Chapter 12

Adrenal Steroid Hormones

Nam Deuk Kim, Ph.D.

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1. The Adrenal Glands • Embedded above each kidney in a capsule of fat

• Composed of two endocrine organs

– Adrenal cortex

• Outer portion

• Secretes steroid hormones

– Adrenal medulla

• Inner portion

• Secretes catecholamines

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1) Anatomy of the Adrenal Glands

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• Adrenal cortex

– Consists of three layers or zones

• Zona glomerulosa – outermost layer

• Zona fasciculata – middle and largest portion

• Zona reticularis – innermost zone

– Categories of adrenal steroids

• Mineralocorticoids – Mainly aldosterone

– Influence mineral balance, specifically Na+ and K+ balance

• Glucocorticoids – Primarily cortisol

– Major role in glucose metabolism as well as in protein and lipid metabolism

• Sex hormones – Identical or similar to those produced by gonads

– Most abundant and physiologically important is dehydroepiandosterone (male “sex” hormone)

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2. Chemistry and Synthesis

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Fig. 15-3. Pathways of

adrenal steroid

hormone biosynthesis.

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Fig. 15-4. Steroid hormone

structure and nomenclature.

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8

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Fig. 15-5. Model for cholesterol homeostasis in the adrenal. 10

Compartmentalization of Steroid Synthesis

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Fatty acids

Cholesterol

cholesterol esterase

activated by ACTH in ZF/ZR (cAMP)

or by angiotensin II in ZG (IP3-DAG)

MITOCHONDRION

matrix

Pregnenolone SER

Cholesterol

esters

storage

vacuole

Cholesterol

Acetyl CoA

LDL

Cholesterol

from plasma

ACAT

biosynthesis

Increased by ACTH

cAMP induction + PKA

phosphorylation

StAR

outer

membrane

inner

membrane

Steroidogenic acute

regulatory protein

P-450scc: ACTH-activated: ZF/ZR

Angiotensin II-activated: ZG Figure 2. Initial events common to the biosyn-

thesis of adrenal, and other, steroid hormones

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Figure 3. Biosynthesis of mineralo-

corticoids in the zona glomerulosa

Cholesterol

Zona glomerulosa P-450scc AII

Pregnenolone

Progesterone

3-OHSD 5,4 Isomerase SER

21-OHase

11-Deoxycorticosterone (DOC)

SER

Aldosterone

primary human mineralocorticoid

11-OHase + 18-OHase +

18-OHDH =

Aldosterone synthase Mitos

Activated by AII

Mineralocorticoid activity

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Cortisol

primary human

glucocorticoid

17-OHpregnenolone 17-OHase

SER

17-OHprogesterone 17-OHase

Progesterone

11-Deoxycortisol

Cholesterol

P-450scc

Pregnenolone

Zona fasciculata

(reticularis also)

Figure 3. Biosynthesis of

glucocorticoids in the zona

fasciculata (reticularis,

secondarily)

ACTH

3-OHSD/5,4 Isomerase

SER

21-Hydroxylase SER

11-Hydroxylase Mitos

11-Deoxycorticosterone (DOC)

X

Corticosterone

X

X

X

Not preferred

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Figure 4. Subcellular compartmentalization of glucocorticoid biosynthesis in zona fasciculata

MITOCHONDRION

Cholesterol

Pregnenolone

SMOOTH

ENDOPLASMIC

RETICULUM

Cortisol

P-450scc/C-20,22-lyase

Progesterone

3-OHsteroid DH/

∆5-∆4 isomerase

17-Hydroxyprogesterone

17-OHase

11-Deoxycortisol

21-OHase

Cortisol 11-OHase

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3. Control of Synthesis and Secretion

• Cortisol

– Stimulates hepatic gluconeogenesis

– Inhibits glucose uptake and use by many tissues, but not the brain

– Stimulates protein degradation in many tissues, especially muscle

– Facilitates lipolysis

– Plays key role in adaptation to stress

– At pharmacological levels, can have anti-inflammatory and immunosuppressive effects

• Long-term use can result in unwanted side effects

– Displays a characteristic diurnal rhythm

– Secretion

• Regulated by negative-feedback loop involving hypothalamic CRH and pituitary ACTH

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Control of cortisol secretion

Pro-opiomelanocortin (POMC)

ACTH MSH β-Endorphin

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Fig. 15-7. Model for the role of

IGFs (especially IGF-II) in the

control of adrenal steroidogenesis.

