The

ovary has both gametogenic

(production of ova) & hormonal functions.
In females the ovary is quiscent in
childhood.
At puberty it begins a period of 30-40 years
of a cyclic function called the menstrual
cycle.
The hypothalamus starts releasing GnRH
which stimulates pituitary to release FSH
and LH.

 FSH

& LH stimulate ovary to produce an

ovum & sex hormones(estrogens &
progesterone).
Estrogen function is to stimulate the
development of female sex organs &
secondary sexual characteristics.
Progesterone + estrogen regulate
menstrual cycle, maintain pregnancy in
presence of a developing embryo or fetus.

 At

the beginning of each cycle, FSH

stimulates development of ovarian
follicles.
Then after 5-6 days the outer theca
and inner granulosa cells of one
dominant follicle starts releasing
estrogen under the influence of LH.
The estrogen inhibits release of FSH
form AP(-ve feed back).

 The

estrogen secretion peaks just

before midcycle & granulosa cells
begin to secrete progesterone.
Rupturing of follicle releases the ovum
near the opening of uterine tube.
The remainder of the ruptured follicle
forms the corpus luteum which
continues releasing estrogen and
progesterone for the remainder of the
cycle or longer if pregnancy occurs.

 If

pregnancy does not occur, the

corpus luteum begins to degenerate
and seases hormone production
eventually becoming corpus albicans.

The

endometrium which proliferated

during the follicular phase and
developed its glandular function
during the luteal phase is shed in the
process of menstruation.

 Steroid

hormones are all derived from

cholesterol
Cholesterol contains
cyclopentanophenanthrene ring
Estrogen and progestins are just two of
the many steroids found in the human
body

Cholesterol

 Mechanism:

- Modulate gene expression inside cell

- Are not water-soluble so travel in blood
attached to protein carriers(SHBG)
- When reaching the cell, they dissociate
from protein carrier and enter membrane
- Some bind to a receptor in the
cytoplasm and move into the nucleus

 Mechanism

(ctd..)
- Hormone binding activates
receptor protein and now both
can bind specific regions of DNA
called HRE
(Hormone Response Elements)

Function as primary female sex hormones

Present in both men & women
Promote development of females secondary
sex characteristics
Stimulate endometrial & uterine growth
Reduce bone resorption, increase bone
formation
Many nonsteriodal synthetic compounds (e.g.
diethyl stilbosterol) have estrogenic activity
Many plants such as soybeans contain
flavonoids with estrogenic activity

Three major types of natural estrogens are

known, these are: estradiol(E2),
estrone(E1),and estriol(E3).Most estrone
and estriol are formed in liver from estradiol
or in tissues from androstendione and other
androgens.

Estrone (E1)

Estradiol (E2)
Most common!

Estriol (E3)

During the first part of menstrual cycle

estrogens are produced in the ovarian follicle
by the theca and granulosa cells.

After ovulation estrogens and progesterone

are synthesized by the lutenized granulosa
and theca cells of corpus luteum.

During pregnancy estrogen is produced by

the fetoplacental unit that consists of fetal
adrenal zone,secreting androgen precursors,
and placenta which aromatizes it to estrogen.

Synthetic
Many

Estrogens:

steroidal compounds with

estrogenic activity were synthesized
Ethinylestradiol,mestranol,and
quinistrol
Many nonsteroidal estrogenic
compounds are also available:
Dienestrol, diethylstilbosterol,
benzesterol, hexesterol,
methesterol,methallenstril and
chlorotrianisene

Pharmacokinetics:
In circulation estradiol binds strongly to sex
hormone binding globulin(SHBG) and to
albumin with lower affinity
Estradiol is converted by the liver to estrone
and estriol and their 2-hydroxylated
derivatives and conjugated metabolites that
are excreted in bile
Estrone and estriol have low affinity to
estrogen receptor
Estrogens are excreted in small amounts in
breast milk of lactating mothers

A-Mechanism of action:
Estrogens

act by binding to nuclear

receptors. These receptors are stabilized
by Hsp90 in the cytoplasm.
Binding of estrogen to the receptor causes
its release from Hsp90, then the receptorhormone complex form dimers that bind to
nuclear receptors called estrogenresponse elements(EREs) on DNA strands
and regulate their transcription

 Then

response genes cause

translation of mRNA that cause protein
synthesis which produce the required
effect.

