Glucocorticoids

and
Mineralocorticoids

Donald P. McDonnell, Ph.D.

 Glucocorticoids and Mineralocorticoids

Learning Objectives

By the conclusion of this lecture, students should be able to:

• Describe the role of the hypothalamus, pituitary and adrenal in

the regulated synthesis of glucocorticoids.
• List both the major medical uses and the potential side effects
of glucocorticoid administration.

• Describe the importance of 11-hydroxysteroid dehydrogenase in

glucocorticoid pharmacology.

• List the medical uses of mineralcorticoid agonists and antagonists.

 Classification of Steroids

Steroids

Sex Hormones Corticosteroids

Progestins Androgens Estrogens Glucocorticoids Mineralocorticoids

Testosterone Estradiol Cortisol Aldosterone

(hydrocortisone)
 Nuclear Receptor Gene Family

N DBD LBD C

Genome Size (Mb) No. of NR Genes

C. elegans 80 228
D. melanogaster 137 20
H. sapiens 3300 48

AR ERRa LRH PPARa reverba SF1

CAR ERR LXRa PPARg reverb SHP
COUPa ERRg LXR PPARd RORa Tlx
COUP FXR MR PR ROR TRa
COUPg GCNF1 NGFI-Ba PXR RORg TR
DAX GR NGFI-B RARa RXRa TR2a
ERa HNF4a NGFI-Bg RAR RXR TR2
ER HNF4g PNR RARg RXRg VDR
 Amino Acid Similarities Among
Steroid Receptor Superfamily

hGR 777 100 100

hMR 984 94 57

hPR-B 934 90 55

hAR 918 78 46

hER 595 52 30

hTRβ 456 47 17

hRARβ 448 45 <15

hVDR 427 42 <15

Mechanisms of Glucocorticoid Receptor Signaling
 An Updated Model of GR Pharmacology

CoR CoR
X
Antagonist GRE

GR SGRMs

GRE

Agonist
CoA CoA

GRE
 Adrenocortical Steroids -
Broad Definitions

Glucocorticoids:
Regulation of carbohydrate metabolism

Mineralocorticoids:
Regulation of electrolyte balance
Regulation of Cortisol Production
Higher centers

Hypothalamus

CRH

Pituitary

Cortisol

ACTH

Adrenal
Corticosteroid Biosynthesis in the Adrenal

Cholesterol

ACTH

Mineralocorticoid excess
Pregnenolone Progesterone Corticosterone Aldosterone (hypokalemia, hypertension,
fluid overload)

17 OH- 17 OH-
11-Deoxycortisol Cortisol Glucocorticoid loss
Pregnenolone Progesterone

DHEA Androstenedione Testosterone DHT Androgen depletion

 Receptor-independent Mechanism for
Conferring Specificity of Glucocorticoid Action

11β-HSD2*
Cortisone Cortisol Aldosterone
11β-HSD1

X
Mineralocorticoid Mineralocorticoid
Receptor Receptor

X Does not bind

Transcriptional
Activation

*Hydroxysteroid dehydrogenase
Integrated Actions of Glucocorticoids in Man
 Glucocorticoid Effects on Metabolism

 protein degradation  amino acids

 protein synthesis
 glucose utilization
muscle
 insulin sensitivity
liver

glucose

 glucose utilization  glycogen storage

 insulin sensitivity  gluconeogenesis
 lipolysis
 glycerol

fat
 Regulation of Aldosterone Production

(-)
Plasma Na+ Plasma Na+

Na+ in stim. Macula Na+

Angiotensinogen
Filtrate Densa Reabsorption
JG cells Renin
Adrenal Distal
(-) Cortex Tubule
Angiotensin I

c.e.
Aldosterone
Angiotensin II
Mineralocorticoids Exert Biological Activity in
the Late Distal Tubule and Collecting Ducts
 Defects in the HPA/Glucocorticoid Axis

• Primary Adrenal Insufficiency (Addison’s Disease)

