MALE GONADAL HORMONES

(Androgens & Anabolic steroids)

&
INHIBITORS
(Antiandrogens)

Androgens
Also called androgenic hormone or testoid
generic term for any natural or synthetic

compound, usually a steroid hormone, that

stimulates or controls the development and
maintenance of male characteristics in vertebrates
by binding to androgen receptors
includes the activity of the accessory male sex
organs and development of male secondary sex
characteristics
The primary and most well-known androgen is
testosterone.

Androgens
Includes testosterone, DHT
&
Androstenedione, Dehydroepiandrosterone
(weak androgens)
- Testosterone serves as a prohormone for
Dihydrotestosterone (DHT)
Oestradiol

Androgens
Biosynthesis

Testis - primary site of androgen synthesis in males

Leydig (95%)
both gametogenic & endocrine functions
Adrenals (5%)

Control of secretion in males

ICSH (interstitial cell stimulating hormone) and FSH

Androgens
Androgens in Females

Sites of synthesis--ovaries, adrenals, placenta

Physiological significance
- apparently not necessary for normalmenstrual
cycling, but may be involved in pubertal growth
libido

REGULATION OF SECRETION

Regulation of secretion

Oestrogen similar to Testosterone

Inhibin inhibits FSH secretion at A.P level

Cholesterol

Pregnenolone

17-- Hydroxy
pregnenolone

Dehydro-epi
androsterone

Progesterone

17- Hydroxy
progesterone

Androstenedione

TESTOSTERONE

Oestriol

Oestrone

OESTRADIOL

Androgens
Negative Feedback
(1) Sex steroids
(2) Inhibin

Physiological effects

(1) Puberty
a. Spermatogenesis
b. Secondary sex characteristics
(2) Protein anabolism

Androgens - Pharmacokinetics
Absorption: undergoes high first pass metabolism/
rapid conversion to inactive metabolites (1/6th
available as active form) Therefore i.m.
injections or synthetic preparations are used.
Transport: highly protein bound
(65% to SHBG (SEX HORMON BG), remaining to
albumin)

Androgens Pharmacokinetics

Metabolism
by liver enzymes major pathway
Reduction

of double bond and ketone in Ring A

production of inactive metabolites

(androsterone & etiocholanolone)

excretion by urine after conjugation

small quantity (1-5%) of oestrogen also

produced from testosterone in peripheral
tissues

8) Metabolism
(1) Liver inactivation
(2) Conjugated urinary products
(3) Peripheral aromatase

Principally in liver

MOA- Androgens
Testosterone / dihydrotestosterone binds with
intracellular androgen receptor & their complex
combines with DNA
Initiating a series of
events such as enhanced DNA transcription is &
effects are expressed through modification of
protein synthesis
Growth, differentiation, synthesis of enzymes &
other functional proteins

cytoplasm

Nucleus

R
T- R

T- R

10%
90%

DHT
R

5- reductase

DHT- R

4) Mechanism of action
(1) Plasma protein binding
- 98% of circulating androgen bound to sex hormone
binding globulin
(2) Receptors
a. Gene activation

MOA

Effects - Testosterone & DHT

growth of genitals in a boy

production of sperm

growth of facial, pubic & axillary hairs

muscular development

growth of larynx & voice deepens

inhibition of bone growth

thickening of skin, loss of s.c. fat

behavioral changes in men

erythropoietin secretion increased

Clinical uses of Testosterone

Androgen

replacement therapy in men

Testicular

Gynecologic
Reduce

failure: Primary & Secondary

disorders with great caution

breast engorgement during postpartum period in

conjunction with estrogens
Replacement therapy in postmenopausal period to eliminate
endometrial bleeding in combination with estrogens
Chemotherapy of breast tumors in postmenopausal period

Use

as protein anabolic agents; in conjunction with

dietary measures & exercise to reverse protein loss
after trauma, surgery, or prolonged immobolisation
in pts with debilitating diseases
Osteoporosis; either alone or in conjunction with
estrogens. Bisphosphonates are preferred

Clinical uses of Testosterone

Anaemia

(refractory)