Rapid

estrogen- induced effects such

as granulosa cell calcium uptake do
not require gene activation

B-Female Maturation:
Estrogens

produce normal sexual

maturation and development and growth
of the female.

They

stimulate development of vagina,

uterus, uterine tubes, and secondary
sex characteristics and accelerates growth
phase and closing of epiphysis of the long
bones that occur at puberty

C-Endometrial effects:
Estrogens with progesterone regulate
periodic bleeding and shedding of the
endometrial lining that occurs during
the normal menstrual cycle.
Continuous exposure to estrogens for
long periods causes endometrial
hyperplasia & bleeding

D-Metabolic Effects:
Maintenance of the normal structure and
function of the skin and blood vessels in
women
Decrease the rate of bone resorption by
promoting apoptosis of osteoclasts and
antagonizing the osteoclastogenic and
proosteoclastic effects of parathyroid
hormone and IL-6

 Stimulation

of production of leptin by
adipose tissue

Metabolic

alterations in the liver

increasing circulating levels of
CBG,TBG, SHBG,transferrin,rennin
substrate and fibrinogen. This leads to
increased circulating levels of
thyroxine,estrogen,testosterone,iron &
copper

 Estrogens

increase plasma levels of high

density lipoproteins(HDL) and a slight
reduction in LDL, and a reduction in total
plasma cholesterol and triglycerides

E-Effects on Blood coagulation:

Estrogens enhance coagulation of blood
by increasing plasma levels of factors
II,VII,IX,and X and decrease antithrombin
III.They also increase plasminogen and
decrease platelet adhesiveness

F-Other Effects:
Induction of progesterone synthesis
Induction of estrous behavior in
animals
Stimulate

central component of stress

system including production of
corticotropin releasing hormone(CRH)
and activity of the sympathetic system
and the sense of well being in women.
They also produce edema and
sodium retension

 Clinical Uses:
Primary hypogonadism as replacement therapy
in estrogen deficient states.
Postmenopausal hormonal therapy;many
disorder occur in these women:
-accelerated bone loss that may lead to
vertebral, hip and wrist fractures
-increased incidence of CVS diseases due to
increased plasma levels of LDL & cholesterol.Thus
hormonal replacement therapy(HRT) is required
in these women
Prevention and treatment of osteoporosis in
postmenopausal women

Adverse Effects:
A-Uterine bleeding mainly in postmenopausal women
B-Cancer:
-increased incidence of breast cancer on long term use
-women taking tamoxifen(partial agonist at estrogen
receptors),show 35% decrease in this cancer
-increased risk of endometrial carcinoma if taken
alone.The concomitant use of progestins reduces this risk
-Risk of adenocarcinoma of vagina in young women
whose mothers were on large doses of diethylstilbosterol
in early pregnancy.Risk of infertility,ectopic pregnancy
and premature delivery in these women

C-Other Effects:
Tenderness of breast,nausea,
hyperpigmentation, migraine
headache, cholestasis,gallblader
disease and hypertension may all
occur

 Estrogens

are not used in patients with

estrogen dependent neoplasms such
as carcinoma of endometrium or
those with or at high risk 0f breast
cancer
Estrogens are not used in patients with
undiagnosed genital bleeding,liver or
a history of thromboembolic disorders
Estrogens should be avoided by
heavy smokers

Preparations available:
Preparation
Replacement dose
Ethinylestradiol...0.005---0.02mg/d
Micronized estradiol.1---2mg/d
Estradiol cypionate2----5mg every 3---4
week
Estradiol valarate2-----20mg every
other week
Estropipate1.25---2.5mg/d
Quinestrol .0.1-----0.2mg/week
Chlorotianisine.12------25mg/d
Methallenestril..3------9mg/d
24/11/2016

The progestins:
Natural Progestins:(Progesterone)
Progesterone is the most important in
humans.
o Has hormonal effects & serves as a
precursor for estrogens, androgens &
adrenocortical steroids.
Synthesized from cholesterol in ovary(by
corpus luteum), in testis,& adrenals; & also
by the placenta during pregnancy under
influence of FSH and LH; &this is liable to
negative feedback.

