1. Adrenal Glands
Part 2

2. Control of Adrenal Cortical Hormone Synthesis
Control of aldosterone synthesis:
The control of aldosterone synthesis is more complex than that of the glucocorticoids
Although cells of the zona glomerulosa express ACTH receptors and ACTH is required for optimal secretion, ACTH is not an important regulator of aldosterone production in most species
Angiotensin II production is the hormonal signal for increase production of aldosterone
Angiotensin II reacts with specific G-protein-coupled membrane receptors, but does not use cyclic AMP as its second messenger

3. Stimulation of Aldosterone Synthesis by Angiotensin II
Angiotensin II (AII) activates G-protein subunits which cause:
Activation of PLC to release IP3 & DAG
IP3 causes increase in Ca2+ release
DAG activates PKC to phosphorylate StAR and to open Ca2+ channels
calmodulin-dependent protein kinase (CAM kinase II) increases the activity and synthesis of the StAR protein
transfer of cholesterol into the mitochondria and the formation of pregnenolone
The increase in cytosolic Ca2+ stimulates the enzymes which catalyzes the critical final reactions in aldosterone synthesis
The resulting depolarization of the membrane opens voltage-gated calcium channels and allows calcium to enter.
PLC: phospholipase C. , DAG: diacylglycerol;
IP3: inositol trisphosphate; PKC: protein kinase C; CAM kinase II calcium: calmodulin-dependent protein kinase II; StAR: steroid acute regulatory protein

4. Regulation of Aldosterone by Potassium and Atrial Natriuretic Factor
Cells of the zona glomerulosa are exquisitely sensitive to changes in concentration of potassium in the extracellular fluid
As extracellular potassium increases
voltage-sensitive calcium channels are activated
This increases intracellular calcium and activates calmodulin kinase II which increases aldosterone as already described
Synthesis and secretion of aldosterone are negatively regulated by atrial natriuretic factor (ANF):
which activates potassium channels and thereby opposes opening of voltage sensitive calcium channels
Additionally, ANF reduces synthesis and phosphorylation of the StAR protein and inhibits transcription of its gene

5. Adrenal Steroid Hormones in Blood
Adrenal cortical hormones are transported in blood bound to a specific plasma protein:
Transcortin or corticosteroid binding globulin (CBG),
and to a lesser extent to albumin
CBG has a single steroid hormone binding site whose affinity for cortisol is nearly 20 times higher than for aldosterone
The androgens bind mainly to albumin
Other endogenous steroids usually do not significantly affect cortisol binding to CBG;
an exception is in late pregnancy, when progesterone may occupy about 25% of the binding sites on CBG

6. Postsecretory Metabolism of Adrenal Cortical Hormones
Metabolic transformations of steroid hormones are not confined to the glands of origin, but may continue after secretion, and may increase, decrease, or otherwise change biological activity
Several steroid metabolizing enzymes are expressed in steroid target tissues
Under normal circumstances the concentration of free or unbound cortisol in plasma is about 100 times that of aldosterone
the mineralocorticoid receptor binds aldosterone and cortisol with nearly equal affinity, it cannot distinguish between the two classes of steroid hormones
Among these are two isoforms of the enzyme 11 β hydroxysteroid dehydrogenase (11 β HSD I and 11 β HSD II)
HSD: hydroxysteroid dehydrogenase
Oxidation of cortisol to cortisone renders the steroid incapable of binding to the mineralocorticoid receptor

7. Postsecretory Transformations of Androgens
Dehydroepiandrosterone sulfate (DHEAS), the major product of the zona reticularis, is the most abundant steroid hormone in the circulation
Neither DHEAS nor its close relative androstenedione bind to the androgen receptor, but these 19 carbon steroids are converted to active male and female sex hormones within some peripheral target cells
For the most part, these peripherally formed hormones do not enter the circulation, and their biological actions are limited to the cells in which they are formed
The term Intracrinology has been used to describe production of hormones by the cells in which they act without escaping into the extracellular fluid

8. Extra-adrenal Synthesis of Testosterone and Estrogens From DHEAS

9. Inactivation of Adrenal Cortical Steroids
Mammals cannot degrade the ring structure of the steroid nucleus
Steroid hormones are inactivated, mainly in the liver, by metabolic changes that make them unrecognizable to their receptors
This also makes them more soluble to pass through renal glomerular capillaries and to be excreted in the urine
Because recognizable hormonal derivatives are excreted in urine, it is possible to estimate daily secretory rates of steroid hormones by the noninvasive technique of measuring their abundance in urine
The major products of adrenal steroid hormone degradation are glucuronide esters of 17-hydroxycorticosteroids (17-OHCS) derived from cortisol, and 17-ketosteroids (17 KS) derived from glucocorticoids and androgens.

10. Physiology of the Mineralocorticoids
Aldosterone is by far the most important mineralocorticoid which can produce mineralocorticoid effects
Reabsorption of sodium is diminished in the absence of aldosterone, and with loss of sodium, there is an:
accompanying loss of water
and a resulting decrease in blood volume
Simultaneous with the loss of sodium, the ability to excrete potassium is impaired, and with continued dietary intake, plasma concentrations of potassium may increase
Causes cardiac arrhythmia and weakness of muscles including the heart

11. Proposed Mechanisms of Action of Aldosterone in The Kidney
Aldosterone sensitive cells, called principal cells
Sodium enters principal cells in the cortical collecting ducts through epithelial sodium channels (ENaC)
Na+ is extruded into the interstitial space by the sodium/potassium ATPase pump
Potassium exits through ROMK (renal outer medullary K) channels in the luminal surface or through basolateral potassium channels

12. Proposed Mechanisms of Action of Aldosterone in The Kidney
After a delay of ~30 minutes aldosterone increases expression of the serum glucocorticoid-induced kinase 1 (SGK1)
SGK1 increases ENaC in luminal membranes by phosphorylating and inactivating the ubiquitin ligase Nedd4-2 that initiates ENaC retrieval
SGK1 also phosphorylates and increases the activity of ROMK channels
ROMK: renal outer medullary K+
MR: mineralocorticoid receptor;
HSD II: 11 β-hydroxysteroid dehydrogenase II

13. Regulation of Aldosterone Secretion

14. Physiology of the Glucocorticoids
Effects on energy metabolism

15. Physiology of the Glucocorticoids
Effects on lung development
Increase maturation and surfactant production during fetal development
Glucocorticoids and responses to injury
Exert anti-inflammatory effects, modulate synthesis, secretion, and actions of inflammatory mediators
Glucocorticoids modulate virtually all aspects of the inflammatory response by multiple tissue-specific actions that modulate synthesis, secretion, and actions of
inflammatory mediators

16. Regulation of Glucocorticoid Secretion
In the absence of ACTH the concentration of cortisol in blood decreases to very low values, and the inner zones of the adrenal cortex atrophy
Vasopressin (AVP) also exerts an important influence on ACTH secretion by augmenting the response to CRH