Recombinant

Use

erythropoietin preferred

as growth stimulators

Stimulate

growth in boys with delayed puberty

careful use

Aging

Clinical uses of Testosterone

Abuse involves obtaining androgens

without legal prescription to be used
in the absence of medical indication
Examples of AAS abuse include:
sporting competitive power sports
recreational bodybuilding
cosmetic body beautiful subculture
occupational security, professional sports

Adverse effects of Testosterone

Virilization:

(Virilization is a condition in whicha female

develops male sex characteristics, or a newborn boy has increased male
characteristics at birth)

Feminizing side effects

Precocious puberty & stunted
Cholestatic jaundice
Enlargement of prostate
Atherosclerosis
Hepatic carcinoma
Oedema

growth

C/Is

Carcinoma of prostate & male breast

Liver and kidney disease
Pregnancy
CHF
Epilepsy, migraine

Pharmacologic preparations
Synthetic
androgens
(no
non-steroidal
androgens presently available)
a. Testosterone esters (parenteral use)
a) testeosterone propionate
b) testosterone ethanthate
b. Orally Active Androgens
a) methyltestosterone
b) fluoxymesterone
c. Orally active protein anabolic agents
a) norethandrolone
b) oxandrolone
c) bolasterone

Androgen Suppression
&
Antiandrogens

Antiandrogens
Steroid synthesis inhibitors: Ketoconazole
Conversion of steroid precursors to androgens
Abiraterone Finasteride

Dutasteride

Receptor inhibitors
Cyproterone

Cyproterone acetate

Flutamide

Bicalutamide

Nilutamide

Spironolactone

Steroid synthesis inhibitors:

Ketoconazole
Primarily

an anti-fungal agent
Inhibitor of adrenal & gonadal steroid synthesis
Displaces estradiol & dihydrotestosterone from
SHBP & increases estradiol: testosterone ratio in
plasma. Men treated develop gynecomastia
Not useful in woman due to toxicity

Conversion of steroid precursors to

androgens
Abiraterone

Finasteride

Dutasteride

Inhibit 17-hydroxylation of progesterone or

pregnenolone preventing the action of the side
chain-splitting enzymes and the further
transformation of these steroid precursors to
active androgens

Abiraterone

Newer

17-hydroxylase inhibitor
May prove to be clinically useful

Finasteride: 5 reductase inhibitors

Orally active
Decreases DHT levels in 8 hrs & lasts 24 hrs
T1/2 : 8 hrs
40-50% metabolism
More than half excreted in feces
Benign prostatic hyperplasia reduces size
Treatment of hirsuitism in women
Also used for baldness in males

Dose: 5mg/day
Side effects: Loss of libido & impotence in 5 % pts.

Dutasteride : 5 reductase inhibitors

A

similar orally active steroid

Slow OOA & longer DOA
Dose 0.5mg/d
Both not approved for use in women or children

Receptor inhibitors
Cyproterone
Cyproterone
Flutamide

acetate

Bicalutamide
Nilutamide

Spironolactone

Cyproterone & Cyproterone acetate

Block

androgen receptors

secretion of gonadotropins
Uses:
Acne
Male pattern of baldness
Hirusitism
CA of prostate
Virilizing syndrome
Precocious puberty
Inappropriate behaviour

Flutamide
Non-steroidal

anti-inflammatory
Antagonise androgens:
Accessory sex organs
Pituitary
Uses:
Cancer of prostate along with GnRH agonist
Female hirusitism
Dose: 250 mg tds.

Bicalutamide & Nilutamide

Orally

active antiandrogens
OD dose
Metastatic carcinoma of prostate
Bicalutamide recommended for use in
combination with GnRH analog & have fewer
Aes than Flutamide

Spironolactone
A

competitive inhibitor of aldosterone

Also competes with DHT for androgen receptors
in target tissues
Also reduces 17 hydroxylase activity, lowering
plasma levels of testosterone & androstenedione
Treatment of hirsuitism in women
As effective as other finasteride, Cyproterone
& Flutamide
Dose: 50-200mg/d

Negative Feedback
(1) Sex steroids
(2) Inhibin
Physiological effects
(1) Puberty
a. Spermatogenesis
b. Secondary sex
characteristics
(2) Protein anabolism

