GONADAL HORMONES

Dr YOGEETA SC WALKE
ASSISTANT PROFESSOR
PH 1.37 Describe the MOA, types, doses, side effects,
indications & contraindications of drugs used as sex
hormones, their analogues & anterior pituitary hormones

PH 1.39 Describe the MOA, types, doses, side effects,

indication & contraindications of the drugs used for
contraception
PH 1.40 Describe the MOA, types, doses, side effects,
indications & contraindications of
1. Drugs used in treatment of infertility
2. Drugs used in erectile dysfunction

PH 1.41 Describe the MOA, types, doses, side effects,

indications & contraindications of uterine relaxants and
stimulants
Hypothalamus Pituitary Gonadal
Axis
HYPOTHALAMUS

GnRH

ANTERIOR PITUITARY

FSH LH

OVARY

Estrogen progesterone
 GnRH
• GnRH is released from hypothalamus.

• GnRH release is intermittent.

• Pulsatile adm. is imp.

• Continuous adm of GnRH desensitization

& down regulation of GnRH receptors on
pituitary gonadotropes.

• Loss of gonadotropin release.

 Synthetic GnRH
GONADORELIN
• Synthetic peptide containing native sequence of GnRH.

Indication
Management of infertility secondary to GnRH deficiency.
Adm by IV pump in pulses.
GnRH analogs
1. Resistant to proteolysis.

2. Prolonged DOA

3. Enhanced potency.
Super active / long acting
GnRH agonists
1. Buserelin Intranasal spray, SC

2. Nafarelin Intranasal spray

3. Goserelin SC/IM

4. Triptorelin SC/IM

5. Leuprolide SC/IM
Super active / long acting
GnRH agonists
Initially increase Gn secretion.
After 1-2 weeks

Down regulation of GnRH rs

Inhibition of FSH & LH secretion

Suppression of gonadal function

Indications
1. Uterine fibroids

2. Endometriosis

3. Central precocious puberty

4. Carcinoma prostate
GnRH antagonists
1. Ganirelix

2. Cetrorelix

3. Degarelix

4. Abarelix
GnRH antagonists
Advantages over long acting GnRH agonists

1. Inhibits Gn secretion without causing

initial stimulation.

2. Lower risk of ovarian hyperstimulation

syndrome
Indications
1. Uterine fibroids

2. Endometriosis

3. Carcinoma prostate

4. Used in specialised centres for inhibiting LH surges

during controlled ovarian stimulation in women
undergoing in vitro fertilization.
Gonadotropins
1. FSH secreted from anterior pituitary
under the influence of GnRH

2. LH

3. HCG Secreted by syntiotrophoblasts cells

of the placenta.
 FSH
Females
1. Follicular development &
development of ovum.

2. Production of estrogen & progesterone.

3. Regulation of menstrual cycle.

 LH
Females
1. Induction of ovulation.

2. Formation & maintenance of corpus luteum.

3. Production of estrogen & progesterone.

4. Regulation of menstrual cycle.

 Males
1. FSH
Stimulate production of proteins & nutrients
required for sperm maturation in sertoli cells.

2. LH
Synthesis of testosterone by leydig cells of
testis.
Gonadotropin Preparation
1. Menotropins: Equal amount of FSH + LH
Obtained from urine of menopausal women

2.Urofollitropin : Pure FSH

3. HCG derived from urine of pregnant women

4. Recombinant human FSH (rFSH)

5. Recombinant human LH Lutropin

.

Indication
1. To diagnose pregnancy testing.

2. Female infertility: deficient production of

Gns by pituitary.

3. Male infertility: Hypogonadotropic

hypogonadism in males.

4. To aid in vitro fertilization.

Hormonal relationship

of human

menstrual cycle
Hormonal relationship of MC
In the early follicular phase of the cycle

1. Pulse generator produces a burst of

neuronal activity release of GnRh.

2. Pulsatile release of LH & FSH from AP.

3. Graafian follicle mature & secrete estrogen.

Hormonal relationship of MC
4. At midcycle serum estradiol level rises >
150-200 pg/dl which exerts a positive
feedback effect on the pituitary to trigger
preovolatory surge of LH & FSH.

5. Midcycle surge in Gn stimulate follicular

rupture & ovulation within 1-2 days.
Hormonal relationship of MC
6. Ruptured follicle then develops into CL
which produces large amount of P & E ( less).

7. In the absence of pregnancy CL ceases to

function steroid level drops & menstruation
occurs.

8 Pulse generator reverts to a firing pattern

New ovarian cycle occurs.

