Testosterone
Prof. Dr. Ubaid ur Rahman
Sex Hormones
• Male sex hormones
– Masculinizing hormones (Androgens)
• Testosterone
• Dihydro Testosterone
– Androgen Precursors
• Dehroepiandrosterone (DHEA)
• Androstenedione
• Female sex hormones
– Feminizing hormones
• Estrogen
• Progesterone
Sex Hormones
• Androgen:
– Any steroid that controls the development and
maintenance of masculine characteristics
• Testosterone:
– A natural male androgen of testicular origin,
controlled by the luteinizing hormone (LH)
Synthesis of Androgens
• Sites
– Adrenal cortex
– Testes
• Substrate in all Sites
– Cholesterol
Testicular
synthesis of androgens
• Leydig cells
– Found in
• Interstitial tissues of Testes
– Intracellular Site
• Smooth Endoplasmic Reticulum
• Mitochondria
***Adrenal Androgens
• Have a keto group at position 17 and therefore
are called 17-ketosteroids.
• The major secreted form is dehydro-epi-andro-
sterone (DHEA)
***Adrenal Androgens
• Although adrenal androgen is the precursor
of the potent androgen testosterone, normally
little is produced in the adrenals because the
enzymes necessary for the conversion are
not present.
• For the same reason, estradiol secretion by
the adrenal is small.
Testosterone
• Circulation
– 65 % bound to a Globulin called SHBG
– 33 % is loosely bound to Albumin
– 2 % is freely circulating Free T (f T)
• BIOAVAILABLE T
– free + albumin bound
• TOTAL T
• Normal levels
– 300—1200 ng / 100 ml
Excretion of Testosterone
• A small amount of circulating testosterone is
converted to estradiol, but most of the
testosterone is converted to 17-ketosteroids,
principally androsterone and its isomer
etiocholanolone, and excreted in the urine.
• About two thirds of the urinary 17-
ketosteroids are of adrenal origin, and one
third are of testicular origin.
• Although most of the 17- ketosteroids are
weak androgens (they have 20% or less the
potency of testosterone),
DihydroTestosterone
• By
– Reduction of double bond at C-5 of ring A
leads to formation of Dihydrotestosterone
5α- REDUCTASE
Potent
NADPH
• DHT is acting in classic target tissues
• Classic target organs have
• Receptor for T
• 5 α - reductase activity
Mechanism of action of Testosterone
• Classic target cells
AR with DHT
Testosterone Ligand
5a-R (Dimerizes)
DHT
Activated AR Enters
Nucleus and Binds
to DNA
AR (Inactive)
EXPRESSION OF
GENES
Androgen
Response Element
Prostate Cell (ARE)
When No Androgens are present
No Testosterone
AR (Inactive)
No Expression of Genes
- No Proliferation
Androgen
Response Element
(ARE)
Prostate Cell
Metabolic functions of
testosterone
• Increase protein synthesis in target organs of
the body
• Classic target organs
– Prostate
– External genitelia
– Genital skin
Target organs of Testosterone
• Some target organs have
– NO 5 α-reductase activity in their cells
• T have direct effect
• ½ potency of DHT
• These are
• Epidydmis > Muscle
• Vas deference > Bone
• Seminal vesicals > Brain
• Spermatogonia
Secondary sexual characters
• Hair distribution
– Skin has receptors of T
– Increase protein synthesis
• Necessary for hair formation
• So leading to
– Male like hair distribution
• Effect on voice
– Hypertrophy of laryngeal mucosa
– & Enlargement of larynx
• Because of
– T receptors
• Effects on skin
– Increase thickness
– Increase secretion of some sebaceous
glands sp. on face
• Which result in
• Acne
Secondary sexual characters
• Effects on muscles
– A 50 % increase in mass over females
– Increase formation & storage of creatine in
muscle
• Effect on bone
– Increase in bone matrix
• Because of osteoid tissue formation
• Effect on Basal metabolic rate
– A 15 % increase because of synthesis of
• Enzymes
• So activities of all cells increase
– cause moderate Na+, K+, H2O, Ca2+,
SO4–, and PO4– retention;
• Increase the size of the kidneys.
• Increase RBC mass
– Due to
• Protein synthesis
Hormonal control
of testicular
function
FSH
Hormonal control
In response to LH, some of the testosterone secreted from the
of testicular
Leydig cells bathes the seminiferous epithelium and provides
function
the high local concentration of androgen to the Sertoli cells that
is necessary for normal spermatogenesis.
