Androgens, Oestrogens, Androgens, Oestrogens, Progestins and Hormonal Progestins and Hormonal

ContraceptivesContraceptivesDepartment of PharmacologyDepartment of Pharmacology

NEIGRIHMS, ShillongNEIGRIHMS, Shillong

IntroductionIntroduction Substances which cause secondary sex characteristics Substances which cause secondary sex characteristics

in Malein Male Natural Androgens:Natural Androgens:

From Testes:From Testes:• Testosterone (5-12 mg daily)Testosterone (5-12 mg daily)• Dihydrotestosterone (more active) by 5 Dihydrotestosterone (more active) by 5 αα-reductase-reductase

From Adrenal cortex: (weak androgens)From Adrenal cortex: (weak androgens)• DehydroepiandrosteroneDehydroepiandrosterone• AndrostenedioneAndrostenedione

{Females – 0.25 – 0.5 mg/day (ovary + adrenals)}{Females – 0.25 – 0.5 mg/day (ovary + adrenals)} Androsterone – metabolite of testosteroneAndrosterone – metabolite of testosterone

Synthetic androgens:Synthetic androgens: Methyltestosterone, FluoxymesteroneMethyltestosterone, Fluoxymesterone Propionate and enanthatePropionate and enanthate

TestosteroneTestosterone

Produced from cholesterol primarily by Leydig cells in testesProduced from cholesterol primarily by Leydig cells in testes Secreted at adult levels during 1st trimesterSecreted at adult levels during 1st trimester11, during neonatal life, during neonatal life22, ,

continually after pubertycontinually after puberty33 Bound in plasma to albumin & sex hormone binding globulin Bound in plasma to albumin & sex hormone binding globulin

(SHBG)(SHBG) Can be converted to the more potent, 5α-dihydrotestosterone Can be converted to the more potent, 5α-dihydrotestosterone

(DHT), which is responsible for many of the responses to (DHT), which is responsible for many of the responses to testosterone in the urogenital tract (e.g. prostate gland hyperplasia)testosterone in the urogenital tract (e.g. prostate gland hyperplasia)

Binds to and activates a single androgen receptor (AR) Binds to and activates a single androgen receptor (AR) Androgen receptors are present in many tissues including Androgen receptors are present in many tissues including

reproductive tissue, skeletal muscle, brain, kidney etc.reproductive tissue, skeletal muscle, brain, kidney etc.

1 2 3

Testosterone 17-alkyl substitution Methyltestosterone

Fluoxymesterone

• All androgens contain a Testosterone structures• Testosterone has 19-carbons and in general its a steroidal structure

Cholesterol

Pregnenolone

Progesterone

Corticosterone

11-Desoxy-corticosterone

18-Hydroxy- corticosterone

ALDOSTERONE

17-α- Hydroxy pregnenolone

11- Desoxy- cortisol

17- Hydroxy progesterone

21,β hydroxylase

CORTISOL

11,β hydroxylase

Dehydro-epi androsterone

Andro-stenedione

Oestrone

Oestriol

TESTOSTERONE OESTRADIOL

ACTH

Regulation of SecretionRegulation of Secretion

• LH – Testosterone secretion• FSH – Spermatogenesis• High testosterone – inhibits LH• Estrogen – feedback inhibition• Inhibin – FSH inhibition

• Plasma level of Testosterone:0.3 to 1 mcg/dl (male)20 to 60 ng/dl (female)

Biological Effects - TestosteroneBiological Effects - Testosterone

Androgenic Effects:Androgenic Effects: In the foetus, testosterone promotes development of male In the foetus, testosterone promotes development of male

reproductive tract – internal genitalia, vas deferens, epididymis and reproductive tract – internal genitalia, vas deferens, epididymis and external genitalia (sex differentiation)external genitalia (sex differentiation)

During puberty, testosterone promotes development of :During puberty, testosterone promotes development of : primary sexual characteristics (e.g. enlargement of penis, scrotum and primary sexual characteristics (e.g. enlargement of penis, scrotum and

testes)testes) secondary sexual characteristics (e.g. male body shape, facial/pubic secondary sexual characteristics (e.g. male body shape, facial/pubic

hair, deeper pitch of voice)hair, deeper pitch of voice)

Adulthood: Baldness, BHP, Prostatic cancerAdulthood: Baldness, BHP, Prostatic cancer

Testes:Testes: Promotion of spermatogenesis and maturation of spermPromotion of spermatogenesis and maturation of sperm Moderately high dose causes testicular atrophy by inhibiting Gn Moderately high dose causes testicular atrophy by inhibiting Gn

secretionsecretion

Testosterone – anabolic effectsTestosterone – anabolic effects

Pubertal spurt of growth at puberty – both boy and girlPubertal spurt of growth at puberty – both boy and girl Bone growth – thickness and lengthBone growth – thickness and length Oestrogen from testosterone – fuse of bones and Oestrogen from testosterone – fuse of bones and

mineralizationmineralization Muscle building – if aided by exerciseMuscle building – if aided by exercise Positive nitrogen, minerals and water balance – increase Positive nitrogen, minerals and water balance – increase

in weightin weight Increase in appetiteIncrease in appetite Acceleration of erythropoiesisAcceleration of erythropoiesis

Androgens – Targets of ActionAndrogens – Targets of Action

Mechanism of ActionMechanism of ActionAndrogen receptor:Androgen receptor: Both, testosterone and DH testosterone – act via Androgen Both, testosterone and DH testosterone – act via Androgen

receptors (AR) – nuclear receptor super familyreceptors (AR) – nuclear receptor super family 5 5 αα-reductase 1 and 2 -reductase 1 and 2 Ligand binding and DNA binding domainsLigand binding and DNA binding domains Mutations in AR: Incomplete sexual developmentMutations in AR: Incomplete sexual development

Kennedy`s disease: in spinal andKennedy`s disease: in spinal and

bulbar muscle atrophybulbar muscle atrophy

Estrogen Receptor:• Teststerone converts to estrogen by CYP19• Deficiency of CYP19 and estrogen receptor – failure to fuse long bones, osteoporosis etc.