Estrogens
Natural estrogens

1. Estradiol

2. Estrone

3. Estriol
Androstenedione Estrone Estriol

Aromatase

Testosterone Estradiol
Source Of Estrogen
1. Premenopausal women: ovaries

2. Early pregnancy: Corpus luteum

3. Late pregnancy :Placenta

4. Post menopausal: Adrenal androgen

4. Men: Aromatisation of testosterone & weak

androgens
Synthetic Estrogens
a. Steroidal
Ethinyl estradiol
Mestranol
Tibolone

b. Nonsteroidal
Diethylstilbestrol
Hexestrol
Dienestrol
1. Sex organs
a. Growth of uterus, fallopian tubes & vagina.

b. Rhythmic contraction of the fallopian tubes

& uterus are increased.

c. Induces watery alkaline secretion from cervix

2. Secondary sex characters
• Growth of breast

• Pubic & axillary hair

• Feminine body contours & behaviour

3. Metabolic effects
a. LDL & HDL & TGs.

b. Blood coagulability by increasing the

synthesis of clotting factors II ,VII ,IX & X.

c. Lithogenicity of bile by cholesterol

secretion.
 Bone
a. Promotes fusion of epiphysis.

b. Maintains bone mass by retarding bone

resorption.

Decreases number & activity of osteoclasts

& regulates osteoblasts.
Mechanism Of Action
Estrogens bind to specific nuclear rs in target
cells & produce effects by regulating protein

synthesis.
Estrogen Receptors
1. ER α uterus, vagina, ovaries,breast,
hypothalamus, Bone & blood vessels

2. ER β prostate gland & ovaries

Pharmacokinetics
• Natural estrogens are inactive by the oral
route due to rapid metabolism in liver.

• Synthetic estrogens are well absorbed orally &

trandermally.
 Transdermal estradiol
(Estradiol TTS)
• A transdermal patch is available in 3 sizes 5,
10 & 20 cm2 delivering 0.025 0.05 & 0.1 mg
in 24 hrs for 3-4 days.

•Cyclic therpy with estradiol TTS is advised

with oral progestin added for last 10-12 days

• Systemic SE are same but milder.

Adverse Effects
1. Suppression of libido, gynaecomastia & feminization
when given to males.

2. Fusion of epiphysis & reduction of adult stature when

given to children.

3. Stilbestrol given to pregnant women during

first trimester increased incidence of vaginal
& cervical carcinoma in the female offspring in
childhood or early adulthood.
Adverse Effects
4. Increased incidence of endometrial and breast cancer
on long term estrogen therapy .

5. long term estrogen therapy doubles the incidence of

gallstones .

6. Nausea, breast tenderness,

hyperpigmentation & hypertension.
 Indication
1. Primary hypogonadism in females

Estrogen started at 11-13 yrs of age

stimulates the development of secondary

sexual characters & menstruation.

Indication
2. Senile vaginitis
Due to estrogen withdrawal from ovary.
Estrogen cream is applied topically.

3. Oral contraceptives.
 Indication
4. Post menopausal syndrome

D/T caessation of ovarian function at menopause

results in decreased estrogen production.

s/s: Hot flushes, anxiety, fatigue, sweating.

Osteoporosis, genital atrophy, CV disease

& psychological disturbances.

 Hormone replacement therapy

HRT
• Dose of estrogen in HRT is lower than that of
contraception.

• Conjugated estrogens
Mixture of various conjugated forms of estrogens.

2 principal components are

sodium estrone sulphate
sodium equilin sulphate.
Dose 0.625 mg/day oral.
a. Cyclically 3 weeks treatment & 1 week gap
 b. Continuous

HRT
• A progestin is added for 10-12 days each
month.

• Progestin is needed to block the increased

risk of dysfunctional uterine bleeding &
endometrial carcinoma due to continuous
estrogenic stimulation.
 HRT
1.Hysterectomised women should receive E
alone, while those with intact uterus be given E+ P.

2. Cyclic HRT should be given rather than

continuous HRT.

3. HRT is not the best option to prevent

osteoporosis & fractures.
 HRT
4. HRT affords no protection against CVD
May even increase the risk of venous
thromboembolism, MI & stroke.

5. HRT does not protect against cognitive

decline may increase the risk of dementia.

6. HRT increase the risk of breast cancer,

gallstones & migraine.
Tibolone
• Estrogenic + progestational +
weak androgenic activity.

• Suppresses menopausal symptoms.

• No endometrial stimulation.

• Indication: HRT
 Antiestrogens
•Clomiphene citrate
Pure estrogen antagonist.

• Blocks both ERα & ERβ.

• Blocks E Rs of hypothalamus & anterior pituitary.

• It induces Gn secretion in women by blocking

estrogenic feedback inhibition of pituitary.
Thus induces ovulation.
Hypothalamus Pituitary Gonadal
Axis
HYPOTHALAMUS

GnRH

ANTERIOR PITUITARY

FSH LH

OVARY

Estrogen progesterone
Adverse Effects
• Ovarian hyperstimulation

• multiple pregnancy.