 Synthetic

Progestins:
many progestational agents are
synthesized, some are active
orally.
The 21-carbon compounds
include hydroxyprogesterone,
and medroxyprogesterone

Cholesterol

Pregnenolone

Progesterone

megestrol and dimethisterone are

chemicals with progestational activity
Desogestrel,gestodene and
norgestimate are a third generation
synthetic progesteins with low
androgenic activity used in oral
contraception

Pharmacokinetics:
Progesterone is rapidly absorbed by any
route.
Is metabolized in liver to pregnandiol
Almost metabolized by first pass effect in
liver.
T1/2 in plasma is 5 min.Thus usual
formulations are not effective
orally.However high dose micronized
formulations give high plasma levels
orally.

 Physiological

A-

Effects:

Mechanism of Action:
similar to estrogen.
Progesterone enters the cell and binds
to progesterone receptors in nucleus
and cytoplasm.
The ligand- receptor complex form
dimers, enter receptors, binding to a
progesterone response element(PRE)on
DNA to activate gene transcription

 B-Effects

of progesterone:
Stimulates lipoprotein lipase &
favors fat deposition
Stimulates basal insulin release &
insulin response to glucose.In liver
it stimulates glycogen storage
It also promotes ketogenesis
It has little effect on protein
metabolism

 Progesterone

competes with aldosterone

for mineralocorticoid receptors in renal
tubules causing a decrease in sodium
reabsorption.
It increases body temperature.
It also alters the function of respiratory
center by increasing ventilatory response
to CO2,this leads to a decrease in arterial
and alveolar Pco2 during pregnancy and
in the luteal phase of the cycle

 It

has depressive & hypnotic effects on

brain
It causes development of
alveolobular secretory apparatus in
the breast
It participates in the preovulatory LH
surge and causes maturation and
secretory changes in the
endometrium that are seen following
ovulation

Clinical use of Progestins:

A-Therapeutic Applications:
Hormonal replacement therapy(HRT)
Components of oral contracetives
Long-term ovarian suppression(eg
medroxyperogesterone 150mg IM every 90
days causes prolonged anovulation and
amenorrhea)
Dysmenorrhea, endometriosis, bleeding
Maintenance of pregnancy or abortion
Endometrial, breast, and prostate carcinoma

 Medroxyprogesterone

in a dose of
1020mg orally twice weekly
prevents menestruation
Treatment of women with difficulty in
conceiving
Relieve of hot flushes in some
menopqusal women

B Diagnostic Use:
Test estrogen secretion.The
administration of progesterone
150mg/d or
medroxyprogesterone 10mg/d for
57 days is followed by
withdrawal bleeding in
amenorrheic patients only when
the endometrium is stimulated by
estrogens

Contraindications,cautions and adverse

effects:
Increased BP in some patients
Reduced plasma HDL levels in women
Weight gain,salt retension and
depression
Combined estrogen +progestin in HRT in
postmenopausal women may increase
the risk of breast cancer

Small amounts of androgens including

testosterone, androstenedione and
dehydroepiandrosterone are produced by
ovary.

Inhibin and activin are peptides secreted by

ovary that inhibit and enhance secretion of
FSH respectively

Relaxin is a peptide secreted by ovary. It

increases glycogen synthesis and water
uptake by myometrium and decreases uterine
contractility.

Menopause
Transition

period in a woman's life

when her ovaries stop producing eggs,
her body produces less estrogen and
progesterone, and menstruation
becomes less frequent.
Symptoms are mood swings, hot
flashes and vaginal dryness. 4/12/2015

 Contraceptives

contain estrogens,
progestins or both
Two types of preparations are used
orally:
(1) Combinations of estrogens and
progestins
(2) Progestins only pills

 The

combination agents are further

subdivided into:
Monophasic forms( constant dosage
of both components during the cycle
Biphasic or triphasic forms(dosage of
one or both components is changed
once or twoice during the cycle)
Oral preparations are adequately
absorbed

 In

combination forms the

pharmacokinetics of neither drug is
altered by the other.
Only etonogestrel is implanted under
the skin(one tube of 68mg).
Several hormonal contraceptives are
available as vaginal rings or
intrauterine devices.
Medroxyprogesterone 150mg I.M.
provides contraception for 90 days

 Pharmacologic

Effects:
Mechanism of Action:
Combination pills act by inhibiting
pituitary function that results in inhibition
of ovulation(by inhibiting FSH and LH
release)

 They

also produce a change in cervical

mucus (becomes more thicker), in
uterine endometrium, and in motility and
secretions in uterine tubes, all of which
decrease the likelihood of conception
and implantation.
The continuous use of progestins does
not inhibit ovulation, thus the above
factors become important.