Danazol

FSH & LH release in both sexes

Binding of steroids to receptors

Enzymes needed for steroid synthesis

Weak androgenic, anabolic, progestational & glucocorticoid action

Uses:

Side effects:

Endometriosis

Dose related

Menorrhagia

Amenorrhea (High doses)

Fibrocystic

breast disease

Androgenic side effects

Hereditary

angioneurotic
oedema

Gynecomastia
Infertility

Testosterone
Synthesis; The conc. of testosterone in the
plasma of males is relatively high during
three periods of life
1.The phase of embryonic development; it
starts to rise after the 8th week of
development and declines prior to birth
2. The neonatal period: It rises during this
period and after a few months returns to Pre
puberty level
3. At the time of male puberty level it rises
steeply .The feedback inhibition mechanism
becomes insensitive during this period .The
reason for this is unknown.
In men approximately 8 mg of testosterone is
produced daily. About 95% is produced by
the Leydig cells and 5% by the adrenal.
Plasma levels of Testosterone in males are
about 0.6 ug/dl after puberty and declines
after the age of 50.In women it is 0.03 ug/dl

Transport and Metabolism

-About 65% of circulating Testosterone is

bound to sex hormone binding globulin, SHBG.
Most of the remaining testosterone is bound to
albumin. Approximately 2 % remains free and
available to enter cells and bind to intracellular
receptors.
Metabolism: In many target tissues,
Testosterone is converted to
Dihydrotestosterone by 5-alpha reductase. In
these tissues Dihydrotestosterone is the major
active androgen. The major pathway for the
degradation of testosterone in humans occur
in the liver. This leads to the production of
inactive substances such as androsterone and
etiocholanolone that are then conjugated and
excreted in the urine.

Mode of Action

Testosterone and Dihydrotestosterone binds to an

intra-cellular protein receptor and the hormone
receptor complex acts in the nucleus at specific
binding sites on the chromosomes and induces
the DNA-RNA transcription process. Within 30
minutes RNA polymerase begins to increase
followed by progressive increase in proteins.
Direct effect of Testosterone on the musculature,
the skeleton, and the larynx and also to promote
spermatogenesis.
Indirect effects of Testosterone, it is converted to
Dihydrotestosterone by 5 alpha Reductase and
act on the following tissues skin ,seminal vesicles,
and epididymis and is also responsible for the
formation of external genitalia

Androgens for replacement

therapy
Oral preparation
Methyltestosterone
25-50 mg/d
Sublingual(buccal)
5-10 mg/d
Fluoxymesterone
5-10 mg/d
Testosterone propionate 5-20 mg/d
Sublingual (buccal)
Intramuscular Injection
Testosterone propionate 10-50mg x 3/week
Testosterone enanthate 200 mg x 2/week
Testosterone cypionate

Androgens for replacement

therapy
Transdermal

system( patches and gels)

Testoderm, 6 mg; Applied to scrotum
without permeation enhancers, ALZA
Corporation Palo Alto
Androderm 2.5 mg and 5 mg: Applied with
permeation enhancers, SmithKline and
Beecham Pharmaceuticals
Testoderm TTS, 5 mg: applied with
permeation enhancers, ALZA Corporation

Pharmacokinetics

Alkylation of Androgens at the 17 position markedly retards

their hepatic metabolism and permits oral use. Such
alkylated androgens can cause hepatotoxicity. Frequent and
large doses have to be given.
Testosterone injections provide a safe means of hormonal
replacement in hypogonadal men. Testosterone is esterified
to inhibit degradation and to make it soluble in oil based
injection vehicles that retain the drug in muscle tissue. In
men 20-50 years an i/m inj. of 200-300 mg testosterone
enanthate is generally sufficient to produce serum
testosterone levels that are supranormal initially and fall
into the normal range over the next 14 days.n

Pharmacokinetics
Fluctuations

in Testosterone levels may

yield variations in libido, sexual function,
energy. and mood.
Scrotal patches produce high levels of
circulating Dihydrotestosterone due to the
high 5-alpha reductase enzyme activity of
scrotal skin. Clinical studies show their
efficacy in providing adequate
testosterone replacement therapy.