• Hot flashes
 Indication
1. Infertility due to failure of ovulation in
women.

• Dose 50 mg OD for 5 days starting from

5th day of menstrual cycle.

• Treatment is given monthly.

 Indication
2. Oligozoospermia

Induces Gn secretion promotes

spermatogenesis & testosterone secretion.

Dose: 25 mg daily for 24 days in a month

with 6 days rest for upto 6 months.
Indication
3. In vitro fertilization.

• Clomiphene given with Gns causes

synchronous maturation of several ova.
• Improves their harvesting.
Selective Estrogen Receptor
Down- Regulator (SERDs)
• Fulvestrant

• Pure estrogen antagonist

• Efficacious in tamoxifen resistant breast cancer in post

menopausal women

• Binds with high efficacy to ER α & ER β

• Increases proteolytic degradation of ER α

 Administered as monthly IM injections

Selective Estrogen Receptor

Modulators ( SERMS)
• Tamoxifen citrate

• Raloxifene

• Ormeloxifene
 SERMS
• Compounds whose estrogenic activities are tissue
selective.

a. Estrogenic antagonistic effects in breast.

b. Estrogenic agonistic effects in bone.

Tissue specific agonist/ antagonistic
activity of SERMS
Drug Breast Endometrium Bone
ESTROGEN +++ +++ +++

TAMOXIFEN - + +

RALOXIFENE - - +

ORMELOXIFENE - - ++
Tamoxifen
1. Agonist in bone & endometrium.

2. Antagonist in breast cancer cells where it

prevents receptor activation by endogenous
estrogens.
Tamoxifen
3.Increases bone density & improves lipid
profile.

4. Promotes endometrial hyperplasia &

increases the risk of endometrial carcinoma
2-3 times.
Tamoxifen
• Effective orally.

• Biphasic plasma t½ 10 hrs & 7 days.

• Long duration of action.

• Excreted in bile.
Side effects
• Hot flushes

• Nausea & Vomiting

• Vaginal bleeding

• Much less toxic than other anticancer drugs.

Indication
• Hormone responsive primary awa metastatic breast
carcinoma in premenopausal women

• In premenopausal women tamoxifen is continued for 5

yrs postmastectomy

• In postmenopausal women it is generally replaced after

2 yrs by an Aromatase inhibitor

Dose : 20 mg daily orally

Raloxifene
• Agonist in bone- strong antiresorptive effect.

• Antagonist in breast & endometrium.

• Undergoes enterohepatic cycling.

• Excreted in faeces.

• t1/2 27 hours.
Raloxifene
• Prevention & treatment of osteoporosis
in postmenopausal women.

Dose: 60 mg daily orally.

Ormeloxifene ( CENTCHROMAN)
• Non steroidal anti estrogenic &
anti progestogenic.

• Agonist in bone.

• Indicated for contraception & osteoporosis.

Aromatase inhibitors
•Inhibits aromatase, an enzyme which
converts androgens to estrogens.

• Letrozole
Nonsteroidal & reversible
inhibitor
• Anastrozole

• Exemestane Steroidal & irreversible inhibitor

Adverse effects
• Hot flashes

• Vaginal dryness

• Thinning of hair

• Bone loss is accelerated

Indication
First line therapy for early awa advanced

breast cancer in ER positive postmenopausal

women
Tamoxifen Aromatase
inhibitors
• Estrogen antagonist in • Inhibits production of
breast & blood vessels, but estrogen from
agonist in uterus, bone & aromatization of
liver testosterone &
androstenedione

• Can be used in pre & post • To be used only in post

menopausal women menopausal women
Tamoxifen Aromatase
inhibitors
1. Causes endometrial 1. No endometrial
hyperplasia, predisposes to hyperplasia
endometrial carcinoma

2. No bone loss 2. Accelerates bone loss,

predisposes to fractures
No increase in fractures

3. No increase in
3. Increases risk of venous thromboembolic risk
thromboembolism
Tamoxifen Aromatase
inhibitors
4. Improves lipid profile 4. No effect on lipid profile
 Tamoxifen vs letrozole
Breast cancer
1. Premenopausal patient
Tamoxifen is the standard treatment.
Dose: 20 mg OD

Aromatase Inhibitors cannot be used since they

do not block ovarian production of estrogen.
Tamoxifen vs letrozole
Breast cancer
2. Postmenopausal patient
a. Tamoxifen
b. Letrozole
Tamoxifen vs letrozole
Breast cancer
Tamoxifen
1. Cannot be given for >5 years.
Thromboembolic events
Uterine hyperplasia & cancer

Letrozole
Osteoporosis & bone fractures
Progestins
These are substances which convert the

estrogen primed endometrium to secretory

& maintain pregnancy.

Progesterone is a natural progestin.

