Male Sex hormones (Androgens
➢ Testosterone and its metabolite 5-dihydrotestosterone (DHT) are the
primary endogenous androgens and play crucial physiological roles in
establishing and maintaining male characteristics.
➢ These endogenous compounds have two important activities: androgenic
activity (promoting male sex characteristics) and anabolic activity (muscle
building).
➢ They cause nitrogen retention by stimulating protein synthesis while decreasing
the rate of protein catabolism (Anabolic effect).
➢ Testosterone is considered as a prohormone and its metabolite (5-DHT)
which is formed by the action of 5-reductase enzyme is the most potent
endogenous androgen
Dr. Maryam Ali El-Attar, PhD
5-reductase
Lecturer of Pharmaceutical Chemistry
Faculty of Pharmacy
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Alexandria University
Androgens and related drugs
Androgens and related drugs
Therapeutic Uses
Androgens
Natural
Anabolics
➢ Androgen replacement therapy in man, either at maturity or in adolescence
due to hypogonadism or hypopituitarism.
Antiandrogens
➢ They are used to treat certain anemias, osteoporosis, and to stimulate
growth in boys.
Luteinizing hormone
releasing hormone
agonists (LHRHa)
➢ Androgens are used as secondary treatment of advanced or metastatic
breast cancer in selected patients
➢ Androgens and anabolics are used to treat certain anemias, osteoporosis, and
to stimulate growth in boys.
Synthetics
Androgen receptors
blockers
Major side effects:
➢ Androgens and anabolics generally alter serum lipid levels and increase
the probability of atherosclerosis, in men and postmenopausal women.
Inhibitors of
androgenic
biosynthesis.
➢ Musculinizing actions (androgenic side effects) in females.
3
1. Androgens
A) Natural Androgens:
1. Androgens
B) Synthetic Androgens:
Testosterone (Andriol®)
1. 17-Methyltestosterone
➢ Testosterone, 17-hydroxyandrost-4-en-3-one, is a
naturally occurring androgen in men.
➢ In women, it mainly serves as a biosynthetic precursor
to estradiol .
R=
H
➢ It is inactive orally due to its rapid metabolism to
relatively inactive 17-ones
➢ Introducing a methyl group at the 17α-position of the testosterone structure
improves oral bioavailability.
➢ Testosterone is available as a transdermal
delivery system (patch) and as implantable
pellets.
➢ This is due to the increases of lipid solubility and prevention of hepatic
oxidation to the less active 17-keto steroid.
➢ Testosterone 17 -esters (such as:Testosterone propionate, heptanoate
and cypionate esters) are available in long-acting IM depot preparations
for replacement therapy in male hypogonadism.
1. Androgens
B) Synthetic Androgens:
2. Fluoxymesterone (Stenox®)
➢ Methyltestosterone is only about 50% as active as testosterone
(intramuscularly), but it has the great advantage of being orally active.
➢ It is used orally as a replacement therapy in male hypogonadism
2. Anabolic Steroids
➢ A complete dissociation of anabolic and androgenic effects is not possible,
leaving drugs with a gradation of anabolic and androgenic activity.
➢ However, increasing the anabolic effect over the androgenic effects of
androgens is important in the anabolic therapy of such wasting conditions
as cancer, trauma, osteoporosis, and the effects of immobilization, which
necessitate nitrogen and mineral retention.
Anabolic Abuse common side effects:
➢ The 9-fluoro substituent increases the anabolic activity by 20 times and
the androgenic activity by 10 times.
➢ The anabolic activity is also enhanced by the presence of 11β-hydroxyl group.
➢ Fluoxymesterone is more potent than methyltestosterone when given orally;
used in the treatment of male hypogonadism
➢ An adverse effect of fluoxymesterone is sodium and water retention that
could lead to edema (WHY??).
In males and females:
• Increased risk of coronary heart disease, stroke, or obstructed blood vessels.
• Increased aggression and antisocial behavior.
• Liver tumors, peliosis hepatis (blood-filled cysts), and jaundice
In men:
• Testicular atrophy with consequent sterility or decreased sperm count and
abnormal motility and morphology.
• Enlarged prostate and breast enlargement and impotency.
In women:
• Beard growth, Baldness, Deepened voice and and Breast diminution
Structure Activity Relationship (SAR) of Androgen and anabolic steroids:
2. Anabolic Steroids
1. Methandrostenolone (Danabol®)
OH
Removal of C19 methyl group
as in 19-norsteroids exhibit a
more favorable anabolic
to androgenic activity ratio.
∆1 double bond
increases the
anabolic activity
O
➢ it is ∆1 analog of 17-methyltestosterone
A
➢ The ∆1 double bond increases the anabolic activity, whereas, the methyl
group increases the oral bioavailability.
