PHYSIOLOGY- 4TH BIMO ALDOSTERONE TRANSPORT AND METABOLISM
THE ENDOCRINE SYSTEM
(THE ADRENAL GLAND)
Dr.Paloma
ANATOMY
ADRENAL GLAND (SUPRARENAL GLANDS)
- Bilateral structures located immediately above the
kidneys
- TWO LAYERS: ADRENAL MEDULLA
ADRENAL CORTEX:
-Zona Glomerulosa
-Zona Fasciculata
-Zona Reticularis
*Histology of the adrenal gland. Low magnification illustrating the
1 outer cortex and inner medulla
ZONA GLOMERULOSA
- Thin outermost zone, produces the
MINERALOCORTICOID ALDOSTERONE (90% of
mineralocorticoid activity), which regulate salt and
volume homeostasis. Regulated primarily by RENIN-
ANGIOTENSIN SYSTEM and minimally by ACTH. Its
cell never make cortisol nor adrenal androgens in
any form.
ALDOSTERONE SYNTHESIS
- Derived from CHOLESTEROL
- Cholesterol is converted to PREGNENOLONE, to
PROGESTERONE to DEOXYCORTICOSTERONE (DOC)
by the enzymes 3B-HSD and CYP21 respectively
*Steroidogenic pathways in the zona glomerulosa. The first common
reaction in the pathway, conversion of cholesterol to pregnenolone
by CYP11A1.
- Binds to ALMBUMIN and CORTICOSTEROID BINDING
PROTEIN in blood with low affinity so has a
biological half life of 20 minutes.
- Almost all aldosterone is inactivated by the liver in
one pass conjugated by glucuronide group and
excreted by the kidney
DocTrojan
*The mineralocorticoid receptor (MR) is protected from
activation by cortisol by the enzyme 11 B-hydroxysteroid
dehydrogenase type 2 (11B-HSD2), which converts cortisol to
inactive cortisone. Cortisone can be converted back to
cortisol in glucocorticoid target cells by the enzyme 11B-HSD
type 1. GTF (General Transcription Factors); MRE
(Mineralocorticoid Response Element); GRE (Glucocorticoid
Response Element)
PHYSIOLOGIC ACTIONS OF ALDOSTERONE
- Stimulates sodium reabsorption in the distal and
collecting tubules
- Increases renal excretion of potassium (Na+K+
counter transport)
- Increases renal excretion of hydrogen (Na-H counter
transport)
- Increases renal reabsorption of anions (eg.Cl-)
- Increases ECF volume by drawing water with NaCl
- Increases NaCl reabsorption in salivary and sweat
glands
ZONA FASICULATA
- Produces GLUCOCORICOID hormone-CORISOL
- This zone is actively STEROIDOGENIC tissue
composed of straight cords of large cells with
“foamy” cytoplasm that represent stored
cholesterol esters.
- These cells synthesize cholesterol de novo but also
import from the blood in the form of LDL and HDL
 CORTISOL SYNTHESIS
- Free cholesterol are esterified and stored in lipid
droplets. Stored cholesterol is continually being
converted back to free cholesterol by CHOLESTEROL
ESTER HYDROLASE; the amount depend on the
degree of stimulation for e.g. by ACTH
- In this zone, the cholesterol is converted
sequentially to PREGNENOLONE, PROGESTERONE,
17-HYDROXYPROGESTERONE, 11-DEOXYCORTISOL,
AND CORTISOL
- A similar pathway involves the conversion of
progesterone to 11-deoxycorticosterone (DOC) to
corticosterone. The production of DOC is significant
because this acts as a weak mineralocorticoid;
elevated levels of DOC can cause hypertension

TRANSPORT AND METABOLISM OF CORTISOL

- Transported in the blood predominantly bound to :
- CORICOSTEROID BINDING GLOBULIN (CBG) or
TRANSCORTIN- 90%
- Albumin- 5-7%
- Circulating half-life is about 70 minutes
- The liver is the predominant site of steroid
inactivation
- It conjugate active and inactive steroid with
glucuronide or sulfate so they can be excreted
readily by the kidney