 Effects

in Ovary:

Depression of ovarian function and they

become smaller.
Follicular development is minimal:
corpora lutea, large follicles, stromal
edema and other morphological
features seen in ovulating women are
absent.
75% of women return to normal ovulation
in first posttreatment cycle,97% by the
thired posttreatment cycle, but about
2% remain amenorrheic for years

 Effects

on Uterus:
Cervix may show some hypertrophy and
polyp formation on prolonged use.
The cervix mucus becomes thicker and
less copious(similar to postovulation
mucus).
Stimulation of glandular secretion in
endometrium for agents containing both
estrogen and progestin throughout the
luteal phase. This effect is due to progestin

 Effects

on Breast:
breast enlargement due to estrogens
estrogen alone or with progestin
suppresses lactation
Small amounts secreted in breast milk
without affecting the child.

Other Effects of Oral Contraceptives:

(1)Effects on CNS;
Estrogens tend to increase excitability
in brain, whereas progestins tend to
decrease it.
Progesterone has thermogenic effect
arising from CNS.
Estrogens are effective in treatment of
premenstrual tension syndrome,
postpartum depression,and
climmacteric depressin.

(2) Effects on Endocrine Function:

Inhibition of FSH and LH secretion

Estrogens increase plasma levels of 2globulins (CBG) that bind cortisol and other
hormones
Oral contraceptives cause alterations in the
renin-angiotensin-aldosterone system by
increasing plasma levels of rennin and
aldosterone and their activities.
Thyroxine binding globulin(TBG) levels are
increased thus free T3 &T4, are decreased.
Also levels of SHBG are increased which bind
androgens and decrease their plasma levels

 (3)

Effects on Blood:
Serious thromboembolism
Increase in factors VII,VIII,IX, and X and a
decrease in antithrombin III.
Increased amounts of coumarin
anticoaglants are required to prolong
prothrombin time
Increased serum iron levels and total iron
binding capacity
Folic acid deficiency anemia in some
patients

 (4)

effects on Liver:
Effects on serum proteins result from
effects of estrogen on synthesis of
various 2-globulins and fibrinogen
Haptoglobins synthesized in liver are
decreased

(5) Effects on Lipid Metabolism:

Estrogens increase serum triglycerides and

free and esterified cholesterol
Phospholipids & HDL are increased while LDL
levels are decreased
These effects are marked with doses of 100mg
of mestranol and ethinylestradiol
The progestins, especially the 19nortestosterone derivatives antagonize these
effects of estrogens
(6) Effects on Carbohydrates:
Reduced rate of absorption of carbohydrates
from GIT

(6) Effects on carbohydrate Metabolism:

Reduction in rate of carbohydrate absorption
from GIT.
Progesterone increases the basal insulin
levels and the rise in insulin release induced
by carbohydrates.
Potent progestins such as norgestrel cause a
progressive decrease in carbohydrate
tolerance over several years.
(7) Effects on CVS:
Increased cardiac output with increased
heart rate and BP.

(8) Effects on the Skin:

Increased

pigmentation of skin(chloasma)
Acne in some patients due to increased
production of sebum caused by androgenlike progestins

Clinical Uses:
Oral

contraception, effective when

taken as directed. Percentage failure
is 0.51%.
Failure may occur if one or more pills
are missed, if phenytoin is taken
concomitantly, or if antibiotics that
alter enterohypatic recycling of
metabolites are taken.
Treatment of endometriosis(progestins
or both)

Adverse effects:
o are divided into:
(A) Mild adverse effects:
Nausea,mastalgia,break through
bleeding and edema, are related to
the amount of estrogen in pill.
Changes in serum proteins and other
effects on endocrine function,must be
considered when thyroid, adrenal or
pituitary functions are evaluated.

 Headache

is mild and transient,but

migraine headache may be
worsened and may lead to
cerebrovascular accidents.
Withdrawal bleeding may sometimes
fail to occur especially with
combinatin pills.