Pharmacodynamics
The mode of action is similar to the natural testosterone.
Physiological and pharmacological effects
in the male at puberty it causes development of the
secondary sexual characteristics.
In the adult male it suppresses the secretions of
gonadotropins which results in atrophy of the interstitial
tissue
In women androgens produce changes similar to prepubertal
male.
They increase protein synthesis and decrease protein
breakdown. They have anabolic effects That is they cause
muscle development especially in the shoulder girdle
The natural androgens stimulate erythrocyte production
They also produce acne in prepubertal boys and women

Clinical Uses

1. Androgen Replacement Therapy in Men.

Androgens are used to replace or augment endogenous

androgen secretion in hypogonadal men.
Therapy is started with long acting agents
Testosterone enanthate in doses of 50 mg i/m,initially every 4,
then every 3,and finally every 2 weeks, with each change
taking place at 3-month intervals.The dose is then doubled
to 100 mg every 2 weeks until maturation is complete.
Finally ,it is changed to the adult replacement dose of 200
mg at 2 week intervals.
Orally Testosterone undecanoate can be given 40 mg twice
daily
Skin patches; two applications daily are required for
replacement therapy.

2. Gynecological disorders
To

reduce breast engorgement during the

postpartum period,usually in conjunction
with an estrogen
The weak androgen danazol is used in
endometriosis
Replacement therapy in post menopausal
period with estroben
They are also used for chemotherapy in
breast tumors in premenopausal women

3. Use as Protein Anabolic

Agent
Androgens

are used in conjunctio

with exercises and diet to reverse
protein loss and after trauma,
surgery or prolonged immobilization
and in patients with debilitatin
diseases

Clinical uses
4. Anemia
5. Osteoporosis
6. Use as growth stimulators
7.Anabolic Steroid and Androgen
Abuse in Sports
8. Aging
9. Hereditary Angioneurotic Edema

Adverse Effects

Masculinization of the females

Menstrual irregularities
In children profound virilization and serious
growth and osseous development, enhances
epiphyseal closure
Prolonged use of androgen in men can lead to
azoospermia
Feminizing effect can occur in men, especially
in the younger age group because of increased
Aromatase activity/
Edema
Cholestatic jaundice
Hepatic carcinoma

Contraindications and
cautions
Contraindicated

in pregnant women
Male patients with carcinoma of the
prostate and breast
Caution :1. In children to produce
growth spurt.
2. In patient with renal or cardiac
disease.

Androgen/Anabolic activity of
some preparations

Testosterone
1:1
Testosterone cypionate
1:1
Testosterone enanthate
1:1
Testosterone propionate
1:1
Methyl testosterone
1:1
Fluoxymesterone
1:2
Methandrostenalone
1:3
Oxymethalone
1:3

Ethylestrenol
Oxandrolone
1:13
Nandrolone
phenpropionate
1:6
Nandrolone
decanoate
1:4
Stanozolol
Dromostanolone
propionate

1:4-1:8
1:3-

1:3-

1:2.51:3-1:6
1:3- 1:4

Anti-Androgens
Compounds

that block the synthesis

or action of androgens.
They are useful in the management
of hyperplasia and carcinoma of the
prostate,acne,male-pattern
baldness,virilizing syndromes in
women and precocious puberty in
boys and in the inhibition of sex drive
in men

Anti -Androgens
GnRH analog,
Leuprolide; administered continuously =plasma levels of LH
and testosterone falls
Androgen receptor antagonists:
Cyproterone acetate
Dose 2mg/d + estrogen
Used for the treatment of Acne, male pattern baldness,
hirsutism and virilizing syndromes
Flutamide
Used for the treatment of prostatic cancer
5 alpha Reductase Inhibitors
Finesteride
Used to reduce Hyperplasia of the prostate

Chemical Contraception in
Men
Testosterone

and testosterone
enanthate in a dose of 400 mg a
month
Testosterone + Danazole
Testosterone enanthate 100 mg+
levonorgestrel 500 mg daily