T DHT DHT- R

T- R

R

R

T- R

Nucleus

90%

10%

5- reductase

cytoplasm

Androgen - PharmacokineticsAndrogen - Pharmacokinetics Absorption:Absorption: undergoes high first undergoes high first

pass metabolism. Therefore IM pass metabolism. Therefore IM injections or synthetic preparations injections or synthetic preparations are usedare used

Transport:Transport: highly protein bound highly protein bound (98%, SHBG, albumin)(98%, SHBG, albumin)

Metabolism:Metabolism: by liver enzymes : androsterone by liver enzymes : androsterone

& etiocholanolone& etiocholanolone excretion by urine after excretion by urine after

conjugationconjugation small quantity of oestrogen also small quantity of oestrogen also

produced from testosteroneproduced from testosteroneMethyltestosterone, Fluoxymesterone Methyltestosterone, Fluoxymesterone

metabolized slowly metabolized slowly

Therapeutic Androgen PreparationsTherapeutic Androgen Preparations

Testosterone is ineffective orally (inactivated by liver), and is usually Testosterone is ineffective orally (inactivated by liver), and is usually given as i.m. injections of testosterone estersgiven as i.m. injections of testosterone esters

Esterification of fatty acid at 17-hydroxyl groupEsterification of fatty acid at 17-hydroxyl group Examples- propionate (25-50 mg), enanthate (100 mg depot Examples- propionate (25-50 mg), enanthate (100 mg depot

preparations)preparations) Undecanoate in oil - orallyUndecanoate in oil - orally effects last for 2-3 weekseffects last for 2-3 weeks

Transdermal preparations: Implants, capsules and patches may Transdermal preparations: Implants, capsules and patches may improve complianceimprove compliance

more stable levels and symptoms, effects last for monthsmore stable levels and symptoms, effects last for months

Therapeutic Uses of AndrogensTherapeutic Uses of Androgens Androgen replacement therapy (ART)Androgen replacement therapy (ART) ART uses derivatives of testosterone, rather than synthetic ART uses derivatives of testosterone, rather than synthetic

Androgens, because they are safe, effective and easy to monitorAndrogens, because they are safe, effective and easy to monitor

1.1. Androgen deficiency:Androgen deficiency: clinical diagnosis confirmed by hormone assaysclinical diagnosis confirmed by hormone assays is usually caused by is usually caused by

• underlying testicular disorders (high LH, but low testosterone levels)underlying testicular disorders (high LH, but low testosterone levels)• hypothalamic-pituitary disorders (low LH and low testosterone hypothalamic-pituitary disorders (low LH and low testosterone

levels)levels)

Goal: Mimic the normal testosterone concentration as closely as possible Goal: Mimic the normal testosterone concentration as closely as possible (serum concentration monitoring)(serum concentration monitoring)

If untreated, does not shorten life expectancy, but is associated with If untreated, does not shorten life expectancy, but is associated with significant morbidity (ambiguous genitalia, delayed puberty & infertility)significant morbidity (ambiguous genitalia, delayed puberty & infertility)

Treated by androgen replacement therapy (ART), usually for the remainder Treated by androgen replacement therapy (ART), usually for the remainder of life. The aim is to restore tissue androgen exposure by using the natural of life. The aim is to restore tissue androgen exposure by using the natural androgen testosteroneandrogen testosterone

Uses – contd.Uses – contd.

2.2. HypopituitarismHypopituitarism Monitoring at anticipated time of pubertyMonitoring at anticipated time of puberty

3.3. AIDS related muscle wastingAIDS related muscle wasting4.4. Hereditary angioneurotic edema (methyltestosterone)Hereditary angioneurotic edema (methyltestosterone)5.5. AgeingAgeingMisuse:Misuse: involves prescription with no acceptable medical involves prescription with no acceptable medical

indicationindication Examples of misuse include:Examples of misuse include:

male infertilitymale infertility male sexual dysfunction or impotencemale sexual dysfunction or impotence ““male menopause” (andropause)male menopause” (andropause)

no convincing evidence that androgen therapy is either no convincing evidence that androgen therapy is either effective treatment or safe for older men unless there is effective treatment or safe for older men unless there is frank androgen deficiencyfrank androgen deficiency

Androgens – Adverse EffectsAndrogens – Adverse Effects Virilization: Virilization:

may occur in women receiving relatively high doses may occur in women receiving relatively high doses for prolonged periods, such as for estrogen-dependent for prolonged periods, such as for estrogen-dependent mammary carcinomamammary carcinoma

Cholestatic JaundiceCholestatic Jaundice may be produced by steroids possessing a 17-alpha may be produced by steroids possessing a 17-alpha

methyl group – oral Vs parenteralmethyl group – oral Vs parenteral Priapism (sustained erection)Priapism (sustained erection) OligospermiaOligospermia Edema--via promotion of salt and water retention. Edema--via promotion of salt and water retention. Precocious puberty and short staturePrecocious puberty and short stature AcneAcne Hepatic carcinoma - oralHepatic carcinoma - oral Gynaecomastia – children and liver diseaseGynaecomastia – children and liver disease

Androgens - contraindicationsAndrogens - contraindications

Carcinoma of Prostate and male BreastCarcinoma of Prostate and male Breast Liver and Kidney diseasesLiver and Kidney diseases PregnancyPregnancy CHF, epilepsy and migraineCHF, epilepsy and migraine

Anabolic SteroidsAnabolic Steroids

Synthetic analogues – higher anabolic but Synthetic analogues – higher anabolic but lower androgenic activity (1: 3 ratio)lower androgenic activity (1: 3 ratio)

Examples;Examples; Nandrolone propionate 10-25 mg/ml (10 – 50 Nandrolone propionate 10-25 mg/ml (10 – 50

mg IM/week) – inj. Durabolinmg IM/week) – inj. Durabolin Nandrolone decanoate 25-100 mg/ml (25-Nandrolone decanoate 25-100 mg/ml (25-

100mg/week) – inj. Decadurabolin100mg/week) – inj. Decadurabolin Stanazolol (2mg tablets (2-6 mg/day)Stanazolol (2mg tablets (2-6 mg/day)

Anabolic Steroids – Therapeutic Anabolic Steroids – Therapeutic usesuses

1.1. Catabolic states: Acute illness, severe Catabolic states: Acute illness, severe trauma, major surgerytrauma, major surgery

