Endocrine disturbances of adrenal glands along with steroid hormone biosynthesis

1. ENDOCRINE DISORDERS OF
ADRENAL GLAND
Dr Subhasish Deb
Burdwan Medical College And Hospital
Department of General Medicine

2. ADRENAL GLAND

3. STEROID HORMONE
BIOSYNTHSIS
 5 hormones produced from cholesterol
Progesterone
Aldosterone
Glucocorticoids
Estrogen
Androgens
Active form of Vit D3 also considered a steroid hormone now a days

4. CHOLESTEROL
MOLECULE
Cholesterol = 27C
Pregnanolone = 21C
Aldosterone
Glucocorticoids
Androgens = 19C Progesterone
Oestrogens = 18C

5. Cholesterol
Pregnanolone
STAR protein
= Steroidogenic acute
Regulator protein
Enzyme = DESMOLASE
•Desmolase is the rate limiting enzyme
•Regulated by ACTH
•ACTH acts on Z.F and Z.R and stimulates
desmolase here to produce glucocorticoids
KETOCONAZOLE inibits desmolase

6. Cholesterol
Pregnanolone
STAR protein
= Steroidogenic acute
Regulator protein
Enzyme = DESMOLASE
Progesterone
DHEA
Glucocorticoids
OH deff
Aldosterone
17 Hydroxylase 17 17-20 lyase
21 Hydroxylase
11 B Hydroxylase
3 B Hydroxy steroid dehydrogenase
Aldosterone synthase

7. DHEA
Androstenidione
Testosterone
in testis
Oesterogen
in graafian follicle
and placentae
DHEA and androstenidione are also called 17 keto steroids
Weak androgens
2 functs in females:
•LIBIDO
•Secondary sexual charc – axl and pubic hair

8. Hydroxylations of hormones
from adrenal cortex
 ALDOSTERONE:
 21, 11, 18
 GLUCOCORTICOIDS:
 17, 21, 11
 ADRENAL ANDROGENS:
 17, and various modifications

9. CONGENITAL ADRENAL
HYPERPLASIA
 AR
 Also called adrenogenital syndrome due
to genital changes
 Due to mutations in gene for enzymes
required in steroidogenesis
 m/c 21hydroxylase deff

10. 17 aOH defficiency
 Sex hormones
1. XY – female like genitilia
no secd. sexual charc.
2. XX – no secd sexual charac
 Glucocorticoids
- hypogycemia
- ACTH increased
 Aldosterone
-Na and water retension, inc BP
-hypokalemia
-alkalosis
PICSlide 6

11. 21 B OH deff & 11 OH deff
Common:
• Glucocorticoid
• Adrenal androgens
1. XY – precocious puberty
2. XX – masculinisation
21 OH def 11 OH def
• Salt and water wasting (bp dec)
• HYPERkalemia
• Acidosis
Slide 6
•BP normal or low
•11 OH cortisone produced
Which has mineralocorticoid act

12.  Penis at 12 Syndrome:
 5 alpha reductase deff
 Lack of dihydrotestosterone
 Small penis till age 12
 Increase in testosterone at puberty after 12

13. HYPERADRENALISM
 Hypercortisolism
(cortisol – ACTH)
 Hyperadosteronism
(aldosterone – Angiotensin II)
 High epinephrine
(epinephrine – Autonomic nervous sys)

14. CUSHING’S SYNDROME
• Any state of cortisol excess
• Cushing’s disease - excess cortisol due
to pituitary adenoma
• m/c/c – Iatrogenic use
• Mostly affects women
• Only 10% pts have adrenal cause
(ACTH independent)

15. ETIOLOGY
ACTH dependant ACTH independant
1. Cushing’s Disease
(ACTH producing pitu aden)
>1cm = macro
2. Ectopic ACTH syndrome
• Small cell lung CA
• Carcinoid
(bronchial,
pancreatic)
• Medullary thyroid
CA
1. Adrenocortical adenoma
2. Adrenocortical carcinoma
3. Other rare causes

16. CLINICAL FEATURES
 Body fat: Weight gain
central obesity
moon facies
buffalo hump
 Skin: Purple abdominal striae
easy bruising
Plethoric appearance
 Bone: Osteopenia
Osteoporosis (vertebral fracture)

17.  Muscle: proximal myopathy
 CVS: diastolic hypertension
hypokalemia
oedema
atherosclerosis
Cortisol can stimulate mineralocorticoid receptors but an
enzyme 11B HSD2 rapidly converts it to inactive cortisone
without mineralocorticoid activity.
In cushing’s, excess cortisol overcomes the ability of 11b hsd2
to breakdown cortisol, hence mineralocorticoid effect seen- BP
& K
 Reproductive sys: amenorrhea, libido
 CNS: irritability, emotional liability, paranoid
psycosis

18.  Blood: increased susceptibility to infections
WBC
hypercoagulation- DVT, P emboism
 Metabolism: impaired glucose tolerance
dyslipidemia