Source of Progestins
1.Females: a. Ovary from corpus luteum during
second half of menstrual cycle.

b. Placenta.

2. Male: Testis

3. Adrenal cortex
Classification
1. Progesterone derivative

2. 19 Nortestosterone derivatives
a. Older compounds

b. Newer compounds
Classification
1. Progesterone derivative

Medroxy progesterone acetate

Megestrol acetate

Dihydrogesterone

Hydroxy progesterone caproate

 Pure progestins
Weak antiovulatory action.

1.Indications
Progesterone derivative
a. HRT

b. Endometriosis
2. 19 Nortestosterone derivatives
a. Older Compounds (NEAL)

1. Norethindrone (Norethisterone)

2. Lynestrenol (Ethinylestrenol)

3. Allylestrenol

4. Levonorgestrel (Gonane)
2. 19 Nortestosterone derivatives
• Weak estrogenic
a. Older Compounds
• Weak androgenic

• Anabolic

• Potent antiovulatory

Indication
• OCP
2. 19 Nortestosterone derivatives
b. Newer Compounds (Gonanes)

Desogestrel

Norgestimate

Gestodene
• Potent Progestins
2. 19 Nortestosterone derivatives
b. Gonanes
• Potent antiovulatory

• No androgenic

Indication
OCP
 Pharmacological Actions
1. Progestins released during luteal phase
decrease endometrial proliferation causing
a more secretory endometrium.

2. High level of progesterone in the serum

prevents ovulation.
During Luteal phase & during pregnancy
ovulation does not occur.
 Pharmacological Actions
3. Luteal phase prepares the endometrium for
embedding the fertilized ovum.

4. Maintains pregnancy hence the name

progesterone (an agent that favours gestation)

5. Endometrial secretion are rendered scant &

viscid.
Pharmacological Actions
6. Reduces uterine contraction & helps
in maintenance of pregnancy.

7. Breast: P acting with E brings about

proliferation of the acini & prepares the
gland for lactation.

8. Sedative effect
MOA
• Progesterone Receptor (PR)

• Female genital tract, breast, CNS, & pituitary.

P + PR (nucleus)

Protein synthesis
Pharmacokinetics
• Progesterone is inactive orally.

• Undergoes high first pass metabolism.

• Injected im in oily solution.

• Synthetic progestins are orally active.

• t ½ 8-24 hrs.
 Adverse Effects
1. Breast discomfort, acne, mood swings.

2. Irregular bleeding or amenorrhoea.

3. 19 nor testosterone derivatives lower HDL

levels may promote atherogenesis.
 Indications
1. Contraceptive

2. Hormone Replacement Therapy

E +P to counteract the risk of inducing
endometrial carcinoma.

3. Dysfunctional uterine bleeding.

4. Endometriosis
 Indications
5. Postponement of menstruation

Norethisterone
5 mg tds
5 days before the expected onset of menses.
Antiprogestins
1. Mifepristone
antiglucocorticoid Progesterone
antiandrogenic Receptor
Modulato
2. Ulipristal

3. Onapristone
Pure progesterone antagonist
 Ulipristal
Selective progesterone receptor modulator (SPRM).

• Inhibits ovulation
• Interferes with implantation

Emergency contraception
 Mifepristone
• Early stages of pregnancy causes decidual
breakdown by blockade of uterine PR.

• This leads to detachment of blastocyst,

which decreases HCG production.

This in turn causes a decrease in P secretion

from corpus luteum which accentuates
decidual breakdown.
 Mifepristone
• Decreased endogenous P coupled with
blockade of PR in the uterus increases uterine
PG levels & sensitizes the myometrium to
their contractile actions.

• Mifepristone causes cervical softening which facilitates

expulsion of the detached blastocyst.
Pharmacokinetics of Mifepristone
• Absorbed orally.

• t½ 20-40 hrs.

• Undergoes enterohepatic cycling.

• Excreted in faeces.
Indications of Mifepristone
1. Termination of pregnancy.

Upto 7weeks or 49 days.

600mg SD oral
+
Misoprostol 400µg 36-48 hrs later.
Indications of Mifepristone
2. Emergency postcoital contraception

600mg SD within 72 hrs of coitus.

3. Induction of labour following

intrauterine foetal death.
Hormonal Contraceptives
• Hormonal preparations.
• Used for reversible suppression of fertility.

I. Female contraception

II. Male Contraception

I. Female contraception
a. Oral
1. Combined Pills
Contains Estrogen + Progestin

Estrogen Ethinyl estradiol

20µg , 30µg or 50µg

Preparations containing 35 mcg or less are referred to as

“low dose” or “modern” pills

Progestin 19 nor testosterone

 potent antiovulatory.

