1. Adrenal Glands

2. Significance
The adrenal glands are complex polyfunctional organs whose secretions are required for maintenance of life
Adrenal cortical hormones directly or indirectly affect almost every physiological process and hence are central to the maintenance of homeostasis
Insufficiency of adrenal cortical hormones produced by pathological destruction or surgical removal of the adrenal cortices results in death within one to two weeks unless replacement therapy is instituted

3. Significance
Virtually every organ system goes awry with adrenal cortical insufficiency, but the most likely cause of death appears to be circulatory collapse secondary to sodium depletion
When food intake is inadequate, death may result instead from insufficient amounts of glucose in the blood (hypoglycemia)

4. Morphology
The adrenal glands are bilateral structures situated above the kidneys
They are comprised of:
Cortex
The outer region
Normally makes up more than three-quarters of the adrenal mass
Medulla
The inner region

5. The Adrenal Cortex
The cortex is subdivided histologically into three zones
Zona Glomerulosa
Cells in the outer region
Arranged in clusters (glomeruli)
Zona Fasciculata
Comprises the bulk of the cortex
rows of lipid-laden cells are arranged radially in bundles of parallel cords (fasces)
Zona Reticularis
The inner region
Consists of a tangled network of cells
The fasciculata and reticularis, which produce both cortisol and the adrenal androgens, are functionally separate from the zona glomerulosa

6. Categories of Adrenal Cortical Hormones
Adrenal cortical hormones have been divided into three categories based on their functions
The mineralocorticoids which are necessary for maintenance of sodium and potassium balance
Aldosterone
Deoxycorticosterone
The glucocorticoids and are so named for their ability to maintain carbohydrate reserves in addition to a variety of other effects
Cortisol
Corticosterone (to a lesser extent)
Deoxycorticosterone is considered as a precursor of aldosterone

7. Categories of Adrenal Cortical Hormones
Androgens, which as their name implies, have biological effects similar to those of the male gonadal hormones
Adrenal androgens mediate some of the changes that occur at puberty
Play an important role during fetal life
They are closely related to steroid hormones produced by the testis and ovary and are synthesized from common precursors
The principal adrenal steroid hormones

8. Synthesis of Steroid Hormones
The starting material for steroid hormone biosynthesis is cholesterol
most of which arrives at the adrenal cortex in the form of low density lipoproteins
taken up avidly from blood by a process of receptor-mediated endocytosis
Adrenal cortical cells also synthesize cholesterol from carbohydrate or fatty acid precursors
Substantial amounts of cholesterol are stored in steroid hormone-producing cells in the form of fatty acid esters

9. Synthesis of Steroid Hormones
Key reactions in the biosynthesis of the adrenal hormones are catalyzed by a particular class of oxidizing enzymes, the cytochromes P450
The rate-limiting step in the biosynthesis of all the steroid hormones is the conversion of the 27-carbon cholesterol molecule to the 21-carbon pregnenolone molecule
The rate of steroid hormone biosynthesis is determined by the rate at which cholesterol is presented to P450scc and converted to pregnenolone
Th is conversion is catalyzed by a unique enzyme, P450 side chain cleavage enzyme (P450scc), which resides on the inner mitochondrial membrane
All reactions are catalyzed by a single enzyme, cytochrome P450 scc

10. Synthesis of Steroid Hormones
To gain access to the enzyme, cholesterol must first be released from its esterified storage form in the cytosol by the action of an esterase
The free, but water insoluble cholesterol must then be transferred to the mitochondrial surfaces through the help of cholesterol binding proteins with participation of cytoskeletal elements, and then must enter the mitochondria
Passage across the mitochondrial membrane bilayer requires synthesis and phosphorylation of the short-lived steroid acute regulatory (StAR) protein
Blockade of StAR synthesis blocks steroidogenesis
The exit of pregnenolone does not need StAR

11. Pregnenolone is the common precursor of all steroid hormones produced by the adrenals or the gonads
Different enzymes are involved in the synthesis of steroid hormones from Pregnenolone which involve different oxidation reactions
Androstenedione: A steroid produced in the adrenal gland that is a precursor to testosterone

12. Control of Adrenal Cortical Hormone Synthesis
Adrenocorticotropic hormone (ACTH) secreted by the anterior pituitary gland maintains normal secretory activity of the zona fasciculata and reticularis of the adrenal cortex
After removal of the pituitary gland, little or no steroidogenesis occurs in the zona fasciculata or reticularis, but the zona glomerulosa continues to function
In cells of all three zones, ACTH interacts with a G-protein-coupled membrane receptor, the melanocortin 2 (MR2) receptor, and triggers production of cyclic AMP
Cyclic AMP activates protein kinase A, which catalyzes the phosphorylation of a variety of proteins and thereby modifies their activity

13. Control of Adrenal Cortical Hormone Synthesis
Stimulation of steroidogenesis by ACTH in zona fasciculata cells
Conversion of cholesterol to pregnenolone requires mobilization of cholesterol from its storage droplet and transfer to the P450scc enzyme on the inner mitochondrial membrane
ACTH may also increase cholesterol uptake by increasing the number or affinity of low density lipoprotein (LDL) receptors
AC: adenylyl cyclase,
StAR: steroid acute regulatory protein

14. Control of Adrenal Cortical Hormone Synthesis
In the zonae fasciculata and reticularis this results in:
accelerated deesterification of cholesterol esters,
increased transport of cholesterol to the mitochondria,
increased activity of preexisting StAR protein
and increased synthesis of StAR protein
Thus the immediate actions of ACTH accelerate the delivery of cholesterol to the P450scc enzyme on the inner mitochondrial membrane to form pregnenolone
With continued stimulation, ACTH, acting through cyclic AMP and protein kinase A, also stimulates transcription of genes encoding the P450 enzymes, the LDL (low density lipoprotein) receptor responsible for uptake of cholesterol, and the StAR protein

15. Control of Adrenal Cortical Hormone Synthesis
ACTH either directly or indirectly also increases blood flow to the adrenal glands
Increased blood flow provides not only needed oxygen and metabolic fuels, but also increases the capacity to deliver newly secreted hormone to the general circulation
Unlike other endocrine cells, steroid-producing cells do not store hormones, and hence biosynthesis and secretion are components of a single process regulated at the step of cholesterol conversion to pregnenolone

16. Control of Adrenal Cortical Hormone Synthesis
ACTH is the only hormone known to control synthesis of the adrenal androgens which are produced primarily in the zona reticularis
Little or no androgen is produced in young children whose adrenal glands contain only a rudimentary zona reticularis
The reticularis with its unique complement of enzymes develops shortly before puberty
Puberty is preceded by a dramatic increase in production of the adrenal androgens principally dehydroepiandrosterone sulfate (DHEAS), which are responsible for growth of pubic and axillary hair