➢ It has several-fold the anabolic activity of the starting 17methyltestosterone.
➢ It has a lower androgenic activity and it is has been given orally as
an anabolic drug.
Ring A–hydroxylated
analogs or oxygen
insertion increase in
anabolic
over
androgenic activity
2. Anabolic Steroids
2. Nandrolone Decanoate (Deca-Durabolin®)
O
R
3. Antiandrogens
➢ An antiandrogen is a substance that antagonizes the actions of
dihydrotestosterone (DHT) at the androgen receptor
Therapeutic uses of antiandrogens:
O
➢ It is an anabolic analog of testosterone (also known as 19Nortestosetrone)
➢ The removal of the 19-CH3 group of the testosterone results in
reduction of its androgenic properties, but retention of its anabolic
and tissue-building properties.
➢ Nandrolone is usually given as decanoate ester in the form of oily
IM injections for a prolonged effect.
➢ It is used as anabolic in severe anemia and osteoporosis.
➢ Such compounds have shown potential therapeutic use in the treatment
of acne, virilization in women and hyperplasia and neoplasia of
prostate.
➢ Estrogens were used as antiandrogenic drugs, but their feminizing
side effects (e.g. loss of libido) have precluded their use.
3. Antiandrogens
A) Luteinizing hormone releasing hormone agonists (LHRHa)
3. Antiandrogens
B) Androgen Receptor Blockers (antiandrogens)
Goserelin (Zoladex ®)
i. Steroidal competitive antiandrogenic agents
Cyproterone acetate (Androcur®)
➢ It is a synthetic decapeptide
analog of LHRH (also known as
gonadotropin releasing hormone
GnRH), given as subcutaneous
injection every 1 or 3 months.
➢ Cyproterone acetate is used in combination of estrogen in the
treatment of acne.
➢ It initially stimulates the release of luteinizing hormone (LH, gonadotropin),
resulting in a transient elevation in serum androgen.
➢ Prolonged administration can cause down-regulation of the LHRH
receptors, thus inhibiting the secretion of LH and ultimately the
androgen.
➢ By decreasing the testicular production of androgen to castrate-level,
LHRHa can inhibit the growth of androgen-dependent prostate cancer.
3. Antiandrogens
B) Androgen Receptor Blockers (antiandrogens)
ii. Non-Steroidal antiandrogenic agents
1. Bicalutamide (Casodex ®)
2. Enzalutamide (Xtandi ®)
3. Antiandrogens
C) Inhibitors of Androgen Biosynthesis
❖ Inhibition of androgen biosynthesis results in a decrease in active androgen
concentration in target tissues.
i. 5-Reductase inhibitors
Finasteride (Proscar®)
➢ Both are oral non-steroidal DHT receptor inhibitors, without lowering the
androgen level.
➢ Bicalutamide is a racemate and its antiandrogenic activity is exclusively
exhibited by the R-enantiomer; whereas the S-enantiomer is essentially
inactive.
➢ Enzalutamide is more active as a powerful DHT antagonist compared with
bicalutamide.
➢ Finasteride is a potent inhibitor of 5-reductase and effectively decreases
5-DHT concentrations in both plasma and in prostate tissues.
➢ Both are indicated for use in combination therapy with (LHRHa) for the
treatment of advanced metastatic carcinoma of the prostate.
➢
It is given orally for the treatment of benign prostatic hyperplasia
(BPH) and management of alopecia in males.
3. Antiandrogens
Androgens and related drugs
C) Inhibitors of Androgen Biosynthesis
ii. 17 α-hydroxylase/C17,20-lyase (CYP17) inhibitors
❖ This enzyme is essential for the synthesis of androgen, and expressed in
testicular, adrenal, and prostatic tumor tissues.
Anabolics
Androgens
OH
Abiraterone acetate (Zytiga ®)
Antiandrogens
Methandrostenolone
Natural
O
R
(LHRHa)
O
Nandrolone Decanoate
O
Testosterone
➢ Abiraterone interferes with androgen biosynthesis starting from the
pregnenolone precursor, via inhibiting 17 α-hydroxylase/C17,20-lyase
(CYP17)
Androgen receptors
blockers
Goserelin
Synthetics
Cyproterone acetate
Androgenic
biosynthesisInhibitors.
➢ When it is orally administered, it is converted in vivo to abiraterone.
17-Methyltestosterone
▪
Enzalutamide
It is specifically indicated for use in combination with chemical castration and
prednisolone for the treatment of metastatic castration-resistant prostate
cancer (mCRPC).
Finasteride
Fluoxymesterone
O
OH
O
O
R
Bicalutamide
Abiraterone acetate