Combined Pills
Levonorgestrel 0.1 mg

Ethinyl estradiol 20 mcg

 Combined method
1 tablet is taken daily for 21 days,
starting on the 5th day of menstruation.

Next course is started after a

gap of 7 days in which bleeding occurs.

Thus a cycle of 28 days is maintained.

 Combined method
2. Phased regimens
a. Biphasic regimens

b. Triphasic regimens

Estrogen dose is kept constant or

varied slightly between 30-40 mcg.
Progestin is low in first phase & progressively
higher in second & third phase.
 Triphasic Pills
1. Levonorgestrel 50-75-125 mcg
+
Ethinyl estradiol 30-40-30 mcg
(6+5+10 tablets)

2. Norethindrone 50-75-100 mcg

+
Ethinyl estradiol 35-35-35 mcg
(7+7+7 tablets)
A
3.low dose progestin
Minipill only pill is taken
(Progestin Only Pill)
continuously without any gap.

Many long term risks have been ascribed to E.

Menstrual cycle tends to become irregular

Efficacy is lower

Less popular method.

Postcoital contraception or
Emergency contraception
a. Yuzpe method

Levonorgestrel 0.25 mg
+
Ethinylestradiol 50 mcg
(2+2 tablets)
2 tabs taken as early as possible but within 72 hrs of
unprotected intercourse & 2 repeated after 12 hrs.
Postcoital contraception or
Emergency contraception
b. Levonorgestrel alone 0.75 mg taken twice
with 12 hour gap within 72 hrs of
intercourse (1+1 tabs)

C. Mifepristone 600mg SD
taken within 72 hrs of intercourse

d. Ulipristal 30 mg SD within 120 hrs of

intercourse
Injectable Contraceptives
• Developed to obviate the need

for daily ingestion of pills.

 Injectable
1. Long acting progestin alone

a. Depot medroxy progesterone acetate (DMPA)

150 mg at 3 months interval.

b. Norethindrone (norethisterone) enanthate

(NEE)
200 mg at 2 months interval.
 Disadvantages
1. Amenorrhoea is frequent.

2. Permanent sterility may occur.

 Injectable
2. long acting progestin + long acting estrogen
Once a month
Medroxy Progesterone Acetate+
Estradiol cypionate

Advantage
Menstrual bleeding pattern is maintained.

Disadvantage
LA estrogen has potential to harm.
 3. Implants
a. Norplant
A set of 6 capsules which contains 36 mg
levonorgestrel for SC implant.
Works for upto 5 years.

b. A progesterone impregnated intrauterine

insert (Progestasert).
Device is replaced yearly.
 MOA
1. Inhibition of Gn release from pituitary by
reinforcement of normal feedback inhibition.

Progestin reduces LH secretion.

Estrogen reduces FSH secretion.
Both synergise to inhibit midcycle LH surge.

As a result follicles fail to develop

& fail to rupture.

Ovulation does not occur.

 MOA
2. Thick cervical mucus secretion hostile to
sperm penetration is evoked by Progestins

3. Even if ovulation & fertilization occur,

the blastocyst may fail to implant endometrium is
either hyperproliferative or
hypersecretory or atrophic & in any case
out of phase with fertilization.
Not suitable for nidation.
 MOA
4. Uterine & tubal contractions may be
modified to disfavour fertilization.

5. Postcoital pill may dislodge a just implanted

blastocyst or may interfere with fertilization or
implantation.
Practical considerations
1. Discontinuation of all OCs results in full
return of fertility within 1-2 months.

2. If a woman on combined pills misses to

take a tablet, she should be advised to take
2 tablets the next day and continue as usual.
Practical considerations
3. If more than 2 tablets are missed, then an
alternate method of contraception used as
backup since cycle is unsafe and next course
started on the 5th day of bleeding.

4. If pregnancy occurs during use of hormonal

contraceptives it should be terminated
because the risk of malformations, genital
carcinoma in female offspring is increased.
Health Benefits of OCPs
1. Prevention of unwanted pregnancy &
the risk during delivery.

2.Lower probability of developing

Endometrial carcinoma
d/t inclusion of progestin which opposes which opposes
estrogen induced proliferation

Ovarian carcinoma.
Health Benefits of OCPs
3. Anaemia: Reduced menstrual blood loss.

Irregular cycles become regular.

Premenstrual tension.

Dysmenorrhoea.
Health Benefits of OCPs
4. Endometriosis & pelvic inflammatory disease
are improved.

5. Reduced incidence of fibrocystic breast

disease and ovarian cyst.
Drug interactions
Contraceptive failure occur
1. Enzyme inducers
Rifampicin Phenytoin, Phenobarbitone &
Carbamazepine.