 (B)

Moderate Adverse effects:

require discontiuance of pills

Breakthrough bleeding with progestins only pills.
Weight gain with combination pills containing
androgen like progestins.
Increased skin pigmentation which is
exacerbated by vitamin B deficiency,common in
dark-skined women.
Acne,that is exacerbated by androgen-like pills.
Hirsutism,that may be aggravated by 19nortestosterone derivatives.
Ureteral dilatation similar to that occuring during
pregnancy

 Vaginal

infections are more common and

more difficult to treat.
Amenorrhea in some women.
(C) Severe Adverse Effects:
(1) vascular disorders:
A-venous thromboembolic disease
Superficial or deep venous risk is increased
three times than in women not taking oral
contraceptives.This risk is related to the
estrogen component.
Antithrom III (inhibitor of thrombin) is
decreased in contraceptive pills users

 (b)

myocardial infarction:
Increased risk of myocardial infraction
in obese women with a history of
preeclampsia,hypertension, or have
hyperlipoproteinemia or diabetes or
smokers
(c) cerebrovascular disease:
The risk of stroke is increased in
women over 35 years,and current
users
Subarachnoid hemorrhage in both
users

 (2)Gastrointestinal
Cholistatic

Disorders:

jaundice in pts.taking

porgestins
Increased incidence of symptomatic
gallbladder disease including cholecytitis
and cholangitis
Increased incidence of hepatic adenoma
Ischemic bowel disease
(3) depression:occurs in about 6% of
patients and may require drug withdrawal

 (4)

cancer: the risk of endometrial and

ovarian cancers is reduced
The risk of breast cancer is not
increased in old women but may
increase in younger women
(5)Others: Risk of alopecia,erythema
multiforme, erythema nodosum and
other skin disorder

 Contraindications:
Patients

with thrombophelebitis,
thromboembolic phenomena and
CVS or cerebrovascular disorders
Not used to treat vaginal bleeding
when cause is not known

 Not

used in pts with or suspected to have

breast or other estrogen-dependent
neoplasms
Should be avoided or used cautiously in
pts with asthma, liver disease
eczema,migraine diabetes, hypertension,
optic neuritis, retobolbar neuritis or
convulsive disorders
Should be used with great caution in pts
with heart failure

 Are

contraindicated in adolescents in
home epiphysial closure is not
completed
Antimicrobials may decrease oral
bioavailability of these drugs since
they interfere with normal GIT flora that
increase enterohepatic recycling of
them.

 Also

administration of hepatic enzyme

inducers such as rifampin increases
metabolism of these agent thus
diminishing their efficacy.

 Contraception
Small

with Progestin alone:

doses of progestins orally or

implanted under the skin produce
contraception, but with a high incidence of
abnormal bleeding.eg 150mg depot
medroxyprogesterone is an effective
contraceptive
Ovulation suppression can persist for up to
18 months after the last injection.
Etonorgestrel implanted under skin gives
contraception for up to 24yrs

Estrogen and Progesterone

Antagonists/SERMs
Estrogen and progesterone antagonists
are compounds that block the actions of
estrogen by binding to estrogen or
progesterone receptors
As a result, estrogen or progesterone
can not bind to their receptors.

Example:
Raloxifene(EVISTA) is a
SERM in some tissues.

Used to prevent
postmenopausal
osteoporosis and
prophylaxis of breast
cancer

SERMs
Selective

Estrogen Receptor Modulators.

Because estrogen receptors differ slightly
in different organs, SERMs can target
receptors of a certain organ
So a SERM that blocks estrogens effects in
breast cells wont impact estrogen binding
in the uterus!
Tamoxifen:SERM used in
palliative treatment of breast
cancer in postmenopausal
women, and prevention of this
cancer in high risk women

Dose is 1020mg/d

 Clomiphene:

is a partial agonist at
estrogen receptors (SERM)that is used as
an ovulation inducer.It increases secretion
of gonadotropins andestrogen by inhibiting
the estradiols ve feedback effect on
gonadotropins

 Mifepristone:
is

a strong progesterone receptor

antagonist.Has luteolytic effect in 80% of
women when given in the midluteal phase
which permits its use as a contraceptive.It
delays endometrial maturation, thus used
to terminate pregnancy.
also a glucocorticoid receptor antagonist
Used in treatment of endometriosis,
Cushings syndrome,breast cancer and
other neoplasms that contain
glucocorticoid or progesterone receptors

 Danazol:
Has

weak progestational, androgenic and

glucocorticoid activity.It binds to
androgen, progesterone and
glucocorticoid receptors
Used to suppress ovarian function.Mainly
treatment of endometriosis.Acts by
inhibiting midcycle surge of LH and FSH

 Also

used to treat fibrocystic disease

of the breast and hematologic or
allergic disorders including
hemophilia, Christmas disease,
idiopatheic thrombocytopenic
purpura and angioneurotic edema
Adverse effects include weight
gain,edema, decreased breast
size,acne and oily skin&others