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• Aldosterone

– Principal action site is on distal and collecting

tubules of the kidney

– Secretion is increased by

• Activation of renin-angiotensin-aldosterone system

(RAAS) by factors related to a reduction in Na+ and a

fall in blood pressure

• Direct stimulation of adrenal cortex by rise in plasma

K+ concentration

– Regulation of aldosterone secretion is largely

independent of anterior pituitary control

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Urinary System

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Nephron

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Nephron

• Two types of nephrons

• Distinguished by location and length of their

structures

– Juxtamedullary

nephrons (20%)

– Cortical

nephrons (80%)

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The juxtaglomerular apparatus.

Renin

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RAAS

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Fig. 15-8. Angiotensin biosynthesis.

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Fig. 15-10. Renin–angiotensin system and Na+ homeostasis.

Arrows indicate increases (up arrow) or decreases (down arrow)

in the factors indicated.

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Fig. 15-11. Kallikrein role in renin activation and bradykinin

production.

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Dual control of

aldosterone secretion of

K+ and Na+.

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Excretion of urine

of varying

concentration

depending on the

body’s needs.

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Fig. 15-12. Summary scheme of the role of aldosterone in

renal renin production.

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An atrial natriuretic peptide (ANP) or atrial

natriuretic factor (ANF) inhibits renal tubular

Na+ reabsorption

• Inhibits Na+ reabsorption

• Secreted by atria in response to being stretched

by Na+ retention, expansion of ECF volume, and

increase in arterial pressure

• Release promotes natriuretic, diuretic, and

hypotensive effects to help correct the original

stimulus that brought about release of ANP (or

ANF).

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Fig. 15-13. Primary structure of atrial natriuretic factor (ANF).

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An atrial

natriuretic

peptide (ANP)

or atrial

natriuretic

factor (ANF)

inhibits renal

tubular

reabsorption

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Fig. 15-14. Biological roles of ANF.

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Fig. 15-15. The role of atrial natriuretic factor (ANF) in

blood volume homeostasis.

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4. Circulation and Metabolism

• Transport proteins: reversibly bound to

• Cortisol:

- transcortin or corticosteroid-binding globulin (CBG)

- α2 globulin

- about 6%: unbound

- t½ : about 80 min

• Aldosterone:

- more than 50% of circulating aldosterone: unbound

- t½ : about 30 min

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Fig. 15-16. One pathway of cortisol metabolism and glucuronide

formation (in the liver).

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Fig. 15-17. Major

effects of excess

cortisol in

intermediary

metabolism.

5. Physiological Roles • Cortisol

– Stimulates hepatic gluconeogenesis

– Inhibits glucose uptake and use by many tissues, but not the brain

– Stimulates protein degradation in many tissues, especially muscle

– Facilitates lipolysis

– Plays key role in adaptation to stress

– At pharmacological levels, can have anti-inflammatory and immunosuppressive effects

• Long-term use can result in unwanted side effects

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Fig. 15-18. Physiological effects of aldosterone on renal distal tubular Na+

resorption and K+ and H+ excretion. In response to aldosterone, sodium is actively

transported across the tubular serosal membrane into the peritubular space.

Potassium and hydrogen ions are passively shunted across the mucosal membrane

in exchange for sodium.

• Aldosterone

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Fig. 15-19. Hypothetical mechanisms of aldosterone action on the kidney.

6. Mechanisms of Action • Aldosterone’s actions are mediated by intracellular

mineralocorticoid receptors.

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Fig. 15-20. AII receptor-cellular response coupling. PLC, phospholipase C; DAG,

diacylglycerol; IP3, inositol triphosphate; G protein, guanosine triphosphate-binding

protein; PKC, protein kinase C; AA, arachidonic acid; PC, phosphatidylcholine; LysPC,

lysophosphatidylcholine; LO, lipoxygenase; CO, cyclooxygenase; HETE, hydroxy-

eicostatetraenoic acid; TXA2, thromboxane A2; PGs, prostaglandins (e.g., prostaglandin

E2); channel, calcium channel; PIP2, phosphatidylinositol diphosphate; LTs, leukotrienes.