2. Supression of intestinal microflora

Tetracyclines , Ampicillin
No deconjugation of estrogens excreted in bile
Their enterohepatic circulation is interrupted blood
levels falls.
Adverse Effects
Non serious SE

a. Nausea & vomiting.

b. Headache

c. Breast discomfort

d. Weight gain
Adverse Effects
e. Chloasma

f. Pruritus vulvae

g. Carbohydrate intolerance &

precipitation of DM.

h. Mood swings, abdominal distention.

Serious Complications
1. Leg vein & pulmonary thrombosis.

2. Coronary & cerebral thrombosis resulting in

myocardial infarction or stroke.
a. Increase in blood clotting factors
b. Decreased antithrombin III
c. Decreased plasminogen activator in
endothelium.
d. Increased platelet aggregation.
Serious Complications
3. Rise in BP

4. Estrogen tends to raise plasma HDL /LDL ratio, but

progestin nullifies this benefit.

5. Genital carcinoma increased incidence of vaginal,

cervical, & breast carcinoma.

6. Benign hepatomas

7. Gallstones.
Contraindication
1.Thromboembolic, coronary & CVD.

2. Moderate to severe HT, hyperlipidaemia.

3. Active liver disease, hepatoma.

4. Suspected /overt malignancy of genitals/
breast.

5. Diabetes Mellitus.
Centchroman (Ormeloxifene)
• Indian discovery by Kamboj et al, CDRI Lucknow.
• National family welfare programme.

• SERM.

• Non steroidal oral contraceptive.

• Acts by preventing implantation of fertilized ovum.

• t½ 1 week.

• 30 mg twice weekly for 12 weeks f/b

once a week as long as fertility is to be

suppressed.
Indications of OCPs
1. Contraception

Non contraceptive use

2. Dysmenorrhoea

3. Premenstrual syndrome

4. Menorrhagia

5. Endometriosis

6. Polycystic ovary syndrome

Male sex Hormones

ANDROGENS
Hypothalamus Pituitary Gonadal
Axis
HYPOTHALAMUS

GnRH

ANTERIOR PITUTITARY

FSH LH

Testis

Testosterone
Androgens
• Testosterone leydig cell of testis.

• Dihydrotestosterone more active form.

Weak androgens
1. Dehydroepiandrosterone

2.Androstenedione

Produced by adrenal cortex

Testosterone
Source
1. Men: Leydig cells of testis in response to LH
from pituitary.

5 α reductase
Testosterone Dihydrotestosterone

2. Women- secreted by corpus luteum

adrenal cortex
Pharmacological Actions
1. Pubertal changes in males.

2. Stimulates secretion of prostatic fluid.

3. Increased muscle mass & strength.

4. Growth of hair.

5. Anabolic Effects increased retention of

Na+, K+, Ca .
Preparations
1. Oral Methyl testosterone
Testosterone undecanoate
Mesterolone

2. IM Testosterone propionate
Testosterone enanthate
Testosterone decanoate

3. Transdermal gel dihydrotestosterone

4. Transdermal patches
Adverse Effects
1. Salt & water retention.
2. Acne & musculinisation in girls.
3. Increases LDL decreases HDL.
4. Oligozoospermia
5. Precocious puberty & shortening of stature d/t early
closure of epiphysis.
7. Hepatic carcinoma.
8. Gynaecomastia.
Indication
1. Male hypogonadism.

2. AIDS related muscle wasting.

Anabolic Steroids
• Synthetic androgen with higher anabolic &
lower androgenic activity.

1. Increased protein synthesis.

2. Muscle development.
Anabolic Steroids
1. Nandrolone decanoate

2. Nandrolone phenyl propionate

3. Methandionone

4. Stanozolol

5. Oxymetholone
Adverse Effects
1. Testicular atrophy.

2. Inhibition of ovulation, hirsutism in women.

3. Jaundice & worsening of lipid profile

Oxymetholone & Stanozolol.

4. Sudden death reported in young athletes.

Indications
1. Enhancement of atheletic performance.

2. Catabolic states acute illness, trauma,

surgery.
Doses
1. Nandrolone decanoate
25-50 mg IM every 3 weeks.

2. Nandrolone phenylpropionate
50 mg IM once or twice weekly.

3. Methandienone 2-5 mg OD/ BD oral

Danazol
• Synthetic androgenic, anabolic &
progestational activities.

• Suppression of Gn secretion from pituitary in both men

& women

• Inhibition of testicular/ ovarian function

Indication
1. Endometriosis.
Marked improvement.
Relief of dysmenorrhoea.
Limiting feature
a. Androgenic SE
b. Elevation of hepatic transaminase.

2. Menorrhagia.
Reduces menstrual blood loss.

3.Fibrocystic breast disease.

Side Effects
1. Complete amenorrhoea.