2.2. Renal insufficiency – frequency of Renal insufficiency – frequency of dialysisdialysis

3.3. Osteoporosis – elderly malesOsteoporosis – elderly males

4.4. Suboptimal growth in boysSuboptimal growth in boys

5.5. AnaemiaAnaemia

6.6. Perfomance enhancementPerfomance enhancement

Anti-androgensAnti-androgens

DanazolDanazol Cyproterone acetateCyproterone acetate FlutamideFlutamide Finasteride attenuatedFinasteride attenuated

DanazolDanazol Ethisterone derivative effective orallyEthisterone derivative effective orally FSH & LH release in both sexes decrease – FSH & LH release in both sexes decrease – inhibition of testicular/ovarian functioninhibition of testicular/ovarian function Binding of steroids to receptors decreaseBinding of steroids to receptors decrease Weak androgenic, anabolic, progestational & glucocorticoid actionWeak androgenic, anabolic, progestational & glucocorticoid action

Uses:Uses: Endometriosis Endometriosis MenorrhagiaMenorrhagia Fibrocystic breast diseaseFibrocystic breast disease Hereditary angioneurotic oedemaHereditary angioneurotic oedema GynecomastiaGynecomastia Infertility: attenuatedInfertility: attenuated

Preparations:Preparations:

50. 100 and 200 mg. tablets50. 100 and 200 mg. tablets Dose is 200 – 600 mg/dayDose is 200 – 600 mg/day

Side effects: Dose related• Amenorrhea (High doses)• Androgenic effects - Decreased breast size, hirsutism, weight gain etc.• Hot flashes, night sweating, cramps

Cyproterone acetateCyproterone acetate Progesterone like activity – inhibits LH causing Progesterone like activity – inhibits LH causing

antiandrogenic actionantiandrogenic action Competes with dihydroteststerone for intracellular Competes with dihydroteststerone for intracellular

receptorreceptorUses:Uses: AcneAcne Male pattern of baldnessMale pattern of baldness hirusitismhirusitism Ca. of prostate Ca. of prostate Virilizing syndromeVirilizing syndrome Precocious pubertyPrecocious puberty Inappropriate behaviourInappropriate behaviour

FlutamideFlutamide Non-steroidal anti-inflammatory and no Non-steroidal anti-inflammatory and no

hormonal activity but specific antiandrogenic hormonal activity but specific antiandrogenic actionaction

Antagonise androgens by competitive block – 2-Antagonise androgens by competitive block – 2-hydroxyflutamide hydroxyflutamide Accessory sex organsAccessory sex organs PituitaryPituitary

Uses:Uses: Cancer of prostate along with GnRH agonistCancer of prostate along with GnRH agonist Female hirusitismFemale hirusitismDose: 250 mg tds.Dose: 250 mg tds.

FinasterideFinasteride MOA:MOA: Competitive inhibitor of 5 Competitive inhibitor of 5 αα-reductase-reductase

Selective of Selective of 5 5 αα-reductase type-2 isoenzyme-reductase type-2 isoenzyme Mainly acts on urogenital tract (prostate) – DHT level lowered Mainly acts on urogenital tract (prostate) – DHT level lowered

but not plasma Testosterone levelbut not plasma Testosterone level Uses:Uses:

1.1. Benign prostatic hypertrophy – decrease in prostate volume, Benign prostatic hypertrophy – decrease in prostate volume, improved urinary flow, reversion of disease progressionimproved urinary flow, reversion of disease progression

– Withdrawal results in regrowth – prolonged therapyWithdrawal results in regrowth – prolonged therapy2.2. Male pattern baldnessMale pattern baldness

– Kinetics:Kinetics: effective orally, metabolized in liver (t1/2 – 4-6 effective orally, metabolized in liver (t1/2 – 4-6 hrs)hrs)

– Side effects:Side effects: loss of libido, impotence, decreased loss of libido, impotence, decreased ejaculationejaculation

– Doses:Doses: 5 mg OD (BHP) or 1 mg OD in baldness 5 mg OD (BHP) or 1 mg OD in baldness

Erectile Dysfunction DrugsErectile Dysfunction Drugs

PDE-5 Inhibitors:PDE-5 Inhibitors: Sidenafil, tadalafilSidenafil, tadalafil Nitric oxide (NO) pathwayNitric oxide (NO) pathway

SidenafilSidenafil Absorbed orally and half-life is 4 HrsAbsorbed orally and half-life is 4 Hrs Inhibits PDE5 in the corpus cavernosa of the penisInhibits PDE5 in the corpus cavernosa of the penis 50mg 1 h before sexual activity50mg 1 h before sexual activity Potentiate nitrate’s hypotension activityPotentiate nitrate’s hypotension activity Ketoconazole, erythromycin, Verapamil increases its Ketoconazole, erythromycin, Verapamil increases its

level – due to CYP3A4 inhibitionlevel – due to CYP3A4 inhibition Renal & hepatic disease increases its levelRenal & hepatic disease increases its level Side effects: Side effects: headache, flushing, dyspepsia, myalgia, loose motionheadache, flushing, dyspepsia, myalgia, loose motion Other Uses:Other Uses: Pulmonary hypertension Pulmonary hypertension

Oestrogens

OestrogensOestrogens

IntroductionIntroduction

Oestrogens include the natural hormones Oestrogens include the natural hormones as well as semi-synthetic and synthetic as well as semi-synthetic and synthetic (stilbene) agents(stilbene) agents

Oestrogens are used as hormone:Oestrogens are used as hormone: replacement therapy (menopause)replacement therapy (menopause) in oncology in oncology contraceptivescontraceptives

Most estrogen in the female is produced in Most estrogen in the female is produced in the ovaries by the the ovaries by the theca interna theca interna and the and the granulosagranulosa cells of the follicles cells of the follicles

CH3OH

H

H

H

HO

ESTRADIOL

CH3

H

H

H

HO

O

ESTRONE

CH3OH

H

H

H

HO

OH

ESTRIOL

Oxidized in liver

hydr

oxyla

tion

Natural Oestrogens

1.

2.

3.