19. Central obesity

20. Moon facies

21. Buffalo Hump

22. Purple striae

23. Diagnostic algorithm
according to the 2008 Endocrine Society clinical practice guideline

24.  urinary free cortisol (UFC). Normal values
less than 220 to 330 nmol/24 hours (80 to 120 μg/24
hours
 Low dose DXM supp test:
Will only suppress normal physiological cortisol
release. Will not suppress any abnormal cortisol
release.
 False positives seen in:
Anti epileptics- carbamazepine, phenytoin
Rifampicin
Eating disorders
Depression
Alcohol withdrawl
(pseudo cushing’s)

26.  The most discriminatory time of day to
measure ACTH is between 11 p.m. and 1
a.m., when ACTH/cortisol secretion is at a
nadir.
 A midnight ACTH result >15 pg/mL in a
patient with biochemical hypercortisolism
confirms that the underlying disease is
ACTH dependent.

27.  Inferior Petrosal Sinus Sampling is the most robust test to
distinguish Cushing’s disease from the ectopic ACTH
syndrome.
 In virtually all patients with ectopic ACTH, ratio of ACTH in
IPS and in simultaneously drawn peripheral venous blood is
less than 1.4 : 1. In contrast, the ratio is elevated to greater
than 2.0 in Cushing’s disease.
 However due to the problem of intermittent ACTH secretion, it
is useful to take measurements at 2, 5 and15 minutes, after iv
100 μg synthetic ovine CRH.

28. Treatment
 ACTH independent : surgical resection
 Cushing’s disease: transsphoidal removal of
tumour
 In overt cushing’s: (difficult to control
hypokalemic htn or acute psychosis)
Medical therapy to treat cortisol excess before
surgery- Ketokonazole (200mg tds)
Metyrapone (500 mg tds)
Hydrocortisone at time of surgery and slowly tapered
following recovery.

29. HYPERALDOSTERONISM
 m/c/c - b/l adrenal hyperplasia.
 Carcinomas considered in younger individuals
Etiology:
Primary
hyperaldosteronism
Secondary
hyperaldosteronism
(Inc aldosterone only) (Inc aldosterone and Renin)
1. Adrenal adenoma
(Conn’s syndrome)
2. B/L (micronodular) adrenal
hyperplasia
3. Glucocorticoid remidiable
hyperaldosteronism
1. B/L renal artery stenosis
2. Cirrhosis of liver
3. CCF
4. Nephrotic syndrome

30. Other rare causes:
1. Syndrome of apparent mineralocorticoid excess:
 Mutation of HSD 11B2
 Cortisol cannot be converted to cortisone
 Excess activation of MR by cortisol
2. Cushing’s syndrome
3. Glucocorticoid resistance – upregulation of cortisol
due to GR mutations
4. Adrenocortical CA
5. CAH – CYP 17A1 and CYP 11B1 deff
6. Liddle’s syndrome – mutant ENaC channels, resulting in
reduced degradation of ENaC, keeping the channel open,
enhancing mineralocorticoid action

31.  Symptoms:
Often asymptomatic. Usually diagnosed in labs
while evaluating hypokalemia or evaluation of
hypertension in a young individual.
 Labs:
 K
 metabolic alkalosis
 Na
Hypertension (Diastolic) without edema.
No features of hypervolemia due to ANP
mediated natriuresis (Aldosterone escape
mechanism)

32. ALGORITHM FOR
MINERALOCORTICOID
EXCESS

34.  Saline infusion test:
It is positive when there is failure of aldosterone to
supress below 140 pmol/lit (5ng/dl) after saline
infusion, indicates autonomous mineralocorticoid
excess.
 AVS (adrenal vein sampling):
Done to differentiate between B/L micronodular
hyperplasia and U/L adenoma in pts >40yrs if a
surgical procedure is feasible and required.

35. Treatment
 U/L adrenal pathology: laparoscopic adrenalectomy
 B/l pathology & not candidates for surg:
Medical therapy with MR antagoinsts
Spironotactone – started at 12.5- 50 bd max 400mg/day
Eplerenone – strt 25 bd titrated max to 200mg/day
Amiloride 5-10 mg bd

36. ADRENAL
INSUFFICIENCY
 m/c/c- suppression of HPA (exogenous
glucocorticoids)
Primary Secondary
1.Autoimune adrenalitis m/c
2. CAH
3. Adrenoleukodystrophy
4. Adrenal infections (tb, hiv,
cmv, cryptococcosis)
5. Adrenal haemorrhage
6. Drug induced (mitotane,
aminoglutethimide,
ketokonazole, RU486)
7. B/l adrenalectomy
1. Pituitar tumours
2. Pituitary irradiation
3. Pituitary apoplexy/Hg
4. Drug induced (chronic
glucocorticoid excess)
5. POMC deff
Chronic = Addison’s dis

37. Primary vs Secondary AI
 Primary AI has defficency of both Gluc and
minlc, while seconday AI has only Gluc deff.
 Hyponatremia is a characteristic biochem
feature of 1` AI. Can be seen in 2` AI due to
diminished inhibition of ADH by cortisol (SIADH)
 1`AI – Hyperpigmentaion, excess POMC derived
peptides stimulate melanocytes.
 2`AI associated with:
 Inv of other endocrine axes (thyroid, gonad, GH,
prolactin)
 Bitemporal hemianopia (chiasmal compression)