2. Androgenic SE
Acne
Hirsutism (Male pattern of hair growth)
Edema
Weight gain
Antiandrogens
Androgen receptor antagonists
1. Flutamide

2. Bicalutamide

3. Nilutamide
Flutamide
•A non steroidal drug having specific
antiandrogenic activity.

• Competitively blocks androgen action on

accessory sex organs awa on pituitary –

increases LH secretion by blocking

feedback inhibition.
Indication
1. Metastatic prostate cancer
Alone or in conjunction with GnRH analogs.
(Combined Androgen Blocked Therapy)

Flutamide is started 3 days before the GnRH agonist to

block the initial flare up that may occur d/t excess release
of LH & testosterone in the beginning
Adverse Effects
1. Gynaecomastia ( males).

2. Breast tenderness ( females).

3. Hepatotoxic

Dose: 250 mg tds

Bicalutamide
• More potent & longer acting congener
of flutamide.

• Metastatic carcinoma of prostate.

• 50 mg OD

• Less hepatotoxic
5α reductase inhibitors
1. Finasteride

2. Dutasteride
Finasteride
Testosterone

5α reductase

Dihydrotestosterone ( more active)

Finasteride
Competitive inhibitor of the enzyme
5α reductase inhibitors type 2 which

predominates in male urogenital tract.

Indication
1.Benign hypertrophy of prostate.

2. Male pattern baldness.

Dose : 5mg daily

Adverse Effects
1. Impotence

2. Gynaecomastia

3. Decreased libido

4. Ejaculation disorder
Drugs for erectile dysfunction
1. Oral Sildenafil
Tadalafil
Vardenafil

2. Intracavernosal Papaverine
Phentolamine

3. Transurethral Alprostadil
Sildenafil
• Synthesized at Pfizer's in England.

• Initially studied for use in HT & angina.

• Drug had little effect on angina,

but it could induce marked penile erection

• Pfizer therefore decided to market it for erectile

dysfunction, rather than for angina.
 Sildenafil
• The drug was approved for use in erectile
dysfunction by the United States FDA in 1998.

• First drug used orally to treat erectile dysfunction

It became an instant hit.

MOA of Sildenafil
cGMP

Phosphodiesterase 5 (PDE5)

Inhibited by sildenafil

5GMP
 MOA
•Inhibits phosphodiesterase 5 in the
corpora cavernosa of the penis.

• PDE 5 inactivates cyclic GMP.

• Accumulation of cGMP causes relaxation of smooth

muscle of corpora cavernosa.

• Permitting inflow of blood into the

sinuses resulting in erection.
Sildenafil
• Reduces pulmonary artery pressure in
patients with primary pulmonary HT.
Pharmacokinetics
• After a single oral dose peak plasma level
is reached in 30-120 minutes.

• Plasma t½ is 2-4 hours.

• Clinical effectiveness lasts for 4 hours.

• Metabolised in liver
Adverse effects
1.Hypotension, flushing, headache & dyspepsia

2.Visual disturbances due to its effect on PDE6

which is involved in photoreceptor
transduction in the retina resulting in
impairment of colour vision especially blue
green
Sudden loss of vision due to Non arthritic
ischemic optic neuropathy (NAION)
Drug Interactions
1.Potentiates the hypotensive effect of nitrates.

2. Carbamazepine, rifampicin, barbiturates

decrease the action by enzyme induction.

3. Ritonavir significantly increases sildenafil

concentration.
Indications
1. Erectile dysfunction.
25-50 mg 1 hour before sexual activity.

2. Primary pulmonary HT.

Tadalafil
• More potent longer acting PDE5 inhibitor.

• t½18 hours.

• DOA 24-36 hours

• Visual disturbances are less d/t

lower affinity for PDE 6.

• Dose: 10 mg 30 mins before sexual activity.

Drugs acting on uterus
• Uterine stimulants ecbolics or oxytocics

• Uterine relaxants or tocolytics

 Uterine stimulants
1. Oxytocin
Ecbolics or Oxytocics
2. Ergometrine, Methyl ergometrine

3. Prostaglandins
PGE2, PGF2α, Misoprostol
Oxytocin
Synthesized in hypothalamic paraventricular nuclei.
Travel along the hypothalamo hypophyseal
tract to the posterior lobe of pituitary.

They are stored & are released under a variety

of stimuli - coitus, parturition & suckling.
 Pharmacokinetics
• Oxytocin is a peptide hence is inactive orally.

• Administered by IM, IV rarely by intranasal spray.

• Plasma t1/2 is 6 mins.

Oxytocin in induction of labour
1. Upper uterine segment , consisting of the
fundus & body is contracted while lower

uterine segment consisting of the cervical

portion is dilated . This results in an expulsion

of the fetus from the uterine cavity.

Oxytocin in induction of labour
2. The period of relaxation which intervene

between the 2 successive contractions allow

refilling of the placental blood vessels by the
maternal arterial blood & thus prevent

asphyxial injury to the foetus.