- Cortisol is reversibly inactivated by conversion to

cortisone by the enzyme 11B-hydroxysteroid *Comparison of a normal hypothalamic-pituitary-adrenal
2 dehydrogenase type 2 (11B-HSD2). It is 11B-HSD1 (HPA) axis to a quiescent HPA axis in individual DocTrojan
receiving
that converts cortisone back to cortisol. exogenous glucocorticoid therapy. The latter causes the zona
fasciculate to atrophy after 3 weeks, thus requiring a careful
CORTISOL MECGANISM OF ACTION withdrawal regimen to allow rebuilding of the adrenal tissue
- Act through the glucocorticoid receptor (GR) before total cessation of exogenous corticosteroid
- In the absence of hormone, GR residues in the administration.
cytoplasm in a stable complex with several
molecular chaperones including heat shock protein CORTISOL PHYSIOLOGUC ACTIONS
and cyclophilins 1. INTERMEDIARY METABOLISM
- Cortisol- GR binding promotes dissociation of the - Increased hepatic glycogenesis
chaperone proteins followed by the following: - Increased hepatic gluconeogenesis
- Increased blood glucose
1. Rapid translocation of the cortisol-GR complex into - Increased protein metabolism
the nucleus - Increased plasma amino acids
2. Dimerization and binding to GLUCOCORTICOID - Increased lipolysis
RESPONSE ELEMENT - Increased plasma lipids and ketone bodies
3. Recruitment of COACTIVATOR PROTEINS and
assembly of general transcription factors to increase 2. FEEDBACK OF ACTH SECRETION
transcription of targeted genes
3. CARDIOVASCULAR
CORTISOL REGULATION OF SECRETION - Maintenance of vascular sensitivity to
1. Corticotropin-releasing hormone (CRH) is released catecholamine
from the hypothalamus in response to stress or 4. GROWTH AND DEVELOPMENT
hypoglycemia - Increased pulmonary surfactant production
2. Passes by way of the hypothalamic-pituitary portal - Development of hepatic and gastrointestinal
system, to the anterior pituitary enzymes
3. It binds and stimulate cells that secrete ACTH 5. HEMATOLOGIC
4. ACTH acts on the adrenal cortex and stimulates the - Increased circulating neutrophils, erythrocytes and
secretion of cortisol platelets
5. Cortisol in turn acts on its largest tissues to increase - Decreased circulating lymphocytes, eosinophils and
protein breakdown and increase blood glucose level monocytes
6. Acts on the hypothalamus to decrease CHR - Inhibition of migration of white blood cells
secretion - Lympholysis and decreased size of lymph nodes and
thymus
 6. RENAL
- Increased ability to excrete free water
- Increased uric acid excretion
7. GASTRIC
- Increased gastric acid secretion Steroidogenic pathways in the zona reticularis. The first
- Decreased gastric mucosal proliferation common reaction in the pathway, conversion of cholesterol
8. CNS to pregnenolone by CYP11A1. Expression of 3B-
- Excess amount can initially produce a feeling of well- hydroxysteroid dehydrogenase (3B-HSD) is relatively low in
being but in long term, can lead to emotional the zona reticularis, so androstenedione is a minor product
liability and depression in comparison to DHEA and DHEAS. The zona reticularis also
- Increase tendency for insomnia and decrease rapid make a small amount of testosterone and estrogens.
eye (REM) sleep
- People deficient in corticosteroid are depressed, ANDROGENS PHYSIOLOGIC ACTIONS
apathetic, and irritable - Negligible contribution of adrenal androgens in men
9. RESISTANCE TO STRESS - Contribute to around 50% of circulating active
androgens in women; these are required for the
CLINICAL CORRELATES growth of axillary and pubic hair and for libido
- No other clear role aside from providing androgen
ADDISONS DISEASE precursors
1. Weakness - DHEAS is the most abundant circulating hormone in
2. Fatigability young adults. It steadily increases until it peaks in
3. Anorexia the mid-twenties, then slowly declines thereafter.
4. Weight loss
5. Hypotension ZONA RETICULARIS REGULATION OF FUNCTION
6. Hyperpigmentation (ACTH) - ACTH is the major regulator of zona reticularis
7. Hypoglycemia
8. Low resistance to stress CLINICAL CORRELATES
1. Adrenal androgen excess (e.g. adrenal tumor,
Cushing’s syndrome, congenital adrenal hyperplasia)
CUSHING SYNDROME can cause MASCULINIZATION IN WOMEN. This
1. Easy bruisability and striae involves:
3 2. Osteoporosis a. MASCULINIZATION OF EXTERNAL DocTrojan
GENITALIA
3. Muscle wasting and weakness (e.g. enlarge clitoris) in utero
4. Moon faces; truncal obesity b. HIRSUTISM- excessive facial and body hair
5. Hypertension c. ACNE in adult women
6. Hirsutism, amenorrhea and acne d. OVARIAN DYSOVULATION (e.g. polycystic
7. Hyperglycemia ovarian syndrome)
8. Euphoria, emotional liability and depression

ZONA RETICULARIS
- Dehydroepiandrosterone (DHEA)
- The innermost zone. Begin to appear after birth at 5
y.o.
- At 6 y.o. DHEA begin to be detectable in the
circulation, termed ADRENARCHE; this contributes
to the appearance of axillary and pubic hair at 8 y.o.
- DHEA levels continues to increase and peaks at mid-
twenties then continuously decline with old age

ANDROGEN SYNTHESIS
- Zona reticularis differ from zona fasciculata with
respect to steroidogenic enzyme activity.

1. Zona reticularis has lower 3B-HSD than zona

fasciculata thus the delta pathway predominates in
the zona reticularis
2. Zona reticularis expresses cofactors or conditions
that enhance the 17, 20 lyase function of CYP17,
thus generating dehydroepiandrosterone (DHEA)
from 17-hydroxyprenenolone
3. Zona reticularis expresses DHEA sulfotansferase
(SULT2A1 gene) which convert DHEA into DHEAS
4. Zona reticularis also synthesize ANDROSTENEDIONE
5. But the most active sex steroids are from peripheral
conversion of DHEAS and androstenedione