38. CLINICAL FEATURES
 Due to glucocorticoid deff:
 Fatigue, lack of energy
 Weight loss, anorexia
 Fever
 Anemia, lymphocytosis, eosinophilia
 Slightly increased TSH (loss of feedback inhibition of TSH
release)
 Hypoglycemia (more in children)
 Hyponatremia (due to lack of feedback inhib of AVP
release)

39.  Due to Mineralocorticoid Deff: (Primary
AI only)
 Nausea, vomiting, abdominal pain
 Dizziness, postural hypotension
 Salt craving
 Low BP
 Increased serum Cr (due to volume depletion)
 Hyponatremia, hyperkalemia
 Due to Adrenal Androgen Deff:
 Lack of energy
 Loss of Libido
 Loss of axilary and pubic hair

40. Diagnostic Algorithm

42. Treatment
 Glucocorticoid replacement:
 Replacement of physiological daily gluc production ~
15-25mg hydrocortisone in two or three div doses
 Pregnancy, increase dose by 50%
 Long acting gluc not preffered such as Prednisolone
and dexamethasone.
 Monitoring of replacement therapy with BP, 24 hr
UFC, plasma ACTH
 Pt must be informed to take double the dose in
illness with fever.
 100 mg iv dialy in case of prolonged vomiting,
surgery or trauma.

43.  Mineralocorticoid replacement:
 In primary adrenal indufficiency
 100-150 ug fludrocortisone
 Monitoring by measuring Na, K, BP – sitting and standing
(to detect postural drop indicative of hypovolemia),
plasma renin.
 Changes in glucocorticoid dose may impact
mineralocorticoid dose. Ex: 40 mg hydrocortison = 100ug
fludro
 If travelling to hot tropical weather, dose of fludro inc by
50-100ug
 Adrenal androgen replacement:
An option in pts with lack of energy despite optimal gluc and
minc replacment.
OD 25-50 mg DHEA
Monitored by measuring DHEAS, androstenidione, 24 after
DHEA dose.

44. ACUTE ADRENAL
INSUFFICIENCY
 a/k adrenal crisis
 Its an endocrine emergency
 Life threatening condition where body is
acutely deprived of cortisol and
sometimes aldosterone.

45. Who’s at risk for crisis?
1. Pts with Addison’s dis or other primary
hypoadrenalism in event of an acute stressor.
2. Pts with meningococcemia – Waterhouse
Fridreichsen Syndrome.
3. Sudden withdrawl of exo steroids
4. Pituitary necrosis (pit apoplexy)
5. Follwing b/l adrenalectomy
6. Follwing administration of ETOMIDATE.

46. Diagnosis
 H/o and physical exam will help a ton!
 Symptoms are not specific. Have to
differentiate it from other causes of shock
as AC will not respond to fluids and
pressors alone. Will need steroids.
 Labs:
 Na
 K
 Pre renal pic, Bun:Cr > 20:1 (due to
dehydration)

47. Treatment
 Start treatment before the serum cortisol
results arrive.
 Rehydration:
 NS @ 1lit/hr
 continuous cardiac monitoring
 Glucocorticoids:
 Hydrocortisone iv bolus 100mg
 Followed by 100-200mh hyrocortisone over
24hrs by cotinous infusion or iv/im inj
 Mineralocorticoid:
 Strated once daily hydrocortisone dose reduced to
<50mg (as high dose hydcor provides suff mincor
action)

48. PHEOCHROMOCYTOMA
 “the great masquerader” as its presentation is
so variable.
 Catecholamine producing tumours from ANS.
 Name reflects the black coloured staining
caused by chromaffin oxidation of
catecholamines.
 Rule of 10:
 10% b/l
 10% extraadrenal
 10% malignant
 10% not associated with HTN
 Usually 10% are familial

49. Clinical features
 Paroxysms or crisis:
 Onset - Sudden
 Ppt factors - Abdominal palpation, stress during
surgery, anaesthesia.
 Feature - triad of episodic palpitation, sweating
and headache.
 Hypertension:
Sustained sustained with some episodic peaks
HTN
normal

50. Diagnosis
 To confirm diagnosis:
 24 urinary vanillyl mandelic acid
 Urinary metanephrins
 To localize tumour:
 CT, MRI of adrenal
 In case of extra adrenal – mri chest, 131I
MIBG scan (metiodobenzyl guanidine),
Dopa PET

51. Treatment
 Therapeutic goal is complete removal of
the tumour.
 Proper fluid balance to be maintained during sx
 Any htn crisis managed by iv phentolamine/ iv
nitroprusside
 Pre operative pre with alpha and then beta blockers
 Metastaic tumour: chemo / Metyrosine (tyrosine
hydroxylase inhibitor)
 Supportive:
 For htn – phenoxybenzamine, start with 5-10mg tds
and gradually increase
 For tachycardia – propranolo 10mg qds (but not
before alpha blockade)

52. Thank you