Source, synthesis and metabolism of androgens

SOURCE , SYNTHESIS,
METABOLISM AND
PHYSIOLOGICAL ROLE OF
ANDROGENS
M.THILAKAR
LS 1154
4’th M.Sc. LIFE
SCIENCES,
BDU.

O
OH
HH
H
TESTOSTERONE
O
OH
HH
H
H
DIHYDROTESTOSTERONE
ANDROGENS

TESTOSTERONES
Testosterone is the principal androgen secreted by the mature testis.
Normal young men produce about 7 mg each day, of which less than 5% is derived from adrenal
secretions.
This amount decreases somewhat with age, so that by the seventh decade and beyond,
testosterone production may have decreased to 4 mg per day, but in the absence of illness or
injury, As with the other steroid hormones, testosterone in blood is largely bound to plasma
protein, with only about 2 to 3% present as free hormone.
About half is bound to albumin, and slightly less to sex hormone-binding globulin (SHBG), which is
also called testosterone-estradiol-binding globulin (TeBG).
This glycoprotein binds both estrogen and testosterone, but its single binding site has a higher
affinity for testosterone.
Its concentration in plasma is decreased by androgen Consequently, SHBG is more than twice as
abundant in the circulation of women than men.
In addition to its functions as a carrier protein, SHBG may also act as an enhancer of hormone
action.

BIOSYNTHESIS OF ANDROGEN
SITE : synthesized in the interstitial tissue by the leydig cells response to LH .
To a minor extent by adrenal glands in both the sexes.
Ovaries also produce a small amount of androgens
PRECURSOR: Cholesterol
It is first converted to pregnenolone by cytochrome p450 side chain cleavage
enzyme which then forms androstenedione by two pathways:
1. Through progesterone (Progesterone (or ∆4) pathway)
2. Through 17-hydroxypregnenolone.(Dehydroepiandrosterone or ∆5
pathway)

HORMONAL CONTROL OF MALE
REPRODUCTIVE SYSTEM

Source, synthesis and metabolism of androgens

SYNTHESIS
OF
TESTOSTERO
NE IN
TESTES

ENZYMES REQUIRED FOR THE
PRODUCTION OF ANDROGENS
The conversion of pregnenolone to testosterone requires the
action of five enzyme activities contained in three proteins:
3β-hydroxyl steroid dehydrogenase (3β-HSD) and ∆5,4-
isomerase;
17α-hydroxylase and C17-20 Lyase and
17β-hydroxyl steroid dehydrogenase (17β-OHSD).
The ∆5 route appears to be most used in human testes.

REGULATION
The production of androgens is under the control of LH and FSH.
Regulated by feedback mechanism
The rate limiting step is the delivery of cholesterol to testosterone by StAR.
Steroidogenic acute protein (StAR)

DIAGRAMMATIC REPRESENTATION OF THE ANDROGEN SYNTHETIC
PATHWAY IN THE LEYDIG CELLS OF THE TESTIS.
PREFERRED PATHWAYS ARE SHOWN BY HEAVY ARROWS.
ONLY SMALL AMOUNTS OF DIHYDROTESTOSTERONE ARE
SYNTHESIZED FROM TESTOSTERONE WITHIN THE LEYDIG CELL.
LHREGULATIONOF
LEYDIGCELLS

LH REGULATION OF LEYDIG CELLS
LH binds to high affinity G protein-coupled plasma membrane receptors on Leydig
cells.
 Following binding, LH receptors aggregate, undergo a conformational change and
bind Gs protein.
 Guanosine triphosphate (GTP) then binds to GsÎ± subunit, displacing guanosine
diphosphate (GDP), and GsÎ± binds and activates adenylate cylase resulting in
generation of cyclic adenosine monophosphate (cAMP).
cAMP then binds to the regulatory subunits of protein kinase A, releasing activated
catalytic subunits that phosphorylate a number of proteins in the Leydig cell and
result in stimulation of steroidogenesis and testosterone production
Both LH and hCG bind to the LH receptor and administration of high concentrations
of either hormone causes a decrease (down regulation) of LH receptor number and
reduction in responsiveness to further stimulation by LH or hCG (desensitization).
 In contrast to the suppression of pituitary LH production induced by continuous
high-dosage GnRH administration, production of testosterone is not inhibited by
high dosage LH or hCG administration, raising questions regarding the clinical
significance of LH receptor down regulation and Leydig cell desensitization.

FSH REGULATION OF SERTOLI CELL
FUNCTION
FSH binds to high-affinity G protein-coupled plasma membrane receptors on Sertoli
cells.
Signal transduction follows a pathway that is analogous to that for LH with FSH
receptor binding leading to G protein activation of adenylate cyclase, generation of
cAMP that activates protein kinase A, followed by protein phosphorylation.
As with the regulation of LH receptors by LH or hCG, FSH administration also down
regulates the number of FSH receptors on Sertoli cells, but the physiological
significance of down-regulation is not known.
FSH binding has also been reported in rat spermatogonia, but direct effects of FSH
on these stem cells

METABOLISM OF ANDROGEN
14
FIRST PATHWAY :
Involves oxidation at the 17 position,
Occurs in many tissues, including liver and produces 17-ketosteroids that are
generally inactive or less active than the parent compound.
SECOND PATHWAY :
Occurs primarily in target tissues
Dihydrotestosterone is Formed From Testosterone in Peripheral tissues.
Involves reduction of the A ring double bond and the 3 Ketosterone, a reaction
catalyzed by the NADPH-dependent 5 α reductase
5 mg of testosterone is produced daily by testes. Approximately 400 µg of DHT is
produced daily
Some estradiol is formed from the peripheral aromatization of testosterone.