• Angiotensin II actions are mediated by cognate G-protein-coupled

receptors, AT1 and AT2.

Nucleus

Induced gene

GRE

GC bound to

CBG

GC receptor

GC-receptor

complex

Free GC

diffusion into cell

CYTOPLASM

mRNA mRNA

transcription translation protein

metabolic

response

Model of glucocorticoid (GC) action. GC is transported in plasma

bound to corticosteroid binding protein (CBG).

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• Physiological roles of adrenal androgens have

yet to be clarified.

• Secretes both male and female sex hormones in

both sexes

– Dehydroepiandrosterone (DHEA)

• Only adrenal sex hormone that has any biological

importance

• Overpowered by testicular testosterone in males

• Physiologically significant in females where it

governs

– Growth of pubic and axillary hair

– Enhancement of pubertal growth spurt

– Development and maintenance of female sex

drive

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Fig. 15-21. Summary scheme of the etiology of

hypocortisolism and hypercortisolism.

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Disorders of Adrenocortical Function

• Adrenocortical insufficiency

– Primary adrenocortical insufficiency

• Addison’s disease

• Autoimmune disease

– Aldosterone deficiency

» Hyperkalemia and hyponatremia

– Cortisol deficiency

» Poor response to stress

» Hypoglycemia

» Lack of permissive action for many metabolic activities

– Secondary adrenocortical insufficiency

• Occurs because of pituitary or hypothalamic abnormality

• Only cortisol is deficient

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급성부신부전증 Primary Acute Adrenocortical Insufficiency

• Corticosteroid를 장기간 투여하여 부신피질이 위축된 환자에게서 급작한 corticosteroid 투여 중지

• 부신기능이 약한 환자에게서 감염 또는 수술 등의 스트레스

• 부신의 출혈성 파괴(adrenal apoplexy: Waterhouse-Friderichsen syndrome)

• 임상증상: 저혈압, 쇼크, 사망

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Primary Acute Adrenal Cortical

Insufficiency

(Waterhouse-Friderichsen

Syndrome)

• Meningococci from blood, spinal

fluid and/or throat

• Circulatory collapse, marked

hypotension

• Extensive purpura, shock,

prostration, cyanosis

• Hemorrhagic destruction of

adrenal gland

• Characteristic fever chart

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Primary Chronic Adrenal

Cortical Insufficiency

(Addison Disease)

1. Autoimmune adrenalitis: 60~70%

2. Infections (e.g., tuberculosis)

3. Metastatic neoplasia

4. etc., histoplasmosis, trauma, etc.

(5%)

• Progressive weakness and easy fatigability

• Gastrointestinal disturbances

• Hyperpigmentation: hair, skin, nipple,

scars, mucous memb.

• Vitiligo

• Hyperkalemia

• Hyponatremia

• Volume depletion

• Hypotension

• Hypoglycemia (rarely)

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Laboratory Findings

In Primary Adrenal

Cortical Insufficiency

(Addison’s Disease) -1

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부신기능항진증

1. Hyperaldosteronism (원발성 알도스테론증):

↑ aldosterone

2. Cushing syndrome (쿠싱증후군): ↑cortisol

3. Adrenogenital or virilizing syndrome (부신-성 증후군):

↑ androgen

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Disorders of Adrenocortical Function

• Aldosterone hypersecretion

– May be caused by

• Hypersecreting adrenal tumor made up of aldosterone-

secreting cells

– Primary hyperaldosteronism or Conn’s syndrome

• Inappropriately high activity of the renin-angiotensin

system

– Secondary hyperaldosteronism

– Symptoms

• Excessive Na+ retention and K+ depletion

• High blood pressure

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원발성 알도스테론증 (Conn Syndrome)

1. Adenoma (부신선종): 80% 2. Uncommon cause

3. Rare cause:

glucocorticoid suppressible

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Fig. 15-22. Genetic defect in 17-hydroxylase activity leading

to hyperaldosteronism.