Synthetic oestrogensSynthetic oestrogens

Steroidal: Steroidal: Ethinyl estradiolEthinyl estradiol, Mestranol and Tibolone, Mestranol and Tibolone

Nonsteroidal: Nonsteroidal: Diethinylstilbestrol, Hexestrol and DienestrolDiethinylstilbestrol, Hexestrol and Dienestrol

Regulation of SecretionRegulation of Secretion

Daily secretion: 10 to Daily secretion: 10 to 100 mcg per day100 mcg per day

During pregnancy – During pregnancy – large quantity by large quantity by placenta – upto 30 placenta – upto 30 mg per daymg per day

Post menopausal: 2 – Post menopausal: 2 – 10 mcg per day only10 mcg per day only

Actions of OestrogensActions of Oestrogens On sexual organs (primary and secondary sexual characteristics)On sexual organs (primary and secondary sexual characteristics) Brings about pubertal changes in vagina, fallopian tube and uterus – Brings about pubertal changes in vagina, fallopian tube and uterus –

growthgrowth

Vagina: cornification of epithelial cells with thickening and stratification Vagina: cornification of epithelial cells with thickening and stratification of epitheliumof epithelium

Ovaries : stimulate follicular growth; small doses cause an increase in Ovaries : stimulate follicular growth; small doses cause an increase in weight of ovary; large doses cause atrophyweight of ovary; large doses cause atrophy

Cervix: Rhythmic contractions of uterus and fallopian tube - increase of Cervix: Rhythmic contractions of uterus and fallopian tube - increase of cervical mucous and alkaline watery secretion with a lowered viscosity cervical mucous and alkaline watery secretion with a lowered viscosity (favoring sperm access)(favoring sperm access)

Secondary Sex CharactersSecondary Sex Characters Metabolic effects: AnabolicMetabolic effects: Anabolic

Oestrogens PhysiologyOestrogens Physiology

Other Pharmacological ActionsOther Pharmacological Actions

Bone:Bone: Important for maintaining bone mass – increased Important for maintaining bone mass – increased expression of bone mass proteins (osteocalcin, alkaline expression of bone mass proteins (osteocalcin, alkaline phosphatase)phosphatase) Generation of vit.D3 – induction of renal hydroxylase Generation of vit.D3 – induction of renal hydroxylase

enzymeenzyme Oedema Oedema – salt and water retention– salt and water retention Increased LDL and decreased HDL levelIncreased LDL and decreased HDL level Increased coagulability: II, VII, IX and XIncreased coagulability: II, VII, IX and X Lithogenicity of BileLithogenicity of Bile Increased SHBG, TBG and CBGIncreased SHBG, TBG and CBG

Mechanism of ActionMechanism of Action

2 ERs are – 2 ERs are – ERERαα and ERß and ERß ERERαα - uterus, vagina, breast and blood vessels - uterus, vagina, breast and blood vessels ERß – Prostate and OvariesERß – Prostate and Ovaries Work via a steroid hormone mechanism.Work via a steroid hormone mechanism. Entering the target cells and binding to specific cytosolic Entering the target cells and binding to specific cytosolic

receptors receptors The steroid-receptor complex is then translocated to the The steroid-receptor complex is then translocated to the

nucleusnucleus Where it alters gene expressionWhere it alters gene expression Coactivator proteins and corepressor proteinsCoactivator proteins and corepressor proteins

Oestrogen - KineticsOestrogen - Kinetics

Absorbed orally, but quick metabolism – Absorbed orally, but quick metabolism – natural ones except ethinyl estradiolnatural ones except ethinyl estradiol

All are absorbed transdermallyAll are absorbed transdermally Bound to plasma protein (SHBG)Bound to plasma protein (SHBG) Conjugated with glucoronic acid and Conjugated with glucoronic acid and

excreted in urineexcreted in urine Enterohepatic circulation – deconjugation Enterohepatic circulation – deconjugation

in intestinein intestine

Oestrogen preparationsOestrogen preparations

Preferred route is oral, but sometimes parenteral Preferred route is oral, but sometimes parenteral when large doses are requiredwhen large doses are required

All estrogen preparations are available – tablet All estrogen preparations are available – tablet and injectionsand injections

Some examples:Some examples: EE: 0.01, 0.05, 1 mg tab for menopauseEE: 0.01, 0.05, 1 mg tab for menopause Conjugated estrogens: 0.625,1.25 mg tab for DUB or Conjugated estrogens: 0.625,1.25 mg tab for DUB or

injections 25 mg/mlinjections 25 mg/ml Mestranol: 0.1 mg tabs to convert to EEMestranol: 0.1 mg tabs to convert to EE Estriol succinate: 1mg/gm cream Estriol succinate: 1mg/gm cream

Transdermal PatchesTransdermal Patches

Sizes: 5, 10 and 20 sq. cm – Sizes: 5, 10 and 20 sq. cm –

0.025, 0.05 and 1 mg/day 0.025, 0.05 and 1 mg/day Menopausal womenMenopausal women Usual dose: 0.5 mg/dayUsual dose: 0.5 mg/day Cyclic therapyCyclic therapy Estrogen + Progestin patchesEstrogen + Progestin patches

Therapeutic UsesTherapeutic Uses Hormone Replacement Therapy to Menopause womanHormone Replacement Therapy to Menopause woman Problems of menopause:Problems of menopause:

Vasomotor disturbancesVasomotor disturbances Urogenital atrophyUrogenital atrophy Osteoporosis and fracturesOsteoporosis and fractures Dermatological changesDermatological changes Risk of cardiovascular diseasesRisk of cardiovascular diseases

Dosage: Oestrogen equivalent to 0.625 mg of EE/day in Dosage: Oestrogen equivalent to 0.625 mg of EE/day in cyclical mannercyclical manner

Progestin preparation (medroxy progesterone/norethisterone) is Progestin preparation (medroxy progesterone/norethisterone) is used – 2.5 mg dailyused – 2.5 mg daily

TTS preparations may be preferredTTS preparations may be preferred

HRT IndicationsHRT Indications Benefits: (Indications)Benefits: (Indications)

Vasomotor and other symptoms of perimenopausal period – Vasomotor and other symptoms of perimenopausal period – smallest effective dosesmallest effective dose

