic failure after whole-brain or head and neck
therapeutic irradiation.
• The development of hormonal abnormalities correlates
strongly with irradiation dosage.
• Up to two-thirds of patients ultimately develop hormone
insufficiency after a median dose of 50 Gy (5000 rad) .
• The development of hypopituitarism occurs over 5–15 years
and usually reflects hypothalamic damage rather than
primary destruction of pituitary cells.
• GH deficiency is most common, followed by gonadotropin
and ACTH deficiency.
• Replace therapy instituted when appropriate .

30. Empty Sella Syndrome
• An empty sella can develop as a consequence of a primary
congenital weakness of the diaphragm Damage to the sellar
diaphragm can lead to arachnoid herniation into the sella.
• Usually have normal pituitary function(incidental finding)
Implying that the surrounding rim of pituitary tissue is fully
functional
• Hypopituitarism may develop insidiously.
• Rarely, functional pituitary adenomas may arise within the rim
of pituitary tissue, and these are not always visible on MRI.
• Aetiology:-
1. Congenital
2. Primary hypophisitis
3. Pituitary Adenoma(silent infarction)
4. Other: Trauma, Surgery, Radiation

31. Empty Sella Syndrome
Often an incidental MRI finding

32. Clinical Presentation
• Can present with features of deficiency of one or more
anterior pituitary hormones.
• Up to 50% of patients with primary empty sella have
associated benign intracranial hypertension
• Clinical presentation depends on:
 Age at onset
 Hormone affected, extent
 Speed of onset
 Duration of the deficiency

33. Empty Sella Syndrome
MRI brain(sagittal section) Specimen showing empty pit
fossa

34. Specific Hormone
Deficiencies

35. Growth Hormone Deficiency
Children
• Short stature
• Micropenis
• Increased fat
• High-pitched voice
• Propensity to hypoglycemia
Adult
• Reduced lean body mass
• Increased fat mass with
selective deposition of
intra-abdominal visceral fat
• Increased waist-to-hip ratio
• Hyperlipidemia
• Left ventricular dysfunction
• Hypertension
• Increased plasma fibrinogen
levels
• ↓ BMD

36. Diagnosis of GH Deficiency
Test Blood sample timing Interpretation
Insulin tolerance test:
Regular insulin(.05-.15U/kg
I.V.)
-30,0,30,60,120 min for
glucose & GH
Glu 40mg/dl˂
GH 3µg/L-Normal˃
Clonidine stimulation test:
Clonidine 150 µg/m2 orally
0,30,60,90,120,150,180 min GH >7µg/L- Normal
GHRH test: 1µg/kg I.V. 0,15,30,45,60,120 min GH 3µg/L-Normal˃
L-Arginine test:30gm I.V. over
30min
0,30,60,120 min GH 3µg/L-Normal˃
L-Dopa test:500mg PO 0,30,60,120 min GH 3µg/L-Normal˃

37. GH replacement therapy
• The starting dose Adult:- 0.1 -0.2mg/d should be titrated (up to a
maximum of 1.25 mg/d) to maintain IGF-I levels in the mid-
normal range for age- and sex-matched controls.
• Children:- 0.02-0.05 mg/kg/day
• Brand available in india:- Norditropin, Eutropin, Saizen, zomacton
Contraindication Side effect
Active intracranial neoplasm Hypertension ,Tachycardia
Intracranial hypertension Headache, paresthesia,
dizziness,
Diabetic retinopathy Acne, alopecia, bullous
eruption
Uncontrolled diabetes
Mellitus
Gynecomastia, gastritis,
abnormal urine,
Otitis media ,ear disorders ,
pharyngitis

39. Gonadotropin Deficiency
Women
 Oligomenorrhea or
amenorrhea
 Loss of libido
 Vaginal dryness or
dyspareunia
 Loss of secondary sex
characteristics (estrogen
deficiency)
Men
 Loss of libido
 Erectile dysfunction
 Infertility
 Loss of secondary sex
characteristics
 Atrophy of the testes
 Gynecomastia (testosterone
deficiency)

41. Diagnosis & Management
• Diagnosis:
• GnRH stimulation test:
• Intravenous GnRH ( 100ug)
• LH and FSH measured at
0,30,60 min
• Normal response
LH ↑ by 10 IU/L
FSH ↑ by 2 IU/L
• Treatment:
MALE
1.Testosterone gel→ 5-10 g/d
2.Testosterone patch→ 5mg/d
3.Testosteron enanthate →
200mg IM every 2 wk
FEMALE
Cyclic estrogen and progesterone
BOTH
1.Gonadotropin inj(hCG or hMG)
for 12-18 month for fertility
2. GnRH Pulse therapy → 25-
150ng/kg every 2h S.C.