 Other

Inhibitors:

Anastrazole is an aromatase inhibitor(the

enzyme required for estrogen synthesis)
Is used for breast tumors resistant to
tamoxifen.Letrezole is a similar compound.
Exemestase is an irreversible inhibitor of
aromatase.Used for advanced breast
cancer
Fadrozole is a nonesteroid inhibitor of
aromatse
Fulvestrant is a pure estrogen receptor
antagonist used for breast cancer resistant
to tamoxifen

Hormone Replacement
Therapy (HRT)
Estrogen + progestins or either!
Medical treatment for menopausal or
post-menopausal women
Progestins keep weight off and stop cell
proliferation
Benefits of estrogen:

Reduction in loss of bone mass (osteoporosis)

Decreased risk of cardiovascular disease
Positive effect on cognitive function

 The

testis has both gametogenic and

endocrine functions
The gametogenic function is controlled by
FSH secretion from anterior pituitary
High concentrations of testosterone locally
are also required for sperm production in
the seminiferous tubules

 The

Sertoli cells in the seminiferous

tubules produce estradiol by
armatization of testosterone
Testosterone is produced by interstitial
or Lideg cells in seminiferous tubules
under stimulation by LH.

Androgens and Anabolic Steroids:

Teststerone

is the most important anabolic

steroid in men,about 8mg is produced
daily(95%by Ledig cells and 5% by
adrenals
Other androgens produced by testes
include dihydrotestosterone,
androstenedione and
dehydroepiandrosterone

 Plasma

level of testosterone is
o.6g/ml,but decline by age 50 years.
In women it is o.03g/ml derived from
ovaries,adrenals and peripheral
aromatization of testosterone
About 50% of testosterone is bound to
SHBG in plasma and the rest to
albbumin

 Metabolism:

Testosterone is converted to dihydroteststerone

by 5-reductase (the active form)
Is also converted to estradiol by P450 aromatase
in some tissues ,eg liver.
It is mainly degraded in liver to inactive
metabolites such as androsterone and
etiochlanolone that are excreted in urine as
conjugates
Androstenedione, dehydroepiandrosterone
(DHEA) and dehydroepiandrosterone sulphate
(DHEAS) are also produced in small amounts in
adrenals.

 Physiological

Effects:
In males testosterone and its active
metabolite 5-dihydrotestosterone
promote growth of body tissues,penile
and scrotal growth,skin changes
including growth of auxillary,pubic
and beard hair.Sebaceous glands
become more active and the skin
becomes more thicker and oilier.

 The

laynex grows and the vocal cords

become thicker.Skeletal growth is
stimulated and epiphysis closure is
accelerated.Growth of the prostate
and semuinal vesicles,darkeing of the
skin,stimulation of sexual function.
Increased lean body mass and
stimulation of body hair growth and
sebum secretion.

 Synthetic

Steroids With Androgenic and

Anabolic activity:

Testosterone is largely converted to inactive

metabolites
The propionate,enanthate,undecanoate and
cypionate esters have prolonged duration of
action
Testosterone derivatives,methyltestosterone
and fluoxymesterone are active orally
Testosterone and its derivatives are used in
cases of deficiency and as anabolic agents

 Pharmacologic Effects:
Testosterone acts intracellularly.
It is converted to 5-dihydrotestosterone by 5reductase
Testosterone and dihydrotestosterone bind to
intracellular androgen receptors leading to
growth, differentiation and synthesis of a variety
of enzymes
Effects:
Development of secondary sex charachteristics
In males large doses suppress secretion of
gonadotropins resulting in some atrophy of testes

 In

females they promote growth of

facial and body hair, deepening of
voice, enlargement of clitoris, frontal
baldness, and prominent musculature
Natural androgens promote
erythrocyte production
Androgens reduce excretion of
nitrogen in urine indicating increased
protein synthesis

 Cilnical

Uses:
As replacement therapy in men cases of
hypogonadal men to achieve normal
spermatogenesis
In gynecological disorders to reduce
breast engorgement in women during
postpartum period in conjunction with
estrogens
The weak androgen danazol is used in
treatment of endometriosis.

 They

are used with estrogens for

replacement therapy in
postmenopausal period to eliminate
endometrial bleeding that may occur
if estrogens are used alone and to
increase lipido.