Oxytocin in induction of labour
3. Uterine contractions are consistently
augmented.

4. Because of its short t½ & slow IV infusion

intensity of action can be controlled & action
can be quickly terminated.

5. Increases synthesis & release of PGs.

PGs are good uterine stimulants &
softens the cervix.
Oxytocin in induction of labour
Dose: 5 IU diluted in 500 ml of glucose or
saline soln slow iv infusion
2. Augmentation of labour
• Uterine contractions are feeble &

labour is not progressing satisfactorily.

3. Post partum haemorrhage
Acts by forcefully contracting the the uterine

muscle which compresses the blood vessels

passing through it to arrest haemorrhage.

Breast
• Has a role in Milk ejection ( Milk Let down).

• Stimulation of breast during suckling induces

oxytocin secretion causing contraction of the
myoepithelium that surrounds the areolar
channels in the breast.

This forces milk from alveolar channels to enter the

sinuses & into the infants mouth.
Adverse effects of oxytocin
1. Injudicious use during labour can produce
too strong contractions forcing the presenting
part through incompletely dilated birth canal
causing maternal and foetal tissue injury

2. Water intoxication: due to ADH like action

when given in large doses along with IV fluids
in toxaemia of pregnancy and renal
insufficiency
Ergot alkaloids
1. Ergometrine or Ergonovine

2. Methyl ergometrine
Post partum haemorrhage
Acts by forcefully contracting the uterine

muscle which compresses the blood vessels

passing through it to arrest haemorrhage.

Dose: 0.2-0.3 mg IM at delivery of the

anterior shoulder.
Not used in induction of labour
1. Ergot alkaloids increase the

force & frequency of uterine contraction

without relaxation in between.

• EA also increase the contraction of LUS.

Not used in induction of labour
2. Sustained contractions without relaxation

causes obliteration of blood flow.

Fetal asphyxia & fetal death.

Tocolytics
1. calcium antagonists Nifedipine.

2. β2 agonist Ritodrine
Isoxsuprine
Salbutamol
Terbutaline

3. Oxytocin receptor antagonist

Atosiban
Actions
1. Cause relaxation of myometrium.

2. Markedly decrease spontaneous &

oxytocin induced contractions.

Indication
1. To delay premature labour.

2. To arrest threatened abortion.

3. Dysmenorrhoea.
Revision
Super active / long acting
GnRH agonists
1. Buserelin Intranasal spray, SC

2. Nafarelin Intranasal spray

3. Goserelin SC/IM

4. Triptorelin SC/IM

5. Leuprolide SC/IM
GnRH antagonists
1. Ganirelix

2. Cetrorelix

3. Degarelix

4. Abarelix
 Antiestrogens
•Clomiphene citrate
Pure estrogen antagonist.

• Blocks both ERα & ERβ.

• Blocks E Rs of hypothalamus & anterior pituitary.

• It induces Gn secretion in women by blocking

estrogenic feedback inhibition of pituitary.
Thus induces ovulation.
Tissue specific agonist/ antagonistic
activity of SERMS
Drug Breast Endometrium Bone
ESTROGEN +++ +++ +++

TAMOXIFEN - + +

RALOXIFENE - - +

ORMELOXIFENE - - ++
Antiprogestins
1. Mifepristone
antiglucocorticoid Progesterone
antiandrogenic Receptor
Modulato
2. Ulipristal

3. Onapristone
Pure progesterone antagonist
Postcoital contraception or
Emergency contraception
a. Yuzpe method

Levonorgestrel 0.25 mg
+
Ethinylestradiol 50 mcg
(2+2 tablets)
2 tabs taken as early as possible but within 72 hrs of
unprotected intercourse & 2 repeated after 12 hrs.
Postcoital contraception or
Emergency contraception
b. Levonorgestrel alone 0.75 mg taken twice
with 12 hour gap within 72 hrs of
intercourse (1+1 tabs)

C. Mifepristone 600mg SD
taken within 72 hrs of intercourse

d. Ulipristal 30 mg SD within 120 hrs of

intercourse
Anabolic Steroids
1. Nandrolone decanoate

2. Nandrolone phenyl propionate

3. Methandionone

4. Stanozolol

5. Oxymetholone
Antiandrogens
Androgen receptor antagonists
1. Flutamide

2. Bicalutamide

3. Nilutamide
5α reductase inhibitors
1. Finasteride

2. Dutasteride
Drugs for erectile dysfunction
1. Oral Sildenafil
Tadalafil
Vardenafil

2. Intracavernosal Papaverine
Phentolamine

3. Transurethral Alprostadil
 Uterine stimulants
1. Oxytocin
Ecbolics or Oxytocics
2. Ergometrine, Methyl ergometrine

3. Prostaglandins
PGE2, PGF2α, Misoprostol
Thank You