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CHAPTER 41: THE DIVERSITY OF THE ENDOCRINE SYSTEM PART 1
Weil, PA (2015) Harper’s Illustrated Biochemistry 30th Ed
...
pg498 - 507





Provide mechanisms of intercellular communication
that are required in the adaptation to a constantly
changing environment
“Hormone”
o Derived from the Greek word  to arouse
to activity
o A substance that is synthesized in one organ
and transported by the circulatory system
to act on another tissue
o Can also act on adjacent cells (paracrine
action) and on the cell in which they were
synthesized (autocrine action) without
entering the systemic circulation




TARGET CELL CONCEPT


A target is defined as any cell in which the hormone
(ligand) binds to its receptor



Table 1
...
Determinants of the Target Cell Response

The number, relative activity, and state of occupancy of
the specific receptors on the plasma membrane or in the
cytoplasm or nucleus
The metabolism (activation or inactivation) of the hormone
in the target cell
The presence of other factors within the cell that are
necessary for the hormone response
Up- or downregulation of the receptor consequent to the
interaction with its ligand
Post-receptor desensitization of the cell, including
downregulation of the receptor


A target must be able to distinguish different
hormones present in very small amounts, but also

between a given hormone and the excess of other
similar molecules
o Provided by cell-associated recognition
molecules called receptors
A target cell is defined by its ability to selectively
bind a given hormone to its cognate receptor
o Biochemical features of hormone-receptor
interactions:
 Binding should be specific
 Binding should be saturable
 Binding should occur within the
concentration range of the
expected biologic response
All receptors have at least two functional domains :
o Recognition domain binds the hormone
ligand
o Generates a signal that couples hormone
recognition to intracellular function
Receptor-effector coupling
o Dual purpose that provides the first step in
amplification of the hormonal response
o Distinguishes the target cell receptor from
the plasma carrier proteins that bind
hormone but do not generate a signal

CLASSIFICATION OF HORMONES


Hormones can be classified according to:
o Chemical composition
o Solubility properties
o Location of receptors
o Nature of the signal used to mediate
hormonal action within the cell

Table 3
...
General Features of Hormone Classes

Group I
Steroids,
Iodothyronines,
Calcitriol, Retinoids

Types

Solubility
Transport
proteins
Plasma halflife
Receptor
Mediator





Lipophilic
Yes

Group II
Polypeptides,
proteins,
glycoproteins,
catecholamines
Hydrophilic
No

Long (hours to days)

Short (minutes)

Intracellular
Receptor-hormone
complex

Plasma membrane
cAMP, cGMP, Ca2+,
metabolites of
complex
phosphoinositols,
kinase cascades

Group I
o After secretion, these hormones associate
with plasma transport or carrier proteins
o The relative percentages of bound and free
hormone are determined by the amount,
binding affinity, and binding capacity of the
transport protein
 Free hormone: readily traverses
the lipophilic plasma membrane of
all cells and encounters receptors
in either the cytosol or nucl eus of
target cells
 Ligand-receptor complex as the
intracellular messenger
Group II
o Water-soluble hormones
o Bind to specific receptors in the plasma
membrane of the target cell
o Hormones communicates with intracellular
metabolic processes through intermediary
molecules (second messengers)

DIVERSITY OF THE ENDOCRINE SYSTEM


Hormones are synthesized in discrete organs
designed for specific purpose
...
1: Ovaries produce oocytes and
reproductive hormones such as
progesterone and estradiol
o Ex
...
3: In specialized cells within other
organs:
 Small intestines – glucagon-like
peptide
 Thyroid – calcitonin
 Kidney – angiotensin II
Hormones are synthesized from a wide variety of
chemical building blocks
...
Mineralocorticoid Synthesis
3β-OHSD

Pregnenolone







B
...


Androgen Synthesis
 Dehydroepiandrosterone
(DHEA):
major
androgen/androgen precursor produced by the
adrenal cortex
o Prehormone converted into
androstenedione via 3β -OHSD and Δ 5,4 isomerase
 Androstenedione: also formed in the adrenal via
conversion of 17-hydroxypregnenolone via 17,20lyase
o Reduced at C17 position to form testosterone
 Testosterone: most potent androgen
o Small amounts produced in the adrenal
o Mainly produced in the testes
 Most of the 17-hydroxypregnenolone follows the
glucocorticoid pathway
o Some subjected to oxidative fission and
removal of the 2-carbon side chain by 17,20lyase
 Dual-function protein
 Important in both adrenals and
gonads
 Acts exclusively on 17α-hydroxycontaing molecules
 ↑Adrenal androgen production: if glucocorticoid
biosynthesis is impeded by the lack of one
hydroxylase
o Adrenogenital syndrome

D
...
However, in the latter two tissues the process
is promoted by LH rather than ACTH
...


11β-hydroxylase: mitochondrial enzyme

Pregnenolone can also be converted to testosterone
by the dehydroepiandrosterone (or Δ 5 ) pathway
o mostly used in the human testes
Metabolism of Testosterone



E
...
Reduction of the A ring double bond and the
3-ketone
 Less efficient pathway
 Occurs in target tissues
 Produces potent DHT
DHT: most significant metabolic product of
testosterone
o active in prostate, external genitalia, and
some areas of the skin
o plasma content in adult male: DHT (~400 μg)
<<< Testosterone (5 mg)
 about 50 to 100 μg of DHT: secreted
by testes
 others: produced peripherally from
testosterone in NADPH-dependent
5α-reductase

Ovarian Steroidogenesis
 17β-Estradiol: primary estrogen of ovarian origin
 Estrogens are formed by the aromatization of
androgens in three hydroxylation processes, each
requires O 2 and NADPH
o Aromatase enzyme complex: include P450
monooxygenase
 Forms of estrogen
o Estrone
 Synthesized in numerous tissues
 More abundant
 Formed from the aromatization of
androstenedione
 Major source of estrogens in
postmenopausal women
o Estriol
 Produced more during pregnancy
o Estradiol
 Formed if the substrate of the
enzyme complex is testosterone
 Theca cells produce androstenedione and
testosterone
o These products are acted upon by
aromatase enzyme in granulosa cells to
form estrone and estradiol
 Progesterone
o Precursor for all steroid hormones
o Produced and secreted by the corpus
luteum as an end-product

4







In human males: peripheral aromatization of
testosterone accounts for 80% of the production of
estradiol
In human females: adrenal androgens are important
substrates since as much as 50% of the E2 produced
during pregnancy comes from the aromatization of
androgens
Aromatase can be found in adipose, liver, skin, and
other tissues



↑aromatase activity = “estrogenization”, that
characterizes diseases such as
o Cirrhosis of the liver
o Hyperthyroidism
o Aging
o Obesity
o Aromatase inhibitors as therapeutic agents
for breast cancer and female reproductive
tract malignancies

Figure 1Pathways involved in the synthesis of the three major classes of adrenal steroids
(mineralocorticoids, glucocorticoids, and androgens)

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