Post hysterectomy patients – estrogen onlyPost hysterectomy patients – estrogen only Young woman with premature menopauseYoung woman with premature menopause Prevention of osteoporosis and fracturesPrevention of osteoporosis and fractures

Facts:Facts: No protection against CVS diseasesNo protection against CVS diseases No protection against cognitive decline – may increaseNo protection against cognitive decline – may increase Increase in risk of breast cancer, gall stone, migraineIncrease in risk of breast cancer, gall stone, migraine

Tibolone:Tibolone: Developed specifically for HRTDeveloped specifically for HRT Estrogenic and progestitional propertyEstrogenic and progestitional property Dose is 2.5 mg dailyDose is 2.5 mg daily

Selective Estrogen Receptor

Modulators (SERMs)

Clomiphene Citrate (Antiestrogen)Clomiphene Citrate (Antiestrogen)

The “Fertility pill” - pure antagonist of The “Fertility pill” - pure antagonist of ESTROGEN receptor in all human tissuesESTROGEN receptor in all human tissues

MOA: Gn secretion and FSHMOA: Gn secretion and FSH Used in women with Used in women with unexplained infertilityunexplained infertility or or

anovulatory anovulatory infertilityinfertility Bind to both, ERBind to both, ERαα and ERß receptors and ERß receptors Blocks estrogenic feedback inhibition of pituitary and Blocks estrogenic feedback inhibition of pituitary and

induces Gn secretioninduces Gn secretion Increase in amount of secretion of FSH/LH at each Increase in amount of secretion of FSH/LH at each

secretary pulsesecretary pulse Creates favorable atmosphere (ovarian stimulation) Creates favorable atmosphere (ovarian stimulation)

for ovulation in ovaries for ovulation in ovaries

Clomiphene Citrate – contd.Clomiphene Citrate – contd.

Dosage: Dosage: 50 mg OD from 550 mg OD from 5thth day onwards for 5 days day onwards for 5 days Continued for 2-3 cyclesContinued for 2-3 cycles Conception occurs within 4-6 cyclesConception occurs within 4-6 cycles If no, dose increasedIf no, dose increased

Other Uses:Other Uses: Assisted reproduction (to develop multiple eggs)Assisted reproduction (to develop multiple eggs) Artificial insemination (irregular ovulation)Artificial insemination (irregular ovulation) (Clomiphene Challenge Test)(Clomiphene Challenge Test) Oligospermia (25 mg daily for 6 months – 6 days Oligospermia (25 mg daily for 6 months – 6 days

rest))rest))

Tamoxifen (SERM)Tamoxifen (SERM)

Actions:Actions: Is a competitive antagonist to estrogen at receptors in the Is a competitive antagonist to estrogen at receptors in the

breast.breast. Partial agonist at other estrogen receptors (thus minimizing side Partial agonist at other estrogen receptors (thus minimizing side

effects due to estrogen deprivation) - bone, uterus, liver and effects due to estrogen deprivation) - bone, uterus, liver and pituitarypituitary

Hot flushes – antiestrogenic actionHot flushes – antiestrogenic action Decrease in LDL level but no change in HDL levelDecrease in LDL level but no change in HDL level Improvement in bone mass and lipid profileImprovement in bone mass and lipid profile

Kinetics: Absorbed orally and has biphasic half life – 10 Kinetics: Absorbed orally and has biphasic half life – 10 Hrs and 7 days – long duration of actionHrs and 7 days – long duration of action

Excreted in BileExcreted in Bile Dose is 10 to 20 mg BDDose is 10 to 20 mg BD

Tamoxifen – contd.Tamoxifen – contd.

Uses: Uses: Breast carcinoma of pre and post menopauseBreast carcinoma of pre and post menopause Adjuvant therapy in early casesAdjuvant therapy in early cases Palliative therapyPalliative therapy

Side effects. Side effects. The drug has a low incidence of adverse reactionsThe drug has a low incidence of adverse reactions Hot flashes, nausea, vomiting, rash, menstrual irregularities and Hot flashes, nausea, vomiting, rash, menstrual irregularities and

bleeding, infrequent depression, headache, hypercalcemia, bleeding, infrequent depression, headache, hypercalcemia, edema, and blood dyscrasiasedema, and blood dyscrasias

Less toxic than anticancer drugsLess toxic than anticancer drugs

Other SERM – Other SERM – Raloxifene, ormeloxifene etc.Raloxifene, ormeloxifene etc. Raloxifene is estrogen antagonist of breast and endometrium Raloxifene is estrogen antagonist of breast and endometrium

while partial agonist of bone and CVSwhile partial agonist of bone and CVS

CH2CH3

O(CH3)2N-CH2-CH2

TAMOXIFEN (NOLVADEX)

Aromatase InhibitorsAromatase Inhibitors

Letrozole, Anastrozole and ExemestaneLetrozole, Anastrozole and Exemestane MOA: LetrozoleMOA: Letrozole

Non steroidal compound, reversible inhibition of Non steroidal compound, reversible inhibition of aromatization all over the bodyaromatization all over the body

Suppression of proliferation of estrogen dependant Suppression of proliferation of estrogen dependant breast carcinoma cellsbreast carcinoma cells

Rapid oral absorption – 100% bioavailability, large Vd, Rapid oral absorption – 100% bioavailability, large Vd, t1/2 – 40 Hrst1/2 – 40 Hrs

Uses: Early breast carcinoma and Advanced Uses: Early breast carcinoma and Advanced breast carcinomabreast carcinoma

Progestins

PreparationsPreparations

Progesterone Derivatives:Progesterone Derivatives: Progesterone, Hydroxyprogesterone Caproate, Progesterone, Hydroxyprogesterone Caproate,

Medroxyprogesterone acet, Megesterol acetateMedroxyprogesterone acet, Megesterol acetate

19-Nortestosterone derivatives:19-Nortestosterone derivatives: Norethindrone, Norethynodrel, Lynestrenol, Norethindrone, Norethynodrel, Lynestrenol,

AllylestrenolAllylestrenol 33rdrd Generation compounds (Gonanes): Generation compounds (Gonanes):

norgestimate, norgestrel, desogestrel and levonogestrelnorgestimate, norgestrel, desogestrel and levonogestrel