TRANSPORT OF ANDROGENS
In the plasma testosterone and DHT bind to two proteins-
1. Sex hormone binding globulin ( SHBG) binds 97 to 99% and
2. Testosterone-estrogen binding globulin( TEBG).
A small fraction is in free form.
Both these proteins are synthesized in liver.
The plasma testosterone level in normal men is about 0.7 µg/dl while in
women it is < 0.1 µg/dl.

MODE OF ACTION
Both testosterone and dihydrotestosterone bind to a single class of
receptors on the target tissues.
The affinity of DHT for the receptor is much higher compared to
testosterone.
Receptor sites for androgens are found in muscle, brain, and other target
tissues.

ANDROGEN ACTION
Diagrammatic representation of the metabolism of
testosterone. After secretion by the Leydig cell,
testosterone travels through the plasma to the liver
or target tissues. After metabolism and conjugation,
products are excreted into the urine.

PHYSIOLOGICAL FUNCTIONS OF
ANDROGEN
The androgens influence
1. Growth, development and maintenance of male reproductive organs.
2. Sexual differentiation and secondary sexual characteristics.
3. Spermatogenesis.
4. Male pattern of aggressive behavior.
5. Pubertal transformation:
 Enlargement of testes, penis and scrotum.
 Pubic and axillary hair.
 Bone growth.
 RBC mass increase.
 Skeletal muscle mass increase.
 Larynx enlarges - deepening of the voice
 Increase in sebaceous glands - often cause of acne
 Development of Beard

BIOCHEMICAL FUNCTIONS OF
ANDROGEN
EFFECT ON PROTEIN METABOLISM:
Androgens promote
RNA synthesis( transcription)
Protein synthesis( translation).
Rapid growth of muscular-skeletal system associated with puberty.
EFFECT ON CARBOHYDRATE AND FAT METABOLISM :
Glycolysis,
Production of D-fructose from D-glucose by seminal vesicles.
Fatty acid synthesis and
Citric acid cycle.
EFFECTS ON MINERAL METABOLISM :
Androgens promote
Mineral deposition and bone growth
Kidney reabsorption of Na+, Cl- and water.

ABNORMALITIES ASSOCIATED
WITH MALE SEX HORMONES
Hypogonadisn is a disorder characterized by a defect in testosterone synthesis.
It may be of two types.
1. PRIMARY HYPOGONADISM : is caused by a failure of testes to produce
testosterone.
2. SECONDARY HYPOGONADISM : is due to an impairment in the release of
gonadotropins.

ANDROGENS IN WOMEN
Because of a deficiency on both ovarian and
adrenal androgens, some women with
hypopituitarism have diminished libido despite
adequate estrogen therapy.
Although experience is limited, small doses of long-
acting androgens (testosterone enanthate, 25-50
mg intramuscularly every 4-8 weeks) may be helpful
in restoring sexual activity without causing
hirsutism.
In addition, some reports have suggested that oral
dehydroepiandrosterone (DHEA) in doses of 25 to
50 mg/d may restore plasma testosterone levels to
normal.
A transdermal delivery system is being evaluated
for use in women, but efficacy appears to be
modest and the long-term safety is unknown.
ANDROGENS IN MEN
The treatment of male hypogonadism.
Testosterone gels (available in packets in doses of
2.5, 5, or 10 g, or from a metered-dose pump in
1.25 g increments) and testosterone patches (in
doses of 2.5 or 5 mg) are applied daily.
Other therapeutic preparations include
intramuscular testosterone enanthate or cypionate
in doses of 100 mg every week or 200 mg every 2
weeks.
Testosterone undecanoate is an intramuscular
preparation available in several countries that can
be given every 3 months.
Oral testosterone preparations available in the
United States are rarely used out of concern for
hepatic side effects.

REFERENCES
1. BASIC ENDOCRINOLOGY by H. Maurice Goodman – 4’th Ed (2009).
Elsevier’s Science & Technology. [245-248]
2. ENDOCRINOOLOGY AT GLANCE by Ben Greenstein (1994).
Blackwell sciences Ltd. [60-65]
3. GRETENSPAN'S BASIC & CLINICAL ENDOCRINOLOGY by Gardner D
and Shoback – 9’th Ed(2011). The McGraw-Hill Companies
4. ENDOCRINOLOGY AND METABOLISM by Felig, Philip; Frohman,
Lawrence A. – 4’th Ed (2001). The McGraw-Hill Companies

Source, synthesis and metabolism of androgens

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