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Primary

Hyperaldosteronism

(Conn Syndrome)

Increased aldosterone

• Extracellular fluid increased

• Body sodium increased

• Body potassium decreased

• Increased fecal potassium loss

• Polydipsia

• Hypertension

• Chvostek’s sign positive

• Trousseau’s positive

• Polyuria

• Increased urinary aldosterone

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Disorders of Adrenocortical Function

• Cortisol hypersecretion

– Cushing’s syndrome

– Causes • Overstimulation of adrenal

cortex by excessive amounts

of CRH and ACTH

• Adrenal tumors that uncontrollably secrete cortisol independent of ACTH

• ACTH-secreting tumors located in places other than the pituitary

– Signs and symptoms • Hyperglycemia and glucosuria (adrenal diabetes)

• Abnormal fat distributions

– “buffalo hump” and “moon face”

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뇌하수체성 쿠싱증후군: 70%(내인성) 부신성 쿠싱증후군: 20%(내인성)

이소성 쿠싱증후군: ~10%(내인성) 의원성 쿠싱증후군: 실제로 가장 흔함

Hypercortisolism(Cushing Syndrome)

소세포폐암

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Cushing’s Syndrome:

Clinical Findings

• Elevated glucocorticoids

• Excessive gluconeogenesis

• Hyperglycemia

• Protein shortage

• Adrenal diabetes

• Red cheeks

• Moon faces: 85%

• Abnormal fat distributions

• Fat pads (Buffalo hump): 85-90%

• Mobilization of amino acids

• Red striae: 50%

• Thin skin

• Bruisability/Ecchymoses

• Poor wound healing

• Osteoporosis: 70%

• High B.P.: 75%

• Thin arms and legs

• Pendulous abdomen

• Compressed (Codfish) vertebrae

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Disorders of Adrenocortical Function

• Adrenal androgen hypersecretion

– Adrenogenital syndrome

– Symptoms • Adult females

– Hirsutism

– Deepening of voice, more muscular arms and legs

– Breasts become smaller and menstruation may cease

• Newborn females

– Have male-type external genitalia

• Prepubertal males

– Precocious pseudopuberty

• Adult males

– Has no apparent effect

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Hormonal interrelationship in adrenogenital syndrome

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Consequences of C-21 hydroxylase

deficiency

Adrenogenital syndrome

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Adult Female Adrenogenital

Syndromes(부신성증후군)

1. Overactivity of adrenal cortex

2. Hyperplasia of adrenal cortex

3. Adnoma of adrenal cortex

4. Carcinoma of adrenal cortex

• Receding hair line, baldness

• Acne

• Facial hirsutism

• Androgenic flush

• Small breasts

• Male escutcheon

• Clitoral enlargement

• Heavy muscular arms and legs

• Generalized hirsutism

17-Ketosteroids

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그림 19-10

Newborn females

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The Biological Actions

of 17-Ketosteroids:

(Dehydroepiandrosterone)

(DHEA)

• Increased muscle mass

• Bone matrix deposition

• Calcium deposition

• Adrenarche

• Pyrogenic effect

• Hair line recession

• Sebaceous gland

• Hypertrophy (Acne)

• Facial hair

• Axillary hair

• Laryngeal enlargement

• Pubic hair

Precocious Pseudopuberty 66

성조숙증 급증: 5년 새 4.4배(2011.5.14)

• 성조숙증(precocious puberty)

• 성조숙증 환자는 여자 아이의 경우 만 8세 이전에 가슴이 발달하고, 남자 아이는 9세 이전에 고환이 커지는 증상을 보임.

•성조숙증으로 진료받은 나이는 지난해를 기준으로 5~9세 아동이 71%를 차지했음.

•성별로는 여자아이가 92.5%로 대부분임.

•성조숙증의 원인은 소아비만과 환경호르몬의 영향 등을 꼽음.

•난소나 중추신경계에 종양이 생겨 호르몬 분비에 이상이 생기는 경우도 드물게 있음.

•성조숙증을 앓게 되면 성장판이 빨리 닫혀 키가 충분히 클 수 없는 문제점이 있음.

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