Micronized formulations – for oral useMicronized formulations – for oral use

Actions of ProgesteroneActions of Progesterone

Uterus:Uterus: Responsible for Luteal phase of endometriumResponsible for Luteal phase of endometrium High level (pregnancy and luteal phase) High level (pregnancy and luteal phase)

prevents secretion of gonadotrophinsprevents secretion of gonadotrophins Maintenance of pregnancy – nidation and Maintenance of pregnancy – nidation and

maintenance of pregnancymaintenance of pregnancy Decrease uterine motilityDecrease uterine motility Depression of T-cell function and CMIDepression of T-cell function and CMI

MenstruationMenstruation

Actions – contd.Actions – contd. Cervix:Cervix: viscid and cellular secretion – no sperm penetration viscid and cellular secretion – no sperm penetration

Vagina:Vagina: Pregnancy like changes – leucocyte infiltration and Pregnancy like changes – leucocyte infiltration and cornified epitheliumcornified epithelium

Breast:Breast: Proliferation of acini in mammary glands Proliferation of acini in mammary glands Prepares breast for lactation together with estrogenPrepares breast for lactation together with estrogen

Metabolism:Metabolism: impairment of glucose toleranceimpairment of glucose tolerance Counteraction of benefits of oestrogensCounteraction of benefits of oestrogens

CNS:CNS: Sedation Sedation Respiration:Respiration: Stimulation Stimulation Body temperature:Body temperature: rise in temperature rise in temperature Pituitary:Pituitary: Weak Gn inhibitor, suppresses ovulation if given during Weak Gn inhibitor, suppresses ovulation if given during

follicular phase follicular phase

Progesterone – contd.Progesterone – contd.

MOA: MOA: Receptors are confined to female genital tracts, Receptors are confined to female genital tracts,

breasts and CNSbreasts and CNS PRs are present in nucleus of target cellsPRs are present in nucleus of target cells PR exists in 2 forms – PR-A and PR-B isoforms PR exists in 2 forms – PR-A and PR-B isoforms

(differing activities)(differing activities)

Kinetics:Kinetics: Inactive orally, high first pass metabolismInactive orally, high first pass metabolism Synthetics are active orally and metbolized slowlySynthetics are active orally and metbolized slowly Half-life of 8-24 HRsHalf-life of 8-24 HRs

Uses of ProgestinsUses of Progestins

ContraceptiveContraceptive Hormonl replcement therapyHormonl replcement therapy Dysfunctional Uterine Bleeding: anovulatory Dysfunctional Uterine Bleeding: anovulatory

cyclescycles Endometriosis: anovulatory hypoestrogenic state Endometriosis: anovulatory hypoestrogenic state

is created by progesteroneis created by progesterone Premenstrual syndromePremenstrual syndrome Threatened and habitual abortionThreatened and habitual abortion Endometrial carcinomaEndometrial carcinoma

Adverse EffectsAdverse Effects

Breast engorgement, headache, rise in body temp., Breast engorgement, headache, rise in body temp.,

oedema, acne & mood swings oedema, acne & mood swings

Masculinization of external genitalia in the foetusMasculinization of external genitalia in the foetus

Increased incidences of congenital abnormalitiesIncreased incidences of congenital abnormalities

Irregular bleeding or amenorrheaIrregular bleeding or amenorrhea

Lower HDL (19-nortestosterone derivatives)Lower HDL (19-nortestosterone derivatives)

HyperglycaemiaHyperglycaemia

Antiprogestin - MifepristoneAntiprogestin - Mifepristone 19-norsteroid compound – antiprogestational, 19-norsteroid compound – antiprogestational,

antiglucocorticoid and antiandrogenic actionantiglucocorticoid and antiandrogenic actionActions:Actions: Follicular phase: attenuation of Gn discharge – slow Follicular phase: attenuation of Gn discharge – slow

follicular development, failure of ovulationfollicular development, failure of ovulation Luteal phase: prevents secretory changes brought about Luteal phase: prevents secretory changes brought about

by progesteroneby progesterone Late cycle: Blocking of Progesterone action, increased Late cycle: Blocking of Progesterone action, increased

PG release – uterine contractionPG release – uterine contraction Sensitization of endometrium to PG – menstruationSensitization of endometrium to PG – menstruation On Implantation: Blocking of decidution and dislodging of On Implantation: Blocking of decidution and dislodging of

conceptusconceptus In Menopause – progestational activityIn Menopause – progestational activity

Mifepristone – contd. Mifepristone – contd.

Kinetics:Kinetics: Absorbed orally and bioavailability is only Absorbed orally and bioavailability is only 25% and half-life is 20-36 hrs25% and half-life is 20-36 hrs

CYP3A4CYP3A4

Uses:Uses:1.1. Termination of PregnancyTermination of Pregnancy2.2. Cervical primingCervical priming3.3. Postcoital contraceptivePostcoital contraceptive4.4. Induction of labour: single dose 2 days after Induction of labour: single dose 2 days after

midcyclemidcycle5.5. Cushing SyndromeCushing Syndrome

– Preparations: Tablet – 200 mg Preparations: Tablet – 200 mg

Pharmacology of Hormonal Pharmacology of Hormonal ContraceptionContraception

Methods of ContraceptionMethods of Contraception

Direct inhibition of spermatogenesisDirect inhibition of spermatogenesis

Indirect inhibition of spermatogenesis Indirect inhibition of spermatogenesis

Immunological techniques (vaccine)Immunological techniques (vaccine)

Inhibition of ovulation (Hormonal contraceptives)Inhibition of ovulation (Hormonal contraceptives)

Prevention of fertilization Prevention of fertilization

Anti-zygotic drugsAnti-zygotic drugs

Inhibition of implantationInhibition of implantation

use of spermicidal in vaginause of spermicidal in vagina

IUCD IUCD

Female ContraceptionFemale Contraception

OralOral Combined pillCombined pill Sequential pillSequential pill Phased regimenPhased regimen Mini pillMini pill Post-coital pillPost-coital pill

InjectableInjectable Long actingLong acting

progesterone progesterone alonealone

Long actingLong acting progesterone + progesterone +

estrogenestrogen Implants:Implants:

NorplantNorplant

HistoryHistory The oral contraceptive pill (combined OC) was first The oral contraceptive pill (combined OC) was first

introduced in 1960introduced in 1960 1970: Introduction low dose or second generation of 1970: Introduction low dose or second generation of

OCSOCS

1980: biphasic or triphasic regimens1980: biphasic or triphasic regimens 1990: 3rd generation OCS 1990: 3rd generation OCS

(O + P has less androgenic activity, (O + P has less androgenic activity,

e.g, norgestimate 0.25mg or desogestrel 0.15 mg)e.g, norgestimate 0.25mg or desogestrel 0.15 mg)

Since then it has undergone many modifications and has Since then it has undergone many modifications and has been used by millions of women worldwide. been used by millions of women worldwide.