Inhibins:
peptide hormones
secreted into the blood in
response to overproduction
of sperms.
They inhibit the secretion of
FSH by pituitary gonadotrophs.
The possible use of inhibins as
Systemically administered testosterone
male contraceptives is now being explored.
does not raise the androgen level in the
testes to a great degree, and it inhibits
Hypothalamus LH secretion. Consequently, the net effect
of systemically administered testosterone
Negative _ GnRH
is generally a decrease in sperm count.
Testosterone therapy has been suggested
feedback + as a means of male contraception.
Pituitary
Systemically
LH FSH administered
Testosterone
Testosterone
T Sperm
Leydig Sartoli count
However, the dose of testosterone needed to suppress
spermatogenesis cause sodium and water retention..
BPH & Prostatic carcinoma
• The cancerous cells are usually stimulated to
more rapid growth by testosterone and are
inhibited by removal of both testes so that
testosterone cannot be formed.
• Prostatic cancer usually can be inhibited by
administration of estrogens.
Removing Androgens
1. Orchiectomy (castration):
• surgical removal of the testicles.
2. Block testosterone production.
3. Block conversion to DHT.
4. Block the effects of testosterone.
Orchiectomy (castration):
Hypothalamus
Negative _ GnRH
feedback +
Pituitary
LH
Testosterone
Testis +
Castration
Receptors and Feedback
AR (in Hypothalamus Cell)
Hypothalamus
Cell LHRH
(Secreted)
Testosterone
LHRH-Receptor circulates back to
hypothalamus and
(On Pituitary Cell) binds to Androgen
Pituitary
Receptors in the
Cell hypothalamus cells.
LH
(Secreted) AR binding and
activity modulates
LH-Receptor expression and
Testes Cell (On Leydig Cell) secretion of LHRH.
(Leydig Cell)
Secreted
Testosterone
LHRH Agonists
LH
Testosterone
Serum
Levels
LHRH Agonist LH Levels Test. Levels Castrate Levels
Administered Peak @ Peak @ 72hrs of Testosterone
24hrs “Flare” @ 3 weeks
Not to scale.
LHRH Agonists
An LHRH agonist is a factor that mimics the
function of LHRH.
Examples: Leuprolide (Lupron), Goserelin
(Zoladex), Buserelin (Suprefact), and Nafarelin
(Synarel).
Used to treat:
prostate and breast cancer
Uterine fibroids
Early puberty
How Do Chronic LHRH Agonists
Decrease Testosterone?
LHRH-Agonist Chronically
LHRH (Secreted
by Added
hypothalamus)
LHRH-Receptor
(On Pituitary Cell)
GnRH agonists,
LH decrease testosterone
(Secreted) Initially: levels in the body
Secreted Levels through a mechanism
of LH Increase known as "down-
(Flare) regulation" or
which typically "desensitization" of the
lasts for about pituitary gland.
1-2 weeks
LHRH Antagonists
An LHRH Antagonist is a factor that blocks the
effect of LHRH.
Examples: Cetrorelix (Cetrotide), Abarelix (Plenaxis),
and Orgalutran (Ganirelix).
For advanced prostate cancer
Mechanism: directly inhibit the LHRH-receptor on
Pituitary cells, resulting in decreased secretion of LH.
LHRH (Secreted
by
hypothalamus) LHRH-Antagonist
prevents LHRH from
LHRH-Receptor binding to receptor.
(On Pituitary Cell) Decreased LH secretion
and thus decreased
testosterone production.
No testosterone “flare”
LH
(Secreted)
5a-Reductase Inhibitors
Purpose: Block the enzyme that converts
testosterone to DHT.
Example: Finasteride (PROSCAR)
Result: decreased Androgen Receptor activity.
OH
OH CH3
CH3
CH3
CH3
O H
O H
Testosterone Dihydrotestosterone
(DHT)
Converting Enzyme: Finasteride
5-alpha-Reductase
Anti-Androgens
Androgen “look-alike” molecules that bind to the
Androgen Receptor and prevent binding of DHT
(competitive inhibition).
Examples: Cyproterone (Cyprostat), Flutamide (Drogenil,
Chimax) , Bicalutamide (Casodex), and Nilutamide
(Nilandron).
Used treatment of androgen dependent conditions:
Acne, excessive hair grwth, early puberty, prostate cancer
Bind and inhibit ARs in prostate as well as hypothalamus.
AR DHT
DHT
Inactive AR Cannot
Bind to AR
Anti-Androgen ?
Hormonal changes in specific
altered states