BIO 5406 Notes, 2/23/05
STEROID BIOCHEMISTRY
I. Chemical Structure. [Hadley, pp. 366-368]
A. Cyclopentanophenanthrene nucleus (fig. 15.4).
1. Three six‑carbon rings in phenanthrene arrangement (A,B,C).
2. One five‑carbon ring (D).
B. Lipid‑soluble.
C. Naturally‑occurring steroids include cholesterol, bile salts,
adrenocortical steroids, sex hormones, vitamin D, ecdysone,
and some plant steroids.
II. Types of Steroid Hormones. [pp. 366-368]
A. Mineralocorticoids (ex. aldosterone).
1. Promote sodium retention by kidneys.
B. Glucocorticoids (ex. cortisol).
1. Affect carbohydrate metabolism.
C. Progestins (ex. progesterone).
1. Maintain pregnancy.
D. Estrogens (ex. estradiol).
1. Stimulate development of female secondary sex characteristics.
E. Androgens (ex. testosterone).
1. Stimulate development of male secondary sex characteristics.
III. Embryology. [pp. 364-365]
A. Steroid hormone‑producing cells originate in mesodermal tissues in
or near gonadal ridge (figure).
B. Migrate to final location.
1. Adrenal cortex.
2. Testes.
3. Ovaries.
IV. Common Biosynthetic Pathways. [pp. 366-370]
A. All adrenal and gonadal steroids share a common biosynthetic
B. Biosynthesis is directed towards certain end products by specific
enzymes.
C. Key enzymes are expressed during differentiation.
1. Presence or absence of key enzymes results in different
hormones produced by different cell types.
V. Steroidogenesis. [pp. 366-370]
A. Steroidogenesis is the conversion of cholesterol into various steroid
hormones.
B. Cholesterol (figure).
1. 27 carbons.
2. Synthesized in liver or obtained from diet.
3. Attached to proteins (lipoproteins) and released into blood.
C. Uptake of cholesterol into steroid hormone‑producing cells.
1. Low-density lipoprotein (LDL) cholesterol binds to membrane
receptors on the steroid‑producing cell.
2. Transferred into the cell cytoplasm by endocytosis.
3. Cholesterol is split from LDL and converted to cholesterol ester
(fatty acid + cholesterol).
4. Stored in lipid droplets.
D. Initiation of steroidogenesis.
1. Activation of cholesterol esterase.
a. Converts cholesterol ester to free cholesterol.
2. Free cholesterol is transported into mitochondria.
E. Side chain hydrolysis ‑‑ rate‑limiting step.
1. Cholesterol (C27) -----> pregnenolone (C21).
2. Catalyzed by desmolase.
3. Occurs in adrenal cortex, testes, ovaries, placenta.
4. After this step, steroid biosynthesis will proceed as far as the enzymes
present in that cell allow.
5. From this point on, the biosynthetic pathways begin to diverge.
VI. Anatomy of the Adrenal Cortex. [pg. 365]
A. Steroid hormone‑producing cells are located in adrenal cortex.
B. Zones of the adrenal cortex (fig. 15.2).
(Section of adrenal cortex (low power))
1. Zona glomerulosa (outer zone).
(Zona glomerulosa (high power))
a. Cells organized in clumps.
b. Produce mineralocorticoids.
2. Zona fasciculata (middle zone).
a. Thickest zone.
b. Cells arranged in fairly straight cords.
c. Produce glucocorticoids.
3. Zona reticularis (nearest medulla).
(Zona fasciculata/reticularis (low power))
a. Cells arranged in cords that run in various directions.
b. Produce adrenal androgens.
C. Circulation of the adrenal gland (figure).
1. Blood flow proceeds from outer zones, between cords in ZF and into
adrenal medulla.
2. Exits via central veins in medulla.
3. Allows the secretions of the adrenal cortex to influence secretion of
hormones by adrenal medulla.
VII. Steroid Hormones of the Adrenal Cortex. [pp. 363-364]
A. 1930's and early 1940's was the golden age of steroid biochemistry.
1. Over 45 different adrenal steroids identified.
3. Edward Kendall (also isolated thyroxine).
B. Potency of corticosteroids can be determined by bioassay.
1. Mineralocorticoid (MC) activity ‑‑ sodium retention in
adrenalectomized animals.
2. Glucocorticoid (GC) activity ‑‑ liver glycogen deposition.
VIII. Mineralocorticoid Pathway. [pp. 366-370]
A. MC biosynthesis takes place in zona glomerulosa.
B. Progesterone is an intermediate occurring early in the pathway.
[Note: HSD = hydroxysteroid dehydrogenase].