Combined PillCombined Pill Low-dose oral contraceptives: products Low-dose oral contraceptives: products

containing less than 50ug ethinyl estradiolcontaining less than 50ug ethinyl estradiol First generation oral contraceptives: First generation oral contraceptives:

products containing 50ug or more of ethinyl estradiolproducts containing 50ug or more of ethinyl estradiol Second generation oral contraceptives: Second generation oral contraceptives:

products containing levonorgestrel, norgestimate and products containing levonorgestrel, norgestimate and other members of northindrone family and 30 or 40ug other members of northindrone family and 30 or 40ug ethinyl estradiolethinyl estradiol

Third generation oral contraceptives: Third generation oral contraceptives: products containing desogestrel or gestodene with 20 or products containing desogestrel or gestodene with 20 or 30ug ethinyl estradiol30ug ethinyl estradiol

Newer progestins (gestodene and desogestrel) have been Newer progestins (gestodene and desogestrel) have been shown to have little or no androgenic activityshown to have little or no androgenic activity

FormulationsFormulations

Formulations may be :Formulations may be :

1.1. Monophasic Monophasic (each tablet contains a fixed (each tablet contains a fixed amount of estrogen and progestin); amount of estrogen and progestin);

2.2. BiphasicBiphasic (each tablet contains a fixed amount (each tablet contains a fixed amount of estrogen, while the amount of progestin of estrogen, while the amount of progestin increases in the second half of the cycle); or increases in the second half of the cycle); or

3.3. TriphasicTriphasic (the amount of estrogen may be fixed (the amount of estrogen may be fixed or variable, while the amount of progestin or variable, while the amount of progestin increases in 3 equal phases).increases in 3 equal phases).

FormulationsFormulations

Biphasic and triphasic Biphasic and triphasic formulations were initially formulations were initially developed with the intent of lowering the total steroid developed with the intent of lowering the total steroid content of combined OCs (estrogen – 30 to 40 mcg)content of combined OCs (estrogen – 30 to 40 mcg)

Two types of estrogen are used in combined OCs: Two types of estrogen are used in combined OCs: ethinyl estradiol and mestranolethinyl estradiol and mestranol

Mestranol is a Mestranol is a “prodrug”“prodrug” that is converted in vivo to that is converted in vivo to ethinyl estradiolethinyl estradiol

Several different progestins, of varying degrees of Several different progestins, of varying degrees of progestational potency, are used in combined OCs progestational potency, are used in combined OCs

Phased Regimens: ExamplesPhased Regimens: Examples

Biphasic:Biphasic: 10 (O+P) + 11 (O+PP) + 7 (DF)10 (O+P) + 11 (O+PP) + 7 (DF)

Triphasic:Triphasic:I 6 (E.O 30 µg + Levonorg. 50 µg)I 6 (E.O 30 µg + Levonorg. 50 µg)II 5 (E.O 40 µg + Levonorg. 75 µg)II 5 (E.O 40 µg + Levonorg. 75 µg)III 10 (E.O 30 µg + Levonorg. 125 µg)III 10 (E.O 30 µg + Levonorg. 125 µg)

Combined preparations:Combined preparations:

21 days (O+P) + 7 days (DF)21 days (O+P) + 7 days (DF)

99 – 100% effective99 – 100% effective

MinipillMinipill

Progesterone only pillProgesterone only pill To eliminate estrogen to avoid long term To eliminate estrogen to avoid long term

risks of estrogenrisks of estrogen Low dose estrogen is taken daily without Low dose estrogen is taken daily without

gapgap Efficacy is 96-98%Efficacy is 96-98%

Postcoital (Emergency)Postcoital (Emergency)

Levonorgestrel 0.5 mg + EE 0.1 mg – Levonorgestrel 0.5 mg + EE 0.1 mg – ovralovral tablet tablet

Levonorgestrel (0.75 mg) alone – 12 Hr Levonorgestrel (0.75 mg) alone – 12 Hr apartapart

Mifepristone – 400 mg (2 tablets)Mifepristone – 400 mg (2 tablets)

InjectableInjectable

Long acting Progestin aloneLong acting Progestin alone1.1. Depot medroxyprogesterone (DMPA) – 150 Depot medroxyprogesterone (DMPA) – 150

mg (1 ml vial) – half life – 50 days)mg (1 ml vial) – half life – 50 days)

2.2. Norethidrone (Norethisterone) – 200 mg (1 Norethidrone (Norethisterone) – 200 mg (1 ml vial) – repeat at 2 monthsml vial) – repeat at 2 months

Long acting progestin + estrogen:Long acting progestin + estrogen: Medroxyprogesterone + estradol cypionate – Medroxyprogesterone + estradol cypionate –

IM injection – monthlyIM injection – monthly Implants – norplants, progestesert etc.Implants – norplants, progestesert etc.