42. ACTH Deficiency
• Results in hypocortisolism
 Malaise
 Anorexia
 Weight-loss,weakness
 Gastrointestinal disturbances- Nausea , Vomiting
 Hyponatremia , hypoglycemia, hyperkalemia
• Pale complexion
 Unable to tan or maintain a tan
 Not accompanied by hyperpigmentation
• No features of mineralocorticoid deficiency
 Aldosterone secretion unaffected

43. Diagnosis of Hypocortisolism
• Basal ACTH secretion
Cortisol < 3 μg/dL, cortisol deficiency
Cortisol > 18μg/dL, sufficient ACTH
Cortisol > 3 μd/dL but < 18 μg/dL - test ACTH reserve

44. Test Time of Sample collection Result(normal response)
ITT: regular insulin
(0.05-0.15U/Kg I.V.)
-30,0,30,60,90 min for
glucose and cortisol
1. Glucose<40mg/dl
2. Cortisol↑ by >7ug/dl or
to>20ug/dl
CRH Test: 1ug/kg CRH I.V. at
8am
0,15,30,60,90,120 min for
ACTH and Cortisol
1. ACTH↑ 2 to 4 fold
2. Cortisol level>20-25 ug/dl
Metyrapone test:
Metyrapone
30mg/kg at midnight
Plasma 11-deoxycortisol,
ACTH, cortisol at 8 am
1. Cortisol< 4g/dl
2. 11-deoxycortisol>7.5ug/dl
3. ACTH> 75pg/ml
Std ACTH stimulation test :
ACTH(1-24 cosyntropin)
0.25mg IM or IV
0,30,60min for cortisol and
aldosterone
1. Cortisol >21g/dl
2. Aldosterone >4ng/dl above
baseline
Low dose ACTH test:
ACTH 1ug IV
0,30,60 min for cortisol Cortisol >21g/dl
3 day ACTH stimulation test:
0.25mg ACTH I.V. 8 hrly
Cortisol >21g/dl
•ACTH Reserve

45. Treatment of ACTH deficiency
1. Hydrocortisone: 10mg a.m. 5mg at noon and 5mg
at evening
2. Cortisone acetate: 25mg a.m. and 12.5mg p.m.
3. Prednisone: 5mg a.m. & 2.5mg p.m.

46. TSH Deficiency
• Hypothyroidism
• Atrophic thyroid gland
• Isolated TSH measurement is not helpful
• FT3, FT4, TSH should be measured
• Low FT3, FT4, TSH seen
• Treatment - Levothyroxine ( 0.075 -0.15 mg daily)

47. Prolactin Deficiency
• Inability to lactate during postpartum period.
• Often 1st
manifestation of Sheehan syndrome.
• Isolated PRL deficiency is very rare.
• Prevelence of hypoprolactinemia parallel the prevelence of
hypopituitarism.
• Normal prolactin>2ug/L and increase > 200% from baseline
with TRH stimulation test.

48. Hormone Replacement

49. 1. Laron dwarfism is due to?
a) GH deficiency
b) GHRH deficiency
c) GH receptor deficiency
d) IGF resistence

50. Ans C. Laron dwarfism:- Autosomal recessive
disorder caused by resistance to action of GH b/c of
defect in GH receptor gene.
So it is characterised by clinical sign of GH
deficiency despite of normal or increase GH but
there is low level of IGF-1.

51. 2. Most common type of Pituitary adenoma?
a) Thyrotropinoma
b)Gonadotropinoma
c) Prolactinoma
d)Corticotropinoma

52. Ans 2. C.

53. 3. Which drug is essential in Sheehan’s syndrome?
a) Estrogen
b)Thyroxin
c) GH
d)Cortisone

54. Ans 3. D.

55. 4. Choose false statement
a) M/C Pit. Adenoma is prolactenoma
b)Most of the adenoma are hyperfunctioning.
c) 45% of adenoma are non functioning.
d)Non functioning adenoma present with mass effect

56. Ans 4. C.

57. 5. Incorrect statement regarding Primary hypophysitis
a) There is Lymphocytic infiltration of pituitary seen
b)Infiltration by Plasma cells seen
c) May present with hypopituitarism
d)ESR raised
e) Most commonly seen during 2nd
trimester of
pregnancy

58. Ans 5. E.

59. 6. Gold standard test for diagnosis GH deficiency
a) GHRH test
b)L- Arginine test
c) ITT
d)L-Dopa test

60. Ans 6. C.

61. 7. Most common symptom of non functioning pit.
Adenoma
a) Pituitary failure
b)Visualfield defect
c) Seizure
d)Opthalmoplegia

62. Ans7. B.

63. 8. Reason behind increase in size of pituitary during
pregnancy
a) PRL mediated
b)Estrogen mediated
c) Gonadotroph cells proliferation
d)NOTA

64. • Ans. 8. B

65. 9. Order(decreasing frequency) of hormone deficiency
after acute pituitary insult
a) GH>TSH>PRL>FSH,LH>ACTH
b)GH>FSH,LH>TSH>ACTH>PRL
c) GH>ACTH>TSH>FSH,LH>PRL
d)GH>PRL>ACTH>TSH>FSH,LH

66. Ans 9 B

67. 10. False regarding Prader willi syndrome
a) Hypogonadotropic hypogonadism
b)Deletion of paternal copy of PENDRIN and NECDIN
gene
c) T2DM
d)Hypotonia
e) Hyperphagia

68. • Ans 10. B.