 (C)

Use as protein anabolic agents in

conjunction with dietary measures to
exercise to reverse protein loss after
trauma,surgery,or prolonged
immobilization and in cases of deblitating
diseases
(D) Anemia:
In large doses to treat refractory anemias
such as aplastic anemia,Fonancs anemia,
sickle cell anemia, myelofibrosis and
hemolytic anemia

 (E)

Osteoporosis:
Androgens and anabolic steroids are
used in treatment of osteoporosis
alone or with
estrogens.Bisphosphonates have
replaced them in this use

 (f)

Use as growth stimulators:

To stimulate growth in boys with delayed
puberty
(g) Use in Sports: doses 10200 times daily
normal production are used by athelets to
increase strength and aggressiveness thus
improving competitive performance. Such
doses may increase adverse effects

 (H)

Aging:
Androgen production in males falls
with age, this may lead to decline in
muscle mass,strength and lipido
Replacement therapy with androgens
may lead to an increase in lean body
mass,hematocrit and a decrease in
bone turnover.

 Adverse

effects:

Masculiniztion,hirsutism,acne,amenorrhea,deepe
ning of voice and clirotial enlargement in women
Increased atherosclerosis incidence in women
Administration in pregnants may lead to
masculinization or under masculinization of
external genitalia in female and male infants
respectively
Synthetic agents with 17-alkyl groups may cause
hepatic dysfunction (eg cholestatic jaundice).

 In

older men prostatic hyperplasia

may occur leading to urine retension
In men acne,sleep
apnea,erythrocytosis, gynecomastia
&azoospermia, decreased testis size
may all occur
High doses of alkylated androgens
may cause peliosis
hepatica,cholestasis,and hepatic
failure.lowering of HDL and incease
LDL levels.Increasd aggressiveness.

 Contraindications:
Not

given to pregnants or who may

become pregnant
Not given to males with prostatic or
breast carcinoma
Should be avoided in infants and
young children since they may affect
CNS development

Androgen Suppression and Antagonists:

Androgen Suppression:
Orchiectomy(testectomy) or large
doses of estrogens suppress
endogenous androgens.Used to treat
advanced prostate cancer.But
continuous doses of GnRH analogs
such as goserelin, nafarelin,buserelin
and leuprolide, that suppress the
gonads are more effective and
prefered

 Antiandrogens:
Steroid

synthesis inhibitors:

Ketoconazole(antifungal)

is an inhibitor of
adrenal and gonadal hormones synthesis
by reducing human aromatse activity
Conversion of Steroid Precursors to
Androgens:
These compounds inhibit the 17
hydroxylation of progesterone or
pregnenolone thus preventing production
of androgens
Abiratone is one such compound

 Finasteride

inhibits 5-reductase thus

preventing production of
dihydrotestosterone in prostate thus
decreasing prostate size in benign
prostatic hyperplasia
Dutasteride is a similar compound
Receptor

Antagonists:

Cyproterone

and cyproterone acetate are

antiandrogens that act by inhibiting
androgen receptors.Are used in women to
treat hirsutism and in men to decrease
excessive sexual derive

 Flutamide

used to treat prostate

cancer
Bicalutamide and nilutamide are
effective oral antiandrogens used to
treat prostate cancer
Spironolactone, a receptor antagonist
of aldosterone and
dihydrotestosterone .It also reduces
17-hydroxlase activity leading to
lowering of testosterone and
dihydrotestosterone. Used to treat
hirsutism on women.

 Fig

.control of androgen secretion and

activity and some sites of action of
antiandrogens(1)competitive
inhibition of GnRH receptors(2)
stimulation of( by pulsatile
administration) or inhibition via
desensitization of GnRH receptors(
continuous administration)(4)
decreased synthesis of testosterone in
testis( 4) decreased synthesis of
dihydrotestosterone by inhibition of
5-reductase (5)competition for
binding to cytosol androgen receptors

Chemical Contraception in Men:

Testosterone and testosterone ethanoate in a
dose of 400mh/month produce azoospermia in
some men
Tsetosterone enanthate in a dose of 100mg/d i.m
+500mg levonorgestrel/d orally produce
azoospermia in 94% of men
Cyproterone acetate( a potent progestin and
antiandrogen) produces oligospermia in men
Gossypol : a cotton seed derivative destroyes
elements of seminiferous tubules epithelium but
does not alter endocrine function of testes.