Missed Pill AdviseMissed Pill Advise If 1 or 2 of 30-35mcg ethinylestradiol pill or 1 of 20 If 1 or 2 of 30-35mcg ethinylestradiol pill or 1 of 20

mcg mcg Advise to take the most recent pill as soon as remembers, Advise to take the most recent pill as soon as remembers,

continue taking remaining pill at usual time, she does not require continue taking remaining pill at usual time, she does not require additional contraception or emergency contraceptionadditional contraception or emergency contraception

If 3 or more of 30-35 or 2 or more 20 mcgIf 3 or more of 30-35 or 2 or more 20 mcg Advise as above, but to use extra method of contraception until Advise as above, but to use extra method of contraception until

pills have been taken for 7 days in a rowpills have been taken for 7 days in a row If pill is missed in week 1 ( days1-7)and unprotected sexual If pill is missed in week 1 ( days1-7)and unprotected sexual

intercourse has taken place in pill free week or wk 1 then intercourse has taken place in pill free week or wk 1 then emergency contraception is neededemergency contraception is needed

If pills missed in wk 3 ( days 15-21), advise to finish pill in pack If pills missed in wk 3 ( days 15-21), advise to finish pill in pack and start new pack the next day, omitting pill free intervaland start new pack the next day, omitting pill free interval

If one has missed > 7 consecutive days then consider as If one has missed > 7 consecutive days then consider as stopped COCP stopped COCP

Mechanism of actionMechanism of action

Combination pill, given daily for 3 of every 4 Combination pill, given daily for 3 of every 4 weeks:weeks: Prevents ovulation by inhibiting gonadotropin secretion Prevents ovulation by inhibiting gonadotropin secretion

via effect on both pituitary and hypothalamic centersvia effect on both pituitary and hypothalamic centers Progestational agent in pill ; suppresses LH Progestational agent in pill ; suppresses LH

secretion(thus prevents ovulation)secretion(thus prevents ovulation) Estrogenic agent ; suppresses FSH secretion (thus Estrogenic agent ; suppresses FSH secretion (thus

prevents selection and emergence of dominant follicle)prevents selection and emergence of dominant follicle) Progestin only preparations – suppresses LH surge and Progestin only preparations – suppresses LH surge and

also by direct actionalso by direct action

Mechanism of action – contd.Mechanism of action – contd.

Thick Cervical mucus secretion making Thick Cervical mucus secretion making hostile for sperm penetrationhostile for sperm penetration

Failure of implantation – hyperproliferative Failure of implantation – hyperproliferative and hypersecretory endometriumand hypersecretory endometrium

Uterine and tubal contraction – peristalsis Uterine and tubal contraction – peristalsis within the fallopian tubewithin the fallopian tube

Dislodging of implanted blastocyteDislodging of implanted blastocyte

Adverse EffectsAdverse Effects Some combined OC users will experience minor side-Some combined OC users will experience minor side-

effects, most commonly during the first 3 cycles.effects, most commonly during the first 3 cycles. These side-effects may lead to discontinuation of the These side-effects may lead to discontinuation of the

combined OCcombined OC The most common reason patients discontinue The most common reason patients discontinue

combined OC use is: combined OC use is: 1.1. Abnormal menstrual bleeding, followed by :Abnormal menstrual bleeding, followed by :2.2. Nausea, Nausea, 3.3. Weight gain, Weight gain, 4.4. Mood changes, Mood changes, 5.5. Breast tendernessBreast tenderness6.6. Headache.Headache.

Adverse Effects - LateAdverse Effects - Late

ChloasmaChloasma Pruritus vulvaePruritus vulvae Carbohydrate intoleranceCarbohydrate intolerance Mood swingsMood swings

Serious ComplicationsSerious Complications

Leg vein and pulmonary thrombosisLeg vein and pulmonary thrombosis Coronary and cerebral thrombosisCoronary and cerebral thrombosis HypertensionHypertension Genital carcinomaGenital carcinoma Benign hepatomasBenign hepatomas GallstonesGallstones

Contraindications (WHO)Contraindications (WHO)

1.1. < 6 weeks postpartum if breastfeeding< 6 weeks postpartum if breastfeeding

2.2. Smoker over the age of 35 (≥ 15 cigarettes per day)Smoker over the age of 35 (≥ 15 cigarettes per day)

3.3. Hypertension (systolic ≥ 160mm Hg or diastolic ≥ 100mm Hg)Hypertension (systolic ≥ 160mm Hg or diastolic ≥ 100mm Hg)

4.4. Current or past history of venous thromboembolism (VTE)Current or past history of venous thromboembolism (VTE)

5.5. Ischemic heart diseaseIschemic heart disease

6.6. History of cerebrovascular accidentHistory of cerebrovascular accident

7.7. Complicated valvular heart disease Complicated valvular heart disease

8.8. Migraine headacheMigraine headache

9.9. Breast cancer (current)Breast cancer (current)

10.10. Diabetes with retinopathy/nephropathy/neuropathyDiabetes with retinopathy/nephropathy/neuropathy

11.11. CirrhosisCirrhosis

12.12. Liver tumour (adenoma or hepatoma)Liver tumour (adenoma or hepatoma)

Relative ContraindicationsRelative Contraindications

1.1. Smoker over the age of 35 (< 15 cigarettes per day)Smoker over the age of 35 (< 15 cigarettes per day)

2.2. Adequately controlled hypertensionAdequately controlled hypertension

3.3. Hypertension (systolic 140–159mm Hg, Hypertension (systolic 140–159mm Hg, diastolic 90–99mm Hg)diastolic 90–99mm Hg)

4.4. Migraine headache over the age of 35Migraine headache over the age of 35

5.5. Currently symptomatic gallbladder diseaseCurrently symptomatic gallbladder disease

6.6. History of combined OC-related cholestasisHistory of combined OC-related cholestasis

7.7. Mentally illMentally ill

8.8. Undiagnosed vaginal BleedingUndiagnosed vaginal Bleeding

Centchroman and male contraceptiveCentchroman and male contraceptive

Thank YouThank You Points to Study:Points to Study:

Pharmacological actions of testosterone, mechanism Pharmacological actions of testosterone, mechanism of action, adverse effects and therapeutic usesof action, adverse effects and therapeutic uses

Danazol, Flutamide and Finasteride detailsDanazol, Flutamide and Finasteride details Anabolic SteroidsAnabolic Steroids Actions of Oestrogens and usesActions of Oestrogens and uses Clomiphene citrate in detailClomiphene citrate in detail Antiprogestin – MifepristoneAntiprogestin – Mifepristone Different contraceptive measureDifferent contraceptive measure Different Hormonal contraceptivesDifferent Hormonal contraceptives Mechanism of action, adverse effects and Mechanism of action, adverse effects and

contraindications of OCPscontraindications of OCPs