C. Key enzymes (figure).
1. 21‑Hydroxylase.
a. Required for MC activity.
b. 11‑Deoxycorticosterone is a potent MC with no GC activity
2. 11‑Hydroxylase.
a. Required for GC activity.
b. Corticosterone has both MC and GC activity.
c. Corticosterone is the major GC secreted by rats.
3. 18‑Hydroxylase.
a. Enhances MC activity.
b. Present only in ZG cells.
c. Aldosterone is the most potent natural MC.
IX. Glucocorticoid Pathway. [pp. 366-370]
A. Takes place in zona fasciculata.
B. Key enzyme ‑‑ 17‑hydroxylase.
1. Key enzyme for entering GC pathway.
2. Absent from ZG cells.
3. Enhances GC activity, reduces MC activity.
4. Cortisol is about 3x more potent than corticosterone as a GC and
15x less potent as a MC.
X. Androgen Pathway. [pp. 366-370, 423-424]
A. Takes place in zona reticularis, thecal cells of ovary, and Leydig
cells of testes.
B. Key enzyme ‑‑ 17,20‑desmolase.
1. Removes carbons 20 and 21.
2. Androgens are C19 steroids.
3. Results in androgenic activity.
4. Principal adrenal androgen ‑‑ dehydroepiandrosterone (DHEA).
XI. Estrogen Pathway. [pp. 366-368, 451-452]
A. Adrenal gland does not produce estrogens.
B. Key enzyme ‑‑ aromatase.
1. Converts ring A to aromatic ring.
2. Estrogens are C18 steroids.
3. Found in ovarian granulosa cells, placenta, and peripheral
tissues (such as fat) in males and females.
XII. Placenta. [pp. 366-368, 477-478]
A. Lacks 17‑hydroxylase and 21‑hydroxylase.
B. Produces progesterone from cholesterol (fig. 19.3).
C. Produces estrogens by aromatization of DHEA from fetus.
1. Fetal adrenal is as large as the fetal kidney.
2. 80% of cortex is composed of an inner fetal zone.
a. Fetal zone produces large amounts of DHEA.
b. Fetal zone degenerates after birth.
3. If fetus is dead or has nonfunctional adrenals, placenta produces only
progesterone.
XIII. Regulation of Steroid Biosynthesis. [pp. 371-372]
A. Example: Regulation of glucocorticoid biosynthesis by ACTH
(figure).
1. ACTH (corticotropin) is secreted by the anterior pituitary.
2. Binds to membrane receptors on ZF cells.
3. Activates adenylate cyclase.
4. Increases intracellular cAMP.
5. Series of phosphorylations leading to activation of cholesterol
esterase.
6. ACTH also promotes uptake of cholesterol into mitochondria.
7. Cholesterol is now available for conversion to pregnenolone.
8. Key enzymes are in place for synthesis of cortisol.
B. Other examples.
Trophic hormone
Cell type
Product
Angiotensin II
Adrenal ZG
Aldosterone
ACTH
Adrenal ZF
Cortisol
ACTH
Adrenal ZR
DHEA
LH
Leydig cells (testis)
Testosterone
LH
Thecal cells (ovary)
Testosterone
XIV. Disorders of Adrenal Steroid Biosynthesis. [pp. 389-391]
A. Congenital deficiencies of every key enzyme have been identified.
B. Congenital adrenal hyperplasia.
1. 21‑hydroxylase deficiency.
1. 1:10,000 live births.
2. Most severe form -- deficient in both aldosterone and cortisol.
3. Feedback hypertrophy of adrenal cortex -- congenital adrenal
hyperplasia.
4. Excess adrenal androgen secretion.
a. Virilization of female.
1. Masculinization of genitalia at birth (figure).
2. Excessive hair growth.
3. Menstrual irregularities.
b. Early sexual maturation of male.
1. Precocious puberty (figure).
2. Early growth spurt.
C. Primary hyperaldosteronism.
1. 17‑Hydroxylase deficiency (rare).
1. Excessive secretion of aldosterone (fig. 15.22).
2. Severe hypertension.
3. Poor gonadal development.
XV. Summary.
A. All steroid hormones are synthesized from cholesterol.
B. Steroid hormone producing cells are found in the three zones of the
adrenal cortex, testes, ovaries, and placenta.
C. Steroid hormone biosynthesis is regulated by cyclic AMP-mediated
activation of cholesterol esterase.
D. The final product of each gland depends on the expression of
specific enzymes in the steroid biosynthetic pathway.
E. Congenital deficiency of a specific enzyme results in a predictable
shift in the biosynthetic pathway, leading to a clinical disorder.
