Hormones

ENDOCRINE SYSTEM

DR.AMJAD H. ABID LECTURE (4)

THE ADRENAL GLANDS

In humans, each adrenal gland lies at the upper pole of each kidney. Each consists of a yellow outer cortex and a gray inner medulla. The cells of the adrenal cortex synthesize steroid hormones, while the cells of medulla synthesize catecholamines (such as dopamine, epinephrine, and nor- epinephrine).

THE ADRENAL CORTEX

It consists of 3 layers; the outermost thin layer (zona glomerulosa) secretes only aldosterone, and the inner 2 layers (zona fasciculata and zona reticularis) which form a functional unit that secretes most of the adrenocortical hormones. In the fetus, there is a wider fourth layer which disappears soon after birth. During fetal life one of its most important functions is that together with the adrenal cortex it synthesizes estriol in association with the placenta. In general, the adrenal cortex synthesizes and releases 3 classes of hormones:

MINERALOCORTRTICOIDS

GLUCOCORTICOIDS
ANDROGENES

General Steroid Chemistry:

Steroids are compounds that contain the cyclopentanoperhydrophenanthrene nucleus as the backbone structure. The six –sided rings (A, B and C) constitute the phenanthrene nucleus to which attached a cyclopentane ring (D). The prefix “perhydro” refers to the saturation of the compound with hydrogen atoms.
This class of compounds includes such natural products as sterol (e.g. cholesterol), bile acids (like cholanic acid), sex hormones (eg. estrogens and androgens), vitamin D and corticosteroids. The steroid hormones contain basically 17 carbon atoms and usually up to 21 C atoms (named 21 steroids) and these atoms are numbered as shown in the following figure:







The C-atoms composing the rings and the hydrogen atoms attached to them are not usually written into the structure unless it's necessary to draw special attention. Additional carbons can be added at position (10) and (13) or as side chain attached to C17.

Note:

These carbon atoms will take the # 18, 19 and 20. This means that the atom which is attached to C13 will take No. 18 and with # 10 will take #19 and so on.

Steroid hormones are three dimensional molecules with their constituting atoms lying in different planes –such spatial arrangements give rise to isomers. The direction of the hydrogen atoms of the basic nucleus and of the attached side chain plays a very important role in the distinction of various isomers. If the H atoms point in same direction as that of the angular methyl group at C-10, the compound is said to be in the Cis or normal form and is presented by drawing solid lines (__). On the other hand, if however, they are on the opposite side the compound is said to be in the (Trans) form, and is represented as dashed lines (--). Although rings A, B may be cis or Trans, the rings C, D have the Trans configuration in all naturally occurring steroid hormones. Steroid hormones are characterized by the presences of double bonds which are referred to by the no. of the preceding carbon atom that is involved with the label of delta.

3

4

Note: the # refers to the initiation or beginning of the double bond; example: 3 means double bond start from C 3 to C4, and so on.

The steroid hormones can be also named according to whether they have angular methyl group (estrange 18 C atom) or two angular methyl groups (androstane with 19 C atom) or two angular methyl groups+ two carbon side chains at C17 (pregnane, 21C).

These hormones share in being acting by combining certain intracellular receptors. The hormone- receptor complex will act on certain areas of DNA synthesis leading to altered gene replication and expression which intermittently leads to altered rate of synthesis of certain proteins that mediate the action on the target tissues like exerting their effects on various metabolic processes e.g. gluconeogenesis and NA and K ions balance, ….etc.


BIOSYNTHESIS OF STEROID HORMONES

The adrenal steroid hormones are synthesized from cholesterol which is mostly derived from the plasma, but a small portion is synthesized insitu from acetyl- CoA ( adrenal cortex ) via mevalonate and squalene cycle. Much of the cholesterol in the adrenal cortex is esterified and stored in the cytoplasmic lipid droplets and kept over there. Upon stimulation of the adrenal cortex by ACTH (or cAMP), an asterase enzyme is activated and free cholesterol will be formed which is transported into mitochondria where a cytochrome p450 scc (side chain cleavage enzyme) converts cholesterol to pregnenolone and alpha – isocapro aldehyde. The first step is hydroxylation of steroidogene which is the hydroxylation of C20 and C22 of the side chain. “Occur in mitochondria.”

The cleavage of C20 to C22 bond is catalyzed by a heme- containing enzyme called cholesterol demolase, which is found in mitochondria yielding the delta 5 pregnenolone and isocaproic aldehyde. Pregnenolone leaves the mitochondria and enters the cytoplasm for further metabolism.
There are 2 additional relatively fast acting hydroxylases located in the endoplasmic reticulum. These are 17 alpha hydroxylase and 21 alpha hydroxylase.
The transformation of cholesterol into corticosteroids has been seen to follow 2 pathways, one terminating in ALDOSTERONE and the other in CORTISOL.





Cleavage of the side chain involves sequential hydroxylation at theC22 carbon atom and the C20 carbon atom. These are followed by side chain cleavage (removal of the six carbon fragments “ isocaproaldehyde to give 21 carbon atom steroids.”)

Zona glomerioloza lies beneath the adrenal capsule and its function is to produce aldosterone where Zona fasiculata is an inner layer of the cortex and serves to produce cortisol. It has been estimated that in normal adult man:
10-20 mg of cortisol.
3mg of corticostrerone. are synthesized daily.
0.3 mg of aldosterone.

Pregnenolone: is produced directly from cholesterol, the precursor molecule for all C18, C19 and C21 steroids


Progesterone: a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstrual cycle, and a differentiation factor for mammary glands

Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake.

Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone.

Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics.

Cortisol: dominant glucocorticoid in humans, synthesized from progesterone in the zona fasciculata of the adrenal cortex, involved in stress adaptation, elevates blood pressure and Na+ uptake, numerous effects on the immune system.