- Autoimmune
- Tuberculosis
- Breast cancer metastasis
- Fungal CMV infection

• Secondary Adrenal Insufficiency

- Following exogenous glucocorticoid treatment
- Hypothalamic and pituitary lesions

• Congenital Adrenal Hyperplasia

- Mutation in the p21 hydroxylase
Diagnosis of Adrenocortical Diseases
–Hypocortisolism

• ACTH stimulation test

• CRH stimulation test

Diagnoses of Adrenocortical Diseases
–Hypercortisolism

• Midnight plasma cortisol measurement

• 24-hour urinary free cortisol

• Low dose Dexamethasone suppression test

• Combination Dex suppression / CRH test

 Serum Cortisol Levels During Circadian Studies
and High and Low Dexamethasone Suppression Tests

circadian studies dexamethasone suppression test

serum 800
cortisol oral 2
600
(nmol/l) dexamethasone
400
(mg/six hours) 1
200
<50 0
Day 1 Day 2 Day 3 Day 4
0900 1800 2400
time (hours)
serum 800
cortisol 600
(nmol/l) 400
200
<50
normal range 0900 0900 0900 0900 0900

normal time (hours)

pituitary-dependent disease
ectopic ACTH syndrome
 Pharmacologic Inhibition of
Glucocorticoid Function

(A) Inhibition of cortisol biosynthesis

Direct - ketoconazole: 11β hydroxylase inhibitor

- metapyrone: 11β hydroxylase inhibitor
- aminoglutethimide: side chain cleavage enzyme
Indirect - mitotane: ACAT1 inhibitors
- pasireotide: Somatostatin 5 agonist

(B) Inhibition of glucocorticoid receptor action

Mifepristone
 Typical Uses of Glucocorticoids

• Allergic diseases:
asthma, atopic dermatitis, anaphylactic shock

• Autoimmune diseases:
Lupus, rheumatoid arthritis, myasthenia gravis

• Inflammatory disorders:
Crohn’s disease

• Graft rejection
Principles of Glucocorticoid Therapy

• Deliver locally if possible

• Deliver for as brief a time as possible

• Taper therapy to permit resumption of

normal adrenal function

• Give alternate day therapy if possible

 Clinically Important Corticosteroids

Hormone Action Use Duration Route

Cortisol GC, MC Replace, Anti-inf Short IM, IV, Oral, Topical

Cortisone GC, MC Replace, Anti-inf Short Topical
Prednisone GC Anti-inf Medium Oral
Triamcinolone GC Anti-inf Medium IM, IV
Betamethasone GC Anti-inf Long Oral, Topical
Dexamethasone GC Anti-inf Long Topical

Beclomethasone GC Anti-inf Long Inhalation

Fluticasone GC Anti-inf Long Inhalation
Fludrocortisone MC Replace Long Oral
 Adrenal Steroid Toxicities
Glucocorticoid Actions

• Hyperglycemia
• Negative nitrogen balance
• Growth failure
• Osteoporosis
• Cataract formation
• Impaired wound healing
• Truncal obesity
• Psychosis
• Prolonged suppression of HPA axis
 Glucocorticoid-induced Osteoporosis

Physiologic
Replacement Dose Pharmacologic Doses

Increasing Risk of GIOP

2.5 5 7.5 10 15 20 25 >1
mg mg mg mg mg mg mg g

Low Dose Moderate Dose High Dose “Pulse”

Physiologic Cutoff
Indications for Mineralocorticoid Antagonists

• Primary hyperaldosteronisms
Adrenal hyperplasia / adenomas
• Edematous conditions
Congestive heart failure
Edema due to cirrhosis of the liver
Nephrotic syndrome
• Essential hypertension

• Hypokalemia
 Spironolactone and Eplerenone are
Mineralocorticoid Antagonists

Spironolactone o Eplerenone

CH3
o

CH3 H